Shifting Conceptions of Type 2 Diabetes Etiology: From the "Thrifty Genotype" to the "Predictive Adaptive Response Model"
Sarah Payne
A Thesis Submitted to the Faculty of Graduate Studies in Partial Fulfillment of the Requirements for the Degree of Master of Science
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Abstract
This thesis is a conceptual history of the research and theories pertaining to type 2 diabetes etiology over the past 50 years. Three theories have been proposed to explain type 2 diabetes etiology. The "thrifty genotype hypothesis" (1962) offered a genetic and evolutionary explanation for diabetes. The "thrifty phenotype hypothesis" (1992), in contrast, did not implicate genes or evolution in the etiology of diabetes; instead it posited environmental cues during fetal development, specifically low birth weight resulting from undernutrition, as the cause of the disease. Then, in 2004, the "predictive
adaptive response model" was proposed within a new epigenetic and evolutionary developmental context; it involved genetic, epigenetic, and environmental influences in
the etiology of disease.
In examining these conceptual shifts, this thesis identifies the major proponents
and critics of each hypothesis. It also places these major scientific shifts within the
context of epidemiology, developmental and evolutionary theory, and evolutionary
medicine. V
Acknowledgments
I would like to express my sincerest gratitude to Dr. Jan Sapp for his advice and guidance. Thank you, Dr. Sapp, for taking the time to read and edit many, many drafts of my thesis. One could not ask for a more dedicated or knowledgeable supervisor.
I would also like to thank the members of my graduate committee for their guidance and suggestions, including Dr. Sam Benchimol, Dr. Rolando Ceddia, and Dr.
Joel Shore.
Finally, I would like to thank my family members for supporting and encouraging me to pursue this degree. vi
Table of Contents
Abstract iv Acknowledgment v Table of Contents vi List of Tables vii List of Figures viii Introduction 1
Chapter 1: The thrifty genotype hypothesis 10 Neel's evolutionary proposal 10 Neglect of the hypothesis 15 Revival and criticisms 17 Response to critics at the turn of the 21st century 22
Chapter 2: The thrifty phenotype hypothesis 24 Hales and Barker's epidemiological proposal 24 First evidence for the hypothesis 29 Criticisms 34 Response to critics 37 Conclusions 42
Chapter 3: Creating a new context for type 2 diabetes: Genes, development, and evolution 46 Diabetes understanding in the 20th century 46 Epigenetic inheritance 48 Epigenetics and type 2 diabetes 51 Evolutionary developmental biology 52 Evolutionary medicine 53
Chapter 4: The predictive adaptive response model 55 Gluckman and Hanson's integrative approach to diabetes 55 The origins of the predictive adaptive response model 57 From the thrifty phenotype to epigenetic inheritance 61 The mismatch hypothesis 71 An evolutionary perspective 73 Implications 76
Chapter 5: Debating the predictive adaptive response model 79 Criticisms of Gluckman and Hanson's model 79 The maternal fitness model: An alternative proposal 85 The Wells versus Gluckman and Hanson debates 90 The predictive adaptive response model today 98
Summary and Conclusion 102 References 113 vii
List of Tables
Table 1: Candidate genes associated with type 2 diabetes risk 47 Table 2: Evidence for transgenerational epigenetic inheritance 70 Table 3: Characteristics of the three etiological models of type 2 diabetes 111 List of Figures
Figure 1: Prevalence of type 2 diabetes in the United States 4 Figure 2: Estimated global prevalence of type 2 diabetes 4 Figure 3: Number of citations of Neel's 1962 publication 15 Figure 4: Number of times "thrifty phenotype" appears in published literature 43 Figure 5: The predictive adaptive response model: Evolutionary and mechanistic perspectives 73 Figure 6: Number of citations of Gluckman and Hanson's 2004 publication 80 Figure 7: Comparison of the number of times the Gluckman/Hanson model and the Wells model have been cited 100 Figure 8: Number of citations of Gluckman and Hanson's 2004 publication by journal 101 Figure 9: Number of citations of Wells' 2003 publication by journal 101 Figure 10: The roles of genotype, phenotype, and epigenetics in the three models of type 2 diabetes etiology 108 Figure 11: Comparison of the number of times the original thrifty genotype, thrifty phenotype, and the predictive adaptive response hypotheses have been cited by year Ill 1
I iilroc! uCtiOii
"The diabetes time bomb has been ticking for 50 years, and it's been getting louder." "Diabetes is fast becoming the epidemic of the 21st century." International Diabetes Federation, 2006 1
This thesis is a historical account of theory change in regard to what determines type 2 diabetes mellitus. Various theories have been proposed for the origin of type 2 diabetes, some purely developmental and some purely genetic. Over the past 50 years, conceptions of type 2 diabetes etiology have shifted alongside changes in our understanding of genetic and developmental phenomena. Indeed, I will show that three conceptual changes have occurred since the 1960s. One hypothesis regarding type 2 diabetes etiology was proposed in 1962; a second hypothesis was proposed in 1992; and a third hypothesis emerged in 2004 and it continues to shape our understanding of type 2 diabetes to the present day. I discuss the scope and significance of these changes.
Diabetes was certainly not a new phenomenon in the twentieth-century. The ry symptoms of diabetes have been recognized since ancient Egyptian times. However, it was not until the seventeenth century that empirical research and effective curative propositions began to be performed. Since this time, several important achievements in diabetes research have contributed to our current understanding of type 2 diabetes.
The distinction between diabetes insipidus and diabetes mellitus was first made in
1794 following the discovery of the sweetness of diabetic urine. At the time, diabetes insipidus was believed to be characterized by "tasteless" mine, while diabetes mellitus was characterized by "sweet" urine. Today, diabetes insipidus is known to be a relatively uncommon condition characterized by the inability of the kidneys to conserve water. It can be caused by damage to the hypothalamus or pituitary gland or it can be inherited, 2 typically in an X-linked manner.3 Conversely, diabetes mellitus is the result of an imbalance between the body's need for insulin and the ability of the pancreas to secrete it.
Seventy-five years after this distinction was first made, in 1869, German pathologist Paul Langerhans first described the anatomy of the insulin-secreting pancreatic islet cells.4 Subsequently, in 1889, German physician Joseph Mering and
Lithuanian physiologist Oskar Minkowski discovered that a canine pancreatectomy causes the development of severe diabetes.5 The link between diabetes and the pancreas was therefore set, paving the way for one of the most important scientific achievements of the twentieth century. In 1922, Canadian medical scientists Frederick Banting and
Charles Best identified and isolated the internal secretions of the pancreas, insulin.6
Thereafter it would be understood that diabetes mellitus is caused by insulin resistance - the inability of cells to effectively store glucose. Insulin resistance results in increased levels of plasma glucose or hyperglycemia, which will ultimately damage small blood vessels and cause long-term complications affecting the nerves, heart, eyes, and kidneys.
In this way, diabetes mellitus increases risk of heart disease, stroke, limb amputation, blindness, kidney failure, and death.7
In 1939, British medical scientist Harold P. Himsworth further distinguished two classes of diabetes mellitus: "insulin-sensitive" due to insulin deficiency, the more severe
type of diabetes; and "insulin-insensitive" diabetes resulting from a lack of bodily response to insulin.8 Forty years later, diabetes mellitus was officially divided into the 3 insulin-sensitive and insulin-insensitive subtypes, though renamed insulin-dependent diabetes (IDDM) and non-insulin-dependent diabetes (NIDDM), respectively.1
However, by 1995, a new classification system was deemed necessary in order to address new insights into diabetes etiology. Sponsored by the American Diabetes
Association, an international committee recommended insulin-dependent and non- insulin-dependent diabetes mellitus be renamed "type 1" and "type 2" diabetes mellitus, respectively.9 Type 1 diabetes is characterized by pancreatic islet beta-cell destruction caused by an autoimmune process that typically leads to absolute insulin deficiency. It was formerly called juvenile-onset diabetes because more than 95% of type 1 diabetics are under the age of 25. Type 2 diabetes, however, is the most prevalent form of diabetes mellitus, representing 90-95% of diabetes cases; it is characterized by insulin resistance and relative insulin deficiency. The diagnosis of type 2 diabetes involves several tests that measure plasma glucose levels after fasting and then 2 hours after consuming an oral dose of glucose. Both a fasting plasma glucose concentration > 7.0 mmol/L and an oral glucose tolerance test >11.1 mmol/L indicate a diagnosis of diabetes.
By the 1990s, there had been a dramatic increase in the reported prevalence of type
2 diabetes in the United States, United Kingdom, and many other countries (figure l).10
As diabetes began to reach epidemic proportions on a global scale, the scientific community began to take notice. Diabetes research, including epidemiological studies, experimental animal models, and genome-wide association studies, similarly increased in the 1990s (figure 2).
1 In 1979, the U.S. National Diabetes Data Group produced a document standardizing diabetes mellitus nomenclature, which was endorsed by the World Health Organization in 1980. 4
'Diabetes publications •US Incidence
<#> 25000 25 5 (A C : c a 0 .= o s 20000 r 20 V) S 1S J5 Saj '2S3 3 «2 15000 15 •s i s D." V) <*- M 10000 o> °u -ga is o> 2 5000 •Cg «W) S3 nj rTTTTTTTrTTTnTTTTTTTTrT I I I I I I I I I 2 U 0 Isc 1958 1963 1968 1973 1978 1983 1988 1993 1998 2003 2008 U 3 eu Year
Figure 1: Estimated prevalence of type 2 diabetes in the United States (US) from 1958 to 2009, and number of publications in the ISI Web of Knowledge regarding "diabetes" (but not "insulin-dependent diabetes," "type 1 diabetes," "type I diabetes," or "gestational diabetes"). Data from the CDC 11 and the ISI Web of Knowledge.
^^Diabetes publications ^^Global Incidence
25000 300 c 20000 a +* 250 £¥ CQ aj (M O a .S 200 o s isJO •— 15000 4) M 3 T3 U C D. ~ - 150 a z «*. M 10000 .2 s o a - 100 « w Im "O > v> 0j u 5000 v
Year figure 2: Estimated global prevalence of type 2 diabetes in 1994, 1997, 2000, 2004, and 2010 as well as the number of publications in the ISI Web of Knowledge regarding "diabetes" (but not "insulin-dependent diabetes," "type 1 diabetes," "type I diabetes," or "gestational diabetes"). Data from the ISI Web of Knowledge.12 5
In the 1990s and 2000s, the funding agencies most involved in diabetes research included the National Institutes of Health, the American Medical Association, Wellcome
Trust, the British Heart Foundation, the Medical Research Council, the Canadian
Diabetes Association, and the National Institute of Diabetes and Digestive and Kidney
Diseases. Diabetes research was also highly funded by pharmaceutical companies,
including Pfizer, Sanofi-aventis, AstraZeneca, Eli Lilly, and Roche. Such research aimed
at understanding the genetics, biochemistry, and physiology of diabetes so that effective
therapies could be developed, and early detection and diagnosis improved.
Funding for diabetes research has greatly increased over the past 20 years. For
example, the National Institutes of Health (NIH), the largest public funder of biomedical
research worldwide, funded $298,920 for diabetes research in 1996, or 6.1% of its total 1 ^ budget for 29 disease categories. Ten years later, in 2006, the NIH funded 1.038 billion
dollars, or 8.7% of its total budget for the same 29 disease categories.14 Similarly,
National Health and Medical Research Council (NHMRC) funding for diabetes research
increased from $10.4 million in the year 2000 to $118.6 million in 2007.15
Funding for diabetes research will become increasingly important in the coming
years. It is estimated by the World Health Organization that at least 346 million people
are affected by type 2 diabetes today, and the prevalence of type 2 diabetes is expected to
drastically increase in the developing world, especially in China and India.16 Type 2 17 diabetes will also affect more and more children and adolescents, in addition to adults.
This thesis has entailed a critical study of central papers in the type 2 diabetes and
developmental origins of adult disease literature, published between the years 1962 and
2011. Since the 1960s, diabetes research has been conducted from various perspectives, 6 spanning many fields of study, including: anthropology, clinical medicine, developmental biology, epidemiology, epigenetics, evolutionary biology, experimental physiology, molecular genetics, and nutrition. We will see how each of these fields of study have contributed to our current understanding of type 2 diabetes.
This thesis represents the first historical study of the conceptual changes that have occurred over the past five decades regarding type 2 diabetes etiology. It explores why
theory change has occurred within the context of changing research methodologies and a
changing understanding of "disease". To explore the nature of the theories regarding type
2 diabetes, this thesis identifies the evidence for and criticisms of each theory, the major
proponents and detractors of each theory, and the underlying assumptions and data.
As we shall see in chapter 1, an evolutionary and genetic hypothesis for diabetes
was proposed in 1962. Termed the "thrifty genotype hypothesis", it sought to explain
how diabetes prevalence has increased within the context of the modern diet. This
hypothesis predicted that the "diabetic genotype" would have been adaptive for our
hunter-gatherer ancestors by providing efficient nutrient utilization. However, the
selection for these "thrifty genes" would now have been rendered disadvantageous by the
nutritionally enriched environment in which many people now live. Thus, diabetes was
understood as a primarily genetic phenomenon and a maladaptation to present conditions.
In chapter 1, we shall also see that the thrifty genotype hypothesis was proposed in
relation to a similar theory regarding sickle cell anemia. Sickle cell anemia served as the
paradigmatic case for this genetic deterministic view of diabetes causation.
The thrifty genotype hypothesis was not rigorously investigated until the 1990s, at
which time diabetes was fast becoming both a global epidemic and a great field of 7 research. Diabetes researchers, including epidemiologists, geneticists, and developmental biologists, attempted to explain the rising incidence of type 2 diabetes. At this time, debates over the roles of "nature" and "nurture" in type 2 diabetes causation were
widespread.
In chapter 2, we shall see the emergence of an alternative hypothesis that was
proposed in 1992 in direct conflict with the belief that diabetes is genetically determined.
Termed the thrifty phenotype hypothesis, it suggested that low birth weight caused by
intrauterine undernutrition causes a fetus to become nutritionally "thrifty," manifesting in
reduced beta-cell growth. Glucose intolerance and type 2 diabetes would then be
triggered when the individual with permanently underdeveloped beta-cell function
encounters a state of good nutrition or nutritional excess in childhood and adult life. This
hypothesis did not include an evolutionary explanation or a molecular mechanism;
instead, it was purely phenomenological and was based solely on the correlation between
in utero nutrition and adult diabetes risk.
Although the thrifty genotype hypothesis was widely criticized by epidemiologists,
anthropologists, and clinical biochemists at this time, so too was the thrifty phenotype
hypothesis. Type 2 diabetes susceptibility could not be fully explained by genetics, as the
search for thrifty genes had been largely unsuccessful. But the thrifty phenotype
hypothesis could not fully explain type 2 diabetes susceptibility either; it was based on
epidemiological associations and did not offer a mechanism for type 2 diabetes
susceptibility at the cellular level.
Thus, there was no consensus regarding type 2 diabetes etiology in the 20th century.
Neither of the thrifty hypotheses were refuted because it remained unclear how much 8 genetic and developmental determinants influence type 2 diabetes susceptibility. Nor were these hypotheses fully accepted, however. An understanding of type 2 diabetes etiology at the cellular level was needed.
As we shall see in chapters 3 and 4, a third major theory was proposed in 2004 that brought together nature and nurture, genetics and development, as well as evolutionary principles to bear on this problem. Called the "predictive adaptive response model", it emphasized that the embryo, fetus, or infant adjusts its development to match its environment. Such "developmental plasticity" would allow for a range of phenotypes to be expressed from a single genotype and thus provide the means by which a developing organism can respond to environmental change.
As discussed in chapter 3, this novel hypothesis was proposed at a time when a new field of evolutionary developmental biology was emerging and molecular mechanisms of gene regulation were becoming better understood. The predictive adaptive response model suggested that epigenetic processes underlie the ability to make predictive adaptive responses, whereby developmentally-induced changes in gene expression could be inherited from one generation to the next. Through epigenetic processes, the fetus or infant can adjust its development in anticipation of its future environment. This model proposed that disease then manifests when the predictive adaptive response made during early life fails to accurately forecast the future environment: an environmental
"mismatch."
In the case of type 2 diabetes, this model suggested that inappropriate predictive adaptive responses made during early life could be related to the growing number of diabetics worldwide. As discussed in chapter 4, it is because the modern human diet is 9 now significantly different from the diet experienced by our hunter-gatherer ancestors that the incidence of type 2 diabetes is so high; there is now a greater frequency of
mismatch.
However, in chapter 5, we will see that criticisms and questions still remain
concerning the predictive adaptive response model. It is still uncertain what exactly the
fetus adapts to; critics argue that the factors a fetus takes into account when predicting the
future environment requires a more critical examination. Additionally, doubts still remain
concerning the evolutionary processes involved in predictive adaptive responses. Critics
argue that human developmental plasticity evolved within a context of environmental
stochasticity, and so predictive adaptive responses would often have led to unreliable and
therefore maladaptive predictions of the adult environment. An alternative hypothesis,
"the maternal fitness model", has been proposed by one such critic to address the
shortcomings of the predictive adaptive response model.
Despite remaining uncertainties, we shall see that the predictive adaptive response
model has received support from an abundance of epidemiological and experimental
animal studies. Indeed, there is now an emerging consensus that type 2 diabetes is a
multifactorial disease, having genetic, developmental, and evolutionary determinants. 10
Chapter 1: The Thrifty Genotype Hypothesis
Diabetes mellitus is in many respects a geneticist's nightmare. As a disease, it presents almost every impediment to a proper genetic study which can be recognized. James V. Neel et ah, 19651
Whether for or against the thrifty genotype hypothesis, epidemiologists and other scientists are likely to continue to be inspired by it to study the frequency, etiology and pathophysiology of type 2 diabetes and associated disorders for some time to come. This ongoing research is probably Neel's greatest legacy. H. King and G. Roglic, 19992
Neel's evolutionary proposal
In the early 1960s, diabetes mellitus was little understood. The distinction between type 1 and type 2 diabetes had not yet been clearly drawn. Nor was the pathophysiological basis of this disease fully understood. It was recognized, however, that diabetes prevalence was high, especially in certain ethnic populations. For population geneticist James Neel of the University of Michigan Medical School, this presented an enigma. He wondered how an apparently genetic disease could attain such a high frequency when there should be an "obvious" and "strong" selection pressure against it by interfering with reproduction and survival. In 1962, Neel posited the "thrifty genotype hypothesis" in order to explain this diabetes "paradox."
As we shall see, Neel aligned his conception of diabetes etiology with his understanding of sickle cell anemia, the mode of inheritance of which he had studied in the early 1950s. Just as sickle cell genes were shown to play an adaptive role in the presence of malaria, so too would genes for diabetes. Thus, he proposed that the increasing diabetes frequency might be attributable to some benefit imparted by the 11
"diabetic genotype." He conjectured that diabetes would benefit the individual through
more efficient nutrient utilization or nutritional "thriftiness."
Neel's thrifty genotype hypothesis offered an adaptationist account, according to
which the "diabetic genotype" had evolved over the course of 99% of human's history in
order for humans to better adapt to fluctuations in food supply. However, in Neel's view,
the high-fat, high-sugar modern diet has today rendered the "diabetic genotype"
detrimental.
In this chapter, I provide an account of how Neel arrived at the thrifty genotype
hypothesis, prompted by his previous success in elucidating the inheritance of sickle cell
anemia. I then examine the early reception of the thrifty genotype hypothesis, the
epidemiological and experimental support for the hypothesis, and how the hypothesis has
been modified in light of new findings regarding diabetes inheritance.
A genetic and evolutionary explanation for diabetes
In 1962, James Neel published his paper entitled "Diabetes Mellitus: A 'Thrifty'
Genotype Rendered Detrimental by 'Progress'?", in which he proposed that diabetes
mellitus originated from a quick insulin trigger response to hyperglycemia. Decades later,
this hypothesis would be considered by some human geneticists to be one of the most
influential hypotheses in genetic epidemiology.3 Neel was a founder of modern human
genetics.4 He completed doctoral research in Drosophila genetics at the University of
Rochester in 1939, and then enrolled in medical school there, graduating in 1944. He
practiced as a physician at several hospitals in Boston before completing his second
military tour from 1946-1947 at the Atomic Bomb Casualty Commission in Hiroshima, 12 studying the aftereffects of atomic radiation on survivors. After accepting a position at the University of Michigan as assistant geneticist, in the late 1940s and 1950s, Neel became concerned with the genetics of sickle cell anemia and thalassemia. In 1949, Neel was the first to establish the genetic basis for sickle cell anemia, distinguishing the heterozygous sickle cell trait from the homozygous sickle cell anemia.5
Similar to his work with Italian-American thalassemia patients in previous years,
Neel conducted hematological testing on an abundance of African-American families known to possess the sickle cell gene.6 He then independently discovered that the erythrocytes of individuals who possess homozygous genes for sickle cell anemia experience more severe sickling than those heterozygous for the sickle cell trait.7 Four months later, famed biochemist Linus Pauling and colleagues at the California Institute of
Technology were able to examine sickle cell anemia and sickle cell trait hemoglobin with the relatively new technique of electrophoresis. Their findings confirmed the distinction between the heterozygous sickle cell trait and the homozygous sickle cell anemia.8
Neel then sought to understand what he considered the genetic paradox of sickle cell anemia: how a disease, often lethal prior to the onset of reproductive age, can attain such a high frequency in certain human populations. As early as 1950, Neel surmised that, in order for the sickle cell trait to have persisted at high frequencies within certain populations, some selective advantage must have offset the negative aspects of the disease:
As in the case of thalassemia, at present we cannot rule out a relatively small selective advantage on the part of the heterozygote; we can only say that no conclusive data exist, the evidence if anything suggesting that the reverse is true.9 Conclusive evidence for the selective advantage offered by the sickle cell trait was found in the early 1950s. During this time, many geneticists and epidemiologists established a link between the incidence of the sickle cell trait and malaria.10 They discovered that, in regions where malaria was hyperendemic, the sickle cell trait was present in greater frequencies. Furthermore, individuals with the sickle cell trait suffered from malaria less often and less severely than did those without the trait. In this way, the persistence of the sickle cell gene at high frequencies in certain populations could be explained; it was established that in the case of sickle cell anemia and the sickle cell trait, a balanced polymorphism exists in these population and is maintained by the existence of malaria.11
Neel's involvement in establishing the genetic basis for sickle cell anemia had a significant impact on his approach to studying diabetes in subsequent years. For Neel, sickle cell anemia was the paradigmatic case, demonstrating how an apparently disadvantageous gene can attain high frequencies within a population. It was a classic case representing the interaction between the changing human environment and the evolution of genes involved in disease. Thus, Neel extended the idea of a balanced polymorphism to diabetes. In so doing, he predicted that those heterozygous for the diabetes "gene" would possess a "thrifty genotype", and this advantage would offset the 19 interference to reproduction experienced by some homozygous diabetics.
Neel suggested that such "thriftiness" would allow for more efficient nutrient utilization in diabetics, resulting in increased fat storage and decreased renal loss of glucose.13 Proposed at a time when the understanding of glucose and insulin metabolism was undeveloped, Neel was unable to articulate the exact physiological basis of such
"thriftiness."14 However, in 1962, he proposed that the emergence of diabetes was related 14 to an imbalance between insulin and what Vallance-Owen had termed "anti-insulin" in
1958.15 Neel further suggested that, in the individual predisposed to diabetes, a "quick insulin trigger" response to hyperglycemia occurs during the early years of life. This increased ability to release insulin after food intake is initially balanced by the production of anti-insulin. However, Neel suggested that this quick insulin trigger would prompt the relative overproduction of anti-insulin in later years, manifesting in clinical diabetes.16
In this way, Neel speculated that the thrifty genotype would have originated as an
adaptation in early humans. He reasoned that, since the relative overproduction of insulin
during early life would be an effective energy-conserving mechanism, it would have been
advantageous in human's hunter-gather past when cycles of feast and famine were
common. If so, he argued that the readily available high-sugar and high-fat foods in more
recent times have led to excessive stimulation of the quick insulin trigger response. In
some individuals, this results in the overproduction of anti-insulin, leading to insulin 17 inefficiency and diabetes.
Neel argued that the imbalance between insulin and anti-insulin was rare in
ancestral times; as a result, it would not have interfered with reproduction to the extent it
does in modern times.18 However, this imbalance has now become increasingly common,
and this, he quipped, was the "biological price of progress."19
To test this mechanism, Neel suggested a long-term comparison of children's
glucose metabolism when they are born to one diabetic parent, two diabetic parents, or no
diabetic parents. He also proposed studies on "primitive" peoples' insulin and anti-insulin
levels, suggesting that this would provide the closest approximation to human's ancestral
hunter-gatherer metabolism.20 15
Neglect of the thrifty genotype hypothesis
Initially, the thrifty genotype hypothesis was not widely discussed or investigated.
It would be three decades before Neel's hypothesis would become influential (figure 3).
In the 1990s, diabetes prevalence had increased in many countries throughout the world and epidemiologists recognized what they called a "diabetes epidemic." Understanding of diabetes had also changed a great deal since the 1960s, and this prompted Neel to reexamine his hypothesis in 1982.
100
90
tfl 80 " .2 70
1963 1967 1971 1975 1979 1983 1987 1991 1995 1999 2003 2007 2011 Year
Tigure 3: Number of citations of Neel's 1962 publication regarding the thrifty genotype hypothesis (J.V. Neel, Am. J. Hum. Genet. 14: 353-362), by year. Data from the ISI Web of Knowledge.
The Thrifty Genotype Hypothesis in J 982
Neel originally proposed that clinical diabetes manifests when anti-insulin production exceeds insulin production. However, by the late 1960s, other laboratories could not confirm the existence of Vallance-Owen's anti-insulin. As a result, Neel recognized that the physiological basis of the thrifty genotype hypothesis had collapsed.21 16
In 1982, Neel attempted to update his hypothesis based on the new understanding of diabetes that had developed over the preceding 20 years:
In subsequent years, the case for insulin antagonists as an important pathogen factor has largely collapsed, and so, in any detail, did my theory. On the other hand, the problem of explaining the relatively high frequency of a genetic disease such as diabetes did not go away. I will therefore attempt to rehabilitate the theory, suggesting that, although incorrect in detail, it may have been correct in principle.2
In the mid-1970s, it had been demonstrated that a specific cellular insulin receptor would vary in number in response to insulin levels. Neel consequently suggested in
1982 that insulin receptors might prove to be a key point of genetic control and a mechanism by which diabetes could develop.24 Similar to the original thrifty genotype hypothesis, Neel hypothesized that the repeatedly high levels of insulin associated with the quick insulin trigger would eventually reduce cellular insulin receptors to subnormal numbers. This would then result in insulin resistance and diabetes. Neel also hypothesized that individuals predisposed to diabetes could have a genetically determined decrease in insulin receptor numbers.
In 1962, Neel had put forth the thrifty genotype hypothesis in an attempt to explain the increasing frequency of diabetes in spite of the reproductive handicap imposed by this disease. The distinction between type 1 and type 2 diabetes had not yet been drawn at this time. In revisiting his hypothesis in 1982, the distinction between the two classes of diabetes posed a problem for Neel's theory. In retrospect, Neel maintained that the thrifty genotype hypothesis had been specifically directed at type 2 diabetes.
However, because type 2 diabetes typically appears later in life than does type 1 diabetes, this called into question whether or not the diabetic genotype truly imposes a reproductive handicap. As Neel expressed in 1982, 17
If it were established that NEDDM [type 2 diabetes] does not result in a reproductive handicap, there would be no special genetic problem to be explained; it would then be simply an aspect of aging...25
Although there were no conclusive data concerning the reproductive handicap imposed by type 2 diabetes, Neel suggested with considerable certainty that some individuals who develop diabetes often exhibit departures from normal glucose metabolism as early as the second decade of life.26 Despite the lack of data, Neel still believed that type 2 diabetes
imposes a reproductive handicap:
I will conclude that although it is difficult to be quantitative, NIDDM [type 2 diabetes](as well as IDDM [type 1 diabetes]) confers a significant biological handicap, so that to the extent the disease existed in ancient times, other than as a rarity, some individuals with the corresponding genotypic predisposition would have to enjoy a sufficient average selective advantage to offset the impaired reproduction of others of the same genotype who happened to develop NIDDM early in life.27
Neel was unable to articulate the precise basis of this genotypic predisposition,
suggesting that the exact genetic mechanisms for both types of diabetes cannot be known
until the heterogeneities of the disease are better understand. "Until that time," Neel
concluded, "devising fanciful hypotheses based on evolutionary principles offers an 9Q intellectual sweepstake in which I invite you all to join.
