disease

The keywords to the article include, "carnivorous marsupial" and "precocious breeding." What better teaser could you possibly hope for?

Tasmanian devils are dying because of a transmissible cell line infection, or "cancer," decimating their population. In fact, in some places it's killing 9 out of 10, which is way beyond decimation.

The new paper by Menna Jones and colleagues claims that the population is evolving toward a radical life history solution to the problem: Tasmanian devils are starting to mate and have large litters after a single year, before they have a chance to succumb to the disease:

This change in life history is associated with almost complete mortality of individuals from this infectious cancer past their first year of adult life. Devils have shown their capacity to respond to this disease-induced increased adult mortality with a 16-fold increase in the proportion of individuals exhibiting precocious sexual maturity. These patterns are documented in five populations where there are data from before and after disease arrival and subsequent population impacts. To our knowledge, this is the first known case of infectious disease leading to increased early reproduction in a mammal.

It's a simple response: young breeders used to have lower fitness, because of competition from older adults. Now, the high mortality after the first year has made it a losing strategy to wait to reproduce. When the early breeders are the only ones having many offspring, the population will evolve quickly to early breeding.

References:

Jones ME, Cockburn A, Hamede R, Hawkins C, Hesterman H, Lachish S, Mann D, McCallum H, Pemberton D. 2008. Life-history change in disease-ravaged Tasmanian devil populations. Proc Nat Acad Sci USA (in press) doi:10.1073/pnas.0711236105

Hebrew University has issued a press release about ongoing research on human and animal bones from the Jericho excavations. They're looking for signs of tuberculosis:

While the origins of tuberculosis and its evolution remain unclear, it is thought it came from the first villages and small towns in the Fertile Crescent region about 9-10,000 years ago. Jericho is one of the earliest towns on earth, dating back to 9,000 B.C., and so a lot of communicable - or town - diseases would have had a good start in this community.

By examining human and animal bones from this site, the researchers will be able to see how the first people living in a crowded situation developed the diseases of crowds and how this affected the disease through changes in DNA -- of both the microbes and the people.

The most significant results of this research will come from a comparison between those data for humans and corresponding animal remains which may allow the identification of animal-human vectors and their interaction.

That's all very interesting, and looking for newly-virulent versions of tuberculosis in Neolithic bones is not a bad idea. But somebody ought to tell them that the zoonosis hypothesis (that tuberculosis was recently derived from domesticated animals like cattle) looks a lot less likely, now that ancient strains of the pathogen up to 3-million-years old have been found in living people, and signs of the disease have been found in a Middle Pleistocene human.

Anyway, that doesn't refute the idea that major changes in the pathogen population may have happened with human population growth, as new large reservoirs of people emerged. And it's quite possible that the germ went from humans to some of its animal hosts at that time, so studying the animal bones may give some information about the event. But they'll want to start with the idea of diversity within humans, not the other way around.

Last week, the NY Times printed an interesting article by Andrew Pollack, titled "Redefining disease, genes and all." The article explores recent (and ongoing) attempts to map the genetic networks underlying common disease phenotypes.

Many people, including me, have criticized the HapMap and other attempts to catalog disease alleles because they depend on an evolutionary fallacy. These projects are best at finding genetic variations that are relatively common in today's human populations -- common because the number of people surveyed in such studies is ultimately limited. But if an allele were bad in an evolutionary sense -- that is, if it lowers fitness -- then it shouldn't be common. So we really shouldn't expect to find alleles associated with common disease phenotypes.

Naturally, there are exceptions, which we can find if we consider some population genetics. A bad allele may become common if its bad effect doesn't really lower fitness. Disease phenotypes that occur late in life, such as Alzheimer's, have a minimal impact on their victims' fitness, because for the most part the childrearing years are long past.

Or, an allele that yields one unpleasant phenotype may actually increase fitness -- sickle cell and other instances of heterozygote advantage are examples of this.

