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Govindaraju Evo Edu Outreach (2020) 13:15 https://doi.org/10.1186/s12052-020-00129-5 : Education and Outreach

BOOK REVIEW Open Access A Chronicle on and the March of Darwinian and Mendelian Medicine Diddahally R. Govindaraju*

Abstract Ken Burns, a well-known documentarian has produced a flm titled, “The : An Intimate History” based on Sid- dhartha Mukherjee’s book by the same name. The flm focuses sharply on the history of genetics, the science of inheritance and variation, in particular, the gene, the central player in genetics, its discovery, structure and function as well as its myriad infuence on development, growth, health, disease and evolution of all organisms. Importantly, he has shown how , physicians, patients and their families as well as society at large must cooperate, develop mutual trust and share ethical responsibilities in order to predict, prevent, manage and cure many inherited disorders. Mr. Burns has reinforced these ideas beautifully with illustrations, archived flm footage, location flming and com- mentaries. The flm also hints at the need for taking a unifed Darwinian-Mendelian and Hippocratic approach toward building a healthier society. In short, this is a beautiful and engrossing documentary on the future of Genetic Medicine. Keywords: Ken Burns, , Garrod, Genetic disorders, Huntington disease, Precision medicine, editing, Genetic medicine

Details of the documentary flm euphoria about genetic research, toward predicting, pre- Burns, K. Te Gene: An intimate history presented in venting and potentially curing inherited disorders, being two parts on April 7, and April 14, 2020 on PBS. popularized as precision medicine. His narrative sharply “As to what constitutes ftness to survive, man and focuses on the common thread shared among in Nature do not see eye-to-eye… Te whole aim of medical the human genome, their structure, the vision to map art, whether therapeutic or preventive, has been to coun- and sequence them as well as the opportunities genetic teract the laws of Nature”-Archibald Garrod (1931). research ofers for alleviating human sufering from dis- A two-part documentary flm titled, “Te Gene: An eases of genetic origin. Te focused approach makes the Intimate History” by Ken Burns, a celebrated documen- documentary more engaging relative to the book. Te tarian, was aired on PBS on April 7, and April 14th. Te objectives of this review are to: (a) briefy introduce the flm is an adaptation from a book with the same title by scope of the original book source, (b) discuss the history Siddhartha Mukherjee (2016). Te frst and the second of genetics and its application to human health as fea- part of the documentary deal with respectively: (a) dawn tured in the documentary, and (c) refect on the emerging of the modern age of genetics, and (b) revolution in the trends toward integrating the Darwininan and Mendelian treatment of (genetic) disease. In the documentary “ava- principles with other advances in modern medicine, and tar” of Mukherjee’s book, Mr. Burns traces the anteced- the plausible impact of such an alliance on future health ent roots of genetics and articulates the contemporary care. In his book, Mukherjee frst refects on the inherit-

*Correspondence: [email protected] ance and distribution of mental illness among his family Institute for Aging Research, Albert Einstein College of Medicine, 1300 members as a prelude to describing the discovery of the Morris Park Avenue, Bronx, NY 10461, USA laws of inheritance and variation among a set of crosses