Revival and criticisms
Neel's thrifty genotype hypothesis was based on several additional assumptions
that were either disproven or subject to heated debate in the 1980s and 1990s. Indeed,
critics questioned the evolutionary rationale of the thrifty genotype hypothesis, the
testability of the hypothesis, as well as the existence of "thrifty genes." Extensive
research into the genetics of diabetes had yet to find a single gene responsible for the
disease and many geneticists turned towards a multifactorial outlook on diabetes in the 18
in late 1960s. Hypotheses regarding a single gene determinant of diabetes susceptibility were deemed untenable because the expected Mendelian ratios were not found in studied
11 populations. Thus, proponents of the multifactorial inheritance of diabetes argued that many genes, with additive effects, contributed to diabetes inheritance.32 Neel himself acknowledged in 1963 that diabetes could have a multigenic basis, though he had previously hypothesized a single-gene mode of inheritance.33 Nonetheless, Neel argued, the thrifty genotype hypothesis could be as easily applied to a one-gene or a multi-gene concept of diabetic predisposition.34
Thus, the specific mechanisms proposed by Neel in 1962 were no longer tenable by the 1970s; Vallance-Owen's insulin antagonists did not exist and diabetes inheritance was increasingly believed to be a multifactorial disease. Nevertheless, Neel's hypothesis began to be discussed all the more in the following decades. Throughout the 1980s, many epidemiologists and anthropologists applied the thrifty genotype hypothesis to explain the high prevalence of type 2 diabetes among certain ethnic groups, especially American
Indians.35 They agreed with Neel's idea that thrifty genes may have been selected for during feast and famine conditions in human's evolutionary past.36
In 1991, M. Wendorf and I. Goldfine of the University of California further developed Neel's claim regarding the selective advantage conferred by the thrifty genotype. Using the archaeological record, they examined how the high incidence of type
2 diabetes among certain American Indian tribes may be rooted in their migratory past.37
Wendorf and Goldfine argued that the discrepancy in diabetes incidence rates between
American Indian tribes might be due to the different timing of ancestral migrations into
Alaska. They posited that the ancestors of the tribes currently experiencing the worst 19 diabetes epidemics were the first to migrate to North America, approximately 23,000 years ago. These Paleo-Indian tribes largely relied on big game as a source of food; but around 11,000 years ago, many species such as mammoths and horses were becoming extinct throughout North America. The Paleo-Indians likely experienced frequent, but short-lived, food shortages during this time. Wendorf and Goldfine conjectured that it is within this context that the "thrifty genotype" may have been selected for.38 The sedentary lifestyle and free access to food today now contributes to the epidemics of
•5Q obesity and diabetes among modern-day Paleo-Indians, such as the Pima Indians.
Furthermore, Wendorf and Goldfine reasoned that the lower prevalence of diabetes among other American Indian tribes, including the Athapaskans, Aleuts, and
Eskimos, may be due to the fact that their ancestors migrated into North America much later than did the Paleo-Indians; nor did they rely as heavily on big game hunting.40 Thus, regarding Neel's hypothesis, Wendorf and Goldfine concluded in 1991 that,
Although his original pathophysiological mechanism of insulin oversecretion and the subsequent development of insulin antagonists has been retracted, the thrifty genotype concept may still be valid.41
Indeed, over the following decade, many anthropologists and geneticists would support the genetic and evolutionary explanations for diabetes etiology embedded within
the thrifty genotype hypothesis. In 1993, epidemiologists G. Dowse and P. Zimmet
argued that Neel's hypothesis remained a "convenient" explanation for high diabetes
prevalence in certain ethnic groups.42 J. Brosseau of the University of North Dakota
School of Medicine also supported a genetic explanation for type 2 diabetes in Indian
populations, commenting in 1993:
Intuition tells us there must be a strong genetic factor which predisposes Indians to diabetes. Neel (1962) suggested a "thrifty genotype" which would be beneficial 20
to a nomadic culture but diabetogenic to a sedentary one. No one has come forth with a better theory.43
Others found it "undoubtedly true that a thrifty genotype exists" and that this genotype is widespread, determining diabetes susceptibility at both the individual and population levels.44 As of 1994, it remained, for some, the predominant evolutionary explanation for diabetes.45
This continued interest into Neel's hypothesis was reflected in the Thrifty Genotype
Symposium held in Auckland in 1994. In considering the fate of the thrifty genotype hypothesis 30 years after it was first proposed, endocrinologist B. Swinburn of the
University of Auckland concluded that the general concepts of this hypothesis remain helpful despite an overall lack of evidence 46 As he reflected in 1996, although other
theories had been proposed concerning diabetes etiology in more recent years, the thrifty
genotype hypothesis continued to be widely discussed and investigated:
Little solid evidence has been produced to substantiate Neel's hypothesis and indeed a variety of other theories have emerged to dilute the theoretical rationale for the concept. Also the mechanisms suggested by Neel have not been substantiated by the experimental data which have subsequently emerged. It is interesting, therefore, that the hypothesis should remain such a widely invoked explanation for the high prevalence of NIDDM [type 2 diabetes] and obesity. In fact, the hypothesis has not only survived, but it seems to be flourishing in a wide variety of fields of research including diabetes, anthropology, energy metabolism, hypertension, human biology, and genetics 47
He considered this continued popularity to be largely due to the "intuitive validity" of the
AO broad concepts offered by the thrifty genotype hypothesis. In subsequent years, others
would agree, acknowledging the inherent logic of the thrifty genotype hypothesis 49
By the late 1990s, Neel's hypothesis had also received a great deal of
epidemiological and experimental support. The concept found support from studies of the
gerbil Psammomys obesus, in which strains susceptible to obesity and diabetes showed 21 lowered metabolic rates, high metabolic efficiency, and increased survival during periods of prolonged fasting.50 In addition to epidemiological findings, these animal models substantiated Neel's hypothesis: that the maladaptation to nutrient excess increases susceptibility to insulin resistance and diabetes.51
Several genes associated with the insulin pathway and lipid metabolism had also been identified as candidate genes for the thrifty genotype by the late 1990s. Genes of interest included the peroxisome proliferator-activated receptors (PPARs) and genes involved in the insulin signaling cascade. As commented by endocrinologist B. Joffe and epidemiologist P. Zimmet in 1998, "Although nearly 40 yr have elapsed since Neel's original postulate, the thrifty gene may soon acquire a biochemical label or series of labels!"53
Criticisms of the thrifty genotype hypothesis
Despite the popularity of Neel's ideas, critics and skeptics of the thrifty genotype hypothesis still remained. Throughout the 1990s, critics argued that the genetics of type 2 diabetes remained poorly understood and that, consequently, the thrifty genotype hypothesis remained a general concept lacking clear linkages to genetic and metabolic mechanisms.54 They claimed that, despite many attempts, the search for thrifty genes had been largely unsuccessful; and that the findings from animal models had been inconsistent and sometimes too extreme to reflect human physiology.55 Indeed, following
the emergence of a non-genetic hypothesis regarding diabetes etiology in 1992,
epidemiologist K. Cruickshank commented that the thrifty genotype hypothesis was
"nearing the end of its useful life" and in "terminal decline."56 22
Critics also argued that the thrifty genotype hypothesis was too ill-defined to be testable.57 While Neel proposed prospective studies of children genetically susceptible to the development of diabetes, some believed that such studies would be unsuccessful in separating gene effects from environmental factors. They claimed that if the thrifty genotype hypothesis cannot be experimentally tested, then it cannot even be considered a hypothesis.58
Response to critics at the turn of the 21st century
In light of these criticisms, Neel reexamined his thrifty genotype hypothesis once more, in 1998. He acknowledged that the term "thrifty genotype" had become obsolete based on the increasing understanding of genetic complexity: "the term 'thrifty genotype' has served its purpose, overtaken by the growing complexity of modern genetic medicine."59 However, as the thrifty genotype hypothesis continued to be invoked in explanations of diabetes etiology, Neel argued that the concept itself "remains as viable as when first advanced."60 Instead, he suggested that a broadening of the original hypothesis was necessary in order to reflect the "etiologically heterogeneous" and
"multigenic" nature of the disease. That there is a genetic basis to diabetes etiology was certain and reinforced by innumerable studies, he claimed; but, terminology should also reflect the vast environmental changes that were brought about by "civilization" and to which we are now exposed. 61 Thus, regarding diabetes and obesity, Neel concluded in
1998:
While the concept of NIDDM [type 2 diabetes] as a "thrifty genotype" now expressing itself under conditions of civilization seemed appropriate 36 years ago, the various recent developments regarding the disease...suggest both a modification and a broadening of the original concept. It now seems preferable to 23
conceptualize these diseases as resulting from previously adaptive multifactorial genotypes, the integrated functioning of whose many-faceted genetic components is seriously disturbed by the complexly altered environment in which they now find themselves.62
However, while acknowledging the complex interaction between genes and the environment, Neel emphasized that environment alone cannot determine diabetes susceptibility. Indeed, he stated, "there can, after all, be no phenotype without an underlying genotype."63 But as we will see in the following chapter, many other diabetes researchers would disagree with the importance of genetics to diabetes susceptibility. 24
Chapter 2: The thrifty phenotype hypothesis
Like other living creatures, human beings are 'plastic' in early life: their growth and development are moulded by the environment. David Barker, 20011
Hales and Barker's epidemiological proposal
Thirty years after the publication of the thrifty genotype hypothesis, in 1992,
Nicholas Hales and David Barker proposed the "thrifty phenotype hypothesis." This hypothesis, named in contradistinction to the thrifty genotype hypothesis, offered an entirely different approach to the explanation of type 2 diabetes etiology.2 The thrifty
phenotype hypothesis proposed that environmental factors affect type 2 diabetes susceptibility "independently of genetic factors."3
Proposed at a time when the Human Genome Project was emerging, and when the human genome was being lauded as the "holy grail" and the "book of man," the
"environmental" thrifty phenotype hypothesis was born into what might be considered a
"hostile environment."4 The Human Genome Project was an international effort that formally began in the year 1990. Its primary goals were to identify all human genes as well as to determine the complete sequence of the 3 billion DNA bases. It was in this "era
of the gene" that British scientists Hales and Barker proposed that environmental factors
determined type 2 diabetes etiology, not genes. Their environmental hypothesis was an
innovative idea at a time when genome mapping promised a new era of gene therapy.
Given the promise of gene-based medicine, as we shall see, the thrifty phenotype
hypothesis generated a great deal of controversy in the early years following its
conception.5 25
Indeed, Hales and Barker were attacked by many critics who claimed that they had misinterpreted data, had major inconsistencies in how they interpreted data, and that their study design was seriously flawed.6 The thrifty phenotype hypothesis was also criticized for being a monocausal explanation for a very complex disease.7 Furthermore, many early responses to the thrifty phenotype hypothesis emphasized the role of genetic factors in type 2 diabetes etiology.8 As one advocate of the phenotypic view of type 2 diabetes causation later commented in 2005, scientists at the time had difficulty accepting the "provocative" environmental hypothesis because it discounted the role of the gene:
"researchers were less enamoured with the concept that environmental factors could have such a dominant influence on disease patterns."9
At the same time, a diabetes crisis was emerging; in the 1990s, the incidence of type 2 diabetes was exploding worldwide. It was in this context of the fast-approaching diabetes epidemic that Hales and Barker proposed their hypothesis. Their immediate concern was to determine the major causative factors of type 2 diabetes so that preventative measures could be taken:
It is important that a concerted effort be made to identify the factors and mechanisms involved so that steps can be taken to prevent this disease. The Thrifty Phenotype hypothesis continues to provide a conceptual basis for this research.10
This chapter will document how Hales and Barker sought to challenge gene- centered thinking with their thrifty phenotype hypothesis and how their collaboration led to this highly-cited, albeit controversial, hypothesis. This chapter will also illustrate the conceptual shift away from gene-centered thinking that the thrifty phenotype hypothesis represented in regard to diabetes. Finally, I provide an account of the criticisms and 26 challenges to the thrifty phenotype hypothesis in the two decades following its conception.
The Thrifty Phenotype Hypothesis
Nicholas Hales (1935-2005) earned an M.D. from Trinity College, Cambridge, in
1960. Over the next four years, he worked on elucidating the biochemical mechanisms underlying insulin secretion as a PhD student in biochemistry at the University of
Cambridge. His interest in diabetes first sprung from his family life: his younger sister
and his mother were diabetic, and he himself developed the disease later on in life.11 In
1963, Hales and his supervisor, Philip Randle, published a major paper that greatly
improved the existing method for the immunoassay of insulin. Previously, the
immunoassay method had made use of radioactive insulin and insulin antibody to 10 measure insulin levels in plasma and serum. But Hales and Randle pre-precipitated the
insulin antibody complex with anti-immunoglobulin serum to allow for the rapid
recovery of antibody-bound insulin by filtration.13 The rapidity and simplicity of their
modification to the immunoassay method meant that it was immediately and widely
adopted.14
After completing his Ph.D. research in 1964, Hales continued to refine methods
for measuring insulin and pro-insulin, first at Cambridge, and then at the Welsh National
School of Medicine from 1970 to 1976. In 1977, Hales returned to Cambridge. His
continued interest in the mechanism of insulin secretion was evident in his 1984
publication in Nature with colleague Daniel Cook. Together they discovered an ATP-
sensitive potassium channel that linked metabolism and membrane potassium 27 permeability in pancreatic beta-cells.15 Understanding of pancreatic beta-cells would later play a key role in the development of the thrifty phenotype hypothesis. Hales then left
Cambridge: from 1985 to 1990, he worked at the Medical Research Council (MRC) and it was on a site visit to a MRC Unit in The Gambia that Hales and Barker fortuitously met in 1989.
David Barker was then professor of clinical epidemiology at the University of
Southampton (1979 - present). He had received his M.D. from Guy's Hospital, London, and his Ph.D. from the University of Birmingham. He was the Director of the Medical
Research Council Environmental Epidemiology Unit in Southampton from 1984 to 2003.
Under Barker's directorship, the MRC Unit discovered the relationship between low birth
weight Mid increased lifetime incidence of coronary heart disease and hypertension.16 In
fact, the thrifty phenotype hypothesis would, in 1995, be renamed the "Barker
Hypothesis" by the British Medical Journal.
Hales and Barker first put forth the thrifty phenotype hypothesis at the Banting
Lecture during the 27th Annual Meeting of the European Association for the Study of
Diabetes in Dublin in 1991. The following year, they published their landmark paper in
Diabetologia entitled "Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty
phenotype hypothesis." Therein they proposed that nutritional deprivation in utero and in
early infancy results in permanent changes in the structure and function of the fetal
pancreas. These changes then predispose the individual to the later development of
glucose intolerance and type 2 diabetes. The authors proposed that these structural
changes would proceed through selective growth retardation - the protection of brain 1 "7 growth at the expense of the viscera, including the pancreas. Hence, in a nutritionally 28 deprived state, the fetus and early infant would be compelled to become nutritionally
"thrifty."
Hales and Barker further suggested that, due to the rapid growth of beta-cells during fetal life, poor intrauterine nutrition would impair the early development of beta- cells and the islets of Langerhans. Abnormal islet vascularization and innervation as well as reduced beta-cell numbers would, in turn, result in poor insulin secretion. The authors suggested that glucose intolerance and type 2 diabetes would then be triggered when the individual with permanently underdeveloped beta-cell function encounters a state of good nutrition or nutritional excess in childhood and adult life. They also asserted that both the time of onset and the severity of type 2 diabetes are influenced by ageing, physical
* a inactivity, and obesity.
Thus, the thrifty phenotype hypothesis proposed a very different etiological model for type 2 diabetes than did the thrifty genotype hypothesis.19 The thrifty genotype hypothesis offered a broad explanation regarding the selection pressures for a genotype predisposing to type 2 diabetes, acting over many generations and at the population level.20 But for the thrifty phenotype hypothesis, undernutrition in utero and in early infancy acted as an environmental influence, functioning in an individual to increase diabetes risk.21 In juxtaposing the two "thrifty" hypotheses, Hales and Barker stated:
We should also reconsider the Neal [sic] "thrifty genotype" hypothesis - that the diabetogenic gene or genes persist at a high level in the population because they somehow confer a survival advantage in times of nutritional deprivation, though detrimental at times of adequate or over nutrition.. .we are suggesting a thrifty phenotype hypothesis. We propose that Type 2 diabetes is the outcome of the fetus and early infant having to be nutritionally thrifty. This thrift results in impaired growth of the Beta cells and the islets of Langerhans. As long as the individual persists in the undernourished state there is no need to produce much insulin. However, a sudden move to good or over-nutrition exposes the reduced state of Beta-cell function and diabetes results.22 29
So, for the thrifty phenotype hypothesis, diabetes was not considered to be a result of our evolutionary history and adaption to a diet no longer in effect. Instead, it was the result of our developmental history, when undernutrition during critical periods of fetal life caused impaired beta-cell growth.
First evidence for the thrifty phenotype hypothesis
Although Hales and Barker did not meet until 1989, the story of how they arrived at the thrifty phenotype hypothesis began years earlier, with epidemiological studies indicating that the environment played a major role in the onset of certain diseases. In
1985, a group of British epidemiologists, Barker among them, compiled an atlas of the common causes of death in areas of England and Wales: Atlas of Mortality from Selected
Disease in England and Wales, 1968-1978. From this work, an important finding emerged: the highest mortality rates from chronic diseases (most significantly ischaemic heart disease) occurred in the least affluent areas.
In 1986, Barker and statistician Clive Osmond further examined the geographical relationship between infant mortality rate from 1921 to 1925 and the rate of adult mortality from coronary heart disease between 1968 and 1978.24 They used infant mortality rate as an indicator of the overall health of the population. Their study was based on almost three hundred thousand infant deaths in England and Wales and one
million deaths from coronary heart disease. They found a strong correlation between
ischaemic heart disease and both neonatal and postneonatal mortality. From this, the
authors concluded that, "poor nutrition in early life increases susceptibility to the effects of an affluent diet,"25
Barker and colleagues conjectured that it was the adverse environmental conditions experienced in utero and in early infancy (those conditions associated with poor living standards) that increased susceptibility to coronary heart disease later in life. This claim, that coronary heart disease is linked with adverse environmental influences in early life, was quite controversial at a time when adult lifestyle was believed to predict incidence of heart disease.26 But in fact, high incidence of cigarette smoking and dietary fat consumption did not have the same geographical distribution as that of past infant mortality.27 This finding demonstrated that the in utero environment was more predictive of ischaemic heart disease than smoking or high dietary fat consumption.
To further test the hypothesis that adverse environmental influences (impairing prenatal and early postnatal growth and development) may be risk factors for ischaemic heart disease later in life, Barker and colleagues used archival records to compare birth weight and cause of death.28 This study, published in 1989, examined 5654 men born in
Hertfordshire, England, between the years 1911 and 1930. Barker and colleagues analyzed the men's causes of death in relation to birth weight and found that weight at one year of age was predictive of death from ischaemic heart disease.29 Since both prenatal and postnatal growth are important in determining weight at one year, Barker and colleagues concluded that the processes linked to growth and acting in prenatal or early postnatal life strongly influence the risk of developing ischaemic heart disease.30
This was especially apparent in their finding that men who had birth weights below 5.5 pounds had the highest death rates from ischaemic heart disease - almost twice that of men with birth weights greater than 9.5 pounds.31 31
This 1989 study of Hertfordshire men also revealed another important finding: death from ischaemic heart disease was graded across the birth weight range. For example, those babies weighing 8 pounds at birth had a lower risk of developing the disease later in life than did those babies weighing 7.5 pounds; babies weighing only 7 pounds had an even greater risk, and so on. This, along with the fact that babies with extreme birth weights were relatively few in number, lent support to the hypothesis that environmental factors in utero influence the risk of developing ischaemic heart disease.
This is so, for if it was a severe pathology (such as a gene defect) causing the relationship between birth weight and ischaemic heart disease, one would not expect to see a graded relationship across a normal range of birth weights.32 Since this was indeed the finding, it suggested that adverse environmental influences could be implicated in the graded relationship between birth weight and ischaemic heart disease.
To further examine what processes link intrauterine life with the risk of cardiovascular disease, Barker and colleagues next explored blood pressure. This study, conducted in 1990, included 449 men and women born in Preston, Lancashire, England, between 1935 and 1943. During this time period, the hospital had maintained records of newborn babies' birth weights and placental weights. Almost 50 years later, Barker and colleagues were able to track down those infants still residing in Lancashire - now adults of approximately 50-years-old - and fieldworkers measured their blood pressure and body mass index. The fieldworkers also inquired into the subjects' alcohol consumption, smoking habits, and family history of cardiovascular disease. Barker and colleagues found that "the highest blood pressures and risk of hypertension were among people who
had been small babies with large placentas".34 A larger placental size was believed to be a 32 marker of poor maternal nutrition, since the placenta will increase its growth in order to compensate for low fetal weight.35 Although higher body mass index and greater alcohol consumption were associated with increased blood pressure, "the relation of placental weight and birth weight to blood pressure and hypertension was independent of these influences and stronger".36 Therefore, intrauterine nutrition was more predictive of the adult development of hypertension than was the adult environment.
Meeting of the minds
It was these findings, linking intrauterine environmental conditions to heart disease and hypertension, which Barker presented to Hales when they first met at the
MRC Unit in The Gambia in 1989. Hales, with a background in diabetes research, suspected that the rapid growth of beta-cells during fetal life would also be vulnerable to poor intrauterine nutrition.37 Together, in 1991, Hales and Barker published a paper titled,
"Fetal and Infant Growth and Impaired Glucose Tolerance at Age 64". In it they showed
once again that intrauterine undernutrition was more predictive of adult diabetes risk than
the adult environment. This publication involved follow-up studies of 468 men born in
Hertfordshire, England, between 1920 and 1930. By testing the glucose tolerance of these
men of known birth weights, this study demonstrated "threefold differences in the
prevalence of impaired [glucose] tolerance and diabetes between men with the lowest and
highest early weights".38 Thus, they concluded in 1991: "reduced growth in early life is
•5q strongly linked with impaired glucose tolerance and non-insulin dependent diabetes".
From this study of glucose tolerance amongst a cohort of Hertfordshire men,
Hales and Barker further hypothesized that the link between fetal and infant growth and 33 impaired glucose tolerance was in the underdevelopment of the islets of Langerhans in utero.40 They concluded that, if poor nutrition continued beyond infancy:
The reduced ability to produce insulin is not a disadvantage. It becomes so only if nutrition becomes abundant, when increased demand for insulin outstrips the capacity for production.41
It is here that we see the beginnings of a non-gene-based account for the rising incidence of diabetes in recent times. The findings from their 1991 study formed the basis of Hales and Barker's thrifty phenotype hypothesis. In September of 1991, Hales presented the thrifty phenotype hypothesis at his Banting Award Lecture in Dublin. The corresponding paper was published in July of the following year.
Syndrome X
From 1986 to 1991, Hales, Barker, and colleagues showed through epidemiological studies the importance of intrauterine and early infancy nutrition in the etiology of many adult diseases, including ischaemic heart disease, hypertension, and type 2 diabetes. With these findings, in 1993, Hales and Barker were able to reassess the influential concept of
"syndrome X", which was originally presented at the Banting Award Lecture in 1988 by
Stanford University Professor, Gerald Reaven.42 Syndrome X was the name given to a combination of abnormalities (including glucose intolerance, hypertension, and some types of hyperlipidaemia) that tend to occur in the same individual and increase risk of developing coronary artery disease 43 Reaven had proposed that the primary defect in syndrome X was insulin resistance, but according to Hales and Barker, "the association of both type 2 diabetes and hypertension with reduced fetal growth has, however, raised the possibility that these and other components of syndrome X may have a common origin in suboptimal development at a particular stage of intra-uterine life".44 Based on 34 their findings regarding the inverse relationship between birth weight and risk of developing syndrome X, they suggested that syndrome X be re-named "the small-baby syndrome."45
Criticisms
The first criticisms came in response to Hales and Barker's 1991 paper linking fetal and infant growth to impaired adult glucose tolerance. R. Jarrett of the Division of
Community Medicine at Guy's Hospital, U.K., charged that Hales and Barker's work had a serious design flaw in addition to several interpretative problems.46 Jarrett questioned how the association between impaired glucose tolerance and birth weight could possibly be as strong as the association between type 2 diabetes and birth weight. Jarrett's views to the contrary were based on his own work, which showed that only a small proportion of
British men who had impaired glucose tolerance went on to develop type 2 diabetes 47
Thus, he claimed that Hales and Barker must have failed to correctly differentiate between impaired glucose tolerance and type 2 diabetes. Finally, Jarrett questioned how
Hales and Barker could account for evidence from twin studies pointing towards a genetic basis for diabetes, stating:
If the authors' environmental hypothesis is to replace the existing genetic one they need to explain the substantially higher concordance rate for non-insulin dependent [type 2] diabetes in monozygotic compared with dizygotic twins 48
D. Davies and J. Matthes at the University of Wales College of Medicine offered an alternative explanation for Hales and Barker's findings, which linked low birth weight to glucose intolerance and type 2 diabetes. They proposed that low birth weight and retarded growth in infancy (as a result of malnutrition) may not actually cause the 35 development of type 2 diabetes in adult life; instead, low birth weight may just be an early outward sign of lifelong nutritional stress. As they stated in 1991 :
Low birth weight and poor weight gain in infancy might be more an early marker for a continuum of nutritional and metabolic stress that extends throughout life and somehow culminates in impaired glucose tolerance and non-insulin dependent [type 2] diabetes.49
Hales and Barker's claim that impaired beta-cell function is the mechanism by
which glucose intolerance and diabetes surfaces in adult life was also criticized for being
far too simple for a disease as complex as type 2 diabetes. As W. Waldhausl and P.
Fasching of the Medical University Vienna saw it in 1993, it was a "rather mechanistic,
mono-causal explanation of the heterogenous and complex metabolic disturbances in
Type 2 diabetes."50 Instead of the high prevalence of type 2 diabetes being chiefly related
to impaired beta-cell function, they suggested it may reflect an intrauterine selection for
those fetuses carrying a thrifty genotype. They stated:
Greater prevalence of Type 2 diabetes in adult life in women and men may, however, not primarily relate to fetally impaired beta-cell function, but rather reflect the sequelae of intrauterine malnutrition permitting better intrauterine survival of those fetuses carrying a thrifty genotype for the development of Type 2 diabetes, while those without such genotype will less frequently survive in utero.51
G. Dowse and colleagues at the International Diabetes Institute in Australia also
questioned whether susceptibility to type 2 diabetes was truly associated with low beta-
cell function.52 Their own work had revealed that the populations with the greatest type 2
diabetes susceptibility were those with the highest beta-cell function. The authors
concluded that the thrifty phenotype hypothesis was fraught by major inconsistencies that
ci needed to be resolved before the hypothesis could gain greater credence. These criticisms were important. But the most common objection to the thrifty phenotype hypothesis was that it discounted the role of genetic factors in the etiology of type 2 diabetes. Many epidemiologists emphasized the strong influence of genes in diabetes causation.54 According to Waldhausl and Fasching (1993) of the Medical
University Vienna, Hales and Barkers' ideas regarding the fetally-acquired type 2 diabetes risk, rather than a genetically-determined risk, "contradict traditional wisdom which regards evolution as a slow process of adaptation to changing circumstances of life by selection through generations as suggested by Neel's 'thrifty genotype hypothesis.'"55
The following year, D. McCance of the Royal Victoria Hospital, and colleagues, proposed an alternative explanation for Hales and Barker's findings. While acknowledging the association between birth weight and type 2 diabetes, an additional
finding arose out of their studies of the Pima Indians. They found that, among Pima
Indians aged 20-39 years old, the highest prevalence of diabetes occurred not only at low
birth weights, but also at high birth weights. According to the researchers, those infants who were born at the highest end of the weight spectrum and who later developed type 2
diabetes did so because their mothers had developed gestational diabetes. To explain the
low end of the U-shaped birth weight spectrum, McCance and colleagues proposed the
"Surviving Small Baby Genotype" hypothesis.56 This hypothesis asserted that the
prevalence of diabetes among individuals of low birth weight reflect the selective
survival of these low birth weight infants who are genetically susceptible to the
development of diabetes. Over many generations, this would lead to a high prevalence of
diabetes and insulin resistance, as seen in the Pima Indians.57 Therefore, once again we can see that many researchers were unwilling to abandon the role of genetics in type 2 diabetes etiology.
Thus, a dichotomy had emerged between what some critics of the thrifty phenotype hypothesis would, 15 years later, term 'believers' and 'non-believers'.58 The
'believers' considered the association between in utero environment and type 2 diabetes causal. There was indeed some immediate support for the thrifty phenotype hypothesis, but the support was overshadowed by controversy.59 The 'non-believers' were those who considered the association between low birth weight and the development of insulin resistance and type 2 diabetes to be the result of flawed methods and erroneous mechanisms. Non-believers also included those epidemiologists who believed that adult lifestyle (and not the in utero environment) was associated with the development of type
2 diabetes.60
In the first few years following the publication of the thrifty phenotype hypothesis, when the data supporting it were weak, it was criticized from every perspective, and the thrifty genotype remained a possible alternative. Each of the criticisms of Hales and Barker's hypothesis needed to be addressed.
Response to critics
Five Years Later
In 1997, Hales and colleagues responded to each of the criticisms in a landmark paper titled "The Thrifty Phenotype Hypothesis: How Does it Look After 5 Years?". 38
Hales and colleagues began by responding to the claims that type 2 diabetes has a genetic basis. The authors recognized that the belief regarding type 2 diabetes as "genetically determined" was still common. They stated:
We acknowledge that the great majority of people concerned with the aetiology of NIDDM [type 2 diabetes] believe that the condition is primarily genetically determined but may be modulated by environmental factors, particularly those relating to energy balance in adult life. In reviewing the present status of an alternative, namely the Thrifty Phenotype hypothesis.. .we shall begin by questioning whether there really are any longer good reasons to suppose that NIDDM is strongly genetically determined. 1
Familial aggregation of type 2 diabetes had been one such argument in support of a genetic basis for diabetes. It was a common belief that the clustering of type 2 diabetics within a family was because relatives share a greater proportion of their genes than do unrelated individuals. For example, in 1993, J. Kaprio and colleagues at the University of
Helsinki argued that, "without clustering of susceptibility genes there will be no familial clustering of diabetes."62 Hales and colleagues denied this claim. If this was so, then parent and sibling genetics would be equally predictive of type 2 diabetes risk; but this was not so, they argued. Instead, they insisted that the number of affected siblings was
more predictive of type 2 diabetes risk in relatives than the number of affected parents.
