Size isn't everything, comparatively speaking

Abstract

New technology continues to drive the discovery of new human-specific brain phenotypes. What can comparative studies of human and non-human primate brains tell us about our unique vulnerability to brain diseases? David Holmes reports.Todd Preuss was in provocative mood when The Lancet Neurology spoke to him in September. From his base at the Yerkes National Primate Research Center at Emory University, USA, Preuss is at the vanguard of a small but growing community of researchers, mostly from a physical anthropology background, whose goal is to find out more about the unique specialisations of the human brain that make our species what it is. And it's a field, says Preuss, that neurologists would do well to pay more attention to.“Modern evolutionary ideas have never really permeated into the neurosciences except among those neuroscientists who come from a zoological tradition rather than a biomedical or a psychological tradition”, says Preuss, who describes himself as a neuroanatomist and biological anthropologist. “Within the neurosciences people either think there are really no differences between humans and animals worth talking about, or they think that human brains are so completely different from all other animals that it's not even worth your while to study animals.” That's a tragedy, Preuss argues, because both positions ignore the unique angle that a comparative evolutionary perspective can give to some of neurology's most pressing questions. “In neurology and psychology a lot of the things we're dealing with in humans are things that are in some way a result of our unique evolutionary history”, he says. “I think Alzheimer's disease is one, and I suspect schizophrenia is as well.”One of the most striking things about the human brain is its size—three times the size of the brains of our closest relatives, the great apes, “It's bizarre”, says Preuss, “it's one of the real oddities of biology.” But just saying overall brain size is big is not really saying much; “humans are distinct from all other primates in a suite of behaviours including altruism, planning and foresight, and most glaringly language”, explains Michael Platt, of the Levine Science Research Centre at Duke University, and it's unlikely that these behaviours are simply a result of a scaled-up chimpanzee brain. “What's been addressed to a much lesser extent, but thankfully now with a much accelerated intensity”, says Chet Sherwood, from the laboratory for evolutionary neuroanatomy at George Washington University, DC, “is besides large brain size, what are the other traits of the human brain that are unique, and can we map those neural traits on to our behavioural and cognitive traits, and also on to our species-specific vulnerability to brain diseases?”Uncovering the detailed differences in anatomy, gene expression, growth, development, and ageing that sets the human brain apart from that of our closest relative, the chimpanzee, clearly means developing a detailed understanding of chimpanzee brains. And this, for understandable reasons, is easier said than done. By working with zoos and research facilities, Sherwood's laboratory and his collaborators have been able to put together one of the best cross-sectional samples of chimpanzee brain tissue in existence, and their studies comparing the development of human, chimpanzee, and macaque monkey brains have yielded some remarkable results, particularly relating to myelin development.The typical primate pattern of myelination, Sherwood explains, seems to be that myelin grows slowly within the cerebral cortex and is finished growing essentially before puberty. “Whereas in humans”, says Sherwood, “every car insurance company knows that the brain continues to mature and remodel well past puberty into the mid-to-late 20s, and we know that is related to improvements in decision making and emotional regulation.” And the comparative studies of myelination bear that pattern out; a prolonged post pubertal increase in myelin in the cerebral cortex that is unique in humans among primates, even compared with chimpanzees. “What's really interesting about that”, Sherwood explains, “is that this distinctive phase of myelination right after puberty is a period of unique human susceptibility to certain psychiatric disorders. This is the period of onset of schizophrenia and of bipolar depression.” The task now is to find out whether some of those genes that are implicated in schizophrenia and other psychiatric disorders might also be regulating this species difference in brain development; “it would be very interesting to know if there is some overlap between those genes”, says Sherwood.The first steps towards uncovering human-specific patterns of gene expression in the brain were taken in the early part of the last decade, with a series of cross-species microarray analyses of RNA transcript levels, but researchers are now increasingly turning to next-generation sequencing to compare gene expression. In