american academy of arts & sciences

winter 2018 www.amacad.org Bulletin vol. lxxi, no. 2

Induction Ceremony 2017 Class Speakers: Jane Mayer, Ursula Burns, James P. Allison, Heather K. Gerken, and Gerald Chan

Annual David M. Rubenstein Lecture Looking at Earth: An Astronaut’s Journey David M. Rubenstein and Kathryn D. Sullivan

ALSO: How Are Different from Other Great Apes?–Ajit Varki, Pascal Gagneux, and Fred H. Gage Advancing Higher Education in America–Monica Lozano, Robert J. Birgeneau, Bob Jacobsen, and Michael S. McPherson Redistricting and Representation–Patti B. Saris, Gary King, Jamal Greene, and Moon Duchin presentations

Morton L. Mandel Public Lecture How Are Humans Different from Other Great Apes?

n October 23, 2017, at the Sanford Consortium for Regenerative Medicine in San Diego, California, the Acad- emy, in collaboration with the Center for Academic Research and Training in Anthropogeny (carta), host- O ed the Morton L. Mandel Public Lecture on “How Are Humans Different from Other Great Apes?” The pro- gram, which served as the 2060th Stated Meeting of the Academy, included a welcome from Gordon N. Gill (Univer- sity of California, San Diego School of Medicine; Chair of the Academy’s San Diego Program Committee) and featured remarks from Pascal Gagneux (University of California, San Diego; carta) on Genomics, Life History and Reproduc- tion; Fred H. Gage (The Salk Institute; carta) on and Brain Development; Margaret J. Schoeninger (Uni- versity of California, San Diego; carta) on and Behavior; and Ajit Varki (University of California, San Diego; carta) on Common Disease Profiles. The following is an edited transcript of some of the presentations.

Introduction

t is a privilege and honor for an organiza- ancestor with Old World monkeys, then Ition that is less than ten years old (name- with Gibbons and other lesser apes, then ly, carta) to partner with one that orig- with orangutans, followed by the gorilla and inated before the U.S. Constitution was eventually with the common ancestor of the written (the American Academy of Arts and chimpanzee and bonobo, the so-called pyg- Sciences). A common theme supported by my chimpanzee. Based on anatomical, phys- both organizations is the discovery and dis- ical, and behavioral features, we humans semination of factual knowledge. Time does classified our closest evolutionary relatives not allow me to provide a description of the as “the Great Apes.” In reality we are more origins and goals of carta, so I will simply similar at the genomic level to chimpanzees read our mission statement: and bonobos than these two species are to “To use all rational and ethical approaches to gorillas. Moreover, at the genomic level, we seek all verifiable facts from all relevant disciplines are more similar to chimpanzees than mice to explore and explain the origins of the and rats are to each other. phenomenon, while minimizing complex organi- Thus, from a genomic perspective, hu- Ajit Varki zational structures and hierarchies, and avoiding mans are nothing more than one kind of Ajit Varki is Distinguished Professor of Med- unnecessary procedural complexities. In the pro- “Great Ape”; the correct term encompass- icine and Cellular & Molecular Medicine and cess, train a new generation of scholars in anthro- ing all these groups is “Hominid.” Asking Co-Director of the Glycobiology Research and pogeny [understanding the origin of humans], how we are different from the other Homi- nids is one way to understand our own evo- Training Center at the University of California, and also raise awareness and understanding of the study of human origins within the academic lutionary origins, an approach that we call San Diego; Executive Co-Director of UCSD/ community and the public at large.” “Comparative Anthropogeny.” Salk Center for Academic Research and Train- The overall question at hand today is: How Carrying out this comparison requires at- ing in Anthropogeny; and Adjunct Professor at Are Humans Different from Other Great tention to a very large body of knowledge. the Salk Institute. He was elected a Fellow of the Apes? At first glance, the last three One of the currently incomplete efforts of American Academy in 2005. words–“Other Great Apes”–may appear carta is to try to collate this knowledge on a bit strange. Let me explain. Humans are, our website under the rubric of The Matrix of course, , who shared a common of Comparative Anthropogeny (moca),

28 Bulletin of the American Academy of Arts & Sciences, Winter 2018 how are humans different from other great apes?

One of the striking differences between humans and their closest living relatives is the schedule of life. In several aspects, humans have slowed down.

