On October 23, 2017, at the Sanford Consortium for Regenerative Medicine in San Diego, California, the Academy, in collaboration with the Center for Academic Research and Training in Anthropogeny (CARTA), hosted the Morton L. Mandel Public Lecture on “How Are Humans Different from Other Great Apes?” The program, which served as the 2060th Stated Meeting of the Academy, included a welcome from Gordon N. Gill (University 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 Reproduction; Fred H. Gage (The Salk Institute; CARTA) on Genetics and Brain Development; Margaret J. Schoeninger (University of California, San Diego; CARTA) on Anatomy 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.
It is a privilege and honor for an organization that is less than ten years old (namely, CARTA) to partner with one that originated before the U.S. Constitution was written (the American Academy of Arts and Sciences). A common theme supported by both organizations is the discovery and dissemination of factual knowledge. Time does not allow me to provide a description of the origins and goals of CARTA, so I will simply read our mission statement:
“To use all rational and ethical approaches to seek all verifiable facts from all relevant disciplines to explore and explain the origins of the human phenomenon, while minimizing complex organizational structures and hierarchies, and avoiding unnecessary procedural complexities. In the process, train a new generation of scholars in anthropogeny [understanding the origin of humans], and also raise awareness and understanding of the study of human origins within the academic community and the public at large.”
The overall question at hand today is: How Are Humans Different from Other Great Apes? At first glance, the last three words – “Other Great Apes” – may appear a bit strange. Let me explain. Humans are, of course, primates, who shared a common ancestor with Old World monkeys, then with Gibbons and other lesser apes, then with orangutans, followed by the gorilla and eventually with the common ancestor of the chimpanzee and bonobo, the so-called pygmy chimpanzee. Based on anatomical, physical, and behavioral features, we humans classified our closest evolutionary relatives as “the Great Apes.” In reality we are more similar at the genomic level to chimpanzees and bonobos than these two species are to gorillas. Moreover, at the genomic level, we are more similar to chimpanzees than mice and rats are to each other.
Thus, from a genomic perspective, humans are nothing more than one kind of “Great Ape”; the correct term encompassing all these groups is “Hominid.” Asking how we are different from the other Hominids is one way to understand our own evolutionary origins, an approach that we call “Comparative Anthropogeny.”
Carrying out this comparison requires attention to a very large body of knowledge. One of the currently incomplete efforts of CARTA is to try to collate this knowledge on our website under the rubric of The Matrix of Comparative Anthropogeny (MOCA), which is a collection of comparative information regarding humans and our closest evolutionary cousins, with an emphasis on uniquely human features.
MOCA is still very incomplete, but it is organized by Domains (each with defined Topics) arranged by areas of interest and scientific discipline. Some examples of MOCA Domains are: Anatomy and Biomechanics, Behavior, Cell Biology and Biochemistry, Cognition, Communication, Culture, Dental Biology and Disease, Development, and Ecology. In the time available today, we cannot possibly cover even a small portion of these Domains of knowledge. Instead, our panelists will explore some specific examples of distinctly human features, ranging from genetic to cognitive to anatomical to behavioral to biomedical, while also considering implications for explaining human origins.
I would like to start with a little bit of geography. Humans are the only peri-planetary ape. In contrast to us, our closest living relatives are restricted to the tropical forests of Africa and Asia. As Ajit has just mentioned, we are more closely related to two species of these Great Apes. Some people have started debating whether we should be in the genus Pan or whether the two species of Pan should be in the genus Homo.
Paradoxically, the living apes, even though their populations are under very intense threat from deforestation and direct hunting, still contain more genetic variability than all seven billion humans on the planet today. The other striking contrast you might notice is that all the other apes, except us, exist 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 pieces of chromatin, reshuffled from our parents. Each of your haploid genomes is about a meter long. So you have about two meters of DNA in each one of your cells. That sounds mighty short, but each meter contains three billion base pairs, and therefore we have two times three billion base pairs.