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of garden pea varieties and their progenies by Gregor scientists with children and their parents, and patients Mendel in 1865 within the confnes of a “Walled Gar- and their families. Tese scenarios seamlessly intercalate den” in Brno, Czechoslovakia. In the same period, Men- with each other and provide a rich tapestry of the sci- del’s contemporaries, Darwin and Wallace successfully ence of genetics (and its evolutionary roots and trajec- advanced the Teory of Natural Selection. While Darwin tories) and what it could ofer to improve human health was inspired by variation exploited by plant and animal in the years ahead. Mr. Burns focuses sharply on genes breeders, Mendel meticulously recorded and analyzed infuencing human traits and specifc inherited disorders, the observed the pattern of variation among his cross- their structure and organization, and illustrates with the ing experiments involving specifc parental lines, their aid of case studies how to predict, prevent and possibly hybrids and the progeny of those hybrids. Note that Dar- cure genetic disorders using genomic information. win also carried out extensive studies on the efects of Te flm opens with the presentation of a bold, but pro- cross and self-fertilization in plants. He notably struggled fessionally and socially irresponsible gene editing experi- to provide a tangible explanation for the inheritance and ment conducted by a Chinese scientist, Dr. He Jiankui. He distribution of variation (both in nature and among his used a novel technique called “CRISPR- crossing experiments), which provides the raw material Cas9” (clustered regularly interspersed short palindromic for all evolutionary processes. Darwin was, however, cog- repeat) system on human embryos (germ-line editing) nizant of the health consequences of inherited variation, in order to cure twin girls from HIV. Te embryos were especially consanguinity (), which took a toll developed from in vitro fertilization involving HIV posi- on the health of his children and grandchildren owing tive father and HIV negative mother. Note that individu- to his marriage to his frst cousin. Indeed, health and als who are heterozygous to “Delta 32” in the disease are inextricable aspects of evolutionary process CCR5 receptor gene are susceptible to HIV, but homozy- (Haldane 1949). Te Mendelian principles rediscovered gous ones show greater levels of resistance. Germ line 120 years ago, were quickly extended to study human editing is irresponsible because the genetic modifca- health and disease (Garrod 1902). Subsequent applica- tions to the developing embryos are inherited and their tion of both Darwinian and Mendelian principles to crop life-course consequences on development and health as and animal breeding has contributed greatly toward ame- well as evolution have not been thoroughly investigated liorating world’s food scarcity. Could these discoveries be by a panel of international body of responsible citizen sci- employed to cure diseases and manage human health? entists. at the CCR5—Delta 32 site occurred Despite a few major omissions and a clear bias toward many generations ago in Europe and spread in human molecular (Govindaraju 2016), Siddhartha populations, obviously much before the appearance of Mukherjee’s historical narrative of the science of genet- HIV. ics or and variation remains as an important Pediatric Dr. Wendy Chung introduces us guide to study the origin and growth of genetics, and to rare childhood diseases, which follow a Mendelian its relevance to modern medicine. It also mirrors the pattern of inheritance. Te introduction is facilitated abuses of genetic discoveries to propagate racism, the through the anxious and devoted couple, Luke and Sally fallacy of biological determinism and warns about the Jackson, and their beautiful young child Susanna. Unfor- consequences of tinkering the human genome with bad tunately, Susanna carries a defective (mutant) in “KiF1A” intentions, which could seriously impede the progress gene, which leads to a degenerative neural disease, of not only genetics and , but also “Hereditary Spastic Paraparesis.” Te disease would not the entire human society. He has also discussed that only take away her childhood but also eats away her brain genetic discoveries made using the same principles that bit-by-bit over time. Dr. Chung patiently plays with the Nature has tinkered with, over billions of years, could be child and observes her subtle movements for diagnos- employed to managing and curing a number of diseases. ing the disease progression. Here we glimpse not only Such changes, prudent or imprudent, could also chart the dedication of Susanna’s parents to discovering the novel trajectories of human evolution. cause of their daughter’s illness, but also of Dr. Chung’s Ken Burns, like other great flm directors, has taken (and many physicians like her) palpable devotion to her only the scafoldings from the original source, and has patients in order to alleviate their sufering and fnd a retold the history of genetics in this documentary from purpose in her profession and life. Te consequences of an astonishingly fresh perspective. In a way, it feels like the mutation on and disruption of cellular func- watching a new and independent flm! Te documentary tion and its eventual manifestation as a disease are beau- is rich with appropriate illustrations and commentaries, tifully illustrated. photographs from archives, flming on actual locations As a rule, mutations exert a broad spectrum of adverse, and footage showing the interaction of physicians and cumulative, pleiotropic and contextual efects on the Govindaraju Evo Edu Outreach (2020) 13:15 Page 3 of 6

