Dr. Ajit Varki, Distinguished Professor of Medicine, UC, San Diego

15th of January

The 6th General K.S. Thimayya Memorial Lecture was held on Saturday, the 15th of January, 2011 at the Bishop George Edward Lynch Cotton Auditorium, Bishop Cotton Boys’ School, St. Mark’s Road, Bangalore – 560 001 at 11:00 am
The Keynote address was delivered to a packed audience by Dr. Ajit Varki, Distinguished Professor of Medicine and Cellular & Molecular Medicine, University of California, San Diego on “Adventures in Anthropogeny: What Makes us Human?” and Old Cottonian (1967, Pope) The Lecture was preceded by Tea at the school premises.
The Introductory Address was delivered by Mr. John Zachariah, Principal, Bishop Cotton Boys’ School. The Commandant’s Address was to be delivered by Lt. Gen. N. C. Marwah, AVSM, Colonel of the Kumaon & Naga, Regiments and Kumaon Scouts, who was unable to be present owing to his new posting to the Andaman Islands. His address was read out to the audience.
The audience comprised of eminent citizens of Bangalore, distinguished old Cottonians, former bureaucrats, senior officers from the armed forces – both serving and retired, students and faculty of the School and family members of General K.S. Thimayya and family members of Dr. Ajit Varki.
The Lecture saw the participation of several distinguished guests, like Dr. Dayalan Devanesan, Old Cottonian and Order of Australia, Mrs. Vatsala Watsa, Addl. Chief Secretary to the Government, Mrs. Jija Hari Singh, Former DGP, Karnataka, former key note speaker Mr. Philip Wollen, Old Cottonian and Order of Australia, patron of the Gen, Thimayya Trust, General Jetley and Mrs. Jetley and the Sub-Area Commander, Karnataka and Kerala, Major General Pradhan.

Lecture Transcript

While theories abound concerning the origin of humans, none has yet scientifically explained our emergence as the dominant species on the planet. A detailed understanding of how we came to be human addresses a most profound issue: who are we, and how did we get to even ask such a question? Definitive scientific answers will come not from a single line of investigation, but from a wide variety of approaches in biological, biomedical and social sciences, as well as aspects of philosophy, arts and humanities, with important support from the physical, chemical, and computing sciences. This arena of “Anthropogeny” also has relevance for practical issues related to medicine, biology, the organization of society, the upbringing of our young, and the interactions of humans with one another and with our environment. The time has come to approach “Anthropogeny” in a systematic manner, attempting to integrate the vast amount of relevant information from many aspects of the human endeavor. Professor Varki entered this field via an improbable route originating from his basic biomedical studies, in which he discovered that molecules called sialic acids are a “hot spot” in human evolution, physiology and disease. After a brief overview of his own research, he will describe a transdisciplinary approach to Anthropogeny that brings together scientists and thinkers from many disciplines to pursue this most basic of human questions, finally closing with a novel theory about how we may have made our transition from simple self-awareness to a full ability to understand ourselves, others and the universe around us.

The Thimayya family, Patrons, Trustees, Principal Zachariah, teachers, my friends and relatives, ladies and gentlemen, boys and girls: it is truly a privilege to present this lecture. In doing so, I face three challenges. The first is to live up to the memory of a very great man. As been said: “ a General Thimayya was not born in every generation; the like of him there will seldom be”. As a student here in 1965 I experienced both the joy of the Cotton’s centenary and the sorrow of his passing. My second challenge is to follow on all the previous Thimayya lectures. Having read their transcripts, I hope that I can manage to match them. My third challenge lies in realizing that this audience is wide ranging, from schoolchildren to eminent scientists. I have tried to put together a lecture that would have a little bit of something for everybody.
When asking what makes us human, there is a modern tendency for genetic determinism: it’s your genes make you human, your genes are the recipe book that makes you human. If you’ll indulge me I’d like to use my own career to show why this assumption is wrong. Right now I’m a well-established professor at the University of California, San Diego (UCSD), have won several awards, and been elected to various academies. So the young people in the audience are probably thinking, “he is just a very smart fellow who has also worked hard.” Nothing could be further from the truth. I am here today mainly because of the institutions and mentors who influenced my life.
Stepping backwards in time I had the good fortune to work with the Stuart Kornfeld, a famous physician-scientist at Washington University in St. Louis, who taught me about medicine and science, along with his wife Rosalind Kornfeld, an eminent biochemist who put me on the path to becoming a scientist. Going back further I also had the good fortune to be a student at Christian Medical College Vellore, one of the most unique institutions in the world. CMC was started by a young American socialite Ida Scudder, who eventually became the beloved “Aunt Ida”. While I never had a chance to meet her, Aunt Ida’s legacy and her insistence on excellence permeated CMC and determined much of what I was able to learn there, along with many wonderful teachers, who I don’t have time to name. And then of course there was Cottons, the institution that first made me who I am. Being blessed with a reasonably good voice, I also sang in both the St. Peter’s Chapel and in St. Mark’s Cathedral choir through all these years, when Rev. Harry Daniels was the pastor. I have wonderful memories of that time.