One of the ongoing research projects in many labs around the world is to identify differences in the genomes of hundreds of different apes and thousands of different humans, which are now available for study because the entire genome, each of the three billion base pairs, has been sequenced.
The results are showing some very surprising findings. There are huge differences in copies. For example, there are copies of segments that can range from a couple of base pairs to millions of base pairs that have expanded in only one species of ape, or in chimpanzees and gorillas, but not in humans. In the reverse, we have copies of chunks of DNA that have only expanded in humans but not in the other apes.
And there are completely novel genes that pop up in different species. There are pseudogenes that are still recognizable based on their DNA sequence, but have stopped encoding proteins. You can mine the genomic data to find evidence for recent positive selection, in which natural selection has forced more changes to the protein-coding DNA than you would expect.
Humans are made of trillions of cells, and different cell types play a different subroutine off the mostly clonal genome that is in all your cells. So by tweaking where you express which combinations of genes, you can actually change how the organism looks.
I thought I would say a few things about the complex nature of the genomic landscape. In these three billion base pairs, we have about twenty thousand protein coding genes, which corresponds roughly to the number of undergraduate students at USCD. There are hundreds of thousands of enhancers – chunks of DNA with a function, even though they never make proteins – that influence the activity of other genes. And many of these are transcribed. We don’t know what that transcription really does. So, we have a vast genomic landscape, and we are only beginning to discover new functions for pieces of DNA that, until recently, were thought of as mere junk.
One of the striking differences between humans and their closest living relatives is the schedule of life. In several aspects, humans have slowed down. Our gestation time is only slightly longer than that of the chimpanzees, for example, but we have invented a couple of key things. Humans seem to have invented childhood, adolescence, certainly grandmotherhood, and sometimes grandparenthood for relatively long periods – up to 30 percent of the total lifespan is comprised of the post-reproductive survival phase.
Some have proposed that this might have been an adaptation to cultural opportunities, given the importance of cultural transfer in our species. Or perhaps it was due to nutritional opportunities, in which mothers with better access to high density-rich foods can actually do novel things in utero. It may also have been facilitated by stronger pair bonds between parents or by allomothering, which is when other individuals in the group help you take care of your kids.
Now, what does this delay in growth allow? The delay allows increased transmission of behavior and concepts. Humans are eminent copiers. We hyper-imitate. In comparative studies of the transmission of tool use, chimpanzees are very good at imitating to achieve a goal. Humans, on the other hand, focus at least as much on how it is done and show normative tendencies.
Human minds are effective copying machines. Somebody comes up with a good idea, and then everybody in the group maintains that idea. We develop a ratcheting culture, in which we build upon each other’s ideas.
One very interesting idea is that this delayed development is actually a biological assimilation of the cultural input. Humans in hunter-gatherer societies have a shorter inter-birth interval than apes. Humans can give birth about every three years, chimpanzees only every five or more years. Even though our babies are costly, we can produce more of them than our living Great Ape relatives. And when humans are done making babies, they actually survive for a long time. Our societies, long before medicine, the Industrial Age, or the farming age, allowed for grandmothers and grandfathers.
Interestingly, in evolutionary biology it is pretty much accepted that toward the end of the reproductive period, there is a minimal force of selection. But if you allow for cultural transmission, post-reproductive individuals can actually facilitate the survival of related, younger individuals, which opens up later stages in life to the action of natural selection.
With regard to forming the next generation, what is striking is that to find strict monogamy in nonhuman primates, you need to look at the lesser apes, the Gibbons. They live only in the forests in Southeast Asia. The other Great Ape close relatives have completely different mating systems: for example, the gorilla’s harem-like societies, with the big Silverbacks that have exclusive access; the dispersed systems of the orangutans, with two types of males: the big males that are chosen by the females and the younger males that bypass female choice and force the females to mate with them; and chimpanzees and bonobos, with multi-male/multi-female societies, in which each ovulating female will mate with every male in the group.