expression of a given trait or a disease; but a fraction However, also published his results that of them contribute to good health as well. Both advan- genes and are composed of DNA in the tageous and harmful mutations are nonetheless main- same year. But the original insight on DNA (nuclein) as tained among individuals and populations of all life forms the material responsible for inheritance came from Frie- including in accordance with Darwinian princi- drich Miescher in 1871, only 6 years after Mendel’s pub- ples. Tis prompts us to ask enduring questions on the lication. I wish the commentators mentioned Meischer’s nature of human existence, inheritance and variation, as contribution to the chemical nature of hereditary mate- well as human destiny. Greek philosophers and think- rial—DNA. Interestingly, the discoveries by Darwin-Wal- ers such as , and also lace, Mendel, and Meischer in a span of about 11 years pondered these questions and speculated wildly on the suggests the intense interest that was prevailing in mid- birth of ofspring, treating diseases and restoring human 19th century Europe to understand the nature of inherit- health. ance and variation. Population growth and the demand for food over the Following Morgan’s pioneering attempt to map genes centuries in Europe needed new innovations in food on chromosomes like beads on a string using the fruit production. , being the son of a farmer fy as the model organism, the next major challenge himself, sought to discover the principles of inheritance, remained–understanding the chemical structure of the on the insistence of F. C. Napp—“what is inherited and DNA molecule. Two very talented and driven scientists, how?” (Henig 2000) with the ultimate goal to increase and meet at Cambridge the food production and expand economic growth in the University to take up this challenge. Both Watson’s and province of 19th century Moravia, based on scientifc Crick’s drive, complementary interests, intuitions, open- principles. Mendel’s experiments on the pattern of inher- minded trans-disciplinary thinking and intuitive grasping itance and distribution of “recessive and dominant” traits of the double-helical structure of the DNA molecule by among the progeny derived from crosses of varieties of Watson, their collaboration, discussions, building mod- peas at his garden in Brno are beautifully presented in the els, interaction with Maurice Wilkins and learning from flm with graphics and commentaries. Mendel’s experi- Erwin Chargaf on pairing are well presented. mental results, however, did not “basically vanish” from Watson’s peek view of the X-ray picture of the DNA the scientifc community (for 35 years) but were ignored molecule prepared by , during his dis- by his more infuential colleagues such as Carl Nageli and cussions with Wilkins, and his conviction that DNA mol- others (Olby 1966). Apparently, this unpretentious Monk ecule must have a double-helical structure reminds me was fond of saying to his friends, “Meine Zeit wird schon of ’s dictum “Chance favors the prepared kommen”–“My time will come” (Henig 2000). Indeed, mind.” sometimes, truth takes longer time to establish itself! Subsequent to the discovery of DNA structure, details Following the rediscovery of Mendelian Laws of heredi- about the components of the central dogma in molecu- tary “Merkmals/factors” (later termed genes), their align- lar biology (DNA codes for RNA which in turn guides ments like beads on a string of chromosomes and their protein synthesis) emerged and its details are beautifully variation were investigated (among others) primarily by presented. Also, new techniques were developed to map- T.H. Morgan and his students at Columbia University’s ping genes based on their degree of correlation with the “Fly Room.” Tis led to discovering the origin of new neighboring genes using DNA markers. In this period, mutations that generate heritable variations is presented a woman named Leonore Wexler was diagnosed with beautifully with illustrations. On the other hand, some Huntington disease (HD), an insidious and devastating other scientists, largely infuenced by the Galton School neurological condition, which shows a dominant pattern were advocating “genetic determinism.” A band of inter- of . Her daughter, Nancy Wex- national scientists led an organized and often militant ler, although lacking formal training in genetics takes up propaganda for applying Darwinian-Mendelian princi- the challenge to discover the genetic basis for HD. Tis ples to “re-engineer” human society by sterilizing “fee- requires collecting information on individuals nested in ble minded” and “unft” individuals carrying undesirable families who carry this disease. Nancy Wexler discovers traits, in the name of . Te eugenics movement that such families live in the village of Barranquitas near is very well brought out in the flm using conditions that Lake Maracaibo, Venezuela. Tis population is derived prevailed in both Hitler’s Germany and the treatment of from a few founding families (founder population) set- mental patients in the United States. tled in this area in the early 19th century. Te mutation What is the nature of hereditary material? It must be that infuences HD came with the founding members. a chemical. Tis idea is attributed to Irwin Schrodinger Over the years, it has gradually spread among the pre- from his popular book “What is Life” published in 1944. sent-day inhabitants of the Barranquitas village. How did Govindaraju Evo Edu Outreach (2020) 13:15 Page 4 of 6