At Cottons, many wonderful teachers imprinted me. But of all the people here, the one who influenced me the most was Rev. I.L.Thomas. This was an amazing man, who overcame what even today would be considered a very significant disability, behaving as if he had none. Some of you may remember a special car he designed for himself. He would hoist himself in, pull in his wheelchair, and head off and do anything he wanted. And he could wheel himself up any ramp with his own arms, with no help from anyone. He was strict and stern, yet sensitive and sympathetic. And because of my time in the choir and as a chapel prefect, I had a lot of contact with Rev. Thomas. My fondest memory was when I won the Stella Cup and Arthur Miles Chaldecott Prize for the Best All-rounder in Junior School life. One requirement was that the winner should lay flowers on the grave of the person for whom the prize was named, and Rev. Thomas insisted on arranging this himself. So he left his wheelchair behind, sat me where his wheelchair would have been, drove me off to the cemetery, drew me a little map, and told me where to go and place the flowers. I just could go on and on about how Rev. Thomas influenced me. One interesting fact that I found in researching this lecture was that he was born in 1916, and delivered by Ida Scudder herself, at CMC Vellore. It is a small world.
Another person who greatly influenced me was my grandfather, Pothan Joseph, the founding editor of the Deccan Herald, who lived at the junction of Brigade Road and Mahatma Gandhi Road. Every Saturday I’d walk over and spend the afternoon with him, little realizing that I was getting a remarkable education about many aspects of life from this amazing man. I’m very glad that T.J.S. George, the writer of important books about my grandfather is here today. One of the things I remember was that my grandfather was a friend of Gandhi. So I learned about Gandhi, and some of these lessons have also influenced me through my life. Hovering in the background was my other late grandfather A.M.Varki who I never met, a triple first class from Madras University and founding Principal of Union Christian College in Kerala. Now, having two famous grandfathers is not something I would recommend for a schoolchild – nothing I did was adequate! But in retrospect this helped me strive harder. I’m going on and on about myself, but as you’ll see, I’ll come back to this as part of my thesis about what makes us human.
From these experiences, I came away with adages to live by: that you should do to others as you would have them do to you (“Whatsoever ye would that men should do to you, do ye even so to them.” Matthew 7:12); that you will be recognized by what you produce (“Ye shall know them by their fruits” Mathew 7:16); that whatever you do, you should do your best (“Whatsoever thy hand findeth to do, do it with thy might” Ecclesiastes 9:10); that there is no point in accumulating worldly goods (“A rolling stone has no use for any moss!” Pothan Joseph); and to be humble, and prepared to confess your errors (“It is unwise to be too sure of one’s own wisdom…. I have humility enough to confess my errors and to retrace my steps” Mahatma Gandhi). Lastly, my experiences in science led me to make a motto for myself, that “absolute intellectual honesty is absolute”.
Let me now go on to my main lecture. You’re probably wondering, why is this physician-scientist lecturing about what makes us human? As I’ll explain, my research on an arcane aspect of biochemistry and molecular biology led me to become very interested in human evolution, and in uniquely human diseases. You’ve probably all heard of the central paradigm of molecular biology: that DNA makes RNA makes protein. There is a tendency to think that this is all there is in biology, creating the illusion of a recipe book that makes a human. But there are two other major classes of molecules required for a more complete view of biology. You need lipids to make membranes, and you need sugars. You normally think of sugars in terms of energy, metabolism or diabetes. But in addition to this, every cell in nature generated by evolution over the last 3 billion years is covered by a dense and complex array of sugars or “glycans”. We have glycoproteins and glycolipids, and these interact with other molecules to produce tissues and organs. And all of this is influenced by our diet, as well as by microbes that live within us (you may not be aware that you have about 30 times more DNA in your body that belongs to other organisms than yourself – you’re just a carrier for many other organisms). There is of course also the physical environment – and in the case of some species like humans, the cultural environment. So this is a more complete view of biology (See Slide 1).
The focus of my research is on these glycans that coat the surface of every cell in the body. So cells are not like the planet Mars – they are like the planet Earth, and everything that’s green is made up of sugars. Now if you were to zoom in on this sugar coating called the “glycocalyx” you would find at the very tip of the glycan chains a class of sugars called sialic acids. This is what I have dedicated my career to studying. But two things happened in 1984 that changed the way my science went. The first was that my daughter was born. Nothing in my education in medicine, pediatrics or biology prepared me for the wonder of seeing a person emerge from this helpless bundle. I also happened to see a patient in 1984, with a case of “serum sickness”. This patient was being given horse serum for certain reasons, and had an immune reaction. When I looked up the literature, somebody had just discovered that the immune reaction was against sialic acids in the horse serum. I thought, “that’s ridiculous – sialic acid is on every cell in the body, how can you have an immune response against it?” It turned out the story had to do with the fact that there are two major kinds of sialic acids in mammalian cells. Don’t worry about the details – one is called Neu5Ac, the other is called Neu5Gc – and they differ by a single oxygen atom. And Neu5Ac gives rise to Neu5Gc.
There was already an old story that Gc (as I’ll call Neu5Gc for short), might be missing in humans. I confirmed this and then decided to take into account the famous adage by Dobzhansky, that “nothing in biology makes sense except in the light of evolution”. As you may know, we shared a common ancestor with orangutans about 13 million years ago; with gorillas, about 8 million years ago; and chimpanzees and bonobos (pygmy chimpanzees) about 6 million years ago. We call these species the “great apes”. We now know that this is a misnomer: we are genetically closer to the chimpanzee than the chimpanzee is to the gorilla! And we are closer genetically to the chimpanzee than mice and rats are to each other. It’s a remarkably close relationship.