They concluded that this "suggested a strong within-generation component which might reflect environmental factors."64
Perhaps the most cogent and widely-held argument in support of the genetic basis
of type 2 diabetes was derived from twin studies. Indeed, the earliest studies of
concordance rates showed highest concordance for type 2 diabetes in monozygotic twins
compared to dizygotic twins.65 However, according to Hales and colleagues, these early
studies suffered from ascertainment bias towards concordance and subsequent studies had shown lower concordance rates.66 Furthermore, even if there was a higher concordance for type 2 diabetes in monozygotic twins than in dizygotic twins, they argued that this does not prove "genetic determination" because it can also be explained by environmental factors. Hales and colleagues asserted:
High concordance rates are merely compatible with a possible genetic determination and do not prove it. This is particularly clear when one starts to envisage a role for the early, fetal and infant, environment in the aetiology of a disease. Monozygotic twins, unlike dizygotic twins, frequently share the same placenta. Thus if fetal nutrition is an issue this may be more concordant in mono- than in dizygotic twins.67
Indeed, Hales and colleagues denied that twin studies even demonstrate a genetic association at all. They cited recent studies that indicated relatively small differences in the concordance rates for type 2 diabetes between monozygotic and dizygotic twins. For example, findings from the Danish Twin Register in 1996 demonstrated concordance rates for type 2 diabetes in monozygotic and dizygotic twins to be 33% and 23%, respectively.68 This difference was not significant based on the number of twin pairs studied. Based on the small difference in concordance rates between monozygotic and dizygotic twins, Hales and colleagues concluded that twin studies fail to provide a strong basis for the genetic hypothesis.69
Hales and colleagues also addressed those critics who wondered how low birth weight could be a major cause of type 2 diabetes when so few diabetics actually have a low birth weight.70 In this regard, Hales argued that the criticism itself was based on a misunderstanding: it is not low birth weight per se causing the development of type 2 diabetes, but that, "low birth weight is simply a crude surrogate index of high exposure to some environmental condition not yet fully identified."71 Furthermore, although the 40 majority of babies fall within the "normal" range of birth weights, the association between type 2 diabetes and birth weight still weakens with increasing weight.
Finally, to address concerns regarding whether type 2 diabetes susceptibility is truly associated with low beta-cell function, the authors turned to recent findings from animal models. Early studies conducted on rats had demonstrated that fetal growth retardation occurred when mothers were fed low protein diets. Most significantly, these neonates of low birth weight also exhibited reduced beta-cell proliferation, islet size, and islet vascularization. These findings clearly demonstrated that reduced beta-cell function is associated with fetal growth retardation. Later studies would also show that the offspring of mothers exposed to protein restriction during pregnancy exhibited glucose
intolerance in late adult life.72 Therefore, the Maternal Low Protein Rat Model supported
the central tenets of the thrifty phenotype hypothesis: maternal protein deficiency results
in offspring with low birth weights, reduced islet vascularization, and reduced beta-cell
proliferation; and these fetal events have permanent effects on adult rats' glucose
metabolism.73
After addressing their critics' concerns, Hales and colleagues then pointed to
numerous epidemiological studies published between 1992 and 1996 that supported the
thrifty phenotype hypothesis. These studies investigated the relationship between low
birth weight and type 2 diabetes in many different populations, in various regions of the
world, including Australian Aborigines (1996), Pima Indians (1994), Jamaican school
children (1996), and Mexican-Americans (1994). The findings from these studies
confirmed the thrifty phenotype hypothesis.74 For example, in 1994, R. Valdez and
colleagues from the University of Texas Health Science Center (San Antonio) studied 41
Mexican-American men and women and found low birth weight to be a major independent risk factor for adult chronic disease.75 They acknowledged: "there must be some powerful environmental factors involved in these chronic disease epidemics, because the time frame of these epidemics is too short for natural selection to have acted."76
Thus, Hales and colleagues argued that, despite much criticism, there was strong evidence mounting in support of an environmental role in type 2 diabetes etiology. In the five years following its original publication, many epidemiological studies and animal studies had lent support to the thrifty phenotype hypothesis.
Ten Years Later
When, in 2001, Hales and Barker came together once again to address the status of the thrifty phenotype hypothesis, they were triumphant. They stated that the validity of the findings relating birth weight to type 2 diabetes had finally become recognized:
"In the intervening years, many data have emerged showing the reproducibility of these epidemiological findings in different populations and ethnic groups. The validity of the findings is now generally accepted."77 Still, they acknowledged that the contributions of 7% genes and environmental factors to this relationship continued to be debated.
Hales and Barker could point to even more studies in favour of the thrifty phenotype hypothesis by this time. Research exploring the relationship between the intrauterine environment and adult disease had flourished in the ten years following their original publication. They could now list at least 32 papers that described an association
<7q between low birth weight and altered glucose and insulin metabolism. 42
Hales and Barker also recognized that they could now refine some of their original claims, in light of the new evidence from epidemiological and animal research published in the intervening years. They included several updates to their original hypothesis, stating:
Whilst we are not aware of data from epidemiological studies or animal research which contradict any of the key features of the thrifty phenotype hypothesis, as originally proposed, it is clear that with increased insight into the biological processes, the content and precision of the hypothesis can be improved.80
There were new data indicating that maternal hyperglycaemia could contribute to the
o| consequences of fetal malnutrition. In addition, they more thoroughly examined the idea of intergenerational constraints on fetal growth. Based on more recent observations linking maternal low birth weight and offspring low birth weight, they now suggested that mothers constrain fetal growth to a degree that is determined within her own fetal lifetime.82 With these refinements, Hales and Barker concluded: "the thrifty phenotype hypothesis continues to provide a useful conceptual framework within which to design and interpret human and animal studies in this field." They suggested that future research should include additional work with animals in order to more fully document the consequences of growth restriction caused by fetal malnutrition. Finally, they also pointed to the need for molecular markers at the protein and RNA level in order to define malnutrition at various stages of fetal life and infancy.84
Conclusions
The thrifty phenotype hypothesis was a prominent and influential hypothesis for diabetes in the 1990s. This is evident in the number of times the phrase "thrifty 43 phenotype" has appeared in published literature (figure 4). Yet this unto itself cannot
gauge the full impact of the thrifty phenotype hypothesis on research into the fetal origins of adult diseases. For example, in the last 15 years of his life, Hales published approximately 100 papers relating to the fetal origins of adult disease.85 Thus far, Barker has published more than 300 papers and written or edited five books regarding the fetal
origins of adult disease 86
1992 1994 1997 1999 2001 2003 2005 2007 2009 2011 Year
Figure 4: Number of times the phrase "thrifty phenotype" appears in published literature in the ISI Web of Knowledge database, by year.
Hales and Barker's hypothesis incurred years of intense criticism.87 The traditional
idea that genetic and environmental factors both influence diabetes susceptibility proved
to be unhelpful in Hales and Barker's view:
To conclude that NIDDM [type 2 diabetes] depends upon a combination of genetic and environmental factors is as safe as it is unhelpful. It is a truism which relates to every single aspect of the outcome of human life.88 44
Nor did they believe that genetic factors alone determine diabetes risk and hold the key to diabetes prevention. This would continue to be a firmly held belief of Barker, whose immediate concern was the prevention of type 2 diabetes. As he commented in a 2007 interview regarding diabetes susceptibility genes:
"Genes are not Stalinist dictators.. .they live in a democracy, and what they do is conditioned by what else is going on around them. If geneticists find molecular mechanisms for this, bully for them! It's just not where I live. I can't wait twenty years for the geneticists to figure this out before we start improving the nutrition of human babies. You know? One-quarter of all babies bom in Southampton are recognizably thin. This will lead to shorter lives as a group. We need to fix it!"89
In rejecting the genetic determination of diabetes risk, the thrifty phenotype encountered a great deal of resistance - especially since it failed to provide an alternative mechanism for diabetes at the cellular level. But this was never the aim of Hales and Barker when they first proposed their hypothesis in the midst of the diabetes epidemic in the 1990s; their primary concern was always diabetes prevention, as expressed by Barker in 2007:
How much do we need to know about how [diabetes] works at the cellular and molecular level to fix it? Maybe we don't need to know anything very much. You almost can't say that - it's such a deeply held belief that you have to really understand something before you fix it. But I don't believe that's how it will work out.90
Nevertheless, although the thrifty phenotype hypothesis was initially criticized for considering type 2 diabetes risk independently of genetic causes, as of 2001, the wealth of epidemiological evidence for the relationship between in utero nutrition and adult chronic disease had converted many skeptics to "believers".91 In 2000, M. Gillman and J.
Rich-Edwards, of Harvard Medical School, stated: "with the recent publication of epidemiological studies that have started to overcome the flaws of the initial work, we have become reluctant converts." However, when discussing the "maturing credibility" of the thrifty phenotype hypothesis, they, like others, acknowledged that this hypothesis 45 was still but one of many possible explanations for the association between fetal growth and adult chronic disease:
Fetal growth is a proxy for a complex interplay of genetic and intrauterine environmental factors that include metabolic, endocrine and vascular phenomena, in addition to maternal nutrition."93
Therefore, as acknowledged by Hales and Barker in 2001, uncertainty still remained regarding the roles of genes and the early environment underlying the relationship between fetal development and adult chronic disease. 46
Chapter 3: Creating a new context for type 2 diabetes: Genes, development, and evolution
The importance of epigenetic inheritance in development is beyond doubt. Its accidental discovery in transgenerational inheritance in so many animals and plants makes it clear that it also has importance in heredity and evolution. Jablonka and Lamb, 19951
Diabetes understanding in the 20th century
As we have seen, there were two key conceptual structures within which type 2 diabetes was viewed in the 20th century. One offered a genetic and evolutionary explanation for diabetes susceptibility; and the other was based solely on phenotypic development. The thrifty genotype hypothesis proposed that the high prevalence of type 2 diabetes in modern times has resulted from the selection of a quick insulin trigger that was once adaptive for our hunter-gatherer ancestors. However, the selection for these
'thrifty genes' has been rendered disadvantageous by the nutritionally enriched
environment in which many people now live.
In contrast, the thrifty phenotype hypothesis proposed that environmental cues
during fetal development, specifically undernutrition, influence the risk of developing
type 2 diabetes in adult life. This hypothesis was devoid of evolutionary theory; it
focused on the organ level and offered no molecular mechanism for diabetes. Indeed,
many critics of the thrifty phenotype hypothesis were unable to fully accept a non-genetic
explanation.
Accordingly, even at the turn of the 21st century, Neel's thrifty genotype
hypothesis continued to be appealed to in order to explain the increasing diabetes
prevalence in many countries around the world. In the year 2000, Nicholas Hales himself
acknowledged that the thrifty genotype hypothesis continued to be the "most generally A accepted" hypothesis for type 2 diabetes causation. Similarly, as late as 2003, Jared
Diamond commented that the thrifty genotype hypothesis remained "the leading evolutionary theory for the possible benefits of genes predisposing to type 2 diabetes."3
Indeed, to date, many genes have been identified as possible candidates for the thrifty genotype. The list of susceptibility loci associated with type 2 diabetes has continued to grow since the 1990s.4 By 2010, genome-wide association studies have identified over 35 independent loci associated with type 2 diabetes risk (table l).5
Nevertheless, genetic markers for type 2 diabetes still account for only a small amount of the risk variance within a population; estimates range from 1-10%.6
Table 1: Selected candidate genes associated with type 2 diabetes risk7 Candidate Association Gene PPARy The Prol2Ala polymorphism in the peroxisome proliferator-activated receptor y2 gene (a transcription factor critical to the regulation of adipocyte differentiation) is associated with higher fasting insulin levels and reduced insulin sensitivity. CAPN10 The gene encoding the cysteine protease for calpain-10 is involved in insulin secretion and insulin resistance. Calpain-10 gene polymorphisms are known to increase susceptibility to diabetes. FTO Variants at FTO (the fat mass and obesity-associated gene) influence type 2 diabetes risk through an effect on BMI. This locus is associated with reduced insulin sensitivity. IGF2BP2 Polymorphisms of IGF2BP2 (insulin-like growth factor 2 (IGF2) mRNA-binding protein 2) are associated with impaired beta-cell function and elevated risk of type 2 diabetes in European, East Asian, and South Asian populations. KCNQ1 This gene encodes a voltage-gated potassium channel required for the repolarization phase of the cardiac action potential. The presence of the risk alleles for the KCNQ1 gene are associated with decreased pancreatic cell functioning and increased fasting glucose levels. The thrifty phenotype hypothesis was also widely discussed and investigated throughout the 1990s; data continued to accumulate, substantiating the link between in utero nutrition and adult diabetes risk. Thus, two competing theories for type 2 diabetes etiology continued to be debated at the turn of the century.
This chapter will document the conditions under which a new theory would, in
2004, synthesize genetic and developmental determinants of type 2 diabetes risk. This theory, called the "predictive adaptive response model", brought together nature and nurture, as well as evolutionary principles to bear on the problem of diabetes causation.
This model was able to bridge the two competing thrifty hypotheses within the new context of evolutionary developmental biology, pointing to molecular epigenetic mechanisms to account for such diseases as type 2 diabetes.
Epigenetic inheritance
British embryologist Conrad Waddington coined the term "epigenetics" in 1942
as a disciplinary term to replace experimental embryology and Entwicklungsmechanik.8
He defined it as the "branch of biology which studies the causal interactions between genes and their products, which bring the phenotype into being."9 Thus, the term
"epigenetics" signified the processes that bridge genotype and phenotype; it integrated the fields of developmental biology and genetics.
Waddington considered an organism's developmental pathway to be determined
by the interaction of many genes, with each other, and with the organismal
environment.10 He proposed the concept of an "epigenetic landscape" in 1957 to
represent how a developing embryo can select different developmental routes based upon 49 gene-environment interactions. Waddington depicted this in the metaphorical image of
the epigenetic landscape, in which a ball rolling through a series of valleys and ridges represents the different developmental routes that will determine the fate of a cell. As
Waddington commented in 1966:
If one thinks of all the different parts of the egg, developing into wings, eyes, legs, and so on, one would have to represent that whole system by a series of different valleys, all starting out from the fertilized egg but gradually diverging and finishing up at a number of different adult organs. 1
"Epigenetics" was not immediately widely discussed or investigated. However,
by the 1960s, several critics of the gene-centric view of biology began to appeal to
epigenetics in order to explain how cells with the same genotype could have different
phenotypes.12 In 1958, David Nanney, an experimental ciliatologist at the University of
Michigan, commented:
The existence of phenotypic differences between cells with the same genotype merely indicates that the expressed specificities are not determined entirely by the DNA present in the cell - that other devices, epigenetic systems, regulate the expression of the genetically determined potentialities.13
But it was not until the 1990s that the field of epigenetic research emerged into
prominence, when there was an explosion of new research into the molecular processes
of epigenetic inheritance.14 By this time, the meaning of "epigenetics" had changed
somewhat from the traditional Waddingtonian sense. As the molecular mechanisms
controlling gene expression began to be better understood, the term "epigenetics" was
increasingly used to refer to the mitotically and/or meiotically heritable changes in gene
expression that occur without affecting the informational content of DNA.15 Such
epigenetic processes include DNA methylation, histone modifications, and the expression
of specific non-coding RNAs.16 These epigenetic phenomena have been documented in 50 organisms as diverse as bacteria, yeast, fungi, plants, and vertebrates; and in some cases, epigenetic marks can be inherited from one generation to the next.17
Epigenetic inheritance occurs when phenotypic variations not originating from variations in DNA sequence are passed onto subsequent generations of cells or organisms.18 According to E. Jablonka and G. Raz of Tel-Aviv University, "epigenetic inheritance" can be considered from both a broad and narrow sense. In the broad sense,
they defined epigenetic inheritance as:
the inheritance of any developmental variations that do not stem from differences in DNA sequence or persistent inducing signals in the present environment. This includes cellular inheritance through the germline, and soma-to-soma information-transfer that by-passes the germline.19
In the narrow sense, Jablonka and Raz considered cellular epigenetic inheritance to be
the transmission of non-DNA-based variations from the mother cell to daughter cell:
Cellular epigenetic inheritance occurs during cell division in prokaryotes, mitotic cell division in the soma of eukaryotes, and sometimes during the meiotic divisions in the germline that give rise to sperm or eggs. In this latter case offspring inherit epigenetic variations through the germline.20
That environmentally-induced epigenetic variations have the potential to be inherited
across generations has far-reaching implications for the understanding of evolutionary
processes.21 According to Jablonka and Raz, epigenetic inheritance necessitates a
broadening of the concept of heredity: one that will incorporate ideas regarding
development and the selection for epigenetic variants in addition to genetic variants.
The study of epigenetic phenomena has today become a recognized field of
inquiry, with international initiatives, meetings, and symposia; there are also several
recent textbooks on the subject.23 Many evolutionary biologists agree that the work of Robin Holliday in the 1980s greatly contributed to the increasing interest into epigenetic mechanisms in the 1990s.24
In the late 1950s and early 1960s, the role of DNA methylation as the means by which X-chromosome inactivation occurs was first discovered. But DNA methylation as an epigenetic mark was first championed by Robin Holliday of the National Institute for Medical Research (London) in 1979. In proposing a new epigenetic theory for carcinogenesis, Holliday considered that "a strong case can be made for an epigenetic or non-mutational origin of cancer." He suggested that the excision of damaged DNA base(s) following carcinogen exposure leads to the formation of non-methylated DNA in dividing cells.27 These heritable changes in DNA methylation, in turn, lead to altered gene expression and can thereby trigger a new and potentially abnormal developmental pathway.28 His 1987 paper on "The Inheritance of Epigenetic Defects" has been described as critical, prompting the great wave of research into epigenetic phenomena that would follow.29 It became clear in the 1990s and 2000s that DNA methylation provided a stable, heritable, and important component of the epigenetic regulation of gene transcription.30
Epigenetics and type 2 diabetes
Neel's thrifty genotype hypothesis was proposed in the early 1960s, long before epigenetic processes were understood. Although research on epigenetic mechanisms would increase in the early 1990s, it was not until the late 1990s that research into epigenetic processes truly became a burgeoning field. Therefore, although epigenetic mechanisms were beginning to be unraveled when Hales and Barker first proposed their 52 hypothesis in 1992, epigenetic inheritance was not a central tenet of their theory regarding type 2 diabetes etiology. It was not until the year 2004, within a new context of evolutionary developmental biology, that a hypothesis for diabetes etiology would be proposed, linking diabetes susceptibility to molecular epigenetic mechanisms.
Evolutionary developmental biology
In the early 1980s, the field of evolutionary developmental biology emerged through the integration of developmental biology and evolutionary biology.31 Although some historians consider the roots of evolutionary developmental biology to date back to the late 19th century, it was officially recognized as an independent research field in 1999 when it was granted its own division in the Society for Integrative and Comparative
Biology (SICB).32
Evolutionary developmental biology aimed to correct or expand the Modern
Synthesis by integrating developmental mechanisms into evolutionary thinking.33 The
Modern Synthesis had emerged in the 1930s and 1940s in an attempt to bridge the gap between Mendelism and Darwinism. It viewed evolutionary processes as being driven largely by random genetic changes and did not consider developmental processes.
Evolutionary developmental biology aimed at correcting the Modern Synthesis by integrating molecular and anatomical development with evolution and medicine.
Evolutionary developmental biology sought to explain how developmental processes are controlled by the interaction of genetic, epigenetic, and environmental factors.34 Indeed, phenotypic plasticity - the capacity of a single genotype to produce different phenotypes 53 in response to variable environmental conditions during development - was one of the prominent theoretical themes of 21st century evolutionary developmental biology.35
It was within this context that the predictive adaptive response model took form in the early 21st century.36 For the proponents of this model, evolutionary developmental biology provided a new set of tools from which to explore developmental plasticity and molecular epigenetics.37 The predictive adaptive response model proposed that, during the "plastic" phase of development, the organism is able to adjust its developmental trajectory based on environmental cues, resulting in heritable epigenetic changes in gene expression.38 However, if the environment experienced during early development is far- removed from the postnatal enviromnent, this "environmental mismatch" can expose the organism to conditions it is not well adapted to. In this way, although genes can increase the propensity for a disease such as type 2 diabetes, environmental factors would trigger the onset of the disease.
Evolutionary medicine
The predictive adaptive response model suggested that environmental mismatches are now becoming more common due to the vastly different nutritional environment humans are subjected to. That the increasing frequency of noncommunicable disease today can arise from what has been called a "dissonance between 'stone age genes' and
'space age' circumstances" is a concept far-removed from the traditional medical model of disease.39 For example, although lactose intolerance has traditionally been viewed as a disorder, 70% of the world's population is unable to digest lactose because human biology evolved in a relatively lactose-free environment. Consequently, can lactose intolerance truly be considered a "disorder" only because we now live in an evolutionary novel environment?40 That disease can arise from normal human biology being placed within an "abnormal" environment, and not pathological failures of the body, is a novel idea in medicine.
By integrating an evolutionary perspective into medical thought, human vulnerability to disease can now be more fully addressed. This is reflected in the relatively new field of evolutionary medicine.41 Some have considered the discipline of modern evolutionary medicine to have been founded by Randolph Nesse and George
Williams in the early 1990s with their publication titled "The dawn of Darwinian medicine."42 Although there had been a great deal of discussion concerning the evolutionary interpretation of disease between the 1960s and 1990s, the field of evolutionary medicine was not cemented and popularized until the 1990s.43 Indeed, since this time, there has been a growing recognition that "nothing in medicine makes sense except in the light of evolution.'^At the core of evolutionary medicine are questions concerning why natural selection has left the human body vulnerable to disease.45
Progress in this interdisciplinary field has been made possible by an increasing understanding of genetics and DNA sequencing.46
Thus, as we shall now see, the predictive adaptive response model arose in the
early 21st century amidst a new context regarding disease. It integrated ideas of genetic susceptibility, epigenetic inheritance, developmental plasticity, and selection, to arrive at a new model for understanding noncommunicable disease etiology. It was able to do so within an evolutionary developmental framework and from an evolutionary perspective on disease. 55
Chapter 4: The predictive adaptive response model
We suggest that a synthesis of genetic, developmental and later environmental and lifestyle factors is necessary to understand disease risk across the lifespan. Gluckman et al., 20041
Evolution has provided the tools for us to try to match our life course to the environment we predict we will face. But while this was a brilliant strategy for raising the probability of reproductive success within the environments in which we evolved, it is now failing. The degree of shift in our environment is far greater than our biology could possibly allow for without a cost and our species has been very good at changing our environment. We really have made things hard for ourselves. Gluckman and Hanson, 20062
Gluckman and Hanson's integrative approach
During the first decade of the twenty-first century a new conceptual framework called the "predictive adaptive response model" was proposed, and it has shaped thinking about the developmental origins of disease to the present day. According to this hypothesis, environmental cues in development and early childhood are linked to adult chronic diseases such as type 2 diabetes. Emphasizing that the embryo, fetus, or infant adjusts its development based on environmental cues, it posited that "developmental plasticity" would allow for a range of phenotypes to be expressed from a single genotype, and thus provide the means by which a developing organism can respond to environmental change.3 Accordingly, an accurate forecast of the organism's future environment would result in an increased fitness. But when the predictive adaptive response fails to accurately predict the adult environment, disease results. In effect, there would be an "environmental mismatch."4
This new model was first proposed by Peter Gluckman and Mark Hanson in 2004. 56
Whereas the thrifty hypotheses had separated the roles of genes and the environment in the etiology of type 2 diabetes, "the predictive adaptive response model" and
"environmental mismatch hypothesis" of Gluckman and Hanson implicated both. In their view, epigenetic processes underpin developmental plasticity and the ability to make predictive adaptive responses. And molecular mechanisms involving environmentally- induced changes in gene expression during development would hold the key to understanding type 2 diabetes.5
This new model, proposed for type 2 diabetes and other noncommunicable diseases, was embedded in both developmental and evolutionary theory. Like the thrifty genotype hypothesis, it examined how human evolutionary history affected disease risk in particular environments.6 However, in Gluckman and Hanson's model, the different diets of modern humans and our hunter-gatherer ancestors are only part of the reason why the incidence of type 2 diabetes is so high today.7 For, unlike the thrifty genotype hypothesis, the predictive adaptive response model also considered the effects of ontogenetic development.
Furthermore, unlike its predecessors, the predictive adaptive response model was
not limited to explaining only type 2 diabetes etiology; it was applicable to many other
noncommunicable diseases, including asthma, osteoporosis, certain cancers, as well as
a some mental health disorders, such as schizophrenia. It was indeed a more general
model for disease than were the "thrifty" hypotheses that preceded it.9
Gluckman and Hanson wrote many research papers and books together, focusing
on the developmental origins of health and disease and expounding their predictive
adaptive response model, including: The Fetal Matrix: Evolution, Development and 57
Disease (2004); Mismatch: Why our World No Longer Fits our Bodies (2006); and they edited the well-known book Developmental Origins of Health and Disease (2006). Then, in 2009, they wrote one of the first textbooks in the emerging field of evolutionary medicine, titled Principles of Evolutionary Medicine.
In this chapter, I document how the predictive adaptive response model of
Gluckman and Hanson arose out of the earlier thrifty hypotheses, although it represented a shift towards an epigenetic conceptual framework for type 2 diabetes etiology. This chapter will also illustrate how they formulated their theory within the context of new concepts at the interface of developmental and evolutionary biology. Finally, I provide an account of the far-reaching implications of the predictive adaptive response model in regard to disease prevention and health promotion.
The origins of the predictive adaptive response model
Gluckman and Hanson had similar educational backgrounds prior to their collaboration.10 Gluckman had completed a Bachelor of Medicine and a Bachelor of
Surgery in Paediatrics and Endocrinology at the University of Otago, New Zealand, in
1971.11 After working for two years as a physician, he completed a Master's degree in
"Medical Science" at the University of Auckland in 1976.12 He then spent four years as a postdoctoral fellow and Assistant Professor at the University of California, San
Francisco, studying the development of fetal hormonal systems. Returning to New
Zealand in 1980, he spent the next 17 years studying human and pastoral animal growth and development. In 2001, he founded the Liggins Institute at the University of
Auckland, today one of the world's leading centers for research on fetal and child health.13 In 2007 he became inaugural Chair of the International Society for
Developmental Origins of Health and Disease.
Hanson completed a Bachelor of Medicine at Oxford University in 1972 and then a D. Phil, in Physiology from St. John's College in 1979. He was Lecturer in
Biochemistry and Physiology at the University of Reading for ten years before moving to
University College London as Professor of Fetal and Neonatal Physiology. Then, in
2000, he moved to the University of Southampton's School of Medicine, first as Director of the Division of Developmental Origins of Health and Disease, and then in 2007, as the founding Director of the Institute of Developmental Sciences. That same year, he succeeded Gluckman as the Chair of the International Society for Developmental Origins of Health and Disease.14
When Gluckman and Hanson first proposed their new model in 2004, they claimed that it represented a new "paradigm" that replaced both the thrifty genotype and thrifty phenotype hypotheses, both of which, they argued, had fatal weaknesses.15 The thrifty genotype hypothesis had proposed that modern humans evolved selecting for genes that promoted insulin resistance in the form of a quick insulin trigger response to hyperglycemia. The selection for such "thrifty genes" would have enhanced survival of
hunter-gatherers because the overproduction of insulin would have been an effective
energy-conserving mechanism. But Gluckman and Hanson argued that genetic variation
plays a much more indirect role in type 2 diabetes etiology, by changing the sensitivity of
the organism to its environment.16 They also asserted that Neel's evolutionary
explanation was incorrect: there was no evidence that "thrifty genes" had been selected
for because they enhanced survival of our hunter-gatherer ancestors during famine times. 59
To the contrary, Giuckman and Hanson referred to new anthropological evidence suggesting that hunter-gatherers had relatively good nutrition and experienced relatively little famine.17
In 2006, D. Benyshek and J. Watson of the University of Nevada conducted a cross-cultural statistical comparison of food availability amongst 94 foraging and agricultural populations, using ethnographic nutritional data. They found no statistical difference between the food security of foragers and agriculturalists - a finding consistent with the bioarchaeological evidence suggesting that malnutrition was more common for agriculturalists than foragers.18 They concluded that the very foundation of the thrifty genotype hypothesis is called into question in light of the increasing evidence against forager malnutrition. Thus, if the cycles of feast and famine experienced by hunter- gatherers were not as common as supposed by Neel, then this also disputes the selective advantage provided by the possession of "thrifty genes."
The thrifty phenotype hypothesis also encountered difficulties. New findings were inconsistent with the assumption that low birth weight was a necessary factor for later disease risk. The Hales-Barker hypothesis had proposed that poor fetal nutrition would result in selective growth retardation. In turn, abnormal pancreatic islet vascularization and reduced beta-cell numbers would result, culminating in poor insulin secretion. This explanation for the later development of type 2 diabetes became inadequate when studies demonstrated that growth-restricted infants only developed insulin resistance late after birth.19 Giuckman and Hanson also pointed to a 2005 study that showed insulin resistance on to be preceded by a period of increased insulin sensitivity. Again, these findings were 60 inconsistent with the thrifty phenotype hypothesis; they implied that any adaptive advantage conferred by insulin insensitivity would manifest after the neonatal period.
Gluckman and Hanson also emphasized additional weaknesses of the thrifty phenotype hypothesis: i) it artificially separated fetal and postnatal environmental cues; ii) it did not consider the critical role of the periconceptual period; and iii) it relied on the erroneous assumption that changes in development were brought about by severe fetal
stress and deprivation.21 The thrifty phenotype hypothesis, they maintained, was also
wrong in its assumption that small birth size was a necessary part of the pathway leading
to increased disease risk.22 Instead, Gluckman and Hanson claimed that many
environmental cues during development can alter disease risk without affecting birth
size.23
Still, Gluckman and Hanson acknowledged that their own model arose out of
Hales and Barker's epidemiological studies, which linked development and subsequent
adult disease. As they commented in 2005, "the original observations of David Barker
pointed us towards the class of developmental choice we termed predictive adaptive
responses."24 But in their view, the observations linking low birth weight to type 2
diabetes provided only one example of the much broader link between developmental
plasticity and adult chronic disease:
We have therefore suggested that the original observations relating birth size to cardiovascular and metabolic disease risk represent a special case of a much broader and generalizable phenomenon that allows the pattern of development to be modified in either direction as a result of developmental cues.25
In developing their own model, Gluckman and Hanson rejected the term "thrifty"
because they claimed that disease does not result solely from poor fetal nourishment;
over-nourishment would also pose a disease risk.26 Developmental plasticity could adjust 61
*5*7 physiology in either direction. Large infants also have an increased risk of developing disease.28
While neither the thrifty genotype nor the thrifty phenotype hypotheses were able to explain the broader range consequences of early life events, the predictive adaptive response model could.29 Gluckman and Hanson pointed to clinical and epidemiological studies published between 2001 and 2004 that showed a broader range of pathological states to be related to early life events; these included truncal obesity, osteoporosis, polycystic ovarian disease, depression, schizophrenia, and certain cancers.