ist in at least two different species, but there is only a single species of humans today that has colonized the entire planet. Each of us, as long as we live, is a unique mosaic of a genome that consists of 46 piec- which is a collection of comparative infor- Pascal Gagneux es of chromatin, reshuffled from our par- mation regarding humans and our closest Pascal Gagneux is Associate Professor of Pathol- ents. Each of your haploid genomes is about evolutionary cousins, with an emphasis on ogy and at the University of Cal- a meter long. So you have about two me- uniquely human features. ifornia, San Diego, and Associate Director of ters of dna in each one of your cells. That is still very incomplete, but it sounds mighty short, but each meter con- moca UCSD/Salk Center for Academic Research and is organized by Domains (each with de- tains three billion base pairs, and therefore Training in Anthropogeny (CARTA). fined Topics) arranged by areas of inter- we have two times three billion base pairs. est and scientific discipline. Some exam- One of the ongoing research projects in ples of moca Domains are: Anatomy and On Genomics, Life History, many labs around the world is to identify , Behavior, Cell Biology and and Reproduction differences in the genomes of hundreds of Biochemistry, Cognition, Communication, different apes and thousands of different Culture, Dental Biology and Disease, Devel- would like to start with a little bit of humans, which are now available for study opment, and Ecology. In the time available I geography. Humans are the only peri- because the entire genome, each of the three today, we cannot possibly cover even a small planetary ape. In contrast to us, our closest billion base pairs, has been sequenced. portion of these Domains of knowledge. In- living relatives are restricted to the tropical The results are showing some very sur- stead, our panelists will explore some spe- forests of Africa and Asia. As Ajit has just prising findings. There are huge differenc- cific examples of distinctly human features, mentioned, we are more closely related to es in copies. For example, there are copies ranging from genetic to cognitive to ana- two species of these Great Apes. Some peo- of segments that can range from a couple tomical to behavioral to biomedical, while ple have started debating whether we should of base pairs to millions of base pairs that also considering implications for explaining be in the genus Pan or whether the two spe- have expanded in only one species of ape, human origins. cies of Pan should be in the genus Homo. or in chimpanzees and gorillas, but not in Paradoxically, the living apes, even though humans. In the reverse, we have copies of their populations are under very intense chunks of dna that have only expanded in threat from deforestation and direct hunt- humans but not in the other apes. ing, still contain more genetic variability And there are completely novel genes than all seven billion humans on the planet that pop up in different species. There are today. The other striking contrast you might pseudogenes that are still recognizable notice is that all the other apes, except us, ex- based on their dna sequence, but have

Bulletin of the American Academy of Arts & Sciences, Winter 2018 29 presentations