Or, the disorder associated with the allele may occur only in the presence of some new environmental factor. Obesity is one such phenotype: lately on the increase, it cannot have been common throughout most of our evolutionary past because of resource limitations.

But aside from these exceptions, we can expect that any common allele is likely to explain relatively little of the overall risk of any given disorder. And indeed, so far, this is precisely what genome surveys have found. Many disorders now have known genetic associations, but these are almost always alleles of relatively weak effect on the phenotype.

Another reason to look for risk alleles, even if they are of weak effect, is that they may help to identify the genetic interactions that lead to disease. This idea has been around for a long time. Mapping the genes that cause Mendelian disorders in a given phenotype led to our current understanding of genetic pathways underlying skin color, inner ear function, blood clotting, and many other biological functions. Finding some genes associated with Alzheimer's is helping to unravel the physiological observations on people with the disorder, particularly the role of beta-amyloid plaques in the disease progression.

Many workers are currently trying to facilitate these kinds of discoveries by developing new functional maps of gene-disease associations and interactions. Pollack's article focuses on the growing discrepancy between symptomology and etiology -- the consequences of a disease and its causes:

Scientists are finding that two tumors that arise in the same part of the body and look the same on a pathologist's slide might be quite different in terms of what is occurring at the gene and protein level. Certain breast cancers are already being treated differently from others because of genetic markers like estrogen receptor and Her2, and also more complicated patterns of genetic activity.

"In the not too distant future, we will think about these diseases based on the molecular pathways that are aberrant, rather than the anatomical origin of the tumor," said Dr. Todd Golub, director of the cancer program at the Broad Institute in Cambridge, Mass.

The process is really one of atomizing disease. As Pollack notes, diseases that once were considered different kinds of cases of a single disorder -- like hemophilia -- were later shown to be due to distinct defects in different genes. A diffuse grouping of "like with like" has given way to much greater specificity at the biochemical and genetic level for many disorders.

Complex disease phenotypes that involve interactions among many genes will fall the last, but computational methods are starting to attack them:

Other scientists use data on which genes appear to cause disease or contribute to the risk of contracting it.

Using such data, Marc Vidal, a biologist at Harvard, and Albert-Laszlo Barabasi, now a physicist at Northeastern University, created a map of what they called the "diseasome" that was published last year in The Proceedings of the National Academy of Sciences.

Diseases were represented by circles, or nodes, and linked to other diseases by lines that represent genes they have in common -- something like the charts linking actors to one another (and ultimately to Kevin Bacon) based on the movies they appeared in together.

But obviously if the genetic associations are weak, they do not give great hope of simple effective treatments for such complex diseases. And some genetic similarities may lead people to infer equivalences that do not really exist.

What is lacking from this story -- and in general from the field -- is an understanding of evolution. If there is one thing that can deal with the genetics underlying complex phenotypes, it is natural selection. Population genetics has been dealing with the theory underlying genetic interactions for a hundred years. Now we have empirical observations on gene networks, all of them products of our evolutionary history.

So it is disheartening to see that some prominent figures in the field of human genetics (and who hold the purse strings for so much funding) have little familiarity with the evolutionary dynamics of gene interactions:

"I'm shaking my head with disbelief that two genes would pop up in these two diseases that have absolutely nothing in common," said Dr. Francis S. Collins, the director of the National Human Genome Research Institute. He said another gene, cyclin-dependent kinase inhibitor 2A, seemed to be involved in cancer, diabetes and heart disease.

I'm shaking my head in disbelief that Collins doesn't seem to be aware of pleiotropy. That's another of the exceptions I pointed out above -- the rare instances where a common allele might really be associated with a common disease. In antagonistic pleiotropy, an allele that has a good effect on one function may proliferate despite having a bad effect on some other function. There's nothing at all surprising about a single gene having different alleles that may have adverse impacts on two different bodily processes, and in fact some have been well known for fifty years or more.