Looking at blood samples we found that while the Neu5Ac sialic acid was present in all these species Neu5Gc was missing only in humans (See Slide 2). We traced this difference to a genetic mutation that occurred in human ancestors about 2 million years ago. This happened in one chromosome of one human a long time ago, and now all of us have this mutation in both our chromosomes. We are sort of like a knockout mouse or a mutant, missing an enzyme and therefore accumulating the precursor molecule. This turned out to be the first known genetic difference between humans and chimpanzees that gave a molecular difference you could see on cells. People had been searching for years and we happened to stumble on the first one. This finding got quite popular and showed up in various media, and even featured in Michael Creighton’s final novel “Next” where he talked about sialic acid changes in a “humanzee”, mentioning San Diego, but fortunately not my name!
This finding triggered in my mind a more general interest in human origins. But while I had a medical background, I had no training in primatology, evolutionary biology, or any of the other relevant sciences. One of the great things about going to medical school is that once you have experienced “drinking from a fire hose” of knowledge, you can learn almost anything else. And so I resolved to learn about primatology and evolutionary biology, first going for several weeks to the Yerkes Primate Center in Atlanta, where they’ve had captive chimpanzees for many years. They also give excellent medical care to the chimpanzees, and I found to my amazement that there were many disease differences between us and chimpanzees, despite their being our closest relatives. And these remarkable differences were not just explained by the fact that we stand up straight. I won’t go through the list but they include many of the very common diseases of humans. So here was a biomedical rationale for studying chimpanzee-human differences, not just a philosophical one!
My hypothesis is that major diseases of a given species are likely to be related to maladaptations during the recent evolutionary past of that species. After all, if something has been working well for millions of years, absent a new toxin or virus one should be fine. But systems that evolved recently are the ones that are not going to work as well. So, comparison of disease incidence and susceptibility between humans and our closest evolutionary relatives should be useful. I suggest that more research on great ape diseases is needed, not because they are useful models of human diseases (the reason why these apes were put in captivity), but because they are bad models of many common human diseases. Further studies of great ape diseases will benefit both humans and apes.
Now, there are less than 60 genes involved in all of sialic acid biology, and you can find a few genetic differences in this system between baboons, orangutans, gorillas and chimpanzees. But we have found many more differences in these pathways between humans and apes – more than 20% of all genes involved in sialic acid biology have undergone uniquely human changes (See Slide 3). So sialic acid biology is a “hot spot” in human evolution, and this has really transformed the way my lab approaches our research. As it happens, many of our sialic acid changes might also relate to some of these disease differences. This is not the usual way of thinking about biology. We’ve all been interested in what is the same (conserved) between mice and monkeys and apes and humans – I think it’s time to start thinking about what is different, because we can learn a lot from that. My belief is that we should do research on apes using the same principles we use in humans. Unfortunately, like most human endeavors, there are two extreme views: those who think that it doesn’t matter what you do to apes, and those who say you should do no research at all. So I co-authored an article in Nature on the ethics of doing research on apes, suggesting that we should do research on them in essentially the same way we do in humans. Various groups then contacted me, saying: ‘please sign this document banning all future research on apes.’ I responded that this would be a terrible idea – would you ban all research on humans? That would be a bad idea for humans, or apes. But we have much bigger problems with regard to the very survival of the species, let alone trying to understand them. Anyway, what we do is we simply get blood samples from apes who are already undergoing routine medical checks, or tissues from autopsies after death from natural causes, and compare them with identical samples from humans. And we compare the diseases of apes with those of humans.
So this explains to you why I’ve gone all the way from a sialic acid with a single oxygen atom difference to studying human origins. These are in fact the oldest questions of humans. Who are we? What are we doing here? Where did we come from? How did we get here? And, where are we going? Some of these questions remain in the realm of philosophy, religion, and other human endeavors. But two of these (‘Where did come from?’ and ‘How do we get here’), are now scientifically tractable issues. New information becoming available allows us to approach these problems in a purely scientific fashion, to seek the truth. More recently, I rediscovered a word, which had actually been coined in 1839, but for some reason was not used very much since: “Anthropogeny”. Not anthropology, which is the study of humans, but anthropogeny, which is explaining the origin of humans. I have resurrected this word and used it to denote this quest.
Pursuing anthropogeny involves many academic disciplines (See Slide 4). It’s not sufficient to look at molecules or physiology. You need the social sciences, biological sciences, the arts, the humanities, the biomedical sciences, and plenty of input from the engineering and computing sciences, while realizing that the physical and chemical sciences (particularly the geological and climate sciences) have a lot to contribute. I have suggested that Anthropogeny sits at the middle of all of these disciplines. One cannot study Anthropogeny effectively without engaging all of them.