For humans, what is striking is that even though humans live in groups, pair bonding is a major phenomenon. This allows humans to participate in reciprocal exogamy, which essentially means exchanging mates across social groups. It allows for linking multiple kin lineages. Now, if you combine the cognitive capacity of our slowly maturing children, the allomothering, and the input of the group into each child, a striking array of things becomes possible. It essentially allows for our social-cultural niche. We share symbols. We have personal names. We have kinship terms, which allows for the formation of tribes. We have shared rituals, dance and music, sacred spaces, and group identity markers, and we can increase the capacity to cooperate with and compete against other groups.
I would like to provide you with an example or two of how a process may have led to the differentiation of humans from our closest relatives, and then talk about a cellular system that allows us to look at potential molecular and cellular differences that might have led to dissimilarities in who we are.
What we know is that the brain has increased in size across species during evolution along the branch that leads to humans. And we have come to the hypothesis that the growth of the brain is causally linked to what it is to be human. The correlation is placed there because as the brain became larger, we acquired features that seemed more unique to the complexity in behavior that humans can exhibit. For example, when we think about what are the measures that allow us to examine how we may have evolved, we can use genetic information. Svante Pääbo has been able to extract DNA from ancient bones and make a hypothesis about how that DNA may differ through evolution, particularly from our closest ancestral relatives.
Sometimes we obtain postmortem brain tissue from our closest ancestral relatives. We can measure the magnitude of gyrations in the cortex and explore specific ideas or hypotheses about how they may be important. In addition, we have fossil crania to study and, from those skulls, we can build casts or make CT scans to get an idea of how the brain size was changing, again building our theories based on these measurements and the correlations that exist.
Furthermore, we have cultural icons as well that give us an idea of how far a species had emerged, given its ability to build, plan, and generate art.
In each case, we have material that we can work with: genetic material, tissues, organs, and cultural artifacts. What has been missing, however, is living tissue from some of our lost ancestors and from our closest relatives, like chimps and bonobos.
So the “missing link” is the ability to interrogate the activity and function of live cells and the phenotypes of the cells. We have established a bank of cellular tissues from many of our closest relatives that allows us to look at distinctions between ourselves and our closest relatives.
As Pascal mentioned, chimpanzees and bonobos are our closest relatives, with 95 percent of our genomes being similar; yet, there are vast differences in phenotype. How can we begin to understand the cellular and molecular mechanisms responsible for these differences?
One of the things we can do is take somatic cells, such as blood cells or skin cells, from all of our closest relatives. Through a process called reprogramming – by overexpression of certain genes in these cells – we can turn the skin or somatic cell into a primitive cell, called an induced pluripotent stem (iPS) cell. These primitive cells are in a proliferating, living state that can be differentiated to form, in a dish, any cell of the body, allowing us, for the first time, to form living neurons or living heart cells from all of our closest relatives and then compare them across species.
These iPS cells represent a primitive state of development prior to the germ cell. So any change detected in these iPS cells will be passed along to their progeny through the germ cell and into their living progeny.
Now a little bit of a disclaimer for those of us who work in this field: these cells have limitations. They are cells in culture. We cannot really look at social experience, and their relevance to a living organism is oftentimes questionable.
But we can ask the question: are there differences that are detectable at a cellular and molecular level that help us understand the origin of humans? We have begun building a library with other collaborators around the world, and have reprogrammed somatic cells from many of these species into iPS cells. They retain common features of embryonic stem cells at the cellular level and they have the same genetic makeup as predicted based on the species.
In our first attempt to see if we could identify differences in these primitive cells, we did what is called a complete transcriptional (mRNA) analysis. If we compare the transcriptional genomes of chimpanzees and bonobos, there are very few differences. So we pooled all our animals together and compared that combined nonhuman primate group to the human group.