In thus addressing the limitations of the thrifty hypotheses, Gluckman and Hanson claimed that their predictive adaptive response model offered a new - broadened - conceptual framework from which to view the link between developmental plasticity and chronic disease.31 And they also embedded it within the context of biology, not just medical etiology: "Biology is based on two fundamental pillars," Gluckman commented in 2007, "understanding the gene and understanding the processes of evolution and development."32 Therefore, Gluckman and colleagues called for a conceptual framework
explaining the developmental origins of disease in terms of the proximate causes - the
physiological mechanisms leading to disease - as well as what they called the ultimate
causes - their evolutionary origin.
From the thrifty phenotype to epigenetic inheritance
The predictive adaptive response model implicated both genetic and
environmental influences in the etiology of metabolic and cardiovascular diseases. Genes
would increase propensity for a disease, but environmental factors would trigger the
onset of the disease; in other words, as Gluckman and Hanson put it, "the genotype 62 merely changes the sensitivity to the environmental interaction."34 As they saw it, their model transcended the venerable debate over "nature" (genotype) versus "nurture"
(phenotype) in the etiology of disease:
Unfortunately, the field became polarized between genetic and environmental enthusiasts and the fundamental point that all developmental phenotypic change is a result of the interaction between the developmental environment and the genome was ignored for some time.35
Gluckman and Hanson championed a new evolutionary model for understanding
disease etiology, based on developmental plasticity.36 But they were not the first to do so.
Patrick Bateson at the University of Cambridge was the first. In an address given at the
First World Congress on Fetal Origins of Adult Disease in 2001, he introduced ideas that
were central to the predictive adaptive response model for disease.37 "The point is," he
said,
that humans, like many other animals, are capable of developing in different ways and, in stable conditions, their characteristics are well adapted to the environmental conditions in which they find themselves... The mechanisms are largely to be discovered. Generally such systems of developmental plasticity work well, but in a changing environment they generate poorly adapted phenotypes because the environmental forecast proved to be incorrect.38
However, Gluckman and Hanson went further, not only in developing the theory, but also
in pointing to molecular epigenetic mechanisms to account for diseases such as type 2
diabetes.39
The field of epigenetics had emerged into prominence in the 1990s, with new
research on molecular processes of gene regulation in eukaryotes.40 Gluckman and
Hanson emphasized three mechanisms by which environmental cues could influence the
developmental program: i) altered tissue differentiation; ii) changes in the homeostatic 63 control mechanisms; and iii) regulation of gene expression resulting from DNA methylation.41
i) Altered Tissue Differentiation
Altered tissue differentiation resulting from maternal nutritional or hormonal manipulation was, for Gluckman and Hanson, an important mechanism by which environmental cues influence molecular developmental programming. Maternal malnutrition was known to have several effects on organ development; although this was suggested by Hales and Barker in the early 1990s, more recent studies have substantiated the link between maternal malnutrition and altered tissue differentiation. Indeed, in 2003, reduced capillary density was reported in several organs following maternal
malnutrition.42 Furthermore, protein deprivation in pregnant rats resulted in elevated
blood pressure and impaired arterial functioning in adult offspring. This was an important
finding because vascular dysfunction is known to precede the development of
atherosclerosis, hypertension, and type 2 diabetes.43
Gluckman and Hanson also pointed to studies indicating that fetal pancreatic islet
cell differentiation is affected by maternal undernourishment44 One study linked low
protein maternal diet to beta-cell deficiency in the fetus. This was due to both reduced
beta-cell proliferation and increased beta-cell apoptosis and was associated with
decreased expression of insulin-like growth factor-II (IGF-II) in the pancreatic islets.
These effects then contributed to glucose intolerance in the adult rats 45
Research published between 1998 and 2003 also showed maternal malnutrition to
be associated with reduced nephron numbers in sheep (which has been linked to an 64 increased risk for hypertension), restriction in skeletal muscle fiber development, and altered adipose tissue development.46 Based on these findings, Gluckman and Hanson concluded in 2004 that altered tissue development was a developmental tradeoff in response to fetal undernutrition:
All of these tissue-specific effects can be viewed as adaptations that restrict energy consumption, whether in terms of nutrient delivery to tissues (reduced capillarity), reduced size of the most metabolically active tissues (e.g. nephrons), or alteration in the balance between energy-consuming and energy-storing tissues (skeletal muscle versus fat).47 ii) Altered Homeostatic Processes
Homeostatic regulatory controls were another mechanism by which environmental cues influence development. Gluckman and Hanson referred to studies linking defects in insulin secretion and insulin postreceptor action in muscle to an increased risk of developing type 2 diabetes.48 Additionally, new studies published in
2004 reported an association between maternal undernutrition and changes in endothelial functioning and hepatic enzyme regulation of glucose metabolism.49 Therefore,
Gluckman and Hanson concluded in 2004 that permanent changes in homeostatic regulatory controls could be induced during the period of developmental plasticity by environmental cues.50 This is yet another mechanism by which an individual could become more susceptible to the development of type 2 diabetes.
iii) DNA methylation
DNA methylation was not a newly recognized phenomenon when Gluckman and
Hanson first proposed their model in 2004. As previously discussed, DNA methylation as an epigenetic mark was championed by Robin Holiday of the National Institute for 65
Medical Research in 1979; Holliday discussed DNA methylation as an "epigenetic or non-mutational origin of cancer."51 It became clear over the next three decades that DNA methylation provides a stable, heritable, and important component of the epigenetic regulation of gene transcription.
DNA methylation in mammals occurs primarily on the cytosine residues of cytosine-guanine (CpG) dinucleotides. When the cytosine becomes methylated, conformational changes to the DNA strand result, and access of protein transcriptional factors to DNA-binding sites is altered.54 Gene expression is then increased or decreased based on whether the transcriptional factor is stimulatory or inhibitory.55 In general, when
CpG dinucleotides in promoter regions are methylated, transcription factor binding is blocked and the gene becomes transcriptionally inactive.56
DNA methylation plays an important role in development: it is involved in X- chromosome inactivation, it is the basis for imprinting processes that determine maternal or paternal allele expression in early development, and it plays a key role in cellular differentiation.57 The pattern of DNA methylation established during development is copied by DNA methyl transferase-1 (DNMT-1) during mitosis, thereby providing an
eg "epigenetic memory" of gene regulation patterns.
Gluckman and Hanson maintained that such "epigenetic memory" was a mechanism by which environmental cues during development could lead to permanent effects on gene expression throughout an individual's life. The mechanism of epigenetic memory is important for understanding type 2 diabetes and other noncommunicable diseases because risk is, at least in part, determined during development.59 Indeed,
Gluckman and Hanson stated in 2007 that epigenetic memory, 66
immediately suggests a mechanism by which the environment may induce stable changes to cell function that persist in the adult organism, by which environmental challenges at different times during development may produce different phenotypic outcomes and in humans differential risk of disease.60
Gluckman and Hanson also discussed the increasing interest in small non-coding
RNAs as a means of epigenetic regulation.61 MicroRNAs have been shown to affect the stability and translation of messenger RNA and to induce gene silencing through gene ft) methylation and alterations in chromatin structure. Gluckman and Hanson argued that small non-coding regulation of gene expression may prove to be an important means of epigenetic control.63 They stated in 2007: "small non-coding RNAs in the gametes may have a direct role in the differentiation and development of the early zygote or may play a part in post-fertilization epigenetic reprogramming."64
There are several lines of evidence supporting the role of epigenetics as a mechanism through which developmental plasticity proceeds. In 2004, Gluckman and
Hanson discussed how recent studies from animal models had provided the most direct proof for developmental plasticity.65 Studies showed that feeding a low protein diet to pregnant rats caused permanent changes in offspring gene expression. Indeed, studies conducted in 2004 and 2005 revealed glucocorticoid receptors and peroxisome proliferator-activated receptor a (PPARa) expression to be increased in the liver as a result of promoter hypomethylation.66 This was significant because the PPARa gene is a key regulator of lipid and carbohydrate metabolism.67 The offspring of dams fed a low protein diet thus showed different patterns of liver gene methylation and this resulted in an altered metabolic profile of the rat offspring.68 More recent studies have revealed that the effects of a low protein diet during pregnancy in the Fo generation can be passed down to both the Fi and F2 generations, without re-exposure to the nutritional challenge.69 F2 offspring showed elevated blood pressure, increased insulin resistance, and endothelial dysfunction. 70 The effects on glucose metabolism have even been shown to extend to the F3 generation.
Gluckman and Hanson also considered the epigenetic effects of endocrine and
"behavioural challenges" on the F2 generation.72 They pointed to a 1998 study that linked maternal environment to the expression of the imprinted agouti gene in the agouti mouse mutant. By supplementing the maternal mouse diet with folate at conception, the degree of imprinting on the agouti gene in her offspring was altered (i.e. the capacity for
<71 methylation was altered). In pregnant rats, folate supplementation reversed the effects of a low protein diet, thereby preventing vascular defects in the offspring.74 Since dietary folates are required as cofactors for reactions involved in one-carbon metabolism, this finding substantiated the link between DNA methylation and developmental programming.75
They also referred to studies conducted in 2000 and 2004 that demonstrated how, by manipulating the mother-offspring behavioural interactions in rats (e.g. grooming behaviour), offspring developed permanent changes in methylation of the glucocorticoid gene promoter.76 In turn, this caused changes in behaviour and in hypothalamic-pituitary- adrenal axis functioning in the rats.77 That the behaviour of Fi offspring can be affected by maternal grooming behaviour in this manner further supported the association between environmental challenges and epigenetic changes. no There is also evidence of transgenerational non-genomic inheritance in humans.
Gluckman and Hanson referred to studies indicating a link between environmental challenges and transgenerational disease risk. 70 A 2002 Swedish study revealed an association between grandpatemal over-nutrition in pre-puberty and increased diabetes mortality in male grandchildren.80 Additionally, they pointed toward the most compelling and well-studied example of transgenerational epigenetic inheritance in humans: the
Dutch Hunger famine of 1944. Following this famine, studies showed that the offspring of women who had experienced severe malnutrition in utero were born with an increased risk of later developing insulin resistance.81
Non-genomic inheritance in humans can even extend to the third-generation.
When pregnant women were exposed to diethylstilbestrol, a synthetic estrogen used by millions of women from the 1940s to the 1970s as an anti-abortion agent, their children
and grandchildren experienced increases in reproductive abnormalities. However, this
finding has not been confirmed in all studied populations.
Taken together, Gluckman and Hanson argued in 2007 that the wealth of
experimental and epidemiological studies (table 1) supporting the existence of
transgenerational non-genomic inheritance have led to a growing realization that:
a range of nutritional, hormonal, xenobiotic and behavioural cues affecting parents (the Fo generation) can have consequences for the next generation (Fi) and in some instances for subsequent generations (F2 onwards), even if they did not experience the same cue.84
That epigenetic modifications can be transgenerationally inherited became central to
Gluckman and Hanson's model because it could explain why the incidence of chronic
noncommunicable disease has exploded in recent times.85 They argued that, through
transgenerational non-genomic inheritance, parents transmit information about their long- 69 term environment to their offspring,86 In so doing, these long-term cues are important in buffering critical developmental periods against short-term environmental fluctuations; this would have been evolutionarily adaptive in coping with climatic variability:
These processes of developmental plasticity leading to nongenomic inheritance may have evolved to enhance fitness during shorter-term environmental shifts than Darwinian selection can necessarily cope with, and/or to ensure a greater match to a variable environment than selection alone can generate.87
However, in more recent times, transgenerational non-genomic inheritance now exacerbates disease risk for multiple successive generations. As we shall see, this is due to an increasing frequency of what Gluckman and Hanson have termed "environmental mismatches".88 70
Table 2: Support for transgenerational epigenetic inheritance from animal models and human studies, as referred to by Gluckman and Hanson
Trait Stimulus Possible Mechanism Effected Reference Generation Animal Models Agouti Methyl- Increased methylation in F, Wolff etal., phenotype in supplemented embryo 1998 89 mice maternal diet Adult glucose In utero low Decreased IGF-II in F! Petrik et al., intolerance in protein diet pancreatic islets causing 1999 90 rats increased beta-cell apoptosis Loss of nephron Uteroplacental Renal p53 hypomethylation Fi Pham et al., numbers in insufficiency 2003 91 glomeruli in rats causing in utero growth restriction Hypothalamic- Maternal grooming Stable alterations of DNA F, Weaver et al., pituitary- behaviour methylation/ chromatin 2004 92 adrenal structure at glucocorticoid response to receptor gene promoter in the stress in rats hippocampus 1 hcj
Increased In utero low Altered methylation of to Lillycrop et al., glucocorticoid protein diet hepatic PPAR-alpha promoter 2005 93; receptor Lillycrop et al., expression in 2008 94; rats Burdge et al., 2007 95 Insulin In utero low Mismatch between maternal F1-F3 Zambrano et resistance protein diet low-protein diet and post- al., 2005 96; weaning diet Benyshek et al, 2006 97 Beta-cell In utero growth Suppression of Pdxl F, Park et al., function and restriction expression 2008 98 development and glucose homeostasis Humans
Cardiovascular Food supply during Changes in gene imprinting f2 Kaati et al., and diabetes- the slow growth 2002 99 related deaths in period of the the human male paternal line grandfather Risk of Mothers exposed to Epigenetic processes Fi - F2 Brouwers et hypospadias diethylstilbestrol in al., 2005 100 utero 71
The mismatch hypothesis
In 2004, Gluckman and Hanson used the concept of developmental plasticity to describe an organism's ability to change structure and function in response to environmental cues. Such plasticity occurs during critical developmental windows and subsequently becomes irreversible. For Gluckman and Hanson, these critical windows of plasticity in humans extend from conception through to the weaning period.101 They reasoned that indefinite developmental plasticity would be unrealistic due to the high energetic costs associated with it.
Gluckman and Hanson differentiated between two types of responses to environmental cues during critical developmental windows: plasticity that is immediately adaptive, and plasticity that is "predicted" to be adaptive in the organism's future.
Immediately adaptive responses are homeostatic responses that can help buffer 10^ the organism against stressors that are immediately threatening. These responses ensure short-term survival, even at the expense of long-term survival. In the thrifty phenotype hypothesis, we see such a tradeoff: plasticity allows the fetus to survive in utero malnourishment by retarding growth, but then the individual has to cope with a postnatal environment it may not be well-suited towards.104
Gluckman and Hanson also proposed that organisms can make predictive adaptive responses to environmental cues during critical developmental windows. By making a predictive adaptive response, a developmental pathway is chosen in expectation of a future environment.105 The adaptive advantage is delayed, and will confer a survival advantage in the predicted adult reproductive environment. In Gluckman and Hanson's view, it is through epigenetic processes that predictive adaptive responses result in permanent changes in physiology.106
The question then became: what happens if the predictive response fails to accurately forecast the organism's future environment? If the prediction is correct, the individual's phenotype will match the adult environment and fitness will be increased.
However, when there is a mismatch between the predicted adult environment and the
actual adult environment, there is an increased risk of disease.107 Gluckman and Hanson
asserted that, the greater the degree of mismatch, the more the organism will be required
to cope with an environment it is unsuited towards. If the organism fails to cope, it will
have an increased risk of disease.108 Gluckman and Hanson termed this the
"environmental mismatch hypothesis" (figure 5). They stated in 2005:
Our fundamental hypothesis is that the developmental origins phenomenon arises because of a mismatch between the usual postnatal environment of the modern world and that which humans evolved to live in.109
The ability to make predictive adaptive responses in expectation of the future
environment thereby opened up the possibility for pathological mismatches to occur. The
environmental mismatch hypothesis became fundamental to their model because it could
explain the increasing incidence of disease in modern humans in comparison to our
hunter-gatherer ancestors.110 An evolutionary perspective thus became central to their
model. 73
immediately Adaptive Response Correct "micr •BiagtigifiM )
Incorrect "Mismatcr)
Figure 5: The predictive adaptive response model. A new lexicon developed out of the phenomenon of developmental plasticity. This model provided a molecular mechanism through which developmental plasticity acts, and it viewed the etiology of adult disease from an evolutionary perspective.
An evolutionary perspective
The predictive adaptive response model explored how evolutionary processes
influence disease vulnerability. It has been described as extending the thrifty phenotype
hypothesis from the clinical and epidemiological realm into the realm of evolutionary
biology.111 Gluckman and Hanson recognized that such an evolutionary perspective was
necessary in order to understand how gene-environment interactions now contribute to
the rising incidence of adult disease, although these interactions were once adaptive.112
They argued that the rising incidence of adult disease is attributable to the increasing
frequency of mismatches between the predicted and actual postnatal environments.
Our hunter-gatherer ancestors experienced high-energy expenditure, poor
nutritional environments, transient environmental change, and shortened life
expectancies.113 Due to poor nutritional environments and shortened longevity,
Gluckman and Hanson argued that the ability to make predictive adaptive responses would have conferred survival advantage to our ancestral hominids.114 They contended that natural selection would have favoured the conservation of predictive adaptation because it enabled the induction of a wider range of phenotypes, thereby allowing for survival in a greater range of environments.115 This was advantageous for our migratory hunter-gatherer ancestors. In fact, mathematic modeling and computer simulations have demonstrated that, without the ability to make predictive adaptive responses, transient environmental change would have carried a high risk of extinction to the gene pool.116
Gluckman and Hanson further suggested that the evolutionary advantages of the predictive adaptive response strategy would have been dependent on several factors, including: the accuracy of the environmental cues the fetus and infant are receiving; the intrinsic costs of plasticity; and the frequency of mismatch between predicted and actual postnatal environments.117 They argued that the predictive adaptive response strategy was able to evolve because energetic costs were minimized by restricting plasticity to early life; and the fidelity of the prediction need not have been very high, as long as is it was correct more often than not.118 Furthermore, even if a mismatch did occur, the consequences would either have manifested in the post-reproductive period or not at all, due to the short lifespan of our ancestral hominids.119
However, the modern-day environment is very different from that of our hunter- gatherer ancestors: humans now live well beyond their peak reproductive age and live in a nutritionally enriched environment.120 Mismatch between the predicted and actual postnatal environments has become increasingly common. Gluckman and Hanson argued that this is largely due to the phenomenon of maternal constraint. In order to ensure that the fetus could exit through the mother's pelvic canal, maternal constraint 75 evolved to limit fetal growth in relation to maternal body size.122 By dictating the maximum size of the fetus, Gluckman and Hanson reasoned: "the phenomenon of maternal constraint effectively overrides purely genetic influences on fetal growth." In so doing, it increases the risk of a mismatch because all human fetuses are born with the default prediction of a restricted postnatal environment. Because this is no longer an accurate prediction for many people, they argued that it results in the increasing incidence of lifestyle diseases.124 This is especially true in populations undergoing rapid nutritional transition since, although the postnatal environment can change rapidly, the fetal
t-jr environment can only improve slowly as a result of maternal constraint. They concluded in 2004:
Indeed, we propose that maternal constraint evolved, or was selected by evolution, because it conferred an additional advantage to that of matching fetal and maternal size. By always limiting nutrient supply to the fetus, constraint ensured that the evolving hominid set the offspring's phenotype toward the default position of predicting an uncertain postnatal nutritional environment.. .With today's high, constant nutrition, the hidden effects of this survival phenotype are frequently manifest as a risk of disease.
Therefore, the environmental mismatch hypothesis, fundamental to the predictive
adaptive response conceptual framework, represented a shift in thinking about disease
etiology.127 The phenomenon of mismatch challenged the traditional medical model of « 19fi disease in viewing disease through an evolutionary context. In so doing, Gluckman and
Hanson addressed a question primary to evolutionary medicine: why has selection left the
human body vulnerable to disease?129 That disease can occur because a person's normal
biology (i.e. maternal constraint) is mismatched to their postnatal environment was
certainly a new view of disease etiology. As stated by Gluckman and Hanson in 2006:
This perspective is radically different from the common view of the aetiology (origin) of disease, which is that either individuals are healthy until they somehow 76
mysteriously 'develop' a disease because of the role of an external agent or that they are born with the gene for that disease.130
Implications
lii The modern human diet favours high-calorie and high-fat food intake. Exercise levels have fallen dramatically in recent years - especially in the developed world.
Obesity has accelerated to the point that high levels are now found in countries of all regions of the globe.133 Longevity has increased, but so has the incidence of chronic
noncommunicable disease.134 Gluckman and Hanson believe that the predictive adaptive response model can explain this current pattern of disease.135 They recognized that the modern environment is far removed from the environment humans evolved in; and that the speed at which the environment has changed is now challenging the evolved biology of the human population.136 This is reflected in what they termed the "changing ecology
of human disease."137
The epidemic of chronic noncommunicable disease is no more evident than in
populations currently undergoing a rapid nutritional transition from a low-fat to a high-
fat, refined food diet.138 India and China are populations currently undergoing such a
nutritional transition.139 Consequently, it has been predicted that, by the year 2020, the
epidemic of chronic noncommunicable disease will disproportionately affect India and
China.140 These are countries that have experienced fast-growing economies and
concomitant improvements in income and food security in recent decades.141 The decline
in undernutrition has been accompanied by a rapid increase in obesity and nutrition-
related noncommunicable disease prevalence.142 This mismatch between improved 77 postnatal growth and constrained fetal growth may explain the high prevalence of type 2 diabetes in nutritionally transitioning societies.143
Similarly, Gluckman and Hanson maintained that the predictive adaptive response model could explain the increasing prevalence of lifestyle disease occurring when populations migrate rapidly from the less developed to the developed world.144 The speed of the nutritional transition amplifies disease risk.145 If an intergenerational passage of disease risk occurs within these nutritionally transitioning populations, it could contribute to the current epidemic of diet-related diseases.146
What does this mean for disease prevention? Gluckman and Hanson argued that
the developmental origins of disease paradigm introduces a new approach to disease
prevention:
This model changes perspectives on how to intervene in the "life-style" disease epidemic. It shows that life-style interventions alone may be only partially effective in that those who are most affected by inappropriate predictive adaptive responses may be difficult to manage with life-style interventions in adulthood. The model suggests that improving maternal and fetal health will allow humans to cope better with current postnatal nutritional conditions — conditions that we did not evolve to inhabit.147
The nutrition and overall health of females of reproductive age will be an important
factor in the prevention of chronic noncommunicable disease in future generations.148 For
Gluckman and Hanson, taking "a life course approach" to disease is a novel concept in
that it considers health within the context of the individual's maternal environment.149
They argued that an understanding of development offers a new approach to disease
prevention, while an understanding of epigenetic processes offers a new approach to
early intervention.150 Although the predictive adaptive response model offered important 78 insights into disease prevention and intervention, as we shall now see, it was not without its critics. 79
Chapter 5: Debating the predictive adaptive response model
The human foetus is not a master economist and cannot predict the future on the basis of the present or the recent past. The forward-looking PAR [predictive adaptive response] model is therefore conceptually flawed, and backward looking models provide a more appropriate approach. The PAR model also overemphasizes the contribution of offspring prediction to developmental strategy, and ignores the role of maternal influence. Human developmental plasticity is therefore best considered as a mechanism for early-life adaptation to maternal phenotype... Wells, 20071
Criticisms of Gluckman and Hanson's model
Gluckman and Hanson claimed that the conceptual framework of evolutionary developmental biology developed during the 1980s and 1990s provided a new set of tools from which to explore developmental plasticity and molecular epigenetics.2 Evolutionary developmental biology had aimed at expanding the Modern Synthesis by integrating developmental mechanisms into evolutionary thinking.3 In more recent years, research at
the molecular level has sought to explain how developmental processes are controlled by
the interaction of genetic, epigenetic, and environmental factors.4 Indeed, many diseases
and behaviours are now linked to epigenetic mechanisms, including cancer,
cardiovascular diseases, and cognitive disorders.5
Gluckman and Hanson's predictive adaptive response model, which proposed that
the fetus chooses a developmental trajectory in expectation of its future adult
environment, is regarded as an important explanation for the developmental origins of
disease; it continues to be widely cited and rigorously discussed today (figure 6).
Gluckman and Hanson's recently published textbook, Principles of Evolutionary
Medicine (2009), has also been well received,6 As one researcher commented in 2007, the 80 predictive adaptive response model is "very heuristic" - a framework that allows for a synthesis of the rapidly accumulating data and ideas regarding the developmental origins of disease.7
2004 2005 2006 2007 2008 2009 2010 2011
"igure 6: Number of times Gluckman and Hanson's original paper "Living with the past: Evolution, development, and patterns of disease"(2004), has been cited in recent years.
However, the predictive adaptive response model has encountered serious criticisms over the past five years. To understand these criticisms I will first summarize three basic premises on which their theory was founded and subsequently criticized: i) the developing organism responds to environmental cues during early life; ii) this response is predictive of the organism's future adult environment; and iii) the ability to make a predictive response is adaptive for the organism.
i) Fetal response to in utero environmental conditions
There are two criticisms today regarding Gluckman and Hanson's claims about the nature of the developmental response. One criticism is in regards to the nature of the 81 environmental cues themselves, while the other pertains to the mechanisms underlying such responses.