The quest that I began almost 20 years ago to educate myself about all these matters eventually lead to an organized research unit called the Center for Academic Research and Training in Anthropogeny, whose goal is “to explore and explain the origins of the human phenomenon” (See Slide 5). As Co-directors of CARTA I have an anthropologist (Margaret Schoeninger) and a neuroscientist (Fred Gage), and an associate director (Pascal Gagneux) who is a primatologist. If you’re interested in finding out more, you can go to the CARTA website (http://carta.anthropogeny.org). What we do in CARTA is bring together linguists, anthropologists, neuroscientists, genome scientists, social scientists, and everyone else who can help approach this question of human origins. This is a question that requires a transdisciplinary approach – not multidisciplinary, not interdisciplinary, but transdisciplinary. We have to throw away our disciplinary boundaries and talk to each other.
So here is an agenda for anthropogeny that we have suggested (See Slide 6). We need to study the last common ancestor of humans and great apes with archaeological data and fossil data; to study the effect of the environment, physical and biological and cultural, on all these species; study the development of the infant to the adult in both humans and apes; the interaction of males and females and all of these with each other; and of course, do comparisons with other primates and other species. Arising from this “agenda for anthropogeny”, the subject areas of relevance are primate genetics and evolution, paleoanthropology and hominid origins, neurosciences, primate biology and medicine, language and cognition, primate society and culture, reproductive biology, geographic and climatic factors affecting the evolution of the species, and, general theories for explaining humans. So what we do is bring together scientists from all these fields in public and private symposia. Listed at http://carta.anthropogeny.org/symposia/past/list are some of the past symposium topics, all the way from sequencing the chimpanzee genome to the evolutionary origin of art and aesthetics, to language as a human trait, and so on. This website also hosts videos from most of the past talks, and some are even on You Tube. This is an ongoing series that we are continuing to organize three times a year.
Let’s get back to a key question: ‘how different are humans and chimpanzees?’ For a long time scientists such as Jane Goodall and others have appropriately emphasized the fact that “chimpanzees are remarkably similar to humans”. Recently though, two science writers without any vested interest have independently explored the matter. These interesting books by Jon Cohen (“Almost Chimpanzee”) and Jeremy Taylor (“Not a Chimp”), serve to point out that “humans are remarkably different from chimpanzees”. Actually, both statements are correct. It is a question of which one you are interested in, and I’m interested in why are we so different? But in some ways I’m also interested in why we are so similar. They’re part and parcel of one larger question.
We have also suggested a “hominid phenome project” to compare humans and chimpanzees (See Slide 7). We now know a lot about the genome of both species and a lot about the phenome (or the phenotypes) of humans. But we know very little about the phenotype of chimpanzees and other apes. The opportunity is vanishing to really learn about the latter. But I believe this can still be done both in the wild and captivity, using methods that are very similar or identical to that which we use in humans. We need to fill this gap if were ever going to put this whole picture together.
Over the years I have collected a listing of phenotypic traits for comparison between humans and apes. This listing went through various phases, and has eventually merged into something called the Museum of Comparative Anthropogeny, which you can also find through the CARTA website http://carta.anthropogeny.org/moca/about. It is called a “Museum” rather than a database, because it not only includes differences but also claimed differences wherein it turned to be wrong. For example, we used to think that only humans were self-aware, but we now know that chimps are as well. The site is incomplete, but is still being filled in by hundreds of people who I’ve managed to get together in this collaborative. It covers every topic area you can think of, from anatomy and biomechanics to pathology to genetics to culture http://carta.anthropogeny.org/moca/domains.
So far I’ve been talking about things that are similar between humans and apes, or that are different and need to be compared. But there are a lot of things that we simply cannot compare. Some years ago I was flying across the Pacific with my daughter, who was then seven or eight, and getting quite bored. As we happened to have a dictionary, I suggested that we check entries on each letter from the top, and stop when we find the first one we thought was unique to humans. And we very quickly came up with abbreviating, bag making, calculus, dots, ear piercing, face lifting, gambling, hacking, illustrating, jet skiing, karate, lacrosse, machining, nailing, operating, panning for gold, quilting, racing, sacrificing, tagging, umpiring, vacationing etc. In an hour we were done. So I said, now take the dictionary and find everything under the letter S that is unique to humans. So we quickly got sacrificing, sack making, saddling, sailing, salt making, saluting, sandcastle building, sandwich making etc. and soon ended up at spice collection and spending, finally getting tired of it and jumping down to steel production, stitching, storytelling, sun tanning, and surfing. The point that I’m trying to make is that while we are very similar to apes, we’re also very different. And I’m particularly interested in what makes us different- not what makes us unique or special, but what makes us different (whether we’re unique or special is a matter of opinion).
So here’s a question: what mechanisms underlie human differences from the great apes? I believe this question should be approached not only by looking at the brain. The worst thing you can do if you end up in the emergency room in a coma and no family members is to have the neurologist come by first. He’ll look at your brain, and possibly miss the fact that you have diabetes or a heart infection or something else. It is better to have a general internist, who will look at the whole picture before coming to any diagnosis. This is also like a murder mystery. Every clue should be taken into account. Don’t leave out any. It may well be a clue from the heart or the skin that will tell us about how the brain became the way it is.
Let’s go back to the point about DNA making RNA making proteins, and the effects of cultural environment. Everybody will agree from the story I told of my own life, that my cultural environment had a huge impact on the outcome of my DNA. But recently I thought, could culture have a more direct impact on the genome itself? See Slide 8 . And not just in one’s own lifetime but in a species? So here’s an interesting question- does culture affect the genome? Now I need to get into some very interesting but rather complex issues, and I hope you’ll bear with me – I’ll try to be as clear as possible.