Human minds are effective copying ma- One of the ongoing research projects in many chines. Somebody comes up with a good labs around the world is to identify differences in idea, and then everybody in the group maintains that idea. We develop a ratch- the genomes of hundreds of different apes and eting culture, in which we build upon each thousands of different humans, which are now other’s ideas. One very interesting idea is that this de- available for study because the entire genome, each layed development is actually a biological assimilation of the cultural input. Humans of the three billion base pairs, has been sequenced. in hunter-gatherer societies have a shorter inter-birth interval than apes. Humans can stopped encoding proteins. You can mine grandmotherhood, and sometimes grand- give birth about every three years, chim- the genomic data to find evidence for re- parenthood for relatively long periods–up to panzees only every five or more years. Even cent positive selection, in which natural se- 30 percent of the total lifespan is comprised though our babies are costly, we can produce lection has forced more changes to the pro- of the post-reproductive survival phase. more of them than our living Great Ape rel- tein-coding dna than you would expect. Some have proposed that this might have atives. And when humans are done making Humans are made of trillions of cells, and been an adaptation to cultural opportuni- babies, they actually survive for a long time. different cell types play a different subrou- ties, given the importance of cultural trans- Our societies, long before medicine, the In- tine off the mostly clonal genome that is in fer in our species. Or perhaps it was due to dustrial Age, or the farming age, allowed for all your cells. So by tweaking where you ex- nutritional opportunities, in which mothers grandmothers and grandfathers. press which combinations of genes, you can with better access to high density-rich foods Interestingly, in evolutionary biology it is actually change how the organism looks. can actually do novel things in utero. It may pretty much accepted that toward the end of I thought I would say a few things about also have been facilitated by stronger pair the reproductive period, there is a minimal the complex nature of the genomic land- bonds between parents or by allomother- force of selection. But if you allow for cul- scape. In these three billion base pairs, we have about twenty thousand protein cod- ing genes, which corresponds roughly to Humans are made of trillions of cells, and different the number of undergraduate students at cell types play a different subroutine off the mostly ucsd. There are hundreds of thousands of enhancers–chunks of dna with a func- clonal genome that is in all your cells. So by tweaking tion, even though they never make pro- teins–that influence the activity of other where you express which combinations of genes, genes. And many of these are transcribed. you can actually change how the organism looks. We don’t know what that transcription re- ally does. So, we have a vast genomic land- scape, and we are only beginning to discover ing, which is when other individuals in the tural transmission, post-reproductive indi- new functions for pieces of dna that, until group help you take care of your kids. viduals can actually facilitate the survival of recently, were thought of as mere junk. Now, what does this delay in growth al- related, younger individuals, which opens One of the striking differences between low? The delay allows increased transmis- up later stages in life to the action of natu- humans and their closest living relatives is sion of behavior and concepts. Humans are ral selection. the schedule of life. In several aspects, hu- eminent copiers. We hyper-imitate. In com- With regard to forming the next gener- mans have slowed down. Our gestation time parative studies of the transmission of tool ation, what is striking is that to find strict is only slightly longer than that of the chim- use, chimpanzees are very good at imitat- monogamy in nonhuman primates, you panzees, for example, but we have invented a ing to achieve a goal. Humans, on the oth- need to look at the lesser apes, the Gibbons. couple of key things. Humans seem to have er hand, focus at least as much on how it is They live only in the forests in Southeast invented childhood, adolescence, certainly done and show normative tendencies. Asia. The other Great Ape close relatives

30 Bulletin of the American Academy of Arts & Sciences, Winter 2018 how are humans different from other great apes?

have completely different mating systems: for example, the gorilla’s harem-like soci- We have established a eties, with the big Silverbacks that have ex- bank of cellular tissues clusive access; the dispersed systems of the orangutans, with two types of males: the big from many of our closest males that are chosen by the females and the younger males that bypass female choice relatives that allows us and force the females to mate with them; to look at distinctions and chimpanzees and bonobos, with multi- male/multi-female societies, in which each between ourselves and ovulating female will mate with every male our closest relatives. in the group. For humans, what is striking is that even though humans live in groups, pair bond- more unique to the complexity in behav- ing is a major phenomenon. This allows hu- ior that humans can exhibit. For example, mans to participate in reciprocal exogamy, when we think about what are the measures which essentially means exchanging mates that allow us to examine how we may have across social groups. It allows for linking Fred H. Gage evolved, we can use genetic information. multiple kin lineages. Now, if you combine Fred H. Gage is Professor in the Laboratory of Svante Pääbo has been able to extract dna the cognitive capacity of our slowly matur- Genetics and the Vi and John Adler Chair for from ancient bones and make a hypothe- ing children, the allomothering, and the in- Research on Age-Related Neurodegenerative sis about how that dna may differ through put of the group into each child, a striking , particularly from our closest an- Disease at the Salk Institute, and Co-Director array of things becomes possible. It essen- cestral relatives. of UCSD/Salk Center for Academic Research tially allows for our social-cultural niche. Sometimes we obtain postmortem brain and Training in Anthropogeny (CARTA). He We share symbols. We have personal names. tissue from our closest ancestral relatives. was elected a Fellow of the American Academy We have kinship terms, which allows for the We can measure the magnitude of gyra- formation of tribes. We have shared rituals, in 2005. tions in the cortex and explore specific ideas dance and music, sacred spaces, and group or hypotheses about how they may be im- identity markers, and we can increase the On Genetics and Brain portant. In addition, we have fossil crania to capacity to cooperate with and compete Development study and, from those skulls, we can build against other groups. casts or make ct scans to get an idea of how would like to provide you with an exam- the brain size was changing, again building I ple or two of how a process may have led our theories based on these measurements to the differentiation of humans from our and the correlations that exist. closest relatives, and then talk about a cellu- Furthermore, we have cultural icons as lar system that allows us to look at potential well that give us an idea of how far a species molecular and cellular differences that might had emerged, given its ability to build, plan, have led to dissimilarities in who we are. and generate art. What we know is that the brain has in- In each case, we have material that we can creased in size across species during evolu- work with: genetic material, tissues, organs, tion along the branch that leads to humans. and cultural artifacts. What has been miss- And we have come to the hypothesis that ing, however, is living tissue from some of the growth of the brain is causally linked our lost ancestors and from our closest rela- to what it is to be human. The correlation tives, like chimps and bonobos. is placed there because as the brain became So the “missing link” is the ability to in- larger, we acquired features that seemed terrogate the activity and function of live