Gluckman and Hanson first proposed that a developing organism responds and adapts to intrauterine environmental conditions in 2004. At the time, this idea was well positioned in the then developing understanding that developmental plasticity is an
q almost universal characteristic of multicellular organisms. The recognition of plasticity
as an adaptive human characteristic emerged as early as the 1960s and has been studied intensively over the past two decades.9 During this time period, human epidemiological evidence and experimental evidence in rats, mice, pigs, and sheep has accumulated,
demonstrating that developmental plasticity within an environmental context is "the rule
rather than the exception."10 This increase in research was driven in large part by Hales
and Barker's findings, which linked environmental conditions experienced in early life to
permanent physiological and metabolic changes persisting into adulthood.11 Although the
ability to make developmentally plastic responses is now generally accepted, there is
disagreement today on just what environmental cues the developing organism responds
to. While Gluckman and Hanson proposed that the fetus and early infant respond to the
conditions experienced in utero, as we shall see, others suggested that the fetus instead
i ii) Is the developing organism's response predictive of the future environment? Gluckman and Hanson also proposed that an organism sets its developmental trajectory in anticipation of its adult environment. Several critics have questioned the validity of this claim, however.13 They emphasized how, especially in long-lived 82 organisms, environmental conditions experienced during the relatively short period of pregnancy may be quite different from those of the adult environment.14 In considering the many intervening years between early development and reproduction, critics questioned how such foresight could have evolved in humans: Considering that in humans, the start of reproduction is separated from early development by more than a decade, and that reproductive lifespan is decades long, is it likely that PARs [predictive adaptive responses] could evolve in our species?15 Critics commented that many of the experimental studies Gluckman and Hanson cited in support of the predictive nature of developmental plasticity examined species with short life spans.16 Because of this short life span, environmental cues experienced during |n development would generally be good indicators of the adult environment. However, critics argued that these studies have limited relevance to understanding predictive 1 Q developmental plasticity in long-lived humans. Furthermore, they claimed that it is "virtually impossible" to test if changes in the developmental trajectory as a result of environmental cues during early life are indeed "predictive" of the adult environment.19 P. Ellison and G. Jasienska of Harvard University stated in 2007 that, even if it is possible to speculate on what the organism is predicting, the validity of the speculation cannot be tested by observations of the adult's environment today; as described in Gluckman and Hanson's environmental mismatch hypothesis, the adult environment may not be representative of the prediction. iii) Is the predictive response adaptive for the organism? In order for the predictive adaptive response strategy to have evolved, the benefits to the organism must have outweighed the physiological costs of maintaining plasticity.91 83 For Gluckman and Hanson, the benefit of predictive adaptation is an increase in fitness, measured by lifetime reproductive performance; organisms live longer and have a better chance of reproducing because of this response.00 But Ellison and Jasienska of Harvard University questioned whether this increase in fitness could actually be demonstrated, since it would require long-term observation of human propagation. In order to falsify the claim that predictive adaptive responses increase fitness, one would have to observe a decrease in fertility. However, such fitness-reducing outcomes are explained away by the environmental mismatch hypothesis; this hypothesis explains why the supposedly adaptive process of developmental plasticity can sometimes culminate in maladaptive outcomes.23 Consequently, Ellison and Jasienska questioned whether or not the predictive adaptive response model can be falsified at all: Although the logic of the PAR [predictive adaptive response] and EM [environmental mismatch] hypotheses is attractive, it is difficult to think of how they can be tested in combination. By itself, the PAR would be falsified if the results of fetal programming could be shown to be maladaptive. The EM hypothesis, however, explains away such falsification, leaving open the question of how to render the joint PAR/EM hypothesis falsifiable.24 In 2007, Ellison and Jasienska developed a new approach to testing the potential adaptive value of predictive adaptive responses. They proposed that, if the alternative explanations for such changes in developmental trajectory could be shown to be untrue, then the observed responses must by default be an adaptation.25 The first alternative explanation, constraint, predicts that physiology is directed at an "optimal phenotype distribution" but development is constrained by resource limitations. The second alternative explanation, pathology, is a failure of normal growth processes caused by the disruption of normal growth physiology. The remaining explanation is adaptation, 84 whereby adaptive developmental responses result in a shift towards an "optimal phenotype distribution" for the encountered environment. In order to distinguish between these three alternatives, Ellison and Jasienska applied the predictive adaptive response model to the well-known link between birth size and adult ovarian estradiol production in women. In analyzing the estradiol levels of a sample of adult Polish women of known birth size, they concluded that the observed patterns indeed demonstrated adaptation, ruling out the alternative explanations. They found ovarian function in women of low birth weight to be more "sensitive" to restrictions on adult energy availability. This meant that women exhibited lower estradiol levels when experiencing "energetic constraint", and higher estradiol levels in times of increased energy availability. They deemed this increased sensitivity to be adaptive because it adjusts the probability of conception in response to energy availability, thus favouring successful pregnancy outcomes. While they considered the predictive adaptive response model to be "on the surface very odd" because of the pathological outcomes often associated with fetal growth retardation, Ellison and Jasienska considered their 2006 study to be the first explicit test of the adaptive nature of this model: "this study represents, to our knowledge, the first direct test of the adaptive nature of fetal programming in humans."29 This was important because other critics have commented on the "notable lack of direct tests of the PAR [predictive adaptive response] model."30 Many critics were unsatisfied with the evidence in support of predictive adaptation; they questioned the lack of longitudinal evidence as well as the applicability of rodent models to long-lived species such as humans. ^ I 85 Nonetheless, additional studies in support of predictive adaptation in a wide variety of species have now been published. For example, in 2007, the predictive adaptive response model was tested with respect to cardiovascular functioning in sheep. It was reported that a modest nutritional mismatch between the pre- and postnatal environment induced altered cardiovascular functioning in adult male sleep. Various writers have claimed this study to be important because, not only are the findings consistent with the Gluckman-Hanson model, but sheep are also known to exhibit a •j-5 developmental trajectory similar to humans. Then, in 2008, it was reported that in utero exposure to a high-fat maternal diet in primates caused alterations in the epigenomic profile of the developing offspring.34 This study supported the epigenetic molecular basis of the developmental origins of disease. To date, many human diseases are known to have an epigenetic molecular cause, including Beckwith-Wiedemann syndrome, Angelman syndrome, and Prader-Willi syndrome.35 The maternal fitness model: An alternative proposal While evidence for and against the predictive adaptive response model is well- published, others have underscored deep conceptual flaws within this model. In this regard, Jonathan Wells of the University College London Institute of Child Health is the most prominent critic.36 Since 2006, Wells has put forth the most detailed criticisms of the predictive adaptive response model. He has argued that the model is "fundamentally flawed" and that it offers an inappropriate theoretical basis for the study of the developmental origins of adult disease.37 However, Gluckman, Hanson, and Wells did 86 find some common ground. Wells agreed with the Gluckman-Hanson model in that: i) developmental plasticity is adaptive and occurs during human development; ii) disease manifests when an environmental mismatch occurs between the nutritional environments at different stages of life; iii) an evolutionary life course approach is necessary to studying noncommunicable diseases with developmental origins; and iv) understanding the developmental origins of disease will be important in designing maternal and childhood interventions, and accordingly, to the prevention of chronic disease. Wells also agreed with Gluckman and Hanson that early nutrition might influence epigenetic or hormonal regulatory mechanisms, which could have long-term effects on body composition.39 Gluckman and Hanson had posited that epigenetic mechanisms such as DNA methylation and histone modifications provide the molecular basis for developmentally plastic responses.40 Wells also recognized that epigenetic modifications are important in the induction of phenotype. In his view, by allowing maternal phenotype to influence the "epigenetic profile" of her offspring, long-term effects on offspring phenotype are induced based on recent matrilineal experience.41 Thus, for Wells, epigenetic processes also had a role to play in the developmental origins of disease.42 Finally, similar to Gluckman and Hanson, Wells recognized that epigenetic effects could be inherited transgenerationally.43 However, in his view, grandchildren do not bear phenotypic resemblance to their grandmothers because the grandmother predicted environmental conditions two generations into the future.44 Instead he claimed that, when the offspring aligns its developmental trajectory with maternal phenotype, the effects are long-lasting and can take multiple generations to become "diluted."45 87 In 2003, in what he would later develop into his "maternal fitness model", Wells addressed "nutritional programming" from an evolutionary perspective.46 He took a life history approach to explaining the link between in utero malnutrition and adult metabolic disease. A life history approach examines the strategic investment of an organism's energy towards growth and reproduction.47 Because of this "trade-off" between growth and reproduction, Wells argued that nutritional programming represents a "battleground" in which maternal-offspring conflict plays out.48 As proposed by Robert Trivers in 1974, because mother and offspring are not genetically identical and because a mother has finite resources available to invest in all her progeny, there are different optimal strategies for the parents and the offspring.49 In what Trivers termed "parent-offspring conflict", the mother and offspring disagree on the length of the investment period as well as on the amount of parental investment.50 In applying parent-offspring conflict theory to nutritional programming, Wells argued that the mother manipulates offspring body composition and size based on the quality of the external environment.51 It is when environmental conditions are poor and resources are scarce that this conflict is most pronounced. According to life history theory, it is in unpredictable environments that parental survival is favoured over reproductive investment. This critical balance between survival and reproduction is also evident in marginal environments, where the initial size and growth of the offspring is reduced in order to minimize both energetic requirements of the offspring and demands on the mother.54 Arising from the conflict between offspring demand and maternal supply, Wells argued: 88 Rather than low birth weight being seen as inherently pathological, all birth weights and underlying body composition may be seen as a compromise between offspring and maternal fitness for a given environment.55 Thus, he concluded in 2003 that nutritional programming represents a dynamic interaction between the environment and the parent-offspring relationship. The mother manipulates the environmental cues being received by the offspring in order to buffer against transient environmental fluctuations, but also to "superimpose her own fitness- maximizing strategies."56 An emphasis on the maternal role in the process of developmental plasticity became the hallmark of Wells' model. In 2007, Wells developed his maternal fitness model further.57 He suggested that because human offspring have an extended period of physiological dependence and Cj> resource dependence on their mother, it puts a strain on the maternal energy budget. Consequently, Wells argued, the mother must regulate the early growth patterns of her offspring based on her own phenotype. The maternal phenotype, in turn, is determined by her own period of development (i.e. her own birth weight) and her nutritional status prior to conception.59 As a result, during pregnancy and during the period of lactation, the growth trajectory of the offspring is aligned with the maternal phenotype.60 Furthermore, according to Wells' maternal fitness model, the risk of disease increases when the alignment between long-term maternal phenotype and offspring development is disrupted.61 Wells considered four means by which disease could occur in the offspring as a result of maternal phenotype: i. Poor maternal metabolic control may be passed onto the offspring, and can manifest as type 1, type 2, or gestational diabetes mellitus, as well as obesity and hypertension.62 89 ii. Placental dysfunction can induce fetal malnutrition, imitating a poor external environment. In the maternal fitness model, undernourished offspring are then susceptible to "catch-up growth" - a rapid postnatal growth rate. This disparity between fetal undernutrition and rapid postnatal growth is then linked to adult metabolic disease risk.64 Wells also implicated exposure to maternally derived toxins (e.g. maternal smoking) as producing similar disease outcomes.65 Thus, he implicated maternal health and behaviour prior to and during pregnancy as a means by which adult disease can be induced. iii. Among social species, low maternal social status represents a "metabolic ghetto," whereby low social status in early life has long-term effects on offspring exposure to stress and disease.66 Wells proposed that the influence of low social status on later disease risk is evident in the current epidemic of type 2 diabetes in economically transitioning populations: Marked increases in the prevalence of type-2 diabetes in populations such as India may prove to be a specific deleterious consequence of long-term economic oppression followed by sudden economic change through the forces of globalization.67 Thus, improvements in social status may not ameliorate disease risk because of the consequences of environmental mismatches, which Wells next considered. iv. In accordance with Gluckman and Hanson's environmental mismatch hypothesis, Wells argued that the disparity between pre- and postnatal environmental quality increases the risk of disease.68 Low birth weight babies are especially at risk of developing adult metabolic disease because they likely undergo rapid catch-up growth in infancy.69 90 The Wells versus Gluekman and Hanson Debates Wells denies the relevance of predictive adaptation to humans Since 2006, a debate has raged between Wells, Gluekman, and Hanson, regarding the theoretical differences in their models. The debates began in 2006 when Wells published an opinion article in Trends in Ecology and Evolution titled, "Is early development in humans a predictive adaptive response anticipating the adult environment?"70 In Wells' view, Gluekman and Hanson's model could not be easily applied to humans; the evidence for it was based on fast-maturing species such as rodents, but the situation would be different in humans who take many years to reach reproductive age. He doubted that the relatively brief in utero period could be predictive of the adult environment: "the issue therefore is whether a developmental trajectory adopted in such a short period of time is genuinely predictive of the environment experienced as an adult." 71 Wells believed that external environmental conditions during pregnancy would not provide a reliable forecast of conditions many years into the future; thus, he concluded, "The idea that the human fetus receives reliable information about the state of the current external environment during pregnancy is therefore flawed."72 He proposed an alternative hypothesis: that the cues received by the offspring from its mother are not those of the newborn's in utero environment, but instead are those of the mother's own early life experiences in utero and during infancy. In applying parent-offspring conflict theory, Wells suggested that phenotypic changes induced during offspring development are driven by a "fitness-enhancing strategy of the mother."73 He argued that, because the only information the fetus receives in regard to the external environment is provided by 91 the maternal phenotype, the fetus is "forced" to select a developmental trajectory reflective of the mother's capacity to provision nutrients and other resources. By "controlling" offspring development in such a manner, the mother can induce "thriftiness" in her offspring - thereby minimizing demands on the maternal energy budget and maximizing maternal fitness.74 Wells concluded that his maternal fitness model would have important implications for developing public health strategies in that it emphasizes health during the period of maternal development, whereas the Gluckman-Hanson model focuses on the health of females during reproductive age.75 Gluckman and Hanson deny that humans have abandoned predictive adaptive responses as a consequence of longer life Gluckman and Hanson quickly responded to each of Wells' criticisms.76 Firstly, they disagreed with Wells' suggestion that the predictive adaptive response model is less relevant to long-lived species such as humans because of the many intervening years between the in utero and reproductive periods. They argued: i) that there is a great deal of evidence from various animal models supporting the predictive adaptive response model; ii) that epidemiological studies support the experimental animal models; and iii) theoretical and empirical evidence demonstrate that the accuracy of environmental cues need not be high in order for developmental plasticity to be a "favoured evolutionary strategy."77 Thus, they concluded in 2006: There is abundant evidence from various animal models concerning PARs [predictive adaptive responses]. Many of the experimentally induced phenomena observed in these species are mirrored in epidemiological data from humans. Furthermore, humans now live much longer than when the species first evolved. We see no reason to think that humans have abandoned PARs, which are 92 apparently universal in the animal models, merely as a consequence of longer life.78 They also challenged Wells' argument that the maternal phenotype is the only means by which offspring receive information about the external environment. They stated that the ovum, embryo, or fetus can gain environmental information by other means as well, such as from maternal exposure to toxins or short-term changes in maternal glucocorticoid levels.79 They did agree with Wells on one point, however: that the interaction between the mother and fetus is important to the understanding of mammalian development and evolution.80 This interaction had not been ignored in the predictive adaptive response model, they claimed. Indeed, Gluckman and Hanson acknowledged the primacy of maternal survival over fetal survival during periods of extreme environmental conditions. Furthermore, even under normal environmental conditions, the fetus will experience maternal constraint; Gluckman and Hanson described this as a strategy employed by the mother to both limit energetic investment in her offspring and to match fetal size to maternal size.81 However, they argued, regardless of extreme environmental conditions and the strategy of maternal constraint, the developing organism will attempt to maximize its own fitness by selecting a developmental trajectory that matches with the prevailing environmental conditions. Wells considers the Gluckman-Hanson model naive in ignoring the role of the mother In October 2007, Wells responded with a more detailed examination of what he considered to be two fundamental flaws in the predictive adaptive response model: i) how it considers environmental information is incorporated into offspring phenotype during 93 early life; and ii) that it is "naive" in ignoring the effect of maternal strategy on development. i) The predictive adaptive response model suggested that the fetus and early infant adjust their development in anticipation of their future adult environment, and it does so based on environmental cues experienced during early life. Wells questioned the validity of this concept. While acknowledging that the process of incorporating information in early life to guide development is adaptive, he challenged the idea that developmental plasticity enables the offspring to align itself with the future adult environment. In his view, during the course of hominin evolution, environmental conditions experienced during pregnancy were likely to be unreliable predictors of the adult environment because of factors such seasonality and migration. Wells argued that human developmental plasticity evolved within this context of environmental stochasticity, causing short-term uncertainties in energy supply. To demonstrate how environmental conditions experienced during pregnancy are an unreliable guide to the future adult energy supply, Wells developed a "simulation model."83 To simulate fluctuations in ecological conditions over time, he modeled the price of gold over several decades. His aim was to test whether or not conditions at one point in time can reliably predict subsequent conditions. In modeling what he termed "predictability of the future," Wells found neither current conditions nor conditions experienced in the recent past to be reliable predictors of future conditions. Thus, he concluded: "in ecosystems, as in economics, the future cannot be predicted with confidence."84 For Wells, this simulation substantiated his view that environmental 94 conditions experienced during pregnancy are unable to accurately forecast or predict the adult environment: In my view, the PAR [predictive adaptive response] model fails because it is mistaken about what information is used in the 'weather forecast'. Information about the quality of the external environment during pregnancy is exactly the information that the human foetus does not want. Rather than targeting development at ecological conditions during a brief period of time, the foetus would be better off being protected from such short-term fluctuations. This protection is achieved by the powerful capacity of maternal physiology to buffer short-term perturbations during pregnancy and lactation.85 ii) In Wells' view, the second major flaw in Gluckman and Hanson's model was that it failed to address the role of maternal influence on developmental strategy; it instead overemphasized the role of "offspring prediction."86 He considered the "forward- looking" approach of the predictive adaptive response model to be inadequate, and instead advocated a "backward-looking" approach: "the human foetus does not look forward, anticipating future external environmental conditions, but backwards to the past to evaluate the phenotype of its own mother." Wells emphasized that the advantage of aligning development with matrilineal experience is not because it provides a source of environmental information. Instead, matrilineal experience represents a "cumulative index of maternal state," thereby providing accurate cues of maternal nutritional provisioning capacity. This distinction was important because, in many primate species, nutritional experience can vary among individuals even within a common environment. In Wells' view, varying maternal social rank provides an example of this phenomenon: mothers of low social rank may have poorer access to resources than do mothers of higher social rank, although the environment may be held in common. Therefore, aligning development with the maternal 95 phenotype rather than external environmental conditions would provide a more accurate on indication of nutritional supply. Wells cited a 2001 study of rural Gambian farmers in support of this phenomenon. This study demonstrated that during the "hungry season" in rural Gambia, moderate to severe fetal and childhood malnutrition did not increase the risk of developing cardiovascular diseases in adulthood. In support of a mother's ability to buffer her offspring against short-term nutritional changes, Wells stated: In direct contradiction to the PAR [predictive adaptive response] model, the offspring of Gambian farmers, who inhabit one of the most seasonally stressful environments on earth, show no association between season of birth and indices of metabolic risk in childhood. Although those born in the 'hungry' season have reduced thymus size, this is likely to represent energy constraint rather than any adaptive prediction of future disease load.89 If evolution has favoured a combined mother-offspring strategy, as Wells proposed, and the mother can buffer her offspring against environmental fluctuations, how does noncommunicable disease then develop? He argued that it is when the "coherence" between the mother-offspring strategy is lost that disease manifests. This could be due to factors such as gestational diabetes or because the maternal strategy is negated by aberrant dietary patterns, such as bottle feeding and the consumption of processed energy-dense foods.90 In terms of type 2 diabetes, Wells argued that the development of insulin resistance is not an "adaptive predictive process"; rather, it is the modern, energy-rich, diet experienced dining childhood that leads to insulin resistance.91 In focusing on the role of the mother in offspring development, Wells argued that novel public health interventions could be developed to aid in the prevention of noncommunicable disease. He hoped that debating the merits of the various evolutionary models concerning the developmental origins of disease would be helpful in stimulating progress in disease intervention strategies.* 92 Gluckman and Hanson cannot comprehend the "evolutionary rationale" of Wells' model In 2008, Gluckman, Hanson, and colleagues responded to Wells' last criticisms. They agreed with Wells that disease manifests when there is a mismatch between nutritional experiences at different phases of life - a claim fundamental to the Gluckman- Hanson model. However, Gluckman and colleagues found it difficult to comprehend the "evolutionary rationale" for a model that focused solely on maternal strategy.94 They argued that maternal effects on offspring development occur in many species, even when there is little maternal investment in offspring, and so there would likely be no maternal advantage.95 Accordingly, Gluckman and colleagues suggested a broader approach to developmental plasticity was necessary because: i) contrary to Wells' model, plasticity is not limited to nutritional and metabolic concerns; and ii) humans select a developmental trajectory based on information from the past as well as the present in order to prepare for the future environment.96 They argued that many cues experienced during early life can influence later life traits; for example, an adverse early environment has also been shown to affect age of sexual maturation, ovarian function, and lifespan. Gluckman and colleagues also emphasized two other aspects of developmental plasticity "unappreciated" by Wells. First, they asserted, a response to environmental change can temporally range from instant (homeostatic processes) to multigenerational (selection). They argued that plasticity allows a lineage to maintain fitness for one or more generations during periods of environmental change; since even relatively inaccurate predictions can be advantageous, this has led to the selection of the predictive adaptive response.98 Secondly, Gluckman and colleagues argued that, with varying 97 degrees of environmental change, different responses will he elicited. Wells' arguments come from the consideration of severe environmental change which cause coping or developmental disruptions; as a result, they stated that Wells had "ignored" the extensive evidence demonstrating that smaller environmental changes can cause subsequent adaptive responses." In order to demonstrate a mother's ability to buffer her offspring against short- term nutritional challenges, Wells had cited an epidemiological study of Gambian farmers. He argued that the findings of this study contradicted the predictive adaptive response model because no association between fetal malnutrition and metabolic disease risk in childhood was exhibited. However, Gluckman et al, argued that this study instead supports their model, since the malnourished in utero environment matched the low-fat diet maintained into adulthood: Wells uses the apparent insensitivity of metabolic indices in adult Gambian subsistence farmers to seasonal early-life malnutrition to argue against the predictive model. But he fails to mention that those individuals 'remain(ed) lean and fit on a low-fat diet' - a match of early and adult nutritional experience that obviously supports our explanation of disease causation.100 Finally, Gluckman et al. disagreed with Wells' suggestion that seasonality was a key selective pressure throughout the course of hominin evolution and that this would often have led to unreliable predictions of the adult environment.101 They, like others, found his formal model of the price of gold to be inappropriate and unconvincing: Wells suggests, partly based on what we believe to be an unsupported view that seasonality was a major selective pressure in early foraging hominins, that seasonal changes occur too rapidly to allow an accurate long-term adaptive response, a claim illustrated with some abstruse and biologically irrelevant modelling of the price of gold.102 Instead, they argued that fetal developmental plasticity and predictive adaptive responses are based on a more integrated assessment of the maternal condition; they reiterated that, 98 even if the forecast of the future is "noisy and possibly inaccurate, the ability to make predictive adaptive responses would still have been selectively favoured.103 Nevertheless, Gluckman et al. were pleased with Wells' conclusion that debating these concepts will aid in the development of maternal and child-based interventions, which will be important for the prevention of noncommunicable disease - a long-held belief of the authors.104 Wells argues that offspring prediction requires a more critical examination In March of the same year, Wells responded once more to Gluckman, Hanson, and colleagues. In this response, he summed up the fundamental issue underlying the entire debate, stating: Where we genuinely differ concerns, very simply, what exactly the offspring adapts to. Gluckman et al. believe that the developing organism attempts to match itself to the future external environment, whereas I argue that it matches itself to maternal phenotype.105 The predictive adaptive response model today The debates over the predictive adaptive response model and the maternal fitness model have not yet been resolved. As recently as 2011, Wells considered his maternal fitness model to be a "competing hypothesis" concerning the adaptive value of human developmental plasticity.106 For their side, Gluckman and Hanson have continued to defend their predictive adaptive response model. In their 2009 textbook Principles of Evolutionary Medicine, they restated their claim regarding the limited nature of a model focused solely on maternal strategy. They recognized that in rare cases of extreme environmental conditions, maternal interests may take precedence. However, even under famine conditions, humans do not completely cease reproduction, which suggests that mothers are still prepared to sacrifice limited resources in order to meet the evolutionary need to reproduce.107 They concluded that the primacy of maternal interests under normal IAO environmental conditions is an "untenable" notion. In spite of the differences between the two models, both the predictive adaptive response model and the maternal fitness model have had a great impact on our understanding of the developmental origins of disease. Gluckman and Hanson's original paper proposing the predictive adaptive response model has been cited over 440 times to date and in over 250 journals (figures 7 & 8). Wells' original article explaining the maternal fitness model has been cited almost 50 times in 30 different journals (figures 7 & 9). Although the maternal fitness model has not been as highly cited as the Gluckman- Hanson model, Wells' arguments have driven much of the academic discourse on evolutionary models concerning the developmental origins of adult disease. 