I first have to talk about the Baldwin effect. In the years following Charles Darwin’s passing, evolutionary theory was in trouble. August Weismann had shown that genetic material passed on to the next generation was only in the sperm and egg. Mendel’s laws of genetics had not yet been rediscovered, and scientists knew nothing about genes or DNA. One of the biggest problems was in explaining complex behaviors. Sure, one could imagine how you’d evolve a better heart, or a better lung or something like that, via evolution and natural selection. But how can you evolve such a complex behavior, like a beaver building a dam? Baldwin came up with his answer simultaneously with Morgan and Osborne, but he gets the credit for some historical reasons – and there’s still much controversy about this effect. It considers the costs and benefits of learning in evolution. The idea is that learning by individuals with organismal plasticity might explain evolutionary phenomena that seem to superficially appear Lamarckian (As you may know, Lamarck incorrectly thought that new abilities that emerged in individuals were handed down from parents to offspring, directly).
Here is the idea of the Baldwin effect. In species that can learn after birth like many mammals, individuals who can learn will create a niche for others. Consider my beaver analogy. One beaver gets some genetic abilities to learn better than the others and starts making a dam. That dam is going to benefit all the other beavers. Other beavers don’t have the genetic ability to make a dam, but they may learn to help make the dam. Now according to the Baldwin Effect, this will create a niche in which those individuals who can build dams survive better, thus selecting for beavers that build dams. I must tell you, many evolutionary biologists don’t like this idea, because it is hard to show that it happened, as it takes place over long periods of time but, abilities that require learning would then be replaced by evolution of genetically determined systems that no longer require that learning. And behaviors initially learned due to plasticity would become instinctive in later generations by genetic assimilation of those few individuals who were successful with that behavior, because the niche was a good thing. The Baldwin Effect has even been credited for evolution of uniquely human features like language. Terry Deacon suggests that gene complexes get integrated into functional groups as environmental changes mask and unmask selection.
However, I think there is a problem with the Baldwin Effect in humans. If a learned behavior fails to become genetically hardwired, it should disappear, because the cost to individuals who have that plasticity to learn is high. For the first beavers it is a difficult thing to do. But eventually all the beavers have to get selected as genetically wired to make a dam. That would be the idea. So let us look at humans. Two things about humans, I think are unusual- not unique but unusual – are innovation and imitation. Innovators are rare. Think of the zero. All of us in this room came from less than 10,000 individuals about 100,000 years ago in Africa. But it was less that 2000 years ago that Aryabhata and his collaborators put together the Indian system of zeros and decimal places. The Romans didn’t have it, nor did the Greeks. But nowadays, a five year-old child will tell you what a zero is. And while innovate and imitate, we also now we have amplifiers – we communicate. As you know the zero went from India to the Arabs who put numerals on it, and took it to southern Spain. The European Renaissance would not have been possible without the zero. And we also instruct, which is exactly what Cottons does. And as the population grows we have more and more innovators. So I think it’s quite unfair to compare the achievements of a few thousand chimpanzees with those of 6 billion humans. If we had 6 billion chimpanzees, there may be some that did very unusual things. But regardless, you can see what people are calling cultural evolution, which humans carry forward very well.
I suggest that human genomes have escaped the need for genetic “hardwiring” of learned behaviors. But learned behaviors that are carried for many generations without hardwiring can become lost. Although details are unclear, it appears that Tasmanians originated from the initial migration wave that came through South India, probably Andaman Islands, New Guinea, Australia, and eventually into Tasmania. And they got lost from contact for thousands of years. When the Europeans arrived they found people who barely had clothes, couldn’t make a fire, didn’t have bows and arrows, and didn’t know how to fish. They decided that these were very primitive people and exterminated them. Later on the archaeologists came and found the Tasmanians indeed had fire, bows and arrows, etc fish use etc. a long time ago. What happened to the Tasmanians is that they came from Africa with all these abilities. But the population shrank; a few old people died or forgot, and didn’t pass their knowledge. Human control of fire is at least 800,000 years old. If the Baldwin effect was operating, by now we should all be genetically wired to make a fire? If you leave a child out somewhere, he or she should be able to make a fire. But if we are not taught how to make a fire, we haven’t the foggiest idea what to do. If I took all of you and put you back in the jungles of Africa, you’d be gone in a few weeks. Without your modern tools, you wouldn’t know how to do anything.
So, I think what happens in humans is that even long standing genetic behaviors that should become genetically hardwired have remained dependent on intergenerational transfer by observation or learning. We have simply thrown away the second phase of the Baldwin effect. Imagine if we could eliminate the knowledge of the zero from all human minds today. How long will it take before we rediscover the zero? May be 50,000 years? I don’t know. So I suggest that humans have escaped the need for the second step of the Baldwin Effect in genetically hardwired behaviors. I think we just use extended development plasticity to invent, disseminate, improve and culturally transmit complex behaviors over many generations without the need to hardwire them. Of course this advantage comes at a great risk, as with the Tasmanians. We need places like Bishop Cottons. We need centers of learning. We need to transmit information, store it, and make sure that our next generation knows what we know.