Um, could somebody brief Collins about ABO?

I very much liked Carl Zimmer's Slate piece about foodborne pathogens and their lessons for defending against bioterrorism. Zimmer has a book about E. coli coming out later this spring, and he visits the topic of the 2006 outbreaks of an especially virulent strain.

This worrisome trend led a team of scientists based at Michigan State University to take a look at the DNA of the bacteria. The researchers compared bacteria from recent outbreaks with hundreds of others samples and published the results last Monday. The scientists drew an evolutionary tree based on the differences in the bacteria's genes. One branch of the tree -- the one that caused the spinach and lettuce outbreaks in 2006 -- is significantly more likely to make people sick than the others. And they found that this lineage has been exploding in recent years. In 2002, it accounted for 10 percent of the E. coli cases recorded in Michigan. In 2006, it accounted for 46 percent.

Whole-genome sequencing found large deletions and insertions of hundreds of genes in the newer virulent clade. Zimmer brings our attention to the complexity of the mechanisms that determine virulence. At present, science still can't predict how these genes will affect the pathogens. On this grounds, one may argue that the prospects are low that an enemy state or mad scientist will soon be able to create such a dangerous strain deliberately.

But this is not grounds to celebrate, since nature is busily creating dangerous strains for us. Natural selection does not design its products in a single leap of invention, but it sifts many millions of variants much more efficiently than any human laboratory.

I think that the last paragraph contains the essential lesson.

But this ignorance [of which genes must be altered to make a killer pathogen] is not cause for much comfort. Even if we don't need to worry about synthetic bacteria just yet, we do need to worry about new pathogens evolving right in our own backyard (or, rather, our own feedlots and factory farms). As things stand, we become vaguely aware of these bacteria only once they've been sickening and killing for years.

Sure, it may be difficult to engineer a more virulent pathogen for bioterror. But it is pretty easy to use the ones we already have. The evil genius is much less a threat than nature. And a saboteur looking to replicate small-scale terror on the order of the D. C. sniper may find hundreds of victims by contaminating one line of the vast American food web.

Defending against this kind of terror is the same task as defending against nature.

A new paper in Current Biology documents the mortality suffered by Taï Forest chimpanzees as a result of common human respiratory ailments during the last ten years. Tissue samples of deceased animals provided information about the pathogens that caused the outbreaks:

Necropsy samples were screened for respiratory pathogens by using different PCR methods. As for most human respiratory cases, a mix of bacterial and viral respiratory pathogens was found in the lungs. The most common bacterium was Streptococcus pneumoniae, which was found in all respiratory outbreaks. In addition, Pasteurella multocida played a role in the 2004 outbreak [10]. All available samples tested positive for one of two paramyxoviruses: human respiratory syncytial virus (HRSV) was diagnosed in two individuals that died in the 1999 north group outbreak and in one adult female (east group) and one infant (south group) who died in the 2006 outbreak, which occurred simultaneously in both groups. The second virus identified was human metapneumovirus (HMPV), detected in three animals that died in the 2004 south group outbreak (Table 1).

Humans have suffered from these respiratory ailments for a long time. The number of human respiratory pathogens almost certainly proliferated greatly during the last 10,000 years, after the advent of agriculture and village life brought the potential of "crowd diseases." For example, human respiratory syncytal virus (HRSV) is closely related to the bovine BRSV and pneumonia virus of mice (PVM). It seems plausible that the human pathogen descended from the mouse or cattle (or sheep) virus, but no one has yet demonstrated this -- and it is after all possible that they got it from us. HRSV is an important cause of lower respiratory tract infections in humans worldwide, especially in children. In an ironic twist, HRSV was first identified in captive chimpanzees as the cause of a respiratory infection with runny nose and sneezing (called coryza) (Blount et al. 1956). It was actually the human RSV virus contracted by the chimpanzees that had caused the infections.