100 Wells 1 Gluckman and Hanson 2003 2004 2005 2006 2007 2008 2009 2010 2011 Year igure 7: Number of times Gluckman and Hanson's, "Living with the past: Evolution, development, and patterns of disease"(2004) and Wells' "The thrifty phenotype hypothesis: Thrifty offspring or thrifty mother?" (2003), have been cited in recent years. 101 EARLY HUMAN DEVELOPMENT JOURNAL OF DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE TRENDS IN ENDOCRINOLOGY AND METABOLISM REPRODUCTIVE TOXICOLOGY HYPERTENSION PEDIATRIC RESEARCH CIRCULATION PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE USA AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY MEDICAL HYPOTHESES PLOS ONE ENDOCRINOLOGY AMERICAN JOURNAL OF HUMAN BIOLOGY BRITISH JOURNAL OF NUTRITION JOURNAL OF PHYSIOLOGY-LONDON 6 8 10 12 14 Number of citations Figure 8: Number of times Gluckman and Hanson's, "Living with the past: Evolution, development, and patterns of disease"(2004) has been cited in 15 journals. Those with the highest number of citations are presented. CURRENT BIOLOGY CELL METABOLISM ARCHIVES OF DISEASE IN CHILDHOOD EVOLUTIONARY ANTHROPOLOGY TRENDS IN ECOLOGY & EVOLUTION EARLY HUMAN DEVELOPMENT MEDICINE AND EVOLUTION EPIGENOMICS TRENDS IN ENDOCRINOLOGY AND METABOLISM INTERNATIONAL JOURNAL OF EPIDEMIOLOGY BRITISH JOURNAL OF NUTRITION BIOLOGICAL REVIEWS PROCEEDINGS OF THE NUTRITION SOCIETY MEDICAL HYPOTHESES AMERICAN JOURNAL OF HUMAN BIOLOGY 4 5 Number of citations Figure 9: Number of times Wells' "The thrifty phenotype hypothesis: Thrifty offspring or thrifty mother?" (2003), has been cited in 15 journals. Those with the highest number of citations are presented. 102 Summary and Conclusion The past fifty years have seen major conceptual changes in our understanding of type 2 diabetes. Three successive theories have been proposed for its origin, each marking a conceptual shift. One was based on genetics and evolutionary theory. Another was based on epidemiological studies and purely environmental causes. And the third theory was based on a combination of genetics, developmental regulation, epidemiology, and evolutionary theory. As I have shown, these shifts in biological thinking reflected changes in diabetes research methodology, new findings regarding diabetes, as well as new perspectives on the nature of noncornmunicable disease. In 1962, when James Neel sought to understand what he called a "diabetes paradox," he wondered how diabetes prevalence could be increasing in the western world when there should be an "obvious" and "strong" selection against it. As discussed in chapter 1, Neel had aligned his conception of diabetes etiology with his understanding of sickle cell anemia, which he had studied in the early 1950s. Just as sickle cell genes were shown to play an adaptive role in the presence of malaria, so too would genes for diabetes. Thus, he proposed that the increasing diabetes frequency might be attributable to some benefit imparted by the "diabetic genotype." He conjectured that diabetes would benefit the individual through more efficient nutrient utilization or "thriftiness." Neel's "thrifty genotype hypothesis" offered an adaptationist account, according to which the "diabetic genotype" had evolved over the course of 99% of human history in order for humans to better adapt to fluctuations in food supply. However, the high-fat, high-sugar modern diet, has today rendered the "diabetic genotype" detrimental. But Neei's hypothesis had no direct data to support it, nor was type 2 diabetes itself viewed as a major medical problem in the western world at the time. Indeed, the thrifty genotype hypothesis was not widely discussed or investigated until the 1990s, by which time diabetes prevalence had drastically increased in many countries throughout the world and epidemiologists recognized what they called a "diabetes epidemic." Although a great deal of research was conducted and aimed at identifying diabetic genes, that search for "thrifty genes" was largely unsuccessful. As recognized by Neel in 1999, his hypothesis had largely collapsed by this time as a result of an increasing understanding of genetic complexity. Although the thrifty genotype hypothesis was highly criticized in the 1990s as being an unclear and untestable evolutionary account, it was not wholly refuted; nor did it disappear from scientific thought. Indeed, as we have seen in chapter 1, some epidemiologists and evolutionary biologists of the early 21st century still consider it have "intuitive validity" and to be the leading evolutionary theory for type 2 diabetes. The "thrifty phenotype hypothesis" was proposed by Nicholas Hales and David Barker in 1992 in direct opposition to the thrifty genotype hypothesis. As discussed in chapter 2, this new hypothesis suggested that nutritional deprivation in utero and in early infancy was the principal cause of type 2 diabetes - not genes or evolution. According to Hales and Barker's hypothesis, such nutritional deprivation would result in permanent changes in the structure and function of the fetal pancreas; this would then predispose an individual to the later development of type 2 diabetes. This hypothesis, which linked the intrauterine environment with adult diabetes, contrasted strongly with Neei's gene- centered perspective. Proposed when the Human Genome Project was emerging, some 104 researchers saw the thrifty phenotype hypothesis to be an innovative idea at a time when genome mapping promised a new era of gene therapy. Based on five years of epidemiological studies linking adverse environmental conditions in utero to disease susceptibility in adult life, the thrifty phenotype hypothesis represented a purely environmental concept of diabetes causation. It did not provide a molecular mechanism to explain how in utero development could induce long-term effects on adult health. Nor did it consider genes. As we have seen, Hales and Barker considered environmental factors to work independently of genetic factors in diabetes etiology. Furthermore, unlike the thrifty genotype hypothesis, it was not embedded in evolutionary or anthropological theory. Instead, the thrifty phenotype hypothesis was practical; for Hales and Barker, it served as a diagnostic tool for identifying type 2 diabetes susceptibility. In light of the increasing prevalence of type 2 diabetes, their immediate concern was to determine the major causative factors so that preventative measures could be taken. Hales and Barker's ideas regarding diabetes were not readily accepted by all and incurred a decade of intense criticism. Indeed, Hales and Barker were criticized for misinterpreting data, having flaws in their study design, and for positing a hypothesis far too simplistic for what their critics saw as a much more complex disease. Nonetheless, a great number of epidemiological studies and experimental studies on rats, mice, pigs, and sheep have provided support for the association between in utero nutrition and adult disease. But it was clear to Hales and Barker's critics that susceptibility to diabetes was not simply due to nurture alone; one could not ignore genetic differences. 105 Those who believed that genes were central to type 2 diabetes etiology were quick to provide evidence against the environmental hypothesis. Perhaps the most widely-held argument in support of the genetic basis of type 2 diabetes was derived from twin studies, indicating higher concordance for type 2 diabetes in monozygotic twins than in dizygotic twins. Still, at the turn of the 21st century, whether type 2 diabetes resulted from genetic or environmental factors continued to be debated. The thrifty phenotype hypothesis represented an important concept in diabetes etiology during the 1990s. The controversy over the roles of genes and the environment in disease causation stimulated much research into type 2 diabetes.1 By the early 2000s, the thrifty phenotype hypothesis became more commonly known as "the fetal origins of adult disease hypothesis." This change in terminology reflected the many diseases associated with in utero malnutrition rather than diabetes alone, including coronary heart disease and high blood pressure. The international interest in this field culminated in the first and second international meetings on the fetal origins of disease, held in 2001 and 2003.2 In 2004, a new hypothesis, the "predictive adaptive response model" would reshape thinking about the origin of noncommunicable disease to the present day. As we saw in chapter 3, this model was more synthetic in that it included evolutionary theory, genetics, and development. It extended the thrifty phenotype hypothesis from epidemiology into the realm of evolutionary biology; it did not rely on correlational findings between early development and disease, but instead provided molecular mechanisms of gene regulation. 106 Championed by Peter Gluckman and Mark Hanson, the predictive adaptive response model explained how environmental cues during ontogenetic development could be linked to adult chronic disease. Gluckman and Hanson proposed that the embryo, fetus, or infant is able to adjust its development based on environmental cues. Such "developmental plasticity" would allow for a range of phenotypes to be expressed from a single genotype, and thus provide the means by which a developing organism can respond to environmental change. The mechanism underlying developmental plasticity was proposed to be epigenetic processes. In 2004, Gluckman and Hanson used this understanding of epigenetic regulation of gene expression to establish the link between the developmental period and adult disease. As discussed in chapter 4, they emphasized three epigenetic mechanisms by which environmental cues could influence the developmental program: altered tissue differentiation, changes in homeostatic control mechanisms, and the regulation of gene expression resulting from DNA methylation. They considered several lines of evidence to be supportive of the association between epigenetic mechanisms and developmental plasticity, including experimental animal models. That epigenetic modifications could also be transgenerationally inherited became central to Gluckman and Hanson's model. It could potentially explain how the incidence of chronic noncommunicable disease, such as type 2 diabetes, has exploded in recent years. They argued that, through transgenerational non-genomic inheritance, parents transmit information about their long-term environment to their offspring as well as to their grandchildren in some instances. In ancestral times, this would have been adaptive in coping with climatic variability. However, in more recent times, it now exacerbates disease risk for multiple successive generations due to "environmental mismatch." That the predictive adaptive response model was situated within an epigenetic context was crucial. It rendered the "nature verses nurture" debate - which was implicit in the thrifty hypotheses - irrelevant and anachronistic by demonstrating the dynamic nature of gene-environment interactions. Similar to Neel's thrifty genotype hypothesis, proposed four decades earlier, they acknowledged that genetic variation is important to understanding type 2 diabetes; but, for Gluckman and Hanson, this genetic influence was manifested in a much more "indirect" manner, being mediated by developmental influences. Gluckman and Hanson also accepted aspects of Hales and Barker's thrifty phenotype hypothesis - including the link between developmental nutrition and adult diabetes risk. However, they rejected the idea that developmental changes are brought about by severe fetal stress and deprivation. Instead, Gluckman and Hanson claimed that many environmental cues during development can alter disease risk without affecting birth size. In extending concepts from the earlier hypotheses regarding type 2 diabetes etiology, Gluckman and Hanson were able to arrive at both a genetic and developmental view of diabetes, and epigenetic processes brought together the genotype and phenotype (figure 10). 108 Thrifty Thrifty Genotype Phervotype Hypothesis Hypothesis Predictive Adaptive Response Model Figure 10: The roles of genotype, phenotype, and epigenetics in the three models of type 2 diabetes etiology. In order to understand how gene-environment interactions now contribute to the rising incidence of adult disease, Gluckman and Hanson argued that an evolutionary perspective was necessary. They considered the rising incidence of adult disease to be attributable to the increasing mismatch between the predicted and actual postnatal environments. They also argued that an intergenerational passage of disease risk through epigenetic processes may now be exacerbating the frequency of chronic disease. Today, many diseases are understood to be influenced by epigenetic processes. This concept of developmental mismatch challenged the traditional medical model of disease in viewing disease through an evolutionary context. Many researchers have expressed their excitement over the possibilities offered by the predictive adaptive response model, as well as the far-reaching implications it will have on human health. 109 Thus, the predictive adaptive response model was novel in offering both a "mechanistic" and evolutionary explanation for type 2 diabetes etiology. It was also robust in that it predicted the etiology of many pathological states in addition to type 2 diabetes. Unlike its predecessors, the predictive adaptive response model was also an important explanatory framework for other noncommunicable diseases, including truncal obesity, asthma, osteoporosis, polycystic ovarian disease, depression, schizophrenia, and certain cancers. It was indeed a more general model for disease than were the "thrifty" hypotheses that preceded it. However, criticisms and questions still remain concerning the theoretical concepts and evidence pertaining to the predictive adaptive response model. As we saw in chapter 5, Jonathan Wells, and others, have questioned the applicability of experimental studies on short-lived animals to predictive developmental plasticity in long-lived humans. Furthermore, Wells has challenged Gluckman and Hanson's hypothesis that developmental plasticity enables the offspring to align itself with the future adult environment. In his view, during the course of hominin evolution, environmental conditions experienced during pregnancy were likely to be unreliable predictors of the adult environment because of factors such seasonality and migration. Instead, Wells claimed that the human fetus aligns its developmental trajectory with the maternal phenotype. Consequently, the fetus adjusts its development based on the health of the mother and her recent ancestors, not in anticipation of the future environment. While Wells found the predictive adaptive response model to be fundamentally flawed, he did agree with several aspects of the Gluckman-Hanson model: i) that developmental plasticity is adaptive for the organism; ii) that disease manifests as a result 110 of environmental mismatch; and iii) that early nutrition may influence epigenetic or hormonal regulatory mechanisms, which could have long-term effects on body composition and be inherited transgenerationally. The debates between Gluckman, Hanson, and Wells have been important to our understanding of type 2 diabetes. The debates revolved around what the organism adapts to - not whether or not the organism adapts at all; thus, it is no longer questioned whether or not evolution has a role to play in the etiology of type 2 diabetes. As evolution has become fundamental to the explanatory framework for diabetes, the approach to diabetes prognosis and treatment will also need to change. An individual's lifestyle and genes can no longer be considered the sole determinants of type 2 diabetes risk. Interventions will need to address maternal (and perhaps grandmaternal) health as well, because the fetus and early infant may be adapting to the environmental conditions experienced by its mother. Nevertheless, questions still remain concerning what information the fetus aligns its development with and whether developmental responses are tightly coupled with early life or are predictive of the adult environment. While a debate over these issues remains, this debate is structured within an evolutionary developmental biology and epigenetic framework. Unlike old questions regarding the roles of genes and the environment in type 2 diabetes causation, today it is understood that type 2 diabetes must be viewed from an evolutionary, developmental, genetic, and epigenetic perspective (table 3). Ill Table 3: Characteristics of the three etiological models of type 2 diabetes Thrifty Genotype Thrifty Phenotype Predictive Adaptive Hypothesis Hypothesis Response Model Genes Phenotypes Development and genes Evolution No evolution Evolution "Nature" "Nurture" Process-based biology Genetic determinism No molecular mechanism Mechanism As this thesis has shown, there have been great conceptual changes in the field of diabetes research in the past 50 years. The three main conceptual frameworks for type 2 diabetes research have each left their own mark on the field (figure 11). Neel's genetic deterministic framework played an important role in inciting ongoing research into type 2 diabetes and provided the earliest suggestion of a link between diabetes and environmental mismatch. - 100 v •C 80 (A s 60 <*- 40 I 20 E 3 0n 1 J I I I 1 I I C F I I I I I I f. I I I I I I I I f 1 5 F fi I I 5 F I I I J I I J—I I [ F I I I i Z 1962 1966 1970 1974 1978 1982 1986 1990 1994 1998 2002 2006 2010 Year •Neel ^"Hales & Barker ^—Gluckman & Hanson Figure 11: Number of times the authors' original papers have been cited in the ISI Web of Knowledge, by year Hales and Barker's thrifty phenotype hypothesis, concentrating solely on the fetal environment, was both controversial and influential. It would drive research on type 2 diabetes from the early 1990s to the present day. 112 Finally, Gluckman and Hanson's epigenetic and evolutionary model built upon the ideas of their predecessors. In introducing epigenetics into type 2 diabetes research, their model, in effect, rendered the dichotomy between nature and nurture meaningless in regard to type 2 diabetes. Although doubts concerning the exact information a fetus will adapt to still remain, many researchers now agree that the secret to understanding type 2 diabetes is in the relations between genes, development, environment, and evolution. This thesis has shown how such an integrated understanding of type 2 diabetes has emerged over the past fifty years. 113 References Notes to Introduction 1 International Diabetes Federation Press Release, December 4, 2006: "Diabetes epidemic out of control" [Internet]. 2006. Cape Town; [cited 2011 Sept 12]. Available from: http://www.idf.Org/node/l 354. 2 Dietrich von Engelhardt, "Outlines of Historical Development," in Diabetes: Its Medical and Cultural History, ed. Dietrich von Engelhardt (Berlin: Springer-Verlag, 1989), 1-9. 3 See Hans Schadewaldt, "The History of Diabetes Mellitus," in Diabetes: Its Medical and Cultural History, ed. Dietrich von Engelhardt (Berlin: Springer-Verlag, 1989), 44- 73. 4 Engelhardt, "Outlines of Historical Development," 1-9. 5 R. Luft, "Oskar Minkowski: Discovery of the pancreatic origin of diabetes, 1889," Diabetologia 32 (1989): 399-401. 6 F. G. Banting and C.H. Best, "The internal secretion of the pancreas," The Journal of Laboratory and Clinical Medicine 7 (1922): 251-266. 7 World Health Organization: "Diabetes Fact sheet" [Internet]; [updated 2011 Aug; cited 2011 Sept 14]. Available from: http://www.who.int/mediacentre/factsheets/fs312/en/index.html 8 H. P. Himsworth and R.B. Kerr, "Insulin-sensitive and insulin-insensitive types of diabetes mellitus," Clinical Science 4 (1939): 119-152. 9 Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 20 (1997): 1183-1197. 10 One million new cases of diabetes appeared in the United States between 1980 and 1990. In the United Kingdom, age-adjusted diabetes prevalence in men rose from 4.3% between 1979 and 1984 to 11.8% between 2003 and 2005. Similarly, there was a 61% increase in diabetes prevalence in southwest England between 1983 and 1996. See: M. C. Thomas, S. L. Hardoon, A. O. Papacosta, R. W. Morris, S. G. Wannamethee et al., "Evidence of an accelerating increase in prevalence of diagnosed type 2 diabetes in British men, 1978-2005," Diabetic Medicine 26 (2009): 766-772; W. Gatling, S. Budd, D. Walters, M. A. Mullee, J. R. Goddard et al., "Evidence of an increasing prevalence of diagnosed diabetes mellitus in the Poole Area from 1983 to 1996," Diabetic Medicine 15 (1998): 1015-1021. 11 Centers for Disease Control and Prevention: "Long-term trends in diabetes, October 2010," [Internet], Atlanta (GA): Centers for Disease Control and Prevention (US); [updated 2011 July 13; cited Sept 14]. Available from: http://www.cdc. gov/diabetes/statistics 12 1994: A. F. Amos, D. J. McCarty, and P. Zimmet, "The rising global burden of diabetes and its complications: Estimates and projections to the year 2010," Diabetic Medicine 14 (1997): S7-S85, at S10 -S14. 1997: Ibid. 2000: Sarah Wild, Gojka Roglic, Anders Green, Richard Sicree, and Hilary King, "Global prevalence of diabetes: Estimates for the year 2000 and projections for 2030," Diabetes Care 27 (2004): 1047-1053. 114 2004: World Health Organization, "The global burden of disease: 2004 update," World Health Organization (2008): 1-146, at 32. Available from: http://www.who.int/healthinfo/global_burden_disease/2004_report_update/en/. 2010: Amos, McCarty, and Zimmet, "The rising global burden of diabetes and its complications," S13-S14. 13 Cary P. Gross, Gerard F. Anderson, and Neil R. Powe, "The relation between funding by the National Institutes of Heath and the Burden of Disease," The New England Journal of Medicine 340 (1999): 1881-1887. 14 Leslie A. Gillum, Christopher Gouveia, E. Ray Dorsey, Mark Pletcher, Colin D. Mathers et al., "NIH disease funding levels and burden of disease," PLoS One 6 (2011): el6837. 15 Australian Government National Health and Medical Research Council: "Diabetes" [Internet]; [updated 2011 May 2; cited 2011 Sept 14]. Available from: http://www.nhmrc.gov.au/grants/research-funding-statistics-and-data/diabetes 16 By the year 2025, it is estimated that 7% of the world's population will have type 2 diabetes, or 380 million people. Type 2 diabetes will continue to be a leading cause of death and economic loss, worldwide. In 2004 alone, 2.3 million years of life were lost due to premature mortality associated with type 2 diabetes. It was the 19th leading cause of death worldwide in 2004, but by 2030 it will likely be the 10th leading cause of death. As more people develop type 2 diabetes around the world, global health expenditure will continue to rise. In the United States alone, 232 billion US dollars were spent on diabetes treatment and associated complications in the year 2007; it is estimated that over 302 billion US dollars will need to be spent in the year 2025. See: World Health Organization: "Diabetes Fact sheet" [Internet]. See, also, Susan van Dieren, Joline W. J. Beulens, Yvonne T. van der Schouw, Diederick E. Grobbee, and Bruce Neal, "The global burden of diabetes and its complications: An emerging pandemic," Journal of Cardiovascular Risk 17 (2010): S3- S8; and World Health Organization, "The global burden of disease: 2004 update," 51. 17 In the early 1990s, type 2 diabetes accounted for only 3% of diabetes cases diagnosed in children and adolescents in the United Kingdom; but by 2005, 45% of new cases diagnosed in adolescents were classified as type 2 diabetes. The rising burden of disease worldwide will continue to have far-reaching societal and economic implications. See Linda Haines, Kay Chong Wan, Richard Lynn, Timothy G. Barrett, and Julian P. H. Shield, "Rising incidence of type 2 diabetes in children in the U.K.," Diabetes Care 30 (2007): 1097-1101. Notes to Chapter 1 1 James V. Neel, Stefan S. Fajans, Jerome W. Conn, and Ruth T. Davidson, "Diabetes Mellitus," in Symposium on Contributions of Genetics to Epidemiologic Studies of Chronic Diseases (Washington: United States Public Health Service, 1965), 105. 2 H. King and G. Roglic, "Diabetes and the 'thrifty genotype': Commentary," Bulletin of the World Health Organization 77 (1999): 692-693, at 693. 115 3 K. M. Weiss and R. H. Ward, "Obituary: James V. Neel, M.D., Ph.D. (March 22,1915- January 31, 2000): Founder Effect," American Journal of Human Genetics 66 (2000): 755-760. 4 Ibid. 5 J. V. Neel, "The inheritance of sickle cell anemia," Science 110 (1949): 64-66. See also F. M. Salzano, "James V. Neel and Latin America- or how scientific collaboration should be conducted," Genetics and Molecular Biology 23 (2000): 557-561. 6 J.V. Neel, Physician to the Gene Pool, Genetic Lessons and Other Stories (New York: John Wiley and Sons, 1994), 43. 7 Neel, "The inheritance of sickle cell anemia." 8 Findings indicated that those possessing one sickle cell allele exhibited 40% sickle cell anemia hemoglobin and 60% normal hemoglobin; while those possessing two sickle cell alleles exhibited 100% sickle cell anemia hemoglobin. See Linus Pauling, Harvey A. Itano, S. J. Singer, and Ibert C. Wells, "Sickle cell anemia, a molecular disease," Science 110(1949): 543- 548. 9 J. V. Neel, "The population genetics of 2 inherited blood dyscrasias in man," Cold Spring Harbor Symposia on Quantitative Biology 15 (1950): 141-158. According to Weiss and Ward, "Obituary (2000), "Although Allison and Beet deserve credit for recognizing the overdominant fitness of the sickle-cell trait, without Jim's [James Neel] groundwork this understanding would have taken far longer to achieve." For a detailed review of the link between malaria and the sickle cell trait, see: A.C. Allison, "Malaria in carriers of the sickle-cell trait and in newborn children," Experimental Parasitology 6 (1957): 418-447. 11 Neel, Physician to the Gene Pool, 48. 12 J. V. Neel, "Diabetes Mellitus: a 'thrifty' genotype rendered detrimental by 'progress'?" American Journal of Human Genetics 14 (1962): 353-362. " Ibid. 14 Ibid., 354. 15 Anti-insulin was proposed to be a substance antagonistic to insulin. See J. Vallance- Owen, E. Dennes, and P.N. Campbell, "Insulin antagonism in plasma of diabetic patients and normal subjects," The Lancet 2 (1958): 336-338. Also, Neel, "Diabetes Mellitus: a 'thrifty' genotype rendered detrimental." 16 Neel, "Diabetes Mellitus: a 'thrifty' genotype rendered detrimental," 356. 17 Ibid. 18 Ibid., 357. 19 Neel, Physician to the Gene Pool, 353-354. 20 Ibid., 358. 21 J. V. Neel, "The Thrifty Genotype Revisited," in The Genetic of Diabetes Mellitus. Proceedings of the Serono Symposia No. 47, ed. J. Kobberling and R. Tattersall (New York: Academic Press, 1982), 283-293. 22 Neel, "The Thrifty Genotype Revisited," 284. 23 For a discussion of membrane receptors, see: Pedro Cuatrecasas, "Membrane receptors," Annual Review of Biochemistry 43 (1974): 169-214. 24 Neel, "The Thrifty Genotype Revisited," 284. 25 Ibid. 116 26 ibid., 285. 27 Ibid. 28 Ibid., 283-293. 29 Ibid., 290. 30 J. Kobberling, "Studies on the genetic heterogeneity of diabetes mellitus," Diabetologia 7 (1971): 46-49. For example, seeN. E. Simpson, "Multifactorial inheritance. A possible hypothesis for diabetes," Diabetes 13 (1964): 462-471. 31 D. S. Falconer, "The inheritance of liability to diseases with variable age of onset, with particular reference to diabetes mellitus," Annals of Human Genetics 31 (1967): 1-19. Ibid. See also Kobberling, "Studies on the genetic heterogeneity of diabetes mellitus." 33 J. V. Neel, S. S. Fajans, and R. T. Davidson, "Diabetes Mellitus," in Genetics and the Epidemiology of Chronic Diseases, ed. J. V. Neel, M. W. Shaw, and W. J. Schull (Washington: U.S. Department of Health, Education and Welfare, Public Health Service Publication, 1963), 105-132. 34 Ibid. 35 William C. Knowler, David J. Pettitt, Peter H. Bennett, and Robert C. Williams, "Diabetes Mellitus in the Pima Indians: Genetic and Evolutionary Considerations," American Journal of Physical Anthropology 62 (1983): 107-114; Kenneth M. Weiss, Robert E. Ferrell, and Craig L. Hanis, "A new world syndrome of metabolic diseases with a genetic and evolutionary basis," Yearbook of Physical Anthropology 27 (1984): 153-178. See, also, Jennie R. Joe and Robert S. Young, "Introduction," in Diabetes as a Disease of Civilization: The Impact of Culture Change on Indigenous Peoples, ed. Jennie R. Joe and Robert S. Young (Berlin: Mouton de Gruyter, 1993), 1-18. 36 Weiss, Ferrell, and Hanis, "A new world syndrome of metabolic diseases." 37 Michael Wendorf and Ira D. Goldfine, "Archaeology of NIDDM: Excavation of the "thrifty" genotype," Diabetes 40 (1991): 161-165. 38 Ibid. 39 Ibid. 40 Ibid. 41 Ibid., 164. 42 Gary Dowse and Paul Zimmet, "The thrifty genotype in non-insulin dependent diabetes: The hypothesis survives," British Medical Journal 306 (1993): 532-533, at 532. 43 Indeed, many researchers posited that American Indians and Australian Aborigines have a high incidence of type 2 diabetes because of a genetic susceptibility towards this disease. They claimed that these groups are genetically different from the Euro- descended populations whom are not experiencing an explosion of type 2 diabetes incidence. However, as recognized by Margery Fee of the University of British Columbia in 2006, this conflation of race and genetics was neither a part of nor the intent of the thrifty genotype hypothesis. According to Neel, the thrifty genotype accounts for the prevalence of type 2 diabetes in all ethnic groups, since there is "no support to the notion that the high frequency of NIDDM in reservation Amerindians might be due simply to an ethnic predisposition- rather it must predominantly reflect lifestyle changes." Specifically, Neel suggests that the difference in type 2 diabetes prevalence between certain populations is a reflection of when they became Westernized, and not because of inherent genetic differences. See J. V. Neel, "The 'Thrifty Genotype' in 1998," Nutrition 117 Reviews 57 (1999): S2-S9; M. Fee, "Racializing narratives: Obesity, diabetes and the 'Aboriginal' thrifty genotype," Social Science and Medicine 62 (2006): 2988-2997; and James D. Brosseau, "Diabetes and Indians: A clinician's perspective," in Diabetes as a Disease of Civilization: The Impact of Culture Change on Indigenous Peoples, ed. Jennie R. Joe and Robert S. Young (Berlin: Mouton de Gruyter, 1993), 47. 44 Richard Cooper, "Diabetes and the thrifty gene," The Lancet 344 (1994): 1648; Robert E. Ferrell and Sudha Iyengar, "Molecular Studies of the Genetics of Non-Insulin- Dependent Diabetes Mellitus," American Journal of Human Biology 5 (1993): 415-424. 