Bulletin of the American Academy of Arts & Sciences, Winter 2018 31 presentations

Chimpanzees and bonobos are our closest relatives, ular parasites of the genome). So what are mobile elements? They are elements that with 95 percent of our genomes being similar; yet, exist in specific locations in the genome and, through unique mechanisms, they can there are vast differences in phenotype. How can make copies of themselves and jump from we begin to understand the cellular and molecular one part of the genome to another. Barba- ra McClintock discovered these elements mechanisms responsible for these differences? through her work on maize. Some of us study a specific form of mo- cells and the phenotypes of the cells. We But we can ask the question: are there dif- bile elements called a line-1 retrotrans- have established a bank of cellular tissues ferences that are detectable at a cellular and poson. They exist in thousands of copies in from many of our closest relatives that al- molecular level that help us understand the the genome, as a dna that makes a strand lows us to look at distinctions between our- origin of humans? We have begun building of rna and then makes proteins that binds selves and our closest relatives. a library with other collaborators around back onto the rna, helping the element As Pascal mentioned, chimpanzees and the world, and have reprogrammed somat- copy itself. This combination of mrna and bonobos are our closest relatives, with 95 ic cells from many of these species into ips proteins then moves back into the nucleus percent of our genomes being similar; yet, cells. They retain common features of em- where the dna resides and pastes itself into there are vast differences in phenotype. bryonic stem cells at the cellular level and the genome at a new location. How can we begin to understand the cellu- they have the same genetic makeup as pre- These line elements continue to be active lar and molecular mechanisms responsible dicted based on the species. in our genome, and they are particularly ac- for these differences? In our first attempt to see if we could tive in neural progenitor cells. Thus, the rea- One of the things we can do is take so- identify differences in these primitive cells, son for our interest in piwil2 and apobec3b matic cells, such as blood cells or skin cells, we did what is called a complete transcrip- is because it has been demonstrated that from all of our closest relatives. Through a tional (mrna) analysis. If we compare the both of these proteins can suppress the ac- process called reprogramming–by overex- transcriptional genomes of chimpanzees tivity of line-1. pression of certain genes in these cells–we can turn the skin or somatic cell into a prim- Are there differences that are detectable at a cellular itive cell, called an induced pluripotent stem (ips) cell. These primitive cells are in a pro- and molecular level that help us understand the liferating, living state that can be differenti- ated to form, in a dish, any cell of the body, origin of humans? allowing us, for the first time, to form liv- ing neurons or living heart cells from all of and bonobos, there are very few differenc- Not only do humans make more of these our closest relatives and then compare them es. So we pooled all our animals together proteins, but as an apparent consequence, across species. and compared that combined nonhuman the lower levels of these L1 suppressors in These ips cells represent a primitive state group to the human group. chimpanzees and bonobos means the L1 el- of development prior to the germ cell. So In analyzing these genomes, we detect- ements are much more active in chimpan- any change detected in these ips cells will ed two very interesting genes. One is called zees and bonobos than in humans. be passed along to their progeny through piwil2 and the other is called apobec3b. When searching the dna libraries (ge- the germ cell and into their living progeny. Why are we interested in these two pro- nomes) that have been sequenced for Now a little bit of a disclaimer for those teins? These two proteins are active sup- chimps, bonobos, and humans, there are of us who work in this field: these cells have pressors of the activity of what we call mo- many more L1 dna elements in the genomes limitations. They are cells in culture. We bile elements, which are genetic elements of chimps and bonobos relative to humans. cannot really look at social experience, and that exist in all of our genomes. In fact, 50 This greater number of L1 elements in their relevance to a living organism is often- percent of the dna in human genomes is non-human primate genomes leads to an times questionable. made up of these mobile elements (molec- increase in dna diversity and, thus, in the