Much the same thing has happened to the wild chimpanzees, but with a high death toll. A 1999 outbreak of HRSV, compounded by Streptococcus pneumoniae, killed 6 out of 32 animals in the affected group, including 5 adults. A 2004 outbreak killed 8 out of 44 animals. These two outbreaks each killed nearly a fifth of the chimpanzees in these groups, and demographic records show that several "multiple mortality events" in the last 24 years are not attributable to poaching or other diseases such as ebola or anthrax (each of which had least one outbreak).

Easily spread respiratory ailments are among the main causes of sickness in contemporary hunter-gatherers, partly because they are able to persist and spread effectively in low-density populations, and partly because they are so common in neighboring groups. Today, respiratory diseases are an important cause of death in these groups -- including adults -- although they count for fewer deaths than gastrointestinal pathogens and parasites. Their ability to infect low-density populations suggests that some human respiratory pathogens surely date to much earlier periods of human evolution.

One thing is certain: humans have undergone thousands of years of selection, in which susceptible individuals have disproportionately been killed by human-infecting respiratory viruses and bacterial strains. Many of these pathogens have adapted very well to humans, including a substantial time or fraction of the population in which they may be present without causing noticeable symptoms.

Chimpanzees lack this history. Relatively minor diseases in humans may have major effects on chimpanzees, and diseases like RSV that cause measurable mortality among human infants may have devastating effects on chimpanzee communities. Together, respiratory illnesses, ebola, and anthrax are having a death toll in the studied chimpanzee groups almost as great as smallpox in post-contact American Indians.

The shocking thing is that this enormous death toll seems likely to have been caused by the researchers themselves, along with ecotourists:

It has long been recognized that respiratory disease is the most important cause of morbidity and mortality among wild great apes habituated to human presence for research or tourism [4], [24], [25], [26] and [27]. However, the etiological agents of such disease have not been documented. Possibly as a consequence of respiratory disease, about half of the long-term chimpanzee research populations have shown major declines [4] and [28]. Our results suggest that the close approach of humans to apes, which is central to both research and tourism programs, represents a serious threat to wild apes (Köndgen et al. 2008:262).

The authors temper this conclusion in two ways. First, they show that the presence of the research station and the tourist site both have significantly decreased the incidence of poaching at and around these areas. Both areas have lots of chimpanzees, but little sign of poachers in contrast to the rest of the protected forest, where poacher sign is common. Poaching accounts for nearly as many documented deaths in the study population as respiratory infection, so this protective effect may be very important.

On the other hand, communicable diseases may well spread beyond a single group, so much of the forest may be at high risk from both poaching and human pathogens. And needless to say, poachers may spend less time around the research and tourist areas, but that hasn't stopped them from killing lots of chimpanzees there. So the protective effect may not be much of a shield.

Second, they provide recommendations that may decrease the risk to the chimpanzees while permitting continued human presence:

In order to reduce the negative effects of research and tourism, strict hygiene protocols, including vaccination requirements for tourists, tourism personnel, park staff, and research personnel against all potentially dangerous diseases for which vaccines are available (e.g., measles, mumps, and rubella), should be implemented [5], [6], [29] and [30]. Only nonsymptomatic visitors and staff should have access to habituated apes. Feces, vomit, and other human debris or wastes should be removed from areas where chimpanzees may come in contact with it or buried at a depth where other animals will not uncover it [29]. Because carriers of human respiratory pathogens are often nonsymptomatic, wearing of masks (e.g., N95 masks as recommended for avian flu) [31] should be mandatory. Human populations living around the parks and reserves should be vaccinated, thereby decreasing the chances of human-pathogen introduction into chimpanzee populations. As in the Taï project, demographic, clinical, and diagnostic monitoring systems should be implemented to objectively document the negative effects of research or tourism. Furthermore, we urge an intensification of research on ways to prevent disease transmission, as well as the development of new methods for vaccine and treatment delivery, to wild apes (e.g., oral baiting) (Köndgen et al. 2008:262-263).