the disease go unnoticed by the community for so long? in life or in a specifc environment and stop functioning Sadly, the disease is an insidious imposter; it is gener- at a diferent stage in life or under diferent environmen- ally expressed in seemingly healthy individuals only after tal conditions? Simply, how are genes regulated? Francois their prime reproductive age. By then, most couple would Jacob and in France provided a convinc- bear healthy looking children, but the gene responsible ing answer to this question known as operon theory. for the disease (HTT) would be concealed in some of I only wish the documentary had mentioned Barbara these individuals and work stealthily and steadily till they McClintock’s “controlling elements” work, which in prin- pass their reproductive age. Tis hide-and-seek pattern ciple, is similar to Jacob and Monod’s study, but preceded of the disease spread continues with the expansion of their work by over a decade! the community. Ms. Wexler’s compassion, understand- Time was ripe for asking an audacious question. Could ing, and interaction with the afected individuals among genetic discoveries made on model organisms to under- families in this community, meticulous note-taking, and stand molecular mechanisms and to manipulate DNA in pedigree construction sets a great example for geneticists microorganisms be employed to cure or manage human and genetic counselors. Te scene in which Dr. Wexler health for the beneft of humankind? If so, could we afectionately picks up and kisses a boy with HD is one of sequence the entire genome to both count and chart the the most poignant pieces of footage in the flm and per- detailed organization of genes in the human genome? haps in all of medical/human genetics. It shows the pas- Tis grand question led to the launching of the “Human sion and dedication these investigators have toward their Genome Project” (HGP) in 1993. Te race to read the study subjects, who cry for help and need relief from their entire human genome, letter-by-letter culminated in diseases. Te collection of blood samples from afected 2003, through “soft power” diplomacy and the announce- pedigrees led to the identifcation of the HD/HTT gene ment of the feat by the then President of the United and the excess of CAG repeats in the HD States, Bill Clinton, is well presented. Two decades since gene among the HD patients. Could the knowledge the completion of the HGP, public awareness of genes gained on HD on the Venezuelan HD patients be used and genetics and their role in health and disease has on others living elsewhere aficted by the same disease? become as common as the Laws of Gravitation or Teory Yes, indeed! A number of individuals in Peter Allen’s fam- of Relativity in everyday parlance. ily in Chelmsford, Essex, U.K., including his mother and Humans are afected by both common genetic dis- grandmother died from this disease. Mr. Allen is now orders such as Type 2 diabetes, heart diseases, asthma, showing signs of the disease; his siblings could be carry- schizophrenia, etc. and nearly 7000 rare genetic (Men- ing this gene as well. Teir mutual struggles and support delian) disorders. Te genetic architecture of many com- as well as their optimism are well documented. mon genetic disorders is more complicated than the Advances in DNA technology heralded by many genetic bases of Mendelian disorders. While the HGP molecular biologists prompted them to create novel was progressing, geneticists contemplated on under- variation as it is done naturally among organisms by a standing both the genetic basis of human disorders and process called recombination, but only at an unprec- curing some of them using recombinant DNA tech- edented speed in Petri dishes. , in particular, niques. In a bold attempt to cure a classic Mendelian dis- attempts to repeat an evolutionary process under labo- order, ornithine transcarbamylase (OTC) defciency in a ratory conditions that have evolved over time. young patient, James Wilson attempted to use genetically Using the same mechanisms used by bacteria in nature, engineered viral particles at Te University of Pennsylva- he engineered “recombinant DNA” in and re- nia. Unfortunately, the patient died of complications on introduced them into bacteria. Tis discovery spawned Sept 17, 1999. Te study was also an ethical and a scien- a new discipline called “.” Tis also tifc quagmire and the hope for “gene therapy all but died led to many demonstrations and public discourse against with him.” recombinant DNA research. Tese experiments have Yet, in the last two decades many new molecular progressed non-stop following the establishment of ethi- approaches to manage or cure genetic disorders have cal standards, and have transformed the face of biological been developed. One of the most promising and sought and medical research. after technique is the CRISPR, discovered by Dr. Jennifer In the second part of the documentary titled, “Revo- Doudna and Dr. . Te technique lution in the treatment of (genetic) disease” the director exploits a trick that bacteria have evolved in order to focuses on the advances made toward understanding the recognize and kill invading viruses. Note that the same genetic bases of diseases and how we could harness the approach was exploited by Dr. He Jiankui for editing emerging ideas in molecular biology to treat human dis- human germ cells. In addition, bright and bold individu- eases. Why are certain genes expressed at certain stage als such as the Rosens, Wexlers and Allens, although not Govindaraju Evo Edu Outreach (2020) 13:15 Page 5 of 6