32 Bulletin of the American Academy of Arts & Sciences, Winter 2018 how are humans different from other great apes?

diversity of their offspring and potential- Why do humans not often ly in their behavior. This led us to speculate that this decrease in genetic diversity that suffer from the fibrotic occurs in humans leads to a greater depen- dence on cultural adaptive changes to sur- heart disease that is so vive as a species rather than genetic adaptive common in our closest changes. For example, if a virus were to in- fect a chimp or a bonobo population, in or- evolutionary cousins? der for that species to survive it would re- quire a member of the species with the ge- chimpanzees, the number one killer was netic mutation that provided protection in heart disease, heart attacks, and heart fail- some form from the virus. Humans do not ure. Again, I thought, well, they are just like wait for the mutation from a member of humans. But then when I started going over the species that would provide protection the textbook with the veterinarian, I noticed from the virus. We build hospitals, we de- that not all the diseases were the same. sign antibodies, we transmit our knowledge So the question arises: are there hu- through cultural information (cultural evo- man-specific diseases? There are a few cri- lution) rather than relying on genetics (ge- teria for human-specific diseases: they are netic evolution) for the spread and the sur- Ajit Varki very common in humans but rarely report- vival of the species. Ajit Varki is Distinguished Professor of Medicine ed in great apes, even in captivity; and they and Cellular & Molecular Medicine, Co-Direc- cannot be experimentally reproduced in tor of the Glycobiology Research and Training apes (in the days when such studies were allowed). The caveat, of course, is that reli- Center, Executive Co-Director of UCSD/Salk able information is limited to data on a few Center for Academic Research and Training in thousand Great Apes in captivity. But these Anthropogeny, and Adjunct Professor at the Salk apes were cared for in nih-funded facilities Institute. He was elected a Fellow of the Ameri- with full veterinary care–probably better can Academy in 2005. medical care than most Americans get–and there were thorough necropsies. On Common Disease Profiles As it turned out, I was even wrong about heart disease. It was not until my spouse n the 1990s, my research group happened and collaborator Nissi Varki looked at the Ito discover the first known genetic differ- pathology that she realized that while heart ence between humans and chimpanzees. disease is common in both humans and Because I didn’t know very much about our chimpanzees, it is caused by different patho- close evolutionary relatives, I took a sabbat- logical processes. While a human heart can ical and went to the Yerkes National Primate show coronary blockage that reduces blood Research Center to learn more about apes flow to the heart and results in myocardial and chimpanzees. Given my medical back- infarction, heart attacks, and heart failure, ground, I paid special attention to diseases, chimpanzees that died of “heart attacks” and I found that the Center was using Harri- and “heart failure” had a completely differ- son’s textbook of Internal Medicine, which ent pathology. They developed massive scar is the same textbook I had used for humans. tissue replacing their heart muscle, which is And so I thought, well, they must be just called interstitial myocardial fibrosis. like us. And, indeed, when I first looked at It turned out that the veterinarians were the major causes of death in adult captive well aware of this, but had not reported

Bulletin of the American Academy of Arts & Sciences, Winter 2018 33 presentations