45 Emoke J. E. Szathmary, "Non-insulin dependent diabetes mellitus among aboriginal North Americans," Annual Review of Anthropology 23 (1994): 457-482. 46 B. A. Swinburn, "The thrifty genotype hypothesis: How does it look after 30 years?" Diabetic Medicine 13 (1996): 695-699, at 695. 47 Ibid. 48 Ibid. 49 John S. Allen and Susan M. Cheer, "The non-thrifty genotype," Current Anthropology 37(1996): 831-842. 50 Dowse and Zimmet, "The thrifty genotype in non-insulin dependent diabetes." 51 Barry Joffe and Paul Zimmet, "The thrifty genotype in type 2 diabetes: An unfinished symphony moving to its finale?" Endocrine 9 (1998): 139-141. See also Ehud Ziv, Rony Kalman, and Eleazar Shafiir, "Psammomys obesus: Nutritionally induced insulin resistance, diabetes, and beta cell loss," in Animal Models of Diabetes: Frontiers in Research, 2d ed., ed. Eleazar Shafrir (Boca Raton, Florida: CRC Press, 2007), 289-310. 52 Candidate genes for the thrifty genotype identified prior to 1998 are reviewed in: Joffe and Zimmet, "The thrifty genotype in type 2 diabetes." 53 Ibid., 141. 54 Cheryl Ritenbaugh and Carol Sue Goodby, "Beyond the thrifty gene: Metabolic implications of prehistoric migration into the new world," Medical Anthropology 11 (1989): 227-236; Ferrell and Iyengar, "Molecular Studies of the Genetics of Non-Insulin- Dependent Diabetes Mellitus"; Szathmary, ''Non-insulin dependent diabetes mellitus among aboriginal North Americans"; Robert L. Hanson, Margaret G. Ehm, David J. Pettitt, Michal Prochazka, D. Bruce Thompson et al., "An autosomal genomic scan for loci linked to type II diabetes mellitus and body-mass Index in Pima Indians," American Journal of Human Genetics 63 (1998): 1130-1138. 55 In 2006, the idea that hunter-gatherers experienced cycles of feast and famine was also challenged by D. Benyshek and J. Watson. Neel had assumed that hunter-gatherers commonly experienced periods of feast and famine, but critics argued this may not have been the case. Using ethnographic nutritional data from 94 foraging and agricultural populations, Benyshek and Watson found no significant difference between the food security of foragers and that of agriculturalists. They concluded that their findings "add to a growing body of research that calls into question assumptions about forager insecurity." Thus, if the cycles of feast and famine experienced by hunter-gatherers were not as common as supposed by Neel, then this also calls into question the selective advantage provided by the possession of "thrifty" genes. See D. C. Benyshek and J. T. Watson, "Exploring the thrifty genotype's food-shortage assumptions: A cross-cultural comparison of ethnographic accounts of food security among foraging and agricultural 118 societies," American Journal of Physical Anthropology 131 (2006): 120-126. See, also, P. D. Gluckman, M. A. Hanson, S. M. B. Morton, and C. S. Pinal, "Life-long echoes- A critical analysis of the Developmental Origins of Adult Disease Model," Biology of the Neonate 87 (2005): 127-139. 56 Kennedy Cruickshank, "Editorial," British Medical Journal 306 (1993): 934. 57 S. E. Ozanne and C.N. Hales, "Thrifty yes, genetic no," Diabetologia 41 (1998): 485- 487. 58 Ibid., 486. 59 Neel, "The 'Thrifty Genotype' in 1998." 60 Ibid., S4. 61 Ibid. See, also, James V. Neel, "Looking ahead: Some genetic issues of the future," Perspectives in Biology and Medicine 40 (1997): 328-348. 62 Neel, "The 'Thrifty Genotype' in 1998," S5. 63 James V. Neel, Alan B. Weder, and Stevo Julius, "Type II diabetes, essential hypertension, and obesity as 'syndromes of impaired genetic homeostasis': The 'thrifty genotype' hypothesis enters the 21st century," Perspectives in Biology and Medicine 42 (1998): 44-74. Notes to Chapter 2 1 David J. P. Barker, "Preface," British Medical Bulletin 60 (2001): 1. 2 Nicholas Hales, "Early programming of glucose metabolism, insulin action and longevity," in Short and Long-term Effects of Breast Feeding on Child Health, ed. B. Koletzko, K. Fleischer Michaelsen, and O. Hernell (New York: Kluwer Academic/Plenum Publishers, 2000), 57-64. 3 Ibid., 58. See, also, David J. P. Barker, "The malnourished baby and infant," British Medical Bulletin 60 (2001): 69-88. 4 Jan Sapp, Genesis: The Evolution of Biology (New York: Oxford University Press, 2003), 202; R. J. Jarrett, "Fetal and infant growth and impaired glucose tolerance," British Medical Journal 303 (1991): 1474. Jarrett describes the thrifty phenotype hypothesis as an "environmental" hypothesis. See, also, Robert Lindsay and Peter Bennett, "Type 2 diabetes, the thrifty phenotype- An overview," British Medical Bulletin 60 (2001): 21-32, at 23. Lindsay and Bennett stated that: "Both the low birth weight and thrifty phenotype hypotheses were bora into what might be considered a hostile environment, consequently they generated enormous controversy." 5 On the controversy generated by the thrifty phenotype hypothesis, see Lindsay and Bennett, "Type 2 diabetes"; Peter Gluckman and Mark Hanson, The Fetal Matrix: Evolution, Development and Disease (Cambridge: Cambridge University Press, 2005), at 87; and Peter Gluckman and Mark Hanson, Mismatch: Why our world no longer fits our bodies (New York: Oxford University Press, 2006), at 63. 119 6 G. K. Dowse, R. Z. Zimmet, and K. G. M. M. Alberti, "Infant nutrition and subsequent risk of type 2 (non-insulin-dependent) diabetes mellitus," Diabetologia 36 (1993): 267- 268; Jarrett, "Fetal and infant growth and impaired glucose tolerance." 7 W. Waldhausl and P. Fasching, "Fetal growth and impaired glucose tolerance in men and women "Diabetologia 36 (1993): 973-974. 8 Ibid. See, also, J. Kaprio, J. Tuomilehto, M. Koskenvuo, K. Romanov, A. Reunanen et al., "Can twin studies assess the genetic component in type 2 (non-insulin-dependent) diabetes mellitus? Response from the authors," Diabetologia 36 (1993): 472. 9 Dowse et al. describe the thrifty phenotype hypothesis as "provocative". Dowse, Zimmet, and Alberti, "Infant nutrition," 267. See Gluckman and Hanson, The Fetal Matrix, 96. 10 C. N. Hales, M. Desai, and S. E. Ozanne, "The thrifty phenotype hypothesis: How does it look after 5 years?" Diabetic Medicine 14 (1997): 189-195, at 193. 11 K. Siddle, J. P. Luzio, and S. E. Ozanne, "Nick Hales: An appreciation of his life and work," Diabetologia 49 (2006): 1131-1133. 12 R. S. Yalow and S. A. Berson, "Immunoassay of endogenous plasma insulin in man," Journal of Clinical Investigation 39 (1960): 1157-1175. 13 Nicholas Hales and Philip J. Randle, "Immunoassay of insulin with insulin-antibody precipitate," Biochemical Journal 88 (1963): 137-146. Ibid., 137. See, also, Siddle, Luzio, and Ozanne, "Nick Hales", 1131. 15 Daniel Cook and Nicholas Hales, "Intracellular ATP directly blocks K+ channels in pancreatic B-cells," Nature 311 (1984): 271-273. The Barker Theory: New insights into ending chronic diseases [Internet]. 2011; [cited 2011 Mar 25]. Available from: http://www.thebarkertheory.org/. 17 Nicholas Hales and David J. P. Barker, "Type 2 (non-insulin-dependent) diabetes mellitus: The thrifty phenotype hypothesis," Diabetologia 35 (1992): 595-601. 18 Ibid. 19 Lindsay and Bennett, "Type 2 diabetes," 24. 20 Ibid. See, also, B. A. Swinburn, "The thrifty genotype hypothesis: How does it look after 30 years?," Diabetic Medicine 13 (1996): 695-699. 21 This point is emphasized in Lindsay and Bennett, "Type 2 diabetes," 24. 22 Hales and Barker, "Type 2 (non-insulin-dependent) diabetes mellitus," 599. 23 David J. P. Barker and Clive Osmond, "Infant mortality, childhood nutrition, and ischaemic disease in England and Wales," The Lancet 327 (1986): 1077-1081. 24 Ibid. 25 Ibid., 1077. 26 This point was emphasized in 2005 by: Gluckman and Hanson, The Fetal Matrix, 87. 27 Barker and Osmond, "Infant Mortality," 1080. See, also, David Barker, "The origins of the Developmental Origins Theory," Journal of Internal Medicine 261 (2007): 412-417. 28 D. J. P. Barker, C. Osmond, P. D. Winters, B. Margetts, and S. J. Simmonds, "Weight in infancy and death from ischaemic heart disease," The Lancet 334 (1989): 577-580. 29 Ibid. 30 Ibid., 579. 31 Ibid. 32 See Gluckman and Hanson, The Fetal Matrix, 86-87. 120 33 D. J. P, Barker, A. R. Bull, C. Osmond, and S. J. Simmonds, "Fetal and placental size and risk of hypertension in adult life," British Medical Journal 301 (1990): 259-262. 34 Ibid., 261. 35 This point was emphasized in Gluckman and Hanson, The Fetal Matrix, 87. 36 Barker, Bull, Osmond, and Simmonds, "Fetal and placental size," 261. 37 Siddle, Luzio, and Ozanne, "Nick Hales", 1132. 38 C. N. Hales, D. J. P. Barker, P. M. S. Clark, L. J. Cox, C. Fall et al., "Fetal and infant growth and impaired glucose tolerance at age 64," British Medical Journal 303 (1991): 1019-1022, at 1021. 39 Ibid., 1019. 40 Ibid., 1019-1021. 41 Ibid., 1022. 42 Gerald Reaven, "Role of insulin resistance in human disease," Diabetes 37 (1988): 1595-1607. 43 Ibid. 44 D. J. P. Barker, C. N. Hales, C. Fall, C. Osmond, K. Phipps et al., "Type 2 (non- insulin-dependent) diabetes mellitus, hypertension and hyperlipidaemia (syndrome X): Relation to reduced fetal growth," Diabetologia 36 (1993): 62-67, at 62. 45 Ibid., 66. 46 Jarrett, "Fetal and infant growth," 1474. 47 Ibid. 48 Ibid., 1474. 49 D. P. Davies and J. Matthes, "Fetal and infant growth and impaired glucose tolerance," British Medical Journal 303 (1991): 1474. 50 Waldhausl and Fasching, "Fetal growth and impaired glucose tolerance," 973. 51 Ibid. 52 Dowse, Zimmet, and Alberti, "Infant nutrition," 267. 53 Ibid. 54 This point is emphasized, in support of their gene-based 'Fetal Insulin Hypothesis', in T. M. Frayling and A. Hattersley, "The role of genetic susceptibility in the association of low birth weight with type 2 diabetes," British Medical Bulletin 60 (2001): 89-101. See, also, Kaprio et al., "Can twin studies," 472; and D. R. McCance, D. J. Pettitt, R. L. Hanson, L. T. H. Jacobsson, W. C. Knowler et al., "Birth weight and non-insulin dependent diabetes: Thrifty genotype, thrifty phenotype, or surviving small baby genotype?" British Medical Journal 308 (1994): 942-945. Waldhausl and Fasching, "Fetal growth and impaired glucose tolerance," 973. 56 McCance et al., "Birth weight," 942-945. 57 Ibid. 58 Vincent W. V. Jaddoe and Jacqueline C. M. Witteman, "Hypotheses on the fetal origins of adult diseases: Contributions of epidemiological studies," European Journal of Epidemiology 21 (2006): 91-102, at 91. See G. C. Cook, "Fetal and infant growth and impaired glucose tolerance," British Medical Journal 303 (1991): 1474. Cook considered his studies at the MRC Unit in Kampala to have produced results entirely consistent with Hales and Barker's findings, linking low birthweight and NIDDM. 121 60 See, e.g., Barbara Hansen and Noni Bodkin, "Primary prevention of diabetes mellitus by prevention of obesity in monkeys," Diabetes 42 (1993): 1809-1815. Hales, Desai, and Ozanne, "The thrifty phenotype hypothesis," 189. 62 Kaprio et al., "Can twin studies," 472 63 Hales, Desai, and Ozanne, "The thrifty phenotype hypothesis," 189-195. 64 Ibid., 189. This point is emphasized in: Terri H. Beaty, James V. Neel, and Stefan S. Fajans, "Identifying risk factors for diabetes in first degree relatives of non-insulin dependent diabetic patients," American Journal of Epidemiology 115 (1982): 380-397. 65 B. Newman, J. V. Selby, M. King, C. Slemenda, R. Fabsitz et al., "Concordance for type 2 (non-insulin-dependent) diabetes mellitus in male twins," Diabetologia 30 (1987): 763-768. 66 Ascertainment bias in diabetes research results because the disease is likely to be overrepresented in families with a diseased member, and so a disproportionate number of family members will be diagnosed with the disease. See Bryan Langholz, Argyrios Ziogas, Duncan C. Thomas, Cheryl Faucett, Mark Huberman et al., "Ascertainment bias in rate ratio estimation from case-sibling control studies of variable age-at-onset disease," Biometrics 55 (1999): 1129-1136. See, also, W. Ewens and Nereda Shute, "A resolution of the ascertainment sampling problem I. Theory," Theoretical Population Biology 30 (1986): 388-412. Ewens and Nereda stated: "We consider the "ascertainment problem" arising when families are sampled by a nonrandom sampling process." 67 Hales, Desai, and Ozanne, "The thrifty phenotype hypothesis," 190. 68 A. Vaag, P. Populsen, K. O. Kyvik, and H. Beck-Nielsen, "Etiology of NIDDM: genetics versus pre- or post-natal environments? Results from twin studies," Experimental and Clinical Endocrinology & Diabetes 104 (1996): 181-182. 69 Hales, Desai, and Ozanne, "The thrifty phenotype hypothesis." 70 Swinburn, "The thrifty genotype," 695-699. 71 Hales, Desai, and Ozanne, "The thrifty phenotype hypothesis," 191. 72 Ibid., 192-193. 73 Ibid. 74 For example: Terrence E. Forrester, Rainford J. Wilks, Franklyn I. Bennett, Donald Simeon, Clive Osmond et al., "Fetal growth and cardiovascular risk factors in Jamaican schoolchildren," British Medical Journal 312 (1996): 156-160. 75 R. Valdez, M. A. Athens, G. H. Thompson, B. S. Bradshaw, and M. P. Stern, "Birthweight and adult health outcomes in a biethnic population in the USA," Diabetologia 37 (1994): 624-631. 76 Ibid., 630. 77 C. N. Hales and D. J. P. Barker, "The Thrifty Phenotype Hypothesis," British Medical Bulletin 60 (2001): 5-20, at 5. 78 Ibid., 5-20. 79 Ibid., 9. 80 Ibid., 16. 81 Ibid. 82 Ibid., 15-18. 83 Ibid., 18. 84 Ibid., 17-18. 122 85 Siddle, Luzio, and Ozanne, "Nick Hales", 1132. 86 The Barker Theory: New insights into ending chronic diseases [Internet]. 87 The "one gene-one phenotype illusion" is discussed in: Mary Jane West-Eberhard, Developmental Plasticity and Evolution (New York: Oxford University Press, 2003), 20. 88 Hales, Desai, and Ozanne, "The thrifty phenotype hypothesis,"193. See, also, Lindsay and Bennett, 'Type 2 Diabetes," 22; and Frayling and Hattersley, "The role of genetic susceptibility," 89-101. 89 Stephen S. Hall, "Small and Thin: The controversy over the fetal origins of adult health" [Internet]. Nov 19 2007; [cited 2011 Apr 13]. Available from: http://www.thebarkertheory.org/press_l 11907_newyorker.php 90 Ibid. 91 Matthew W. Gillman and Janet W. Rich-Edwards, "The fetal origins of adult disease: from sceptic to convert," Paediatric and Perinatal Epidemiology 14 (2000): 192-193. 92 Ibid., 192. 93 Ibid., 193. See, also Frayling and Hattersley, "The role of genetic susceptibility." Frayling and Hattersley discuss an alternative explanation for the observed findings that link fetal growth and adult chronic disease. Their hypothesis, the "Fetal Insulin Hypothesis", claims that the adult phenotype of diseases is a reflection of the person's genotype, their intrauterine environment, and their post-natal environment. Notes to Chapter 3 1 Eva Jablonka and Marion J. Lamb, Epigenetic Inheritance and Evolution: The Lamarckian Dimension (New York: Oxford University Press, 1995), 288. 2 Nicholas Hales stated in 2000: "Despite this problem with how the thrifty genes might actually operate and a lack of insight as to which they might be this genetic theory of the aetiology of type 2 diabetes is probably the most generally accepted even at the present time." See: Nicholas Hales, "Early programming of glucose metabolism, insulin action and longevity," in Short and Long-term Effects of Breast Feeding on Child Health, ed. B. Koletzko, K. Fleischer Michaelsen, and O. Hernell (New York: Kluwer Academic/Plenum Publishers, 2000), 57-64, at 58. 3 Jared Diamond, "The double puzzle of diabetes," Nature 423 (2003): 599-602, 600. 4 Georgia Salanti, Lorraine Southam, David Altshuler, Kristin Ardlie, Ines Barroso et al., "Underlying genetic models of inheritance in established type 2 diabetes associations," American Journal of Epidemiology 170 (2009): 537-545. 5 Gene-wide association studies involve the process of assaying several hundred thousand to more than a million single nucleotide polymorphisms (SNPs) in individuals in order to investigate the genetic makeup of complex diseases. See: Teri A. Manolio, Francis S. Collins, Nancy J. Cox, David B. Goldstein, Lucia A. Hindorff et al., "Finding the missing heritability of complex diseases," Nature 461 (2009): 747-753. See, also, Benjamin F. Voight, Laura J. Scott, Valgerdur Steinthorsdottir, Andrew P. Morris, Christian Dina et al., "Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis," Nature Genetics 42 (2010): 579-589. 6 2.5%: Salanti et al., "Underlying Genetic Models of Inheritance." 123 6%: Manolio et a!., "Finding the missing heritability." 10%: Voight, et al., 'Twelve type 2 diabetes susceptibility loci." 7 PPARy: Tuomas O. Kilpela Inen, Timo A. Lakka, David E. Laaksonen, Jaana Lindstro, Johan G. Eriksson et al., "SNPs in PPARG associate with type 2 diabetes and interact with physical activity," Medicine & Science in Sports & Exercise 40 (2008): 25-33. See, also, Peter Gluckman, Alan Beedle, and Mark Hanson, Principles of Evolutionary Medicine (New York: Oxford University Press, 2009), 193. CAPN10: Stephanie M. Fullerton, Angelika Bartoszewicz, Gustavo Ybazeta, Yukio Horikawa, Graeme I. Bell et al., "Geographic and haplotype structure of candidate type 2 diabetes- Susceptibility variants at the Calpain-10 locus," The American Journal of Human Genetics 70 (2002): 1096-1106; Mark D. Turner, Paul G. Cassell, and Graham A. Hitman, "Calpain-10: From genome search to function," Diabetes/Metabolism Research and Reviews 21 (2005): 505-514. FTO: Voight et al., "Twelve type 2 diabetes susceptibility loci." See, also, April J. Hoa, Jason L. Stein, Xue Hua, Suh Lee, Derrek P. Hibar et al., "A commonly carried allele of the obesity-related FTO gene is associated with reduced brain volume in the healthy elderly," Proceedings of the National Academy of Sciences 107 (2010): 8404-8409. IGF2BP2: Hongxia Jia, Lili Yu, Zhiwei Jiang, and Qiuhe Ji, "Association Between IGF2BP2 rs4402960 polymorphism and risk of type 2 diabetes mellitus: A Meta analysis," Archives of Medical Research 42 (2011): 361-367. KCNQ1: Kazuki Yasuda, Kazuaki Miyake, Yukio Horikawa, Kazuo Hara, Haruhiko Osawa et al., "Variants in KCNQ1 are associated with susceptibility to type 2 diabetes mellitus," Nature Genetics 40 (2008): 1092- 1097; Hiroyuki Unoki, Atsushi Takahashi, Takahisa Kawaguchi, Kazuo Hara, Momoko Horikoshi et al., "SNPs in KCNQ1 are associated with susceptibility to type 2 diabetes in East Asian and European populations," Nature Genetics 40 (2008): 1098- 1102; Jonathan T. Tan, Siti Nurbaya, Daphne Gardner, Sandra Ye, E. Shyong Tai et al., "Genetic variation in KCNQ1 associates with fasting glucose and cell Function: A Study of 3,734 subjects comprising three ethnicities living in Singapore," Diabetes 58 (2009): 1445- 1449. 8 Conrad H. Waddington, "The epigenotype," Endeavour 1 (1942): 18-20. 9 Ibid. 10 C. H. Waddington, Principles of Development and Differentiation (New York: The Macmillan Company, 1966), 48-49. See also, D. Haig, "The (Dual) Origin of Epigenetics," Cold Spring Harbor Symposia on Quantitative Biology LXIX (2004): 1-4. 11 Waddington, Principles of Development and Differentiation, 49. 12 Haig, "The (Dual) Origin of Epigenetics." 13 D. L. Nanney, "Epigenetic control systems," Proceedings of the National Academy of Sciences 44 (1958): 712-717. 14 Although epigenetics did not achieve widespread use until the 1990s, there were some individuals who accepted epigenetic mechanisms long before. This is reviewed in Haig, "The (Dual) Origin of Epigenetics" and Eva Jablonka and Marion J. Lamb, "The changing concept of epigenetics," Annals of the New York Academy of Sciences 981 (2002): 82-96, 86 and 89. 124 15 Haig, "The (Dual) Origin of Epigenetics." For a discussion of the limitations of this definition of epigenetics, see: Jablonka and Lamb, "The changing concept of epigenetics." For T. Tollefsbol, a consensus definition for epigenetics now exists: "epigenetics is the collective heritable changes in phenotype due to processes that arise independent of primary DNA sequence." See Trygve Tollefsbol, ed., Handbook of Epigenetics: The New Molecular and Medical Genetics (Boston: Academic Press, 2011), xiii. See, also, Aaron D. Goldberg, C. David Allis, and Emily Bernstein, "Epigenetics: A Landscape Takes Shape," Cell 128 (2007): 635-638. 17 Gertrudis V. an de Vijvir, Linda V. an Speybroeck, and Dani de W. Aele, "Epigenetics: A Challenge for Genetics, Evolution, and Development?" Annals of the New York Academy of Sciences 981 (2002): 1-6. 18 Eva Jablonka and Gal Raz, "Transgenerational epigenetic inheritance: Prevalence, mechanisms, and implications for the study of heredity and evolution," The Quarterly Review of Biology 84 (2009): 131-176. 19 Eva Jablonka, "Some Problems with Genetic Horoscopes," in International Conference "Bioscience and Society: Biodiversity." Ljubljana, Slovenia, 1-2 October 2009, 1-18, at 9. See, also, Jablonka and Raz, "Transgenerational epigenetic inheritance." 20 Ibid. 21 Jablonka and Lamb, Epigenetic Inheritance and Evolution, 274-288. 22Jablonka and Raz, "Transgenerational epigenetic inheritance." See, also, Jablonka and Lamb, "The changing concept of epigenetics." 23 Goldberg, Allis and Bernstein, "Epigenetics," 635. Textbooks include: D. Allis, T. Jenuwein, D. Reinberg, and M. L. Capparros, ed., Epigenetics (New York: Cold Spring Harbor Laboratory Press, 2007); Tollefsbol, ed., Handbook of Epigenetics, 24Jablonka and Lamb, "The changing concept of epigenetics"; Haig, "The (Dual) Origin of Epigenetics." 25 Allis et al., Epigenetics, 17. 26 R. Holliday, "A new theory of carcinogenesis," British Journal of Cancer 40 (1979): 513- 522; see, also, Haig, "The (Dual) Origin of Epigenetics," 3. 27 Holliday, "A new theory of carcinogenesis," 514. 28 Ibid., 513-522. 29 Haig, "The (Dual) Origin of Epigenetics," 3. See, also, Jablonka and Lamb, "The Changing Concept," 87 and 89; and Robin Holliday, "The Inheritance of Epigenetic Defects," Science 238 (1987): 163-170. 30 Goldberg, Allis, and Bernstein, "Epigenetics." 31 Gerd B. Miiller, "Evo-devo: Extending the evolutionary synthesis," Nature Reviews 3 (2007): 943-949. 32 Corey Goodman and Bridget Coughlin, "The evolution of evo-devo biology," Proceedings of the National Academy of Sciences 97 (2000): 4424-4425. For a detailed history of the origins of evo-devo biology, see: Lennart Olsson, Georgy S. Levit, and Uwe HoBfeld, "Evolutionary developmental biology: Its concepts and history with a focus on Russian and German contributions," Naturwissenschaften 97 (2010): 951-969. 33 The Modern Synthesis viewed evolutionary processes as being driven largely by random genetic changes and neglected development. Evo-devo biology sought to 125 reintroduce development into the evolutionary synthesis. For a description of the Modern Synthesis, see Jan Sapp, Genesis: The Evolution of Biology (New York: Oxford University Press, 2003), 143. For a description of evolutionary developmental biology in relation to the Modern Synthesis, see: Miiller, "Evo-devo," 943-949. 34 Miiller, "Evo-devo," 946. 35 Ibid., 944-945. See, also, Manfred D. Laubichler and Jane Maienschein, Form and Function in Developmental Evolution (New York: Cambridge University Press, 2009), 31. See, also, Mary Jane West-Eberhard, Developmental plasticity and Evolution (New York: Oxford University Press, 2003), 18 and 89; as she wrote in 2003, "now is a good time for an evolutionary synthesis that connects knowledge of the genome to the facts of phenotypic plasticity and development" since "development is the missing link between genotype and phenotype." 6 For a description of evolutionary developmental biology and ecological developmental biology, see Scott F. Gilbert and David Epel, ed., Ecological Developmental Biology: Integrating Epigenetics, Medicine, and Evolution (Sunderland, MA: Sinauer Associates, 2009), xii - xv. 37 Peter D. Gluckman, Felicia M. Low, Tatjana Buklijas, Mark A. Hanson, and Alan S. Beedle, "How evolutionary principles improve the understanding of human health and disease," Evolutionary Applications 4 (2011): 249-263. 38 Peter Gluckman and Mark Hanson, Mismatch: Why our world no longer fits our bodies (New York: Oxford University Press, 2006), 168; Peter D. Gluckman, Mark A. Hanson, and Catherine Pinal, "The developmental origins of adult disease," Maternal and Child Nutrition 1 (2005): 130-141; Peter D. Gluckman, Mark A. Hanson, and Alan S. Beedle, "Non-genomic transgenerational inheritance of disease risk," BioEssays 29.2 (2007): 145-154. 39 S. Boyd Eaton, Beverly I. Strassman, Randolph M. Nesse, James V. Neel, Paul W. Ewald et al., "Evolutionary health promotion," Preventative Medicine 34 (2002): 109- 118, at 110. 40 Gluckman, Beedle, and Hanson, Principles of Evolutionary Medicine, 5. 41 This question was asked in 2008 by Randolph Nesse (evolutionary psychologist at the University of Michigan), and Stephen Stearns (Professor of Ecology and Evolutionary biology at Yale University): Randolph Nesse and Stephen Stearns, "The great opportunity: Evolutionary applications to medicine and public health," Evolutionary Applications 1 (2008): 28-48. 4 George C. Williams and Randolph M. Nesse, "The dawn of Darwinian medicine," The Quarterly Review of Biology 66 (1991): 1-22. For a detailed account of the history of Darwinian medicine, see: Fabio Zampieri, "Medicine, evolution, and natural selection: An historical overview," The Quarterly Review of Biology 84 (2009): 333-355. See, also, Randolph M. Nesse, Carl T. Bergstrom, Peter T. Ellison, Jeffrey S. Flier, Peter Gluckman et al., "Making evolutionary biology a basic science for medicine," Proceedings of the National Academy of Sciences 107 (2010): 1800-1807. 43 For a discussion of the evolutionary explanations for disease prior to the 1990s, see Zampieri, "Medicine, evolution, and natural selection." 44 This is a reworking of the famous quote by Theodosius Dobzhansky (1900-1975), "Nothing in biology makes sense except in the light of evolution." See, Theodosius 126 Dobzhansky, "Nothing in biology makes sense except in the light of evolution," The American Biology Teacher 35 (1973): 125-129. Many authors, since this time, have substituted the word "biology" with medicine, including Gluckman and Hanson in 2009. 45 Nesse and Stearns, "The great opportunity." 46 Nesse et al., "Making evolutionary biology a basic science." Notes to Chapter 4 1 Peter Gluckman, Mark Hanson, Susan Morton, and Catherine Pinal, "Life-long echoes- A critical analysis of the developmental origins of adult disease model," Biology of the Neonate 87 (2005): 127-139, at 128. 2 Peter Gluckman and Mark Hanson, Mismatch: Why our World No Longer Fits our Bodies (New York: Oxford University Press, 2006), 177. 3 Peter D. Gluckman, Mark A. Hanson, and Alan S. Beedle, "Early life events and their consequences for later disease: A life history and evolutionary perspective," American Journal of Human Biology 19 (2007): 1-19, at 3; P. Gluckman, M. Hanson, and T. Buklijas, "A conceptual framework for the developmental origins of health and disease," Journal of Developmental Origins of Health and Disease 1 (2010): 6-18, at 9. 4 Peter D. Gluckman, Mark A. Hanson, and Hamish G. Spencer, "Predictive adaptive responses and human evolution," Trends in Ecology and Evolution 20 (2005): 527-533, at 531. 5 Ibid., 529. 6 Peter D. Gluckman, Felicia M. Low, Tatjana Buklijas, Mark A. Hanson, and Alan S. Beedle, "How evolutionary principles improve the understanding of human health and disease," Evolutionary Applications 4 (2011): 249-263. 7 Ibid. 8 Gluckman, Hanson, and Buklijas, "A conceptual framework," 8; Gluckman, Hanson, and Beedle, "Early life events," 2. 9 Gluckman, Hanson, and Buklijas, "A conceptual framework," 10. 10 Gluckman and Hanson, Mismatch, ix. 11 The MBChB is the Bachelor of Medicine and Bachelor of Surgery degree awarded in the U.K and New Zealand. 12 The MMedSc is a Master of Medical Science degree awarded in New Zealand. 13 Liggins Institute, University of Auckland, New Zealand [Internet]; [cited 2011 Jun 13]. Available from: http://www.liggins.auckland.ac.nz/uoa/ 14 In 2002, Hanson became the British Heart Foundation Professor of Cardiovascular Science at the University of Southampton. Hanson's research focuses on how developmental conditions before and after birth can influence the risk of disease in later life, including heart disease, obesity, and type 2 diabetes. 15 P. D. Gluckman and M. A. Hanson, "Developmental plasticity and human disease: Research directions," Journal of Internal Medicine 261 (2007): 461-471, at 468; Gluckman, Hanson, and Beedle, "Early life events," at 2 and 8. 16 Gluckman and Hanson, Mismatch, 162-163. 17 D. C. Benyshek and J. T. Watson, "Exploring the thrifty genotype's food shortage assumptions: A cross-cultural comparison of ethnographic accounts of food security 127 among foraging and agricultural societies," American Journal of Physical Anthropology 131 (2006): 120-126. 18 C. S. Larsen, "Post-Pleistocene human evolution: Bioarchaeology of the agricultural transition," in Human diet: Its Origin and Evolution, ed. P. S. Ungar and M. F. Teaford (Westport, CT: Bergin and Garvey, 2002), 19-36. 19 V. Mericq, K. K. Ong, R. A. Bazaes, V. Pena, A. Avila et al., "Longitudinal changes in insulin sensitivity and secretion from birth to age three years in small- and appropriate- for-gestational-age children," Diabetologia 48 (2005): 2609-2614; B. Reusens and C. Remade, "Programming of impaired insulin secretion versus sensitivity: cause or effect?" in Early Nutrition Programming and Health Outcomes in Later Life: Obesity and Beyond, ed. B. Koletzko, T. Decsi, D. Molnar, and A. De la Hunty (Dordrecht, Netherlands: Springer, 2009), 125-131. See, also, Gluckman, Hanson, and Buklijas, "A conceptual framework," 8-9. 20 Ibid. 21 Ibid., 8-10. 22 Gluckman, Hanson, and Beedle, "Early life events," at 2. 23 Ibid. 24 Gluckman and Hanson, Mismatch, 168; Peter D. Gluckman, Mark A. Hanson, and Catherine Pinal, "The developmental origins of adult disease," Maternal and Child Nutrition 1 (2005): 130-141, at 130. 25 Gluckman, Hanson, and Beedle, "Early life events," at 3. 26 Ibid. See, also, Peter Gluckman and Mark Hanson, The Fetal Matrix: Evolution, Development and Disease (Cambridge: Cambridge University Press, 2005), 88. 27 Ibid. 28 Gluckman, Hanson, and Beedle, "Early life events," 2-3. 29 Gluckman et al., "Life-long echoes," 133. 30 Truncal obesity: C. S. Yajnik, H. G. Lubree, S. S. Rege, S. S. Naik, J.A. Deshpande et al., "Adiposity and hyperinsulinemia in Indians are present at birth," Journal of Clinical Endocrinology & Metabolism 87 (2002): 5575-5580. Osteoporosis: C. Cooper, M. K. Javaid, P. Taylor, K. Walker-Bone, E. Dennison et al., "The fetal origins of osteoporotic fracture," Calcified Tissue International 70 (2002): 391-394. Polycystic ovary syndrome: L. Ibanez, C. Vails, N. Poyau, M. V. Marcos, and F. de Zegher, "Polycystic ovary syndrome after precocious pubarche: Ontogeny of the low- birth-weight effect," Clinical Endocrinology 55 (2001): 667-672. Depression: C. Thompson, H. Syddall, I. Rodin, C. Osmond, and D. J. Barker, "Birth weight and the risk of depressive disorder in late life," British Journal of Psychiatry 179 (2001): 450-455. Schizophrenia: K. Wahlbeck, C. Osmond, T. Forsen, D. J. Barker, and J. G. Eriksson, "Associations between childhood living circumstances and schizophrenia: A population- based cohort study," Acta Psychiatrica Scandinavica 104 (2001): 356-360. Breast cancer: S. I. Dos Santos, B. L. de Stavola, R. J. Hardy, D. J. Kuh, V. A. McCormack et al., "Is the association of birth weight with premenopausal breast cancer risk mediated through childhood growth?" British Journal of Cancer 91 (2004): 519-524. See also, Gluckman, Hanson, and Beedle, "Early life events," at 2. 128 31 Gluckman, Hanson, and Buklijas, "A conceptual framework," 10; Gluckman and Hanson, The Fetal Matrix, 101. 32 Peter D. Gluckman, "Evolving a definition of disease," Archives of Disease in Childhood 92 (2007): 1053-1054, at 1054. 33 Gluckman, Hanson, and Buklijas, "A conceptual framework." For a description of proximate and ultimate causes, see: Peter Gluckman, Alan Beedle, and Mark Hanson, Principles of Evolutionary Medicine (New York: Oxford University Press, 2009), 17. 34 Gluckman and Hanson, The Fetal Matrix, 17-18. 35 Gluckman et al., "Life-long echoes," 128,133. 36 Gluckman, Hanson, and Buklijas, "A conceptual framework," 9. 