What does this have to do with the genome? Are human genome’s escaping Darwinian natural selection and Baldwinian fixation of learned behaviors? Remember, that while the phenotype of animals is affected by external and internal environment, the behavioral response is usually hardwired and instinctive. But warm-blooded animals show a greater dependence on postnatal learning and the influence of learning from prior generations, with humans being at the extreme end of the trend. In mammals, this behavior can have profound effects in the genome and the phenotype by affecting the functional output of the genome. That’s just in one generation.
The confounding issue is culture. It is now known that many warm blooded animals have various forms of culture, but humans have much more of it. Many of our behaviors and artifacts are not hardwired, but handed down by observation. And in humans, also by teaching, learning, conscious choice, or even imposition by cultural practices – or by institutions, as we do at a place like Cottons. We insist that the children must learn.
Now here is what really surprises me. Even stereotyped mammalian behaviors that are crucial for species survival, such as mothering, seemed to require observation and learning in humans and great apes. If you have a cat, rat or a dog that has never seen babies and has them, it kind of knows what to do. It’ll take care of things, by instinct. It’s almost the definition of being a mammal. In contrast Sarah Hrdy will tell you that the firstborn of a monkey has a bit of trouble and sometimes dies, because the mother is looking around, not entirely sure what she’s supposed to do. Chimpanzees who have not previously seen another baby being mothered have no idea what to do. In humans of course we require the previous generation to tell us what to do.
Why would you take something absolutely crucial genetically such as mothering (it’s almost a definition of being a mammal) and throw it away? It’s because we have layered it over with culture. An analogy is vitamin C, which we humans cannot make. Our prosimian ancestors could make vitamin C. We primates then developed tricolor stereoscopic vision, went on to eat a lot fruit, thus being exposed to vitamin C all day, all the time. So nobody noticed when a critical gene for making vitamin C gene got knocked out. And then one day you go onto the high seas without any fresh food and you discover scurvy. But it’s too late, you’ve lost your gene, and you cannot get it back. In a similar manner we humans have lost a lot of our genetically wired abilities, and transferred them over to culture. This is very powerful because it seems unlimited, but also dangerous. So my speculation is that apes in general and humans in particular have partially escaped Darwinian control of the genome. Humans have even escaped Baldwinian genetic hardwiring of longstanding species-specific learned behaviors.
What does this have to do with genome? You’ve heard the standard statement: human and chimpanzee genome differ by less than 1%. That is true in any region of the genome that you can lineup between the two species. When I was involved partly in the chimpanzee genome project, one of the amazing findings was that 1.5% of the human genome does not exist in the chimpanzee genome. And 1.5% of the chimp genome does not exist in the human genome. If you look at the genomes of humans, there are big chunks of DNA that have been thrown about here and there, lying around, with broken pieces, etc. It’s a mess. These changes are very prominent in human genomes, and a colleague of mine with whom I wrote this article, Evan Eichler, says that this seems to be greater in humans than in rodents, worms, and insects. In other words this is a feature of animals like primates, particularly humans. We don’t yet have data to know, but I would predict that humans have more of this than great apes.
While risky, you can derive some benefit from this mechanism. An example is a thing called gene “copy number variation”. Some people have 10 copies of a gene to digest starch instead of one copy. That’s great if you’re in an agricultural society. You can use this genomic mechanism to power ahead in various ways. But it is also very dangerous because such large-scale genomic changes have been recognized in significant relationship to autism and schizophrenia. One of the big puzzles is why does autism and schizophrenia persist in the human population? Those people don’t reproduce as well as healthy humans, so evolution should select against their genes. And yet the diseases keep showing up over and over and over again, across every society and every culture. I have suggested these events are common in humans because they’re better tolerated, because they’re buffered by dependence on learning rather than hardwired behavior. I suggest that most of you would never make it to reproductive age without your society and culture that supports you. And this cultural support can go further, bringing out some wonderful talents. If you want to read about this, you can look in the 2008 Nature Review Genetics outline of what I just said(See Slide 9.)We didn’t go as far as to say it in this review, but I do wonder whether the human genome is in “meltdown”. Are we allowing our genomes to drift so much that we are no longer dependent on them for many things? That is very powerful, and on the other hand very risky.
This brings me to “Wallace’s Conundrum”. Some of you know that Alfred Russel Wallace was the true co-discoverer of evolution via natural selection, who independently came up with the idea, co-published with Darwin and then lived 20 years longer. Yet you hardly ever hear about Wallace. He lost his reputation partly because he questioned whether natural selection could account for the evolution of the human mind, saying: “I do not consider that all nature can be explained on the principles of which I am so ardent an advocate; and I am now myself going to state objections, and to place limits, to the power of ‘natural selection’. How could ‘natural selection’, or survival of the fittest in the struggle for existence, at all favor the development of mental powers so entirely removed from the material necessities of savage men….?” (Wallace, A. R. in Contributions to the Theory of Natural Selection. A Series of Essays, Macmillan, London, 1870). What he said was, I can take babies from Borneo and bring them to England, and if I give them the opportunities, they’ll become Englishmen. How can it be that all the abilities of the human mind were already evolved, a hundred thousand years ago, before we left Africa? So Wallace said “an instrument has been developed in advance of the needs of it predecessors”. More than 99.9% of what you did yesterday did not exist when the genes for your brain evolved. How can that be? Wallace was criticized for evoking spiritual explanation, but I think his point remains valid. It is difficult to explain how natural selection selected ahead of time for the capabilities of a human mind that we are continuing to exploit today.