a study published in August, UCLA's Daniel Geschwind and colleagues used next-generation sequencing to compare gene expression in the brains of humans, chimpanzees, and rhesus macaques. Geschwind's team looked specifically at three different brain areas, the caudate, the hippocampus, and frontal pole, which was of particular interest, they explained in the journal Neuron, because of its key role in higher-order cognition and its possible malfunction in disorders such as autism and schizophrenia. They found that although the caudate showed a high level of conservation across all three species, the frontal cortex was different in humans, with eight human-specific gene-coexpression modules in the frontal pole. Of particular note, say the authors, was the discovery of a human-specific frontal pole gene-coexpression module that “includes several psychiatric disease genes”, and which appears to be coordinated by CLOCK—a gene strongly implicated in bipolar depression.At the other end of the lifespan, comparative studies are also starting to shed some light on the question of why humans are uniquely susceptible to Alzheimer's disease (AD). The recent sequencing of the gorilla genome threw up the striking finding that a variant of the growth factor progranulin (PGRN) that is thought to be associated with dementia in humans was the only version found in the gorilla genome-wide sequence data. The same variant has also been found in the chimpanzee and macaque genomes, and yet none of these non-human primates are known to develop dementia.“My colleagues measured beta-amyloid levels in [brain samples from] humans, chimps, macaques, and some other primates”, explains Preuss. “Non-demented humans actually have very low levels of beta-amyloid compared with non-human primates, and in people with AD those levels come up to the levels that you find in non-human primates.” The question then is why is beta-amyloid deposition toxic to humans when it isn't to chimps and macaques? “That's an angle on this question that you can get from comparative research that you can't get anywhere else. It doesn't have anything to do with the sequence of the beta-amyloid peptide, because that's actually the same across species”, Preuss says. “So it must be something about how that peptide interacts with the particular biochemical milieu of humans that is different from chimps and other non-human primates.”According to Sherwood, our elongated lifespan is a major contributory factor to degenerative diseases like AD. “The period of life when AD pathology in humans is most pronounced is well past the natural lifespan of any ape.” Most apes in the wild are dead by their 45th year. Humans, even those in modern foraging societies without access to modern medicine, potentially have another 40 or more years of life after that, during which neurons are being exposed to the general wear and tear of oxidative stress and damage over a much longer period. “That's the portion of the human lifespan when those neurons show the most failure”, says Sherwood. “So I think a combination of some genetic susceptibility, behavioural and environmental risks, and just the wear and tear of a very long lifespan in humans; that's when we start to see the very progressive degenerative pathology of AD.”In a study published last year, Sherwood's group showed that aged chimpanzee brains do not show any significant signs of age-related change, whereas the severity of the degeneration of neocortical grey matter in elderly humans was such that it was detectable as “overt volume loss”. But although the elongated lifespan of humans is likely to be a significant factor, says Preuss, it might not be the whole story. “From the PET studies of cerebral metabolism it looks like human brains are burning glucose at the same rate as macaque brains are, per unit tissue”, he explains. “And that's really odd, because in physiology big things usually run slower, so big animals have lower per unit tissue metabolic rates than smaller animals, and that seems to be at least broadly true of brains as well. So it's possible, because we know that metabolism generates lots of nasty and destructive byproducts, perhaps one reason why human brains might start to deteriorate faster is because we have a higher level of oxidative stress than other animals.” One idea is that the huge size of the human brain has evolved as a coping strategy to make it possible for it to degrade more gently, Preuss explains; “the idea of cerebral reserve, that's one of the interesting ideas that this field has generated”.As new technology continues to drive the discovery of new human-specific brain phenotypes, and brings the possibility of comparing human and chimpanzee neural connectomes into sight, there can only be many more such ideas to come. New technology continues to drive the discovery of new human-specific brain phenotypes. What can comparative studies of human and non-human primate brains tell us about our unique vulnerability to brain diseases? David Holmes