37 Patrick Bateson received his PhD from the University of Cambridge in 1963. His main research interest is in the development of behaviour; specifically, understanding how genetic and environmental influences result in behavioural outcomes. At the University of Cambridge, Bateson was Director of the Sub-Department of Animal Behaviour from 1976-1988; Head of the Department of Zoology from 1994-1996; and Professor of Ethology from 1984-2005. He was also the Biological Secretary and Vice-President of the Royal Society of London from 1998-2003. 38 Patrick Bateson, "Fetal experience and good adult design," International Journal of Epidemiology 30 (2001): 928-934, at 933. 3 Although Gluckman and Hanson arrived at the predictive adaptive response model independently of Bateson, in 2004 Bateson and Gluckman collectively published a paper in Nature titled "Developmental plasticity and human health." See, also, Gluckman, Hanson, and Buklijas, "A conceptual framework," 9. 40 Although epigenetics did not achieve widespread use until the 1990s, there were some individuals who accepted epigenetic mechanisms long before. This is reviewed in D. Haig, "The (Dual) Origin of Epigenetics," Cold Spring Harbor Symposia on Quantitative Biology LXIX (2004): 1-4. 41 Peter D. Gluckman and Mark A. Hanson, "Living with the past: Evolution, development, and patterns of disease," Science 305 (2004): 1733-1736, 1734. 42 Ibid. See, also, L. Brawley, L. Poston, and M. A. Hanson, "Mechanisms underlying the programming of small artery dysfunction: Review of the model using low protein diet in pregnancy in the rat," Archives of Physiology and Biochemistry 111 (2003): 23-35. 3 Brawley, Poston, and Hanson, "Mechanisms Underlying the Programming." 44 J. Petrik, B. Reusens, E. Arany, C. Remacle, C. Coelho et al., "A low protein diet alters the balance of islet cell replication and apoptosis in the fetal and neonatal rat and is associated with a reduced pancreatic expression of insulin-like growth factor-II," Endocrinology 140 (1999): 4861- 4873; Peter D. Gluckman and Mark A. Hanson, "Developmental origins of disease paradigm: A mechanistic and evolutionary perspective," Pediatric Research 56 (2004): 311-317, 314. 5 Petrik et al., "A low protein diet alters the balance." 46 E. M. Wintour, K. M. Moritz, K. Johnson, S. Ricardo, C. S. Samuel et al., "Reduced nephron number in adult sheep, hypertensive as a result of prenatal glucocorticoid treatment," The Journal of Physiology 549 (2003): 929 -935; P. L Greenwood, A. S. Hunt, J. W. Hermanson, and A.W. Bell, "Effects of birth weight and postnatal nutrition on neonatal sheep: I. Body growth and composition, and some aspects of energetic 129 efficiency," Journal of Animal Science 76 (1998): 2354-2367; P. L. Greenwood, A. S. Hunt, J. W. Hermanson, and A. W. Bell, "Effects of birth weight and postnatal nutrition on neonatal sheep: II. Skeletal muscle growth and development," Journal of Animal Science 78 (2000): 50-61; Gluckman and Hanson, "Developmental origins of disease paradigm"; Gluckman and Hanson, "Living with the past," 1734. 47 Gluckman and Hanson, "Developmental origins of disease paradigm," 314. 48 S. E. Ozanne, G. S. Olsen, L. L. Hansen, K. J. Tingey, B. T. Nave et al., "Early growth restriction leads to down regulation of protein kinase C zeta and insulin resistance in skeletal muscle," Journal of Endocrinology 177 (2003): 235-241; Gluckman and Hanson, "Living with the past," 1734. 49 Endothelial tissue is involved in the control of blood flow, clotting, inflammation, and growth. See: D. O'Regan, C. J. Kenyon, J. R. Seckl, and M. C. Holmes, "Glucocorticoid exposure in late gestation in the rat permanently programs gender-specific differences in adult cardiovascular and metabolic physiology," American Journal of Physiology - Endocrinology and Metabolism 287 (2004): E863-E870; Robert D. Roghair, Fred S. Lamb, Francis J. Miller, Jr., Thomas D. Scholz, and Jeffrey L. Segar, "Early gestation dexamethasone programs enhanced postnatal ovine coronary artery vascular reactivity," American Journal of Physiology - Regulatory, Integrative and Comparative Physiology 288 (2004): R46-R53; Gluckman et al., "Life-long echoes," 132. 50 Gluckman et al., "Life-long echoes," 132. 51 R. Holliday, "A New Theory of Carcinogenesis," British Journal of Cancer 40 (1979): 513- 522; see Haig, "The (Dual) Origin of Epigenetics," 3. 52 Aaron D. Goldberg, C. David Allis, and Emily Bernstein, "Epigenetics: A landscape takes shape," Cell 128 (2007): 635-638. 53 Holliday, "The inheritance of epigenetic defects." 54 Gluckman, Beedle, and Hanson, Principles of Evolutionary Medicine, 88-89. 55 Ibid. 56 Ibid. 57 Ibid. See, also, Allis et al., Epigenetics, 17; and Scott F. Gilbert and David Epel, ed., Ecological Developmental Biology: Integrating Epigenetics, Medicine, and Evolution (Sunderland, MA: Sinauer Associates, 2009), 253-254. 58 Keith M. Godfrey, Karen A. Lillycrop, Graham C. Burdge, Peter D. Gluckman, and Mark A. Hanson, "Epigenetic mechanisms and the mismatch concept of the Developmental Origins of Health and Disease," Pediatric Research 61 (2007): 5R-10R, at 7R. 59 Peter D. Gluckman and Mark A. Hanson, "The developmental origins of the metabolic syndrome," Trends in Endocrinology and Metabolism 15 (2004): 183-187. Godfrey et al., "Epigenetic mechanisms," 7R. 61 Gluckman, Beedle, and Hanson, Principles of Evolutionary Medicine, 88. 62 Ibid., 88-89. 63 Ibid., 88-89 and 153. See, also, Peter D. Gluckman, Mark A. Hanson, and Alan S. Beedle, "Non-genomic transgenerational inheritance of disease risk," BioEssays 29.2 (2007): 145-154. " Ibid., 149. 65 Gluckman and Hanson, "Developmental origins of disease paradigm," 313. 130 66 K. A. Lillycrop, E. S. Phillips, A. A. Jackson, M. A. Hanson, and G. C. Burdge, "Dietary protein restriction of pregnant rats induces and folic acid supplementation prevents epigenetic modification of hepatic gene expression in the offspring," Journal of Nutrition 135 (2005): 1382-1386; G. C. Burdge, E. S. Phillips, R. L. Dunn, A. A. Jackson, and K. A. Lillycrop, "Effect of reduced maternal protein consumption during pregnancy in the rat on plasma lipid concentrations and expression of peroxisomal proliferator-activated receptors in the liver and adipose tissue of the offspring," Nutrition Research 24 (2004): 639-646; Godfrey et al., "Epigenetic mechanisms." 67 Godfrey et al., "Epigenetic mechanisms." 68 Gilbert and Epel, Ecological Developmental Biology, 254. 69 G. C. Burdge, J. Slater-Jefferies, C. Torrens, E. S. Phillips, M. A. Hanson et al., "Dietary protein restriction of pregnant rats in the F0 generation induces altered methylation of hepatic gene promoters in the adult male offspring in the F1 and F2 generations," British Journal of Nutrition 97 (2007): 435-439. C. Torrens, L. Brawley, C. S. Dance, S. Itoh, L. Poston et al., "First evidence for transgenerational vascular programming in the rat protein restriction model, Journal of Physiology 543 (2002): 41P—42P; E. Zambrano, P. M. Martinez-Samayoa, C. J. Bautista, M. Deas, L. Guillen et al., "Sex differences in transgenerational alterations of growth and metabolism in progeny (F2) of female offspring (Fl) of rats fed a low protein diet during pregnancy and lactation," Journal of Physiology 566 (2005): 225 - 236. 1 D. C. Benyshek, C. S. Johnston, and J. F. Martin, "Glucose metabolism is altered in the adequately-nourished grand-offspring (F3 generation) of rats malnourished during gestation and perinatal life," Diabetologia 49 (2006): 1117-1119. Gluckman, Hanson, and Beedle, "Non-genomic transgenerational inheritance," 147. 73 G. L Wolff, R. L. Kodell, S. R. Moore, and C. A. Cooney, "Maternal epigenetics and methyl supplements affect agouti gene expression in Avy/a mice," The Journal of the Federation of American Societies for Experimental Biology 12 (1998): 949-957; Gluckman and Hanson, "Developmental origins of disease paradigm," 313; Gluckman and Hanson, "Living with the past," 1734. 74 L. Brawley, C. Torrens, F. W. Anthony, T. Wheeler, A. A. Jackson et al., "Dietary folate supplementation prevents the attenuated relaxation to vascular endothelial growth factor (VEGF) in the uterine artery of protein-restricted pregnant rats," Pediatric Research 53 (2003): 497-504; Gluckman and Hanson, "Developmental origins of disease paradigm." Ji-Hoon E. Joo, Roberta H. Andronikos, and Richard Saffery, "Metabolic regulation of DNA methylation in mammals," in Handbook of Epigenetics; The New Molecular and Medical Genetics, ed. Trygve Tollefsbol (Boston: Academic Press, 2011), 281-293, at 286; Gluckman and Hanson, "Living with the past," 1734. 76 J. A. McCormick, V. Lyons, M. D. Jacobson, J. Noble, J. Diorio et al., "5'-heterogenity of glucocorticoid receptor messenger RNA is tissue specific: Differential regulation of variant transcripts by early-life events," Molecular Endocrinology 14 (2000): 506-517; I. C. G. Weaver, N. Cervoni, F. A. Champagne, A. C. D'Alessio, S. Sharma et al., "Epigenetic programming by maternal behavior," Nature Neuroscience 7 (2004): 847- 854;Gluckman and Hanson, "Developmental origins of disease paradigm," 313. 77 Ibid. 131 78 Gluckman, Hanson, and Beedle, "Non-genomic transgenerational inheritance." 79 Gluckman and Hanson, "Living with the past," 1735. 80 G. Kaati, L. O. Bygren, and S. Edvinsson, "Cardiovascular and diabetes mortality determined by nutrition during parents' and grandparents' slow growth period," European Journal of Human Genetics 10 (2002): 682-688. 81 L. H. Lumey and A. D. Stein, "Offspring birth weights after maternal intrauterine undernutrition: A comparison within sibships," American Journal of Epidemiology 146 (1997): 810-819; R. C. Painter, T. J. Roseboom, and O. P. Bleker, "Prenatal exposure to the Dutch famine and disease in later life: An overview," Reproductive Toxicology 20 (2005): 345-352; Godfrey et al., "Epigenetic mechanisms." 82 M. M. Brouwers, W. F. J. Feitz, L. A. J. Roelofs, L. A. L. M. Kiemeney, R. P. E. de Gier et al., "Hypospadias: A transgenerational effect of diethylstilbestrol?" Human Reproduction 21 (2006): 666-669; Gluckman, Hanson, and Beedle, "Non-genomic transgenerational inheritance." 83 Ibid. 84 Gluckman, Hanson, and Beedle, "Non-genomic transgenerational inheritance." 85 Ibid. 86 Ibid. 87 Ibid. Godfrey et al., "Epigenetic mechanisms," 8R. 88 Gluckman, Hanson, and Beedle, "Non-genomic transgenerational inheritance." 89 Wolff et al., "Maternal epigenetics and methyl supplements." 90 Petrik et al., "A low protein diet alters the balance of islet cell replication." 91 Tho D. Pham, Nicole K. MacLennan, Christina T. Chiu, Gisella S. Laksana, Jennifer L. Hsu et al., "Uteroplacental insufficiency increases apoptosis and alters p53 gene methylation in the full-term IUGR rat kidney," American Journal Physiology- Regulatory, Integrative and Comparative Physiology 285 (2003): R962-R970. 92 Weaver et al., "Epigenetic programming by maternal behavior." 93 Lillycrop et al., "Dietary protein restriction of pregnant rats." 94 Karen A. Lillycrop, Emma S. Phillips, Christopher Torrens, Mark A. Hanson, Alan A. Jackson et al., "Feeding pregnant rats a protein-restricted diet persistently alters the methylation of specific cytosines in the hepatic PPARa promoter of the offspring," British Journal of Nutrition 100 (2008): 278-282. 95 Burdge et al., "Dietary protein restriction of pregnant rats." 96 Zambrano et al., "Sex differences in transgenerational alterations of growth." 97 D. C. Benyshek and J. T. Watson, "Exploring the thrifty genotype's food shortage assumptions: A cross-cultural comparison of ethnographic accounts of food security among foraging and agricultural societies," American Journal of Physical Anthropology 131 (2006): 120-126. 98 Jun H. Park, Doris A. Staffers, Robert D. Nicholls, and Rebecca A. Simmons, "Development of type 2 diabetes following intrauterine growth retardation in rats is associated with progressive epigenetic silencing of Pdxl," The Journal of Clinical Investigation 118 (2008): 2316-2324. 99 Kaati, Bygren, and Edvinsson, "Cardiovascular and diabetes mortality." 100 Brouwers et al., "Hypospadias." 101 Gluckman, Hanson, and Buklijas, "A conceptual framework," 9. 132 102 Peter D. Gluckman and Mark A. Hanson, "The conceptual basis for the developmental origins of health and disease," in Developmental Origins of Health and Disease, ed. Peter Gluckman and Mark Hanson (New York: Cambridge University Press, 2006), 34-35. 103 Gluckman, Hanson, and Spencer, "Predictive adaptive responses and human evolution," 528. 104 Gluckman et al., "Life-long echoes," 132. 105 Gluckman, Hanson, and Beedle, "Early life events," at 4. 106 Gluckman and Hanson, "The conceptual basis," 36. 107 Gluckman, Hanson, and Beedle, "Early life events," at 10. 108 Gluckman and Hanson, Mismatch, 46. 109 Gluckman, Hanson, and Pinal, "The developmental origins," 137. 110 Gluckman and Hanson, "The conceptual basis," 41-45. 111 Gilbert and Epel, Ecological Developmental Biology, 260. 112 Gluckman and Hanson, "The developmental origins of the metabolic syndrome," 183. 113 Gluckman, Hanson, and Spencer, "Predictive adaptive responses and human evolution," 530. 114 Ibid., 530-531. 115 Godfrey et al., "Epigenetic mechanisms," 8R. 116 Gluckman, Hanson, and Beedle, "Early life events," at 3; Gluckman and Hanson, The Fetal Matrix, 88; Gluckman and Hanson, "The developmental origins," 185. 117 P.D. Gluckman and M.A. Hanson, "Developmental and epigenetic pathways to obesity: an evolutionary-developmental perspective," International Journal of Obesity 32 (2008): S62-S71. See, also: Gluckman, Hanson, and Buklijas, "A conceptual framework." 118 S. E. Sultan and H. G. Spencer, "Metapopulation structure favors plasticity over local adaptation," The American Naturalist 160 (2002): 271-283; Gluckman, Hanson, and Buklijas, "A conceptual framework," 10. 119 P. Gluckman and M. Hanson, "Adult disease: echoes of the past," European Journal of Endocrinology 155 (2006): S47-S50, S47. 1 0 Gluckman and Hanson, Mismatch, 170. 121 Gluckman, Hanson, and Spencer, "Predictive adaptive responses and human evolution," 530. 122 Gluckman, Hanson, and Pinal, "The developmental origins," 135; Gluckman and Hanson, "Adult disease: echoes of the past," S48. 123 Gluckman, Hanson, and Buklijas, "A conceptual framework," 11. 124 Gluckman, Hanson, and Beedle, "Early life events," 15. 125 Gluckman, Hanson, and Spencer, "Predictive adaptive responses and human evolution," 530-531. 126 Gluckman and Hanson, "Developmental origins of disease paradigm," 315. Gluckman, "Evolving a definition of disease," 1054. 128 Ibid. 129 This question was asked in 2008 by Randolph Nesse, evolutionary psychologist at the University of Michigan, and Stephen Stearns, Professor of Ecology and Evolutionary biology at Yale University: Randolph Nesse and Stephen Stearns, "The great 133 opportunity: Evolutionary applications to medicine and public health," Evolutionary Applications 1 (2008): 28-48. Gluckman and Hanson, Mismatch, 201. 131 Gluckman and Hanson, "Adult disease: echoes of the past," S47. 132 Barry M. Popkin, "What can public health nutritionists do to curb the epidemic of nutrition-related noncommunicable disease!" Nutrition Reviews 67 (2001): S79-S82. See, also, M. Hayes, M. Chustek, S. Heshka, Z. Wang, A. Pietrobelli et al., "Low physical activity levels of modern Homo sapiens among free-ranging mammals," International Journal of Obesity 29 (2005): 151-156. 133 Popkin, "What can public health nutritionists do"; Gluckman, Hanson, and Beedle, "Early life events," 3; and Gluckman and Hanson, The Fetal Matrix, 183-191. 134 Ibid. 135 Gluckman, Hanson, and Pinal, "The developmental origins," 138. 136 Gluckman and Hanson, "Adult disease: echoes of the past." 137 Gluckman, Hanson, and Pinal, "The developmental origins," 137. 138 Gluckman and Hanson, The Fetal Matrix, 192-194. 139 Ibid. 140 Popkin, "What can public health nutritionists do?" 141 Ibid. See, also, Fengying Zhai, Huijun Wang, Shufa Du, Yuna He, Zhihong Wang et al., "Prospective study on nutrition transition in China," Nutrition Reviews 67 (2009): S56-S61. 142 Ibid. 143 Gluckman and Hanson, "The developmental origins of the metabolic syndrome." 144 Gluckman, Hanson, and Beedle, "Early life events." 145 Gluckman and Hanson, "The developmental origins of the metabolic syndrome," 185. 146 Gluckman, Hanson, and Buklijas, "A conceptual framework." 147 Gluckman and Hanson, "Developmental origins of disease paradigm," 316. 148 Gluckman and Hanson, "Living with the past." 149 Peter D. Gluckman, Mark A. Hanson, Patrick Bateson, Alan S. Beedle, Catherine M. Law et al., "Towards a new developmental synthesis: Adaptive developmental plasticity and human disease," Lancet 373 (2009): 1654-1657; Gluckman, Hanson, and Buklijas, "A conceptual framework," 14. 150 Gluckman, Hanson, and Beedle, "Early life events." Notes to Chapter 5 1 Jonathan C. K. Wells, "Flaws in the theory of predictive adaptive responses," Trends in Endocrinology and Metabolism 18 (2007): 331-337, at 336. 2 Gluckman et al. commented in 2011: The evo-devo domains... provide another important conceptual framework in which to tackle questions concerning health and disease. An especially exciting new set of tools comes from understanding that environmental influences in early life can adaptively change the fetal trajectory to affect traits in later life through the processes of developmental plasticity and molecular epigenetics. 134 Peter D. Gluckman, Felicia M. Low, Tatjana Buklijas, Mark A. Hanson, and Alan S. Beedle, "How evolutionary principles improve the understanding of human health and disease," Evolutionary Applications 4 (2011): 249-263, at 250. 3 Gerd B. Miiller, "Evo-devo: Extending the evolutionary synthesis," Nature Reviews 3 (2007): 943-949. 4 Ibid., 946. Lennart Olsson, Georgy S. Levit, and Uwe HoBfeld, "Evolutionary developmental biology: Its concepts and history with a focus on Russian and German contributions," Naturwissenschaften 97 (2010): 951-969, at 966. 5 Jay T. Stock and Claudia R. Valeggia, "Diet and Nutrition Workshop," in "Evolution of Diseases of Modern Environments" World Health Summit. Berlin, 14-18 October 2009, 1-38, at 20; Bob Weinhold, "Epigenetics: The science of change," Environmental Health Perspectives 114 (2006): A160-A167. 6 See, e.g., Wenda Trevathan, "Book Reviews: Principles of Evolutionary Medicine," American Journal of Physical Anthropology 143 (2010): 650-651. 7 Peter T. Ellison and Grazyna Jasienska, "Constraint, pathology, and adaptation: How can we tell them apart?" American Journal of Human Biology 19 (2007): 622-630, at 626; Imran Khan, Vasia Dekou, Lucilla Poston, Paul Taylor, and Mark Hanson, "Response to Letter Regarding Article by Khan et al, 'Predictive adaptive responses to maternal high-fat diet prevent endothelial dysfunction but not hypertension in adult rat offspring'- Response," Circulation 111 (2005): El66. 8 Grazyna Jasienska, Inger Thune, and Peter T. Ellison, "Fatness at birth predicts adult susceptibility to ovarian suppression: An empirical test of the Predictive Adaptive Response hypothesis," Proceedings of the National Academy of Sciences 103 (2006): 12759-12762; Peter Gluckman and Mark Hanson, "The plastic human," Infant and Child Development 19 (2010): 21-26. 9 In 1965, A. D. Bradshaw wrote of the ability of plants to be modified by the environment, coining "phenotypic plasticity". Then, in 1969, Lasker discussed "ontogenic plasticity" as one means of human biological adaptability to what he believed to be a greatly changing world. See A. D. Bradshaw, "Evolutionary significance of phenotypic plasticity in plants," in Advances in Genetics 13, ed. E. W. Caspari (New York: Academic Press, 1965); and Gabriel W. Lasker, "Human biological adaptability," Science 166 (1969): 1480-1486. See, also, Sonia E. Sultan, "Development in context: The timely emergence of eco-devo," Trends in Ecology and Evolution 22 (2007): 575- 582, at 575. 10 Sultan, "Development in context," 575. 11 Christopher W. Kuzawa and Elizabeth A. Quinn, "Developmental origins of adult function and health: Evolutionary Hypotheses," Annual Review of Anthropology 38 (2009): 131-147. 12 Ellison and Jasienska, "Constraint, pathology, and adaptation." See, also, Wells, "Flaws in the theory of predictive adaptive responses." 13 Ellison and Jasienska, "Constraint, pathology, and adaptation"; Jonathon C. K. Wells, "Is early development in humans a predictive adaptive response anticipating the adult environment?" Trends in Ecology and Evolution 21 (2006): 424-425. 14 Ibid. 135 15 Ian J. Rickard and Virpi Lummaa, "The predictive adaptive response and metabolic syndrome: Challenges for the hypothesis," Trends in Endocrinology and Metabolism 18 (2007): 94-99, at 95. 16 Kuzawa and Quinn, "Developmental origins of adult function." 17 Ibid. 18 Rickard and Lummaa, "The predictive adaptive response." 19 Ellison and Jasienska, "Constraint, pathology, and adaptation." 20 Ibid. 21 Rickard and Lummaa, "The predictive adaptive response." 22 Peter Gluckman and Mark Hanson, The Fetal Matrix: Evolution, Development and Disease (Cambridge: Cambridge University Press, 2005), at 69. 23 Ellison and Jasienska, "Constraint, pathology, and adaptation." 24 Ibid., 626. See, also, Jasienska, Thune, and Ellison, "Fatness at birth predicts adult susceptibility,"12759. In Popperian logic, if a hypothesis is to be considered "scientific", a hypothesis must be falsifiable: there must exist a logically possible "observation statement" that is inconsistent with the hypothesis; see A. F. Chalmers, What is this thing called Science (Queensland: University of Queensland Press, 1976): 36-37. 25 Ellison and Jasienska, "Constraint, pathology, and adaptation," 626. 26 Ibid. 27 Ibid. See, also, Jasienska, Thune, and Ellison, "Fatness at birth predicts adult susceptibility." 28 Jasienska, Thune, and Ellison, "Fatness at birth predicts adult susceptibility." 29 Ibid, at 12761. 30 Rickard and Lummaa, "The predictive adaptive response," 95. 31 Kathryn Clancy and Benjamin Campbell, "Early Development and Reproductive Health in Later Life," in "Evolution of Diseases of Modern Environments" World Health Summit. Berlin, 14-18 October 2009,1-38, at 23; Godefroy Devevey, Pierre Bize, Sara Fournier, Emilie Person, and Philippe Christe, "Predictive adaptive response in a host- parasite system," Functional Ecology 24 (2010): 178-185. Jane K. Cleal, Kirsten R. Poore, Julian P. Boullin, Omar Khan, Ryan Chau et al., "Mismatched pre- and postnatal nutrition leads to cardiovascular dysfunction and altered renal function in adulthood," Proceedings of the National Academy of Sciences 104 (2007): 9529-9533. 33 Ibid. 34 Kjersti M. Aagaard-Tillery, Kevin Grove, Jacalyn Bishop, Xingrao Ke, Qi Fu et al., "Developmental origins of disease and determinants of chromatin structure: Maternal diet modifies the primate fetal epigenome," Journal of Molecular Endocrinology 41(2008): 91-102. 35 Beckwith-Wiedemann Syndrome is a congenital disorder that involves overgrowth and hyperinsulinaemia. Prader-Willi syndrome involves obesity and mental retardation. Angelman syndrome is characterized by developmental delay, seizures, and a happy disposition. Michael R. DeBaun, Emily L. Niemitz, and Andrew P. Feinberg, "Association of in vitro fertilization with Beckwith-Wiedemann Syndrome and epigenetic alterations of LIT1 and HI 9," American Journal of Human Genetics 72 (2003): 156-160; Eleni Kopsida, Mikael A. Mikaelsson, and William Davies, "The role 136 of imprinted genes in mediating susceptibility to neuropsychiatric disorders," Hormones and Behavior 59 (2011): 375-382. 36 Jonathan Wells is a Reader in Paediatric Nutrition at the University College London Institute of Child Health. Wells completed his Ph.D. at the University of Cambridge and he subsequently spent seven years at the MRC's Dunn Nutrition Unit in Cambridge. Using evolutionary and anthropological approaches, his research is focused on paediatric energetics and the biological function of human adiposity. In 2010, Wells published a book addressing the evolutionary role of body fat, titled The Evolutionary Biology of Human Body Fatness. 37 Wells, "Flaws in the theory of predictive adaptive responses." 38 Ibid. See, also, Peter D. Gluckman, Mark A. Hanson, Alan S. Beedle, and Hamish G. Spencer, "Predictive adaptive responses in perspective," Trends in Endocrinology and Metabolism 19(2008): 109-110. 39 Jonathan C. K. Wells, "The programming effects of early growth," Early Human Development 83 (2007): 743-748. 40 Keith M. Godfrey, Peter D. Gluckman, and Mark A. Hanson, "Developmental origins of metabolic disease: Life course and intergenerational perspectives," Trends in Endocrinology and Metabolism 21 (2010): 199-205. 41 Jonathan C. K. Wells, "Maternal capital and the metabolic ghetto: An evolutionary perspective on the transgenerational basis of health inequalities," American Journal of Human Biology 22 (2010): 1-17. 42 Jonathan C. K. Wells, "Environmental quality, developmental plasticity and the thrifty phenotype: A review of evolutionary models," Evolutionary Bioinformatics 3 (2007): 109-120. 43 Wells, "Flaws in the theory of predictive adaptive responses." 44 Ibid, 335. 45 Ibid. 46 In 2010 and 2011, Wells also termed his "maternal fitness model" the "maternal capital hypothesis." Jonathan C. K. Wells, "The thrifty phenotype hypothesis: Thrifty offspring or thrifty mother?" Journal of Theoretical Biology 221 (2003): 143-161. 47 Ze'ev Hochberg, "Evo-devo of child growth II: Human life history and transition between its phases," European Journal of Endocrinology 160 (2009): 135-141. 48 Wells, "The thrifty phenotype hypothesis," 147. 49 Robert L. Trivers, "Parent-offspring conflict," American Zoologist 14 (1974): 249-264; Wells, "The thrifty phenotype hypothesis." 50 Trivers, "Parent-offspring conflict." 51 Wells, "The thrifty phenotype hypothesis," 149. 52 Ibid. 53 Ibid. 54 Ibid, 149-150. 55 Ibid, 157. 56 Ibid, 157. 57 Wells, "Environmental quality, developmental plasticity." 58 Ibid. 59 Ibid, 112-115. 137 60 Ibid. 61 Ibid, 114. 62 See: Jonathan C. K. Wells, "The thrifty phenotype as an adaptive maternal effect," Biological Reviews 82 (2007): 143-172. 63 Jonathan C. K. Wells, "Historical cohort studies and the early origins of disease hypothesis: Making sense of the evidence," Proceedings of the Nutrition Society 68 (2009): 179-188. Wells, "The thrifty phenotype as an adaptive maternal effect." 65 Ibid. 66 Ibid. 67 Ibid, 163. 68 Ibid, 159. 69 Ibid, 159. 70 Wells, "Is early development in humans a predictive adaptive response." 71 Ibid., 424. See, also, Kuzawa and Quinn, "Developmental origins of adult function." 72 Wells, "Is early development in humans a predictive adaptive response." 73 Ibid., 425. 74 Ibid. 75 Ibid. 76 Hamish G. Spencer, Mark A. Hanson, and Peter D. Gluckman, "Response to Wells: Phenotypic responses to early environmental cues can be adaptive in adults," Trends in Ecology and Evolution 21 (2006): 425-426. 77 Ibid. 78 Ibid, at 426. 79 Ibid. 80 Ibid. 81 P. D. Gluckman and M. A. Hanson, "Maternal constraint of fetal growth and its consequences," Seminars in Fetal and Neonatal Medicine 9 (2004): 419-425. 82 Wells, "Flaws in the theory of predictive adaptive responses." 83 Ibid., 332-334. 84 Ibid, 331. 85 Ibid, 333. 86 Ibid, 336. 87 Ibid, 333. 88 In addition to being advantageous for the offspring, Wells argued that the alignment of offspring development with maternal phenotype would also be valuable for the mother.88 In humans, offspring continue to make demands on the maternal energy budget long into childhood. Hence, being able to manipulate the developmental trajectories of her offspring allows the mother to distribute maternal resources between multiple competing offspring over the long-term. Ibid., 331-337. 89 Ibid., 335. See, also, S. E. Moore, I. Halsall, D. Howarth, E. M. E. Poskitt, and A. M. Prentice, "Glucose, insulin and lipid metabolism in rural Gambians exposed to early malnutrition," Diabetic Medicine 18 (2001): 646-653. 90 Wells, "Flaws in the theory of predictive adaptive responses," 336. 91 Ibid. 138 92 Ibid. 93 Gluckman et al., "Predictive adaptive responses in perspective." 94 Ibid, at 110. 95 Ibid. 96 Ibid, at 109. 97 C. Cooper, D. Kuh, P. Egger, M. Wadsworth, and D. Barker, "Childhood growth and age at menarche," British Journal of Obstetrics and Gynaecology 103 (1996): 814-817; C. Cooper, M. K. Javaid, P. Taylor, K. Walker-Bone, E. Dennison et al., "The fetal origins of osteoporotic fracture," Calcified Tissue International 70 (2002): 391-394; S. E. Ozanne and C. N. Hales, "Lifespan, catch-up growth and obesity in male mice," Nature All (2004): 411—412; Gluckman et al., "Predictive adaptive responses in perspective." 99 Ibid. Gluckman and Hanson include a discussion of homeostatic coping and developmental disruptions in many of their early articles, terming these responses "immediately adaptive responses." 100 Moore et al., "Glucose, insulin and lipid metabolism." See, also, Gluckman et al., "Predictive adaptive responses in perspective," 109. 101 Gluckman et al., "Predictive adaptive responses in perspective," 109-110. 102 Bateson also criticized Wells' 2007 paper on the flaws of the predictive adaptive response model, stating that "if flaws lie anywhere in this dispute, they lie in the structure of Wells' argument." He also calls Wells' price of gold model "inappropriate." Gluckman et al., "Predictive adaptive responses in perspective," 109-110; and Patrick Bateson, "Preparing offspring for future conditions is adaptive," Trends in Endocrinology and Metabolism 19 (2008): 111. 103 Gluckman et al., "Predictive adaptive responses in perspective." 104 Ibid. 105 Wells, "Response to Gluckman et al. and Bateson." 106 Wells, "The thrifty phenotype," 68. 107 Peter Gluckman, Alan Beedle, and Mark Hanson, Principles of Evolutionary Medicine (New York: Oxford University Press, 2009), 86. 108 Keith M. Godfrey, Peter D. Gluckman, and Mark A. Hanson, "Developmental origins of metabolic disease: Life course and intergenerational perspectives," Trends in Endocrinology and Metabolism 21 (2010): 199-205; Peter D. Gluckman, Mark A. Hanson, and Felicia M. Low, "The role of developmental plasticity and epigenetics in human health," Birth Defects Research Part C 93 (2011): 12-18, at 13. Notes to Conclusion 1 The epidemiologists Robert Lindsay and Peter Bennett commented in 2001, "One cannot doubt, however, the enormous importance of the thrifty phenotype hypothesis in stimulating research examining the aetiology of this common disease. It serves to remind us that despite the recent triumphs of genetics and molecular biology, an understanding of environmental influences and how genes and the environment interact is likely to be critical to our understanding of many 139 common, chronic human diseases." See: Robert Lindsay and Peter Bennett, 'Type 2 diabetes, the thrifty phenotype- An overview," British Medical Bulletin 60 (2001): 21-32, at 30. 2 Following the 2003 meeting, the International Society for the Developmental Origins of Health and Disease was formed; in 2005, the third Congress meeting was held vmder this name. The change in title from the Fetal Origins of Adult Disease to the Developmental Origins of Health and Disease was proposed to recognize "the broader scope of developmental cues, extending from the oocyte to the infant and beyond, and the concept that the early life environment has widespread consequences for later health." The name change also emphasized disease prevention and the health promotion, instead of focusing solely on disease causation. See: Matthew W. Gillman, David Barker, Dennis Bier, Felino Cagampang, John Challis et al., "Meeting Report on the 3rd International Congress on Developmental Origins of Health and Disease (DOHaD)," Pediatric Research 61 (2007): 625-629, at 625. 3 Furthermore, the term "predictive adaptive response" has also entered into the developmental origins of disease lexicon. This is no more evident than in Z. Hochberg's analysis of what he termed "the theory of evolutionary predictive adaptive strategies": As a consequence of life conditions under changing environment, children may be stunted for short or longer periods, be underweight or overweight, and be at risk for disease. In the endocrine jargon, this has been labeled 'developmental programming.' The evolutionary language for the same is 'predictive adaptive response. See Ze'ev Hochberg, "Evo-devo of child growth II: human life history and transition between its phases," European Journal of Endocrinology 160 (2009): 135-141.