trained in genetics or medicine, are strengthening the Application of new molecular techniques has paved the hands of dedicated physicians such as Dr. Wendy Chung way for understanding the nature of human diversity and toward diagnosing and treating patients with genetic dis- the prevalence of diseases including Mendelian disorders. orders. On the other hand, some of these patients, their But, approaches to decipher the genetic bases of most families and support groups are also striving equally hard complex diseases, have worked “less well than hoped for,” to understand the genetic bases of the diseases they are also implies that gene centric approaches may not ofer a carrying so that they could manage their own diseases general panacea to treat all genetic disorders. slightly better and lead a relatively healthy life. Tey are Nonetheless, by applying new discoveries made in also joined by scores of laboratory scientists, their tech- genetic medicine, Ms. Winklesas’ grip strength has nical and nursing staf as well as the dedicated members improved. Te Yoder’s second child walks across the of society around the globe. Te global community of room into her parents’ open arms, and walks next to him, collaborators generate public interest on specifc genetic he carries the child on his shoulders. Teir jubilation is disorders and build disease specifc networks, in order to priceless. Mr. Williams is energized and his mother is alleviate the sufering (and stigma) inficted by deleteri- happy. Mr. Allen, out in the UK, receives “genetic medi- ous mutations among genes on the individuals and fami- cine” contained in a “small vial of hope.” As a result, Mr. lies that carry them. Allen, who couldn’t draw a shape or write clearly, could Take for instance, Ms. Audrey Winkelsas, a young and do both reasonably well. His satisfed wife watches his bright graduate student working at the NIH and Oxford, progress with a sigh of relief. We come to appreciate that is sufering from Spinal Muscular Atrophy (SMA). Te lessons learned by understanding the origin and evolu- disease gradually attenuates muscle strength, but the rate tion of cancer are also identical to evolutionary mecha- of its progression varies among individual patients. She is nisms common to all organisms, including humans. In determined to fnd the molecular bases of the cause and fact, cancer has been recognized as an evolutionary dis- a potential cure or at least to stall its progression. She has ease. Terefore, application of Darwinian and Mendelian taught her mother to perform the required laboratory principles together with classical and medical treatments analyses, while the clinical team monitors her progress. has become integral part of clinical care and manage- Audrey’s physician’s confession about his evaluation of ment of cancer patients (Swanson 2020). Such nexus her disease reminds us of the old adage, “An old patient is approaches, now armed with rapidly evolving genome better than a new doctor.” Similarly, Mr. and Mrs. Jeremy editing (both germ-line and somatic line) techniques, and Cheryl Yoder have their daughter Ariel. Te child is could change the future course of not only cancer treat- severely afected by SMA, but her disease has progressed ment, but also diseases caused by single or only a few to the point of no return. Cheryl gives birth to another changes, such as progeria, sickle cell anemia, child. Unfortunately, the new baby also has SMA! Teir hemophilia, cystic fbrosis, deafness, blindness and hun- pediatrician suggests that they could try an experimental dreds of similar genetic conditions (Rosen 2020). drug if they could bring the child for treatment before the Te scenes showing helpless innocent looks of children disease is overtly expressed. Te timing of diagnosis is and the faces of anxious and tired parents of patients are critical if some of these therapies to be efective. Another very touching. Tese images haunt us all. Watching the patient, Ms. Lessie Lassiter has breast cancer, which is agony of innocent children, their parents and caregivers a complex evolutionary disease. She receives an experi- reminds us of the Buddha’s counsel to Kisa Gotami that mental drug, which is improving her situation. Ms. Las- their losses and the pain they endure are ours as well. siter is happy and hopes she would lead a normal healthy In short, Ken Burns and his team deserve accolades for life like the rest of us! Her case serves as a beacon of hope making this beautiful documentary on the convergence for all breast cancer patients that the culprit mutation(s) of genetics, evolution, and the future of genetic medicine could be identifed and treated with precision with little (Childs 1999). Tis flm reminds me of another beautiful or no side efects. On a similar note, Mr. David Williams documentary, “Ascent of Man,” by the late Jacob Bronow- is sufering from sickle cell disease, which afects nearly ski on the aired over 40 years ago on 250 million children worldwide. A new technique involv- PBS. Mr. Burns has gradually and meticulously shown ing correcting the mutation that causes red blood cells to the need for understanding in order assume a crescent shape is used to re-engineer stem cells to chart new territories in the future medical practice harvested from Williams’ own body. Te newly “engi- ranging from cancer to COVID-19, recently touted as neered” stem cells are transfused into Williams’ body “Precision Medicine.” In doing so, he and his team have using the standard medical procedures. With just one emphasized the ethical and moral responsibilities human such “somatic cell therapy” treatment, he expects to lead society as a whole has to share and shoulder in order to a relatively long and healthy life. fully harness the Promethean power of evolution and Govindaraju Evo Edu Outreach (2020) 13:15 Page 6 of 6