The standard explanation is “exaptation” e.g., dinosaurs had feathers and then birds adapted them to fly. But that doesn’t mean that if I bring a dinosaur here, it’s going to fly. But if I take 1000 newborn babies from 50,000 years ago bring them here today and give them every opportunity, some of them will get admission to Cottons. Conversely, if I take 1000 newborn babies from today and transport them back 100,000 years ago, they’ll be thinking like the people of that time. How can that be? Experts in human evolution and cognition, I believe, have yet to provide a satisfactory explanation. Wallace’s conundrum remains unresolved. “…that the same law which appears to have sufficed for the development of animals, has been alone the cause of man’s superior mental nature,… will, I have no doubt, be overruled and explained away. But I venture to think … that they can only be met by the discovery of new facts or new laws, of a nature very different from any yet known to us.”(Wallace, A. R. in Contributions to the Theory of Natural Selection. A Series of Essays, Macmillan, London, 1870). Is this ‘Wallacean’ evolutionary mechanism related to our suggestion – that aspects of human uniqueness arose following relaxation of selection for maintenance of genome integrity, allowing partially escape from Darwinian and Baldwinian selection, and more dependence on inter-generational cultural transfer? There are some other animals that do cultural transfer, but there are none quite like us.
In the final part of my talk, I want to try and address more directly some of the critical features required for a human mental abilities, including self-awareness. Self-awareness is also present in dolphins, some whales, chimpanzees, and orangutans, even some birds – they all recognize themselves in a mirror, they know who they are. So self-awareness has been around for a long time. The critical step is to move on to having a full “theory of mind”. Studies show that a chimpanzee can recognize another chimpanzee as an individual that can make certain actions and responses. So many animals may have this rudimentary theory of mind. But what we humans have, which has not been found to date in any other animals, is a full theory of mind. For example I know that Philip Wollen in the audience has a mind and that Principal Zachariah has a mind, and that all of you have minds. And I have still have a theory of mind of I.L. Thomas. I can even have a theory of mind of Gandhi. So on and so on. This full theory of mind, (sometimes called “the attribution of mental states to others”), has so far not shown up in any other animals. Elephants and chimpanzees seem to be right on the brink, but just don’t pass that barrier. There is another related feature that seems also uniquely human, the ability to hold false beliefs against the facts. There are lots of other terms you might come across to describe these features, e.g., multi-level intentionality, intersubjectivity, other regarding-ability, empathy, prosociality etc. In contrast, there are many things that we couldn’t do without a full theory of mind. I couldn’t give this lecture to you if I didn’t have a full theory of mind of all of you. Other examples including acting, care of the infirm and elderly, healing the sick, social control of paternity, torture, etc. Theory of mind gives you wonderful abilities, and helps a lot to explain the human mind. In contrast, one of the things about autism is that theory of mind is partially or completely lost, and these individuals often have difficulties in empathy.
So this finally brings me to something very unusual that happened a few years ago. I was at the University of Arizona giving a lecture like this one. Whenever I do so, someone will come up to me later and say, “I’ve got the right answer.” Usually it’s someone with a crazy idea. So this tall, thin fellow sits next to me and says, “you’re asking the wrong question.” Turns out he’s Danny Brower, professor at the University of Arizona, a well-known insect geneticist. And he proceeded to give me this idea that helps to explain some of the issues we have been discussing. I said, “Danny this is excellent, you should write this up.” He said, “No, I’m just an insect geneticist.” For the next 2 years I couldn’t get Danny’s idea out of my head. So, I wrote to him a long e-mail explaining the idea, and encouraging him to get it published. I never heard back from him. In 2008 I looked him up on the Internet and found that he had dropped dead. He was one year younger than me, but had an unusual cardiovascular disease. So now I had an idea from a man who was dead. I looked everywhere, couldn’t find any evidence he’d written anything. Finally I found one of his friends who said yeah, Danny had this crazy idea and he was working on it when he died. I happened to know Philip Campbell the editor of the journal Nature, so I contacted him and asked what do I might do with this? Campbell asked me to write him a letter, which was published at the end of 2009, entitled “Human Uniqueness and the Denial of Death.”
So here is Danny’s novel insight into human origins, yet to be tested by experts and aficionados. Chimpanzee, orangutans, elephants, dolphins, magpies, and likely other animals we haven’t yet tested are self-aware – they recognize themselves in a mirror, and likely have a rudimentary theory of mind. Danny said “you shouldn’t be asking what special brain cells got together and made us so smart. You should be asking instead – What’s the problem? How come we don’t have human-like elephant? How come we don’t have human-like whale? What’s holding back all these species? They’ve been on the brink for tens of millions of years of this evolutionary time. So why have human-like mental abilities not emerged more often?” Danny pointed out the full awareness of other minds is accompanied by awareness of your own mortality. While elephants, chimpanzees and other animals can grieve, and seem to understand death to some extent, there’s nothing like human grief. We fully understand death because we have a full theory of mind of the individual who died.