We can draw several conclusions: The disease various other animals . . . but we were never able to arrive at anything in animals similar profiles of humans and chimpanzees are rather to the cholera process.” So, Vibrio cholerae does not induce diar- different. Chimpanzees are actually poor models of rhea in adult animals other than in humans many human diseases. Humans are likely to be poor and many people are trying to figure out why. models of many chimpanzee diseases. There are many other candidates for hu- man-specific diseases. There is another set it because they thought it wouldn’t be in- ciparum arose from P. reichenowi by a single of diseases in which various bacteria car- teresting because it was not like humans! transfer from a Great Ape. Pascal Gagneux ry out molecular mimicry, in which bacte- There is now a special project called The and I wrote an article that explains what rial capsular polysaccharides mimic com- Great Ape Heart Project, which is providing might have happened. There are multiple mon motifs on sialoglycans of mammalian clinical, pathologic, and research strategies forms of ape malaria that are mild through- cells–like a wolf in sheep’s clothing. to aid in the understanding and treatment of out Africa. At some point, we escaped be- Another difference is in carcinomas, can- cardiac disease in all of the ape species. cause of a change in the surface sialic acid cers of epithelial origin. To date, no captive There are actually two mysteries to be molecule. One of them finally “figured out” Great Apes have reported carcinomas of the solved: why do humans not often suffer how to bind to the sialic prominent in us, esophagus, lung, stomach, pancreas, colon, from the fibrotic heart disease that is so and that is now P. falciparum malaria. uterus, ovary, or prostate. They do devel- common in our closest evolutionary cous- Another candidate for human-specif- op cancer in the hematopoietic system and ins? They all can get it–the orangutans, ic diseases is typhoid fever. More horrible elsewhere. gorillas, chimpanzees, bonobos–and we studies were done in the 1960s that showed There are a few thousand Great Apes liv- don’t. Conversely, why do the Great Apes that large doses of Salmonella typhi did not ing in captivity, and living well into their fif- not often have the kind of heart disease that result in severe cases of typhoid fever in ties and sometimes into their sixties. So you is common in humans? chimpanzees. Working with Jorge Galán would expect a few carcinomas based on the Nissi and I then worked with Kurt Be- and others we found that, in fact, what hap- incidence in humans. Nissi and I wrote an nirschke and with others and wrote an arti- cle on the “Biomedical Differences Between Humans and Nonhuman Hominids: Poten- Why do the Great Apes not often have the kind of tial Role for Uniquely Human Aspects of Si- heart disease that is common in humans? alic Acid Biology,” which focused somewhat on our own research on sialic acid biology. We put together a list of candidates of pened is that the typhoid toxin, which is the article that reviewed the subject, and con- human-specific diseases that meet the cri- soluble molecule that really mediates the cluded that while relative carcinoma risk teria I mentioned earlier, and myocardial severe symptoms of typhoid fever, cannot is a likely difference between humans and infarction is number one. Malignant malar- bind to the chimpanzee cell surface. It can chimpanzees (and possibly other Great ia is number two. In studies done from the only bind to the human cell surface (again, Apes), a more systematic survey of available 1920s to the 1940s, people actually did hor- because of the sialic acid difference between data is required for validation of this claim. rible two-way cross-transfusions between the species). Time does not permit me to talk about chimpanzees and humans infected or not Another candidate is cholera, which is a Alzheimer’s Disease, hiv, hepatitis B com- infected with malaria, and there was no ev- major killer in humans. Robert Koch com- plications, muscular dystrophy, preeclamp- idence of cross-infection. In fact, the para- plained in 1884 that “. . . although these ex- sia, frequency of early fetal wastage, fre- sites looked the same, but they were actually periments were constantly repeated with quency of premature labor and birth, and completely different. material from fresh cholera cases, our mice frequency of chronic female iron deficiency. More modern work done by Francisco remained healthy. We then made experi- But bronchial asthma is interesting. Great Ayala and others showed that, in fact, P. fal- ments on monkeys, cats, poultry, dogs and Apes don’t seem to get bronchial asthma,

34 Bulletin of the American Academy of Arts & Sciences, Winter 2018 how are humans different from other great apes?

an extremely common disease in all human populations. I found this claim a little hard to believe until I came across a paper enti- tled “Eosinophilic Airway Inflammation in a Monkey.” The article concluded that the present case that was studied was “remark- able because there is a paucity of reports of naturally occurring allergic airway disor- ders in nonhuman primates.” So we can draw several conclusions: 1) The disease profiles of humans and chim- panzees are rather different. 2) Chimpan- zees are actually poor models of many hu- man diseases. We should pay more atten- tion to that. 3) Humans are likely to be poor models of many chimpanzee diseases. The ethics of research on Great Apes has shifted and changed for good reasons. Pascal and I wrote an article with Jim Moore in 2005 that suggested we should conduct research on Great Apes that follows principles as simi- lar as possible to those accepted for human research. We also suggested that researchers should volunteer to be subjects in the same experiments! But like all things human, there are always two extremes and the people in the middle do not necessarily get a say. And so the ques- tion is whether the current ban on chimpan- zee research will do more harm than good. I personally think it will do more harm be- cause chimpanzees would also benefit from more ethical studies of their own diseases. But that is where we stand right now. n

© 2018 by Ajit Varki, Pascal Gagneux, and Fred H. Gage, respectively

To view or listen to the presentations, visit https://www.amacad.org/ great-apes.

Bulletin of the American Academy of Arts & Sciences, Winter 2018 35