In analyzing these genomes, we detected two very interesting genes. One is called PIWIL2 and the other is called APOBEC3B. Why are we interested in these two proteins? These two proteins are active suppressors of the activity of what we call mobile elements, which are genetic elements that exist in all of our genomes. In fact, 50 percent of the DNA in human genomes is made up of these mobile elements (molecular parasites of the genome). So what are mobile elements? They are elements that exist in specific locations in the genome and, through unique mechanisms, they can make copies of themselves and jump from one part of the genome to another. Barbara McClintock discovered these elements through her work on maize.
Some of us study a specific form of mobile elements called a LINE-1 retrotransposon. They exist in thousands of copies in the genome, as a DNA that makes a strand of RNA and then makes proteins that binds back onto the RNA, helping the element copy itself. This combination of mRNA and proteins then moves back into the nucleus where the DNA resides and pastes itself into the genome at a new location.
These LINE elements continue to be active in our genome, and they are particularly active in neural progenitor cells. Thus, the reason for our interest in PIWIL2 and APOBEC3B is because it has been demonstrated that both of these proteins can suppress the activity of LINE-1.
Not only do humans make more of these proteins, but as an apparent consequence, the lower levels of these L1 suppressors in chimpanzees and bonobos means the L1 elements are much more active in chimpanzees and bonobos than in humans.
When searching the DNA libraries (genomes) that have been sequenced for chimps, bonobos, and humans, there are many more L1 DNA elements in the genomes of chimps and bonobos relative to humans.
This greater number of L1 elements in non-human primate genomes leads to an increase in DNA diversity and, thus, in the diversity of their offspring and potentially in their behavior. This led us to speculate that this decrease in genetic diversity that occurs in humans leads to a greater dependence on cultural adaptive changes to survive as a species rather than genetic adaptive changes. For example, if a virus were to infect a chimp or a bonobo population, in order for that species to survive it would require a member of the species with the genetic mutation that provided protection in some form from the virus. Humans do not wait for the mutation from a member of the species that would provide protection from the virus. We build hospitals, we design antibodies, we transmit our knowledge through cultural information (cultural evolution) rather than relying on genetics (genetic evolution) for the spread and the survival of the species.
In the 1990s, my research group happened to discover the first known genetic difference between humans and chimpanzees. Because I didn’t know very much about our close evolutionary relatives, I took a sabbatical and went to the Yerkes National Primate Research Center to learn more about apes and chimpanzees. Given my medical background, I paid special attention to diseases, and I found that the Center was using Harrison’s textbook of Internal Medicine, which is the same textbook I had used for humans. And so I thought, well, they must be just like us. And, indeed, when I first looked at the major causes of death in adult captive chimpanzees, the number one killer was heart disease, heart attacks, and heart failure. Again, I thought, well, they are just like humans. But then when I started going over the textbook with the veterinarian, I noticed that not all the diseases were the same.
So the question arises: are there human-specific diseases? There are a few criteria for human-specific diseases: they are very common in humans but rarely reported in great apes, even in captivity; and they cannot be experimentally reproduced in apes (in the days when such studies were allowed). The caveat, of course, is that reliable information is limited to data on a few thousand Great Apes in captivity. But these apes were cared for in NIH-funded facilities with full veterinary care – probably better medical care than most Americans get – and there were thorough necropsies.
As it turned out, I was even wrong about heart disease. It was not until my spouse and collaborator Nissi Varki looked at the pathology that she realized that while heart disease is common in both humans and chimpanzees, it is caused by different pathological processes. While a human heart can show coronary blockage that reduces blood flow to the heart and results in myocardial infarction, heart attacks, and heart failure, chimpanzees that died of “heart attacks” and “heart failure” had a completely different pathology. They developed massive scar tissue replacing their heart muscle, which is called interstitial myocardial fibrosis.
It turned out that the veterinarians were well aware of this, but had not reported it because they thought it wouldn’t be interesting because it was not like humans! There is now a special project called The Great Ape Heart Project, which is providing clinical, pathologic, and research strategies to aid in the understanding and treatment of cardiac disease in all of the ape species.