These are necessary precautions, but they are unlikely to be enough. There is no effective or widely available for RSV, or HMPV. S. pneumoniae normally exists in the respiratory tract of 10 percent of healthy adults. There is no way that chimpanzees can hold off these diseases if they are in recurrent contact with people.

References:

Blount RE Jr, Morris JA, Savage RE. 1956. Recovery of cytopathogenic agent from chimpanzees with coryza. Proc Soc Exp Biol Med 92:544-549.

Köndgen S and 17 others. 2008. Pandemic human viruses cause decline of endangered great apes. Curr Biol 18:260-264. doi:10.1016/j.cub.2008.01.012

I read two interesting articles today on brain performance-enhancing of one kind or another. Denise Grady of the New York Times contributes a long article about the quest for an Alzheimer's cure:

Answers are urgently needed. Alzheimer's was first recognized 100 years ago, and in all that time science has been completely unable to change the course of the disease. Desperate families spend more than $1 billion a year on drugs approved for Alzheimer's that generally have only small effects, if any, on symptoms. Patients' agitation and hallucinations often drive relatives and nursing homes to resort to additional, powerful drugs approved for other diseases like schizophrenia, drugs that can deepen the oblivion and cause severe side effects like diabetes, stroke and movement disorders.

It's a good article with lots of history about the disease and its social and economic toll. But I found this passage the most significant:

The potential market for prevention and treatment is enormous, and drug companies are eager to exploit it. If a drug could prevent Alzheimer's or just reduce the risk, as statins like Lipitor do for heart disease, half the population over 55 would probably need to take it, Dr. Thies said.

If new drugs do emerge, they will come from studies in patients who already have symptoms, Dr. Thies said. But he said the emphasis would quickly shift to treating people at risk, before symptoms set in. Many researchers doubt that even the best preventive drugs will be able to heal the brains of people who are already demented.

Treating preventively, Dr. Thies said, "will be more satisfying to patients and physicians, and there will be an economic incentive because you'll wind up treating more people."

The only thing that could slow the drive for early treatment, he said, would be serious side effects -- and Dr. Morris, at Washington University, said drugs powerful enough to treat Alzheimer's would probably have strong side effects.

It's interesting to me because of the recent genetic stuff I've been working on. But also in light of this other story in today's LA Times, by writers Karen Kaplan and Denise Gellene:

Drugs to build up that mental muscle

Academics, musicians, even poker champs use pills to sharpen their minds, legally. Labs race to develop even more.

People are already using various psychoactive drugs to get a leg up in whatever mental competitions they pursue. Some of this is no more sophisticated than late-night coffee drinking for the Ritalin generation. But some is more surprising:

"There isn't any question about it -- they made me a much better player," said Paul Phillips, 35, who credited the attention deficit drug Adderall and the narcolepsy pill Provigil with helping him earn more than $2.3 million as a poker player.

...

The growth of the brain drugs bears a striking resemblance to the post-World War I evolution of plastic surgery -- developed to rehabilitate badly disfigured soldiers but later embraced by healthy people who wanted larger breasts and fewer wrinkles.

The use of cognitive-enhancing drugs has been well documented among high school and college students. A 2005 survey of more than 10,000 college students found 4% to 7% of them tried ADHD drugs at least once to remain focused on exams or pull all-nighters. At some colleges, more than one-quarter of students surveyed said they had sampled the pills.

The article discusses the "blockbuster drug that labs are racing to develop," a memory pill. Which of course brings us full circle to Alzheimer's treatment.

You may be thinking there is something unnatural about this; maybe even something unfair -- like an athlete using steroids to enhance his performance. But with psychological factors, it is a little more evident that there is a continuum of uses, some of which are pretty clearly acceptable. For example, the performance artists who take a pill to calm their nerves before appearing on stage are literally enhancing their performance, but in a way that is arguably different from their skill as artists.