reports. Todd Preuss was in provocative mood when The Lancet Neurology spoke to him in September. From his base at the Yerkes National Primate Research Center at Emory University, USA, Preuss is at the vanguard of a small but growing community of researchers, mostly from a physical anthropology background, whose goal is to find out more about the unique specialisations of the human brain that make our species what it is. And it's a field, says Preuss, that neurologists would do well to pay more attention to. “Modern evolutionary ideas have never really permeated into the neurosciences except among those neuroscientists who come from a zoological tradition rather than a biomedical or a psychological tradition”, says Preuss, who describes himself as a neuroanatomist and biological anthropologist. “Within the neurosciences people either think there are really no differences between humans and animals worth talking about, or they think that human brains are so completely different from all other animals that it's not even worth your while to study animals.” That's a tragedy, Preuss argues, because both positions ignore the unique angle that a comparative evolutionary perspective can give to some of neurology's most pressing questions. “In neurology and psychology a lot of the things we're dealing with in humans are things that are in some way a result of our unique evolutionary history”, he says. “I think Alzheimer's disease is one, and I suspect schizophrenia is as well.” One of the most striking things about the human brain is its size—three times the size of the brains of our closest relatives, the great apes, “It's bizarre”, says Preuss, “it's one of the real oddities of biology.” But just saying overall brain size is big is not really saying much; “humans are distinct from all other primates in a suite of behaviours including altruism, planning and foresight, and most glaringly language”, explains Michael Platt, of the Levine Science Research Centre at Duke University, and it's unlikely that these behaviours are simply a result of a scaled-up chimpanzee brain. “What's been addressed to a much lesser extent, but thankfully now with a much accelerated intensity”, says Chet Sherwood, from the laboratory for evolutionary neuroanatomy at George Washington University, DC, “is besides large brain size, what are the other traits of the human brain that are unique, and can we map those neural traits on to our behavioural and cognitive traits, and also on to our species-specific vulnerability to brain diseases?” Uncovering the detailed differences in anatomy, gene expression, growth, development, and ageing that sets the human brain apart from that of our closest relative, the chimpanzee, clearly means developing a detailed understanding of chimpanzee brains. And this, for understandable reasons, is easier said than done. By working with zoos and research facilities, Sherwood's laboratory and his collaborators have been able to put together one of the best cross-sectional samples of chimpanzee brain tissue in existence, and their studies comparing the development of human, chimpanzee, and macaque monkey brains have yielded some remarkable results, particularly relating to myelin development. The typical primate pattern of myelination, Sherwood explains, seems to be that myelin grows slowly within the cerebral cortex and is finished growing essentially before puberty. “Whereas in humans”, says Sherwood, “every car insurance company knows that the brain continues to mature and remodel well past puberty into the mid-to-late 20s, and we know that is related to improvements in decision making and emotional regulation.” And the comparative studies of myelination bear that pattern out; a prolonged post pubertal increase in myelin in the cerebral cortex that is unique in humans among primates, even compared with chimpanzees. “What's really interesting about that”, Sherwood explains, “is that this distinctive phase of myelination right after puberty is a period of unique human susceptibility to certain psychiatric disorders. This is the period of onset of schizophrenia and of bipolar depression.” The task now is to find out whether some of those genes that are implicated in schizophrenia and other psychiatric disorders might also be regulating this species difference in brain development; “it would be very interesting to know if there is some overlap between those genes”, says Sherwood. The first steps towards uncovering human-specific patterns of gene expression in the brain were taken in the early part of the last decade, with a series of cross-species microarray analyses of RNA transcript levels, but researchers are now increasingly turning to next-generation sequencing to compare gene expression. In a study published in August, UCLA's Daniel Geschwind and colleagues used next-generation sequencing to compare gene expression in the brains of humans, chimpanzees, and rhesus macaques. Geschwind's team looked specifically at three different brain areas, the caudate, the