What’s the corollary? It means that we know that we are going to die, for sure. Danny suggested that the resulting paralyzing fear would initially direct one’s focus on personal survival, over success in reproduction. Remember all that matters in evolution is to reproduce. You can be very smart, have any genes you like, but if you don’t pass your genes on, it doesn’t matter. So imagine an elephant today in Africa who finally understands the full theory of mind. He looks around and realizes that all the other elephants are individuals like him, have minds – but they’re not yet equally ready to communicate with him, a very difficult situation. And then another elephant dies. He realizes he is going to die and says; I’ve got to protect myself. So what happens is that he dies without reproducing. So Danny suggests that many animals have been trying to make this transition many times, and we finally did it. Our solution to this evolutionary psychological barrier was to deny our mortality. We’re aware of death, but we deny it. So in other words, we have a very intellectual and clinical view of death. And until it faces us, we don’t really worry about it. We jump out of planes, we get into boats and go off into unknown territory, and we go to war. But we’re convinced it’s OK, death won’t happen to us it’ll happen to somebody else. We smoke cigarettes and think it’s OK; someone else will get the lung cancer. We eat bad food and think we will get away with it, and so on.
I thought I’d done my duty for this idea, which is not really in my field. And then I was contacted by Danny’s widow, who said, “that’s a wonderful thing you did. The reason Danny never contacted you, was that he was spending all his time trying to write a book on his idea, and he dropped dead when he finished his second draft. But nobody will publish it because it’s incomplete, and it’s not fully researched”. So I now have Danny Brower’s manuscript. I have decided that this needs to be published because it’s not just about denial of mortality (which I think is an important idea in evolution). Danny also points out that our ability to deny goes far beyond mortality. We deny everything we don’t like. We even deny the mortality of our biosphere. We have the facts, but we just deny the reality.
On the other hand I think there is a positive side of denial that Danny doesn’t go into too much. What is optimism? Optimism is denial of reality. What did Gandhi do? He completed denied the reality of the British Empire he was facing, and forged ahead because he denied the possibility that he is going to fail. So denial can be a very positive force or a terrible negative force. It gives us theory of mind with all its abilities, and that’s a bonus. We need to engage the positive aspects of denial and deal with the fact that there are a lot of negative aspects of denial. I’m not sure when this book will see the light of day because of my extremely busy schedule, but I’m convinced that I must get it out. It will be co-authored by both Danny and me, with Sharon Brower’s permission.
It turns out that the first part of Danny Brower’s idea is not new. Some of you are probably aware of Ernest Becker’s book on Denial of Death where he says that “the human animal is characterized by two great fears that other animals are protected from: the fear of life, and fear of death” And this is a popular area of psychology, with a follow up field called “terror management theory”, i.e., how do we manage the terror of knowing we are going to die? Kalyan Banda from my lab (also a Cottonian, and whose father is in the audience) then came to me and said, “the second evolutionary part of the idea is truly unique, but the first part is as old as time”. So Kalyan told me about the story of Yudhisthira in the Mahabharata, how the Pandavas were captured by the Yaksha, who told Yudhisthira that he must answer the great questions of life, to set his brothers free. The final question the Yaksha asked was: “What is the greatest surprise?” Yudhishthira replied, “People die everyday making us aware that men are mortal. Yet we live, work, play, plan, etc. as if assuming we are immortal. What is more surprising than that?” So this idea has been around a long time. The new idea is the evolutionary one, the denial part and how that helps us on.
Thank for your attention to my remarks. I need to acknowledge Cottons and CMC, members of my lab, mentors and collaborators, NIH, the Mather’s Foundation, Yerkes Primate Center and, many institutions I’ve been associated with. Of course as you probably know, behind every successful man there is a surprised woman! In my case there are four. First and foremost my mother who is here today, who made me what I am; secondly my daughter who turned out to be a model child, and thus allowed me a lot of time to pursue my work; thirdly, Sandra Diaz who has run my lab for the last 25 years; and, last but not least my spouse Nissi Varki, without whom I would not be here today.
So, I’d like to leave you with the thought that anthropogeny is actually an agenda for humanity (see Slide 4). This is not just some philosophical pursuit. We need to know, for medicine, for biology, for the way we bring up children, for the way we run institutions, what is this thing that we call the human mind? How did it come about? How did we get here? What are the molecules, what are the systems, what are the social constructs? This is a transdisciplinary agenda for all of us.

Commandant’s Address

1. Every year the Thimayya Memorial Trust organizes a lecture to commemorate and pay tribute to one of the Greatest Generals of our great nation. Gen Thimayya, popularly known as ‘The Soldiers General’ is reverred not only in India but also in the entire world for his service to the United Nations in Korea & Cyprus. KUMAON Regiment indeed has been blessed to have him at its helm as Colonel of the Regiment for more than ten years.
2. On taking over the reigns of the KUMAON Regt from the likes of Gen Thimayya, I feel humbled and privileged to continue that legacy.
3. Much that I wanted to be present on this solemn occasion but having taken over as Commander- in- Chief Andaman & Nicobar Command only on 01 Jan 2011. I as Army C-in-C after a spell of six years, had to be present for the Army Day on 15 Jan 11. Therefore, I am unable to be with you all.
4. I wish the event very best and am sure the Trust will grow from strength to strength and will continue to do the good work from times to come.

Press Coverage

http://www.deccanherald.com/content/130024/we-need-all-possible-human.html