There are actually two mysteries to be solved: why do humans not often suffer from the fibrotic heart disease that is so common in our closest evolutionary cousins? They all can get it – the orangutans, gorillas, chimpanzees, bonobos – and we don’t. Conversely, why do the Great Apes not often have the kind of heart disease that is common in humans?
Nissi and I then worked with Kurt Benirschke and with others and wrote an article on the “Biomedical Differences Between Humans and Nonhuman Hominids: Potential Role for Uniquely Human Aspects of Sialic Acid Biology,” which focused somewhat on our own research on sialic acid biology.
We put together a list of candidates of human-specific diseases that meet the criteria I mentioned earlier, and myocardial infarction is number one. Malignant malaria is number two. In studies done from the 1920s to the 1940s, people actually did horrible two-way cross-transfusions between chimpanzees and humans infected or not infected with malaria, and there was no evidence of cross-infection. In fact, the parasites looked the same, but they were actually completely different.
More modern work done by Francisco Ayala and others showed that, in fact, P. falciparum arose from P. reichenowi by a single transfer from a Great Ape. Pascal Gagneux and I wrote an article that explains what might have happened. There are multiple forms of ape malaria that are mild throughout Africa. At some point, we escaped because of a change in the surface sialic acid molecule. One of them finally “figured out” how to bind to the sialic prominent in us, and that is now P. falciparum malaria.
Another candidate for human-specific diseases is typhoid fever. More horrible studies were done in the 1960s that showed that large doses of Salmonella typhi did not result in severe cases of typhoid fever in chimpanzees. Working with Jorge Galán and others we found that, in fact, what happened is that the typhoid toxin, which is the soluble molecule that really mediates the severe symptoms of typhoid fever, cannot bind to the chimpanzee cell surface. It can only bind to the human cell surface (again, because of the sialic acid difference between the species).
Another candidate is cholera, which is a major killer in humans. Robert Koch complained in 1884 that “. . . although these experiments were constantly repeated with material from fresh cholera cases, our mice remained healthy. We then made experiments on monkeys, cats, poultry, dogs and various other animals . . . but we were never able to arrive at anything in animals similar to the cholera process.”
So, Vibrio cholerae does not induce diarrhea in adult animals other than in humans and many people are trying to figure out why.
There are many other candidates for human-specific diseases. There is another set of diseases in which various bacteria carry out molecular mimicry, in which bacterial capsular polysaccharides mimic common motifs on sialoglycans of mammalian cells – like a wolf in sheep’s clothing.
Another difference is in carcinomas, cancers of epithelial origin. To date, no captive Great Apes have reported carcinomas of the esophagus, lung, stomach, pancreas, colon, uterus, ovary, or prostate. They do develop cancer in the hematopoietic system and elsewhere.
There are a few thousand Great Apes living in captivity, and living well into their fifties and sometimes into their sixties. So you would expect a few carcinomas based on the incidence in humans. Nissi and I wrote an article that reviewed the subject, and concluded that while relative carcinoma risk is a likely difference between humans and chimpanzees (and possibly other Great Apes), a more systematic survey of available data is required for validation of this claim.
Time does not permit me to talk about Alzheimer’s Disease, HIV, hepatitis B complications, muscular dystrophy, preeclampsia, frequency of early fetal wastage, frequency of premature labor and birth, and frequency of chronic female iron deficiency. But bronchial asthma is interesting. Great Apes don’t seem to get bronchial asthma, an extremely common disease in all human populations. I found this claim a little hard to believe until I came across a paper entitled “Eosinophilic Airway Inflammation in a Monkey.” The article concluded that the present case that was studied was “remarkable because there is a paucity of reports of naturally occurring allergic airway disorders in nonhuman primates.”
So we can draw several conclusions: 1) The disease profiles of humans and chimpanzees are rather different. 2) Chimpanzees are actually poor models of many human diseases. We should pay more attention 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 similar 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 question is whether the current ban on chimpanzee research will do more harm than good. I personally think it will do more harm because chimpanzees would also benefit from more ethical studies of their own diseases. But that is where we stand right now.