genetics which could potentially and perhaps perma- Funding The author received no fnancial support from any source for this work. nently transform human micro-evolutionary processes as well as future health care. An old saying goes, that “A Availability of data and materials picture is worth thousand words.” If so, this flms speaks Because this article is classifed as a Book Review, No datasets were used or generated and analysed for writing this article. volumes on the place of genetics and evolution as well as the challenges that lie ahead in the practice of future Competing interests medicine. Tis flm deserves to be watched not only by The author declares that he has no competing interests. geneticists, evolutionary biologists, and medical profes- Received: 25 June 2020 Accepted: 27 June 2020 sionals but also anyone who wants to know who we are? Where did we come from? Why we look the way we do? Why we get certain diseases, why some of us live longer than others—that means each and every one of us! Te References Gordian knot between evolution and medicine recog- Childs B. Genetic medicine: a logic of disease. Baltimore: The Johns Hopkins University Press; 1999. nized by Garrod (1931), the father of precision medicine Garrod AE. The incidence of Alcaptonuria: a study in chemical individuality. (Perlman and Govindaraju 2016) nearly a century ago is Lancet. 1902;2:1616–20. being gradually disentangled with Darwinian and Men- Garrod AE. The inborn factors in disease: an essay. Oxford: Oxford University Press; 1931. delian mechanisms themselves. Te flm clearly dem- Govindaraju DR. The Chasmed Gene. Evolution, Education and Outreach. onstrates the transformative power of the confuence Berlin: Springer; 2016. p. 1–6. among Darwinian, Mendelian and Hippocratic medicine Henig RM. The Monk in the garden. New York: Houghton Mifin Company; 2000. as well as the shared moral and ethical responsibilities Haldane JBS. Disease and evolution. Ric Sci. 1949;19:3–10. of geneticists and physicians toward building a healthier Mukherjee S. The gene: an intimate history. New York: Scribner; 2016. human society. Olby RC. Origins of mendelism. New York: Schocken Books; 1966. Perlman RL, Govindaraju DR. Archibald E. Garrod: the father of precision medi- Acknowledgements cine. Genet Med. 2016;18:1088–9. I am grateful to Dr. Adam Goldstein and Dr. Robert Perlman for their encour- Rosen M. Precision Genome Editing Enters the Modern Era. HHMI News. 2020. agement and for ofering many constructive comments on the manuscript. Swanson C. Take lessons from cancer evolution to the clinic. Nature. My thanks are due also to Dr. S. M. Raj and Mr. Yashasvi Raj for reading an 2020;581:382–3. earlier version of the article.

Authors’ contributions Publisher’s Note The author conceived the ideas and wrote the paper. All authors read and Springer Nature remains neutral with regard to jurisdictional claims in pub- approved the fnal manuscript. lished maps and institutional afliations.

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