hippocampus, and frontal pole, which was of particular interest, they explained in the journal Neuron, because of its key role in higher-order cognition and its possible malfunction in disorders such as autism and schizophrenia. They found that although the caudate showed a high level of conservation across all three species, the frontal cortex was different in humans, with eight human-specific gene-coexpression modules in the frontal pole. Of particular note, say the authors, was the discovery of a human-specific frontal pole gene-coexpression module that “includes several psychiatric disease genes”, and which appears to be coordinated by CLOCK—a gene strongly implicated in bipolar depression. At the other end of the lifespan, comparative studies are also starting to shed some light on the question of why humans are uniquely susceptible to Alzheimer's disease (AD). The recent sequencing of the gorilla genome threw up the striking finding that a variant of the growth factor progranulin (PGRN) that is thought to be associated with dementia in humans was the only version found in the gorilla genome-wide sequence data. The same variant has also been found in the chimpanzee and macaque genomes, and yet none of these non-human primates are known to develop dementia. “My colleagues measured beta-amyloid levels in [brain samples from] humans, chimps, macaques, and some other primates”, explains Preuss. “Non-demented humans actually have very low levels of beta-amyloid compared with non-human primates, and in people with AD those levels come up to the levels that you find in non-human primates.” The question then is why is beta-amyloid deposition toxic to humans when it isn't to chimps and macaques? “That's an angle on this question that you can get from comparative research that you can't get anywhere else. It doesn't have anything to do with the sequence of the beta-amyloid peptide, because that's actually the same across species”, Preuss says. “So it must be something about how that peptide interacts with the particular biochemical milieu of humans that is different from chimps and other non-human primates.” According to Sherwood, our elongated lifespan is a major contributory factor to degenerative diseases like AD. “The period of life when AD pathology in humans is most pronounced is well past the natural lifespan of any ape.” Most apes in the wild are dead by their 45th year. Humans, even those in modern foraging societies without access to modern medicine, potentially have another 40 or more years of life after that, during which neurons are being exposed to the general wear and tear of oxidative stress and damage over a much longer period. “That's the portion of the human lifespan when those neurons show the most failure”, says Sherwood. “So I think a combination of some genetic susceptibility, behavioural and environmental risks, and just the wear and tear of a very long lifespan in humans; that's when we start to see the very progressive degenerative pathology of AD.” In a study published last year, Sherwood's group showed that aged chimpanzee brains do not show any significant signs of age-related change, whereas the severity of the degeneration of neocortical grey matter in elderly humans was such that it was detectable as “overt volume loss”. But although the elongated lifespan of humans is likely to be a significant factor, says Preuss, it might not be the whole story. “From the PET studies of cerebral metabolism it looks like human brains are burning glucose at the same rate as macaque brains are, per unit tissue”, he explains. “And that's really odd, because in physiology big things usually run slower, so big animals have lower per unit tissue metabolic rates than smaller animals, and that seems to be at least broadly true of brains as well. So it's possible, because we know that metabolism generates lots of nasty and destructive byproducts, perhaps one reason why human brains might start to deteriorate faster is because we have a higher level of oxidative stress than other animals.” One idea is that the huge size of the human brain has evolved as a coping strategy to make it possible for it to degrade more gently, Preuss explains; “the idea of cerebral reserve, that's one of the interesting ideas that this field has generated”. As new technology continues to drive the discovery of new human-specific brain phenotypes, and brings the possibility of comparing human and chimpanzee neural connectomes into sight, there can only be many more such ideas to come. CorrectionsHolmes D. Size isn't everything, comparatively speaking Lancet Neurol 2012; 11: 844–85—The following margin links should have appeared in this report: For the study in Neuron see Neuron 2012; 75: 601–17. For the PGRN finding see Nature 2012; 483: 169–75. For the report on beta-amyloid levels see Neurobiol Ageing 2011; 32: 223–34. For the study by Sherwood et al see Proc Natl Acad Sci USA 2011; 108: 13029–34. This correction has been made to the online version as of Oct 15, 2012. Full-Text PDF