Likewise, there is a continuum among normal people -- how do we justify allowing Adderall for the student who has trouble taking an eight-hour exam, but denying it to the student who had trouble sleeping before the exam?

Progress on these kinds of drugs will only come with understanding the continuum of psychological and cognitive variation among living people -- along with the causes of that variation, both developmental and genetic. We might like some chemical to increase memory performance. But the brain is a complicated place with countless interactions of different structural and regulatory processes. Maybe some people already have the chemicals that enhance memory, and other people don't, or don't express them in the right places in the right amounts. If so, then Alzheimer's treatment may focus on the metabolic processes of non-Alzheimer's brains, for example.

Plus, as we've learned recently with respect to traumatic stress, it's not always good to remember things well, so there is no reason to assume that the human population has been adapting toward longer or better memory. In general, it's not obvious exactly what memory characteristics have tended to increase fitness recently or during earlier phases of human evolution. Aside from the energy and life history constraints of large brains, we don't know what evolutionary trade-offs exist with respect to memory or other aspects of cognitive function.

Athletes take performance-enhancing drugs for a relatively slight advantage. Pharmaceutical firms are pursuing brain drugs on the expectation that millions of people will take a daily pill for years on end, in order to stave off Alzheimer's. Unshackling the mind power of a large proportion of the older population will no doubt have a tremendous impact on the societies of the future.

Pretty exciting stuff, if only we could figure it out.

Viral evolution is different from human evolution chiefly because viruses mutate faster, exist in larger populations, have much shorter generations, and have a sharp multifold population structure, including within-host subpopulations and global (and potentially local, regional, or species-specific) metapopulations.

So maybe we shouldn't read too much into this free PLoS essay by Eddie Holmes, "Viral Evolution in the Genomic Age."

But then again, viral evolution sets the context for much of recent human adaptation, including strong recent selection on genes related to pathogen defense.

If there is a lesson to be learned from the history of population genetics, it is that the more fine-scaled the data available for analysis -- from allozymes to genomes -- the more powerful the biological inference. Not only does the comparison of complete genomes invariably provide greater resolution of the spatial and temporal dynamics of viral spread, but it obviously enables the study of genome-wide interactions. As a case in point, the complex evolutionary processes that underpin the recent dramatic rise of resistance to adamantane drugs in influenza A virus, including the central role played by epistasis, were not revealed until an analysis of complete genome sequences was undertaken [10]. Rather than focusing on single genes in isolation, it is therefore essential that we examine the similarities and differences in evolutionary patterns among all the genes in a viral genome.

Holmes begins his essay by noting that the influenza A virus project has so far generated "around 2,500 complete viral genomes." Of course, such widespread sequencing is essential for studying the processes of virus evolution and the rise of new virulent strains.

But it also gives a hint of what will happen to human population genetics when large numbers of complete genomes start coming online. Considering that humans have rather less genomic diversity than influenza A, SNP surveys already have much of the power to detect polymorphisms. Coming attractions: larger and larger samples of people from different populations.

References:

Holmes EC. 2007. Viral evolution in the genomic age. PLoS Biol 5:e278. doi:10.1371/journal.pbio.0050278

A nice essay by Dr. Barron H. Lerner in the New York Times looks at a long-time survivor of sickle cell anemia, and the ways that treatment options have developed. Now nearly 60, Gladys Jacobs has lived with the disease for 44 years:

On top of all this, Gladys suffered disrespect. Too many physicians and nurses assumed she was faking symptoms to get pain medication. "The impression," she said, "is that we are all addicts."

Doctors' fear of promoting drug addiction led them to underprescribe drugs to sickle cell patients — for example, insisting on checking blood tests before giving pain medications. Gladys never really cared about the test results. "I know how I feel," she said.

Race, as Mr. [Keith] Wailoo shows in his book, was central to the conundrum of treating sickle cell patients, a vast majority of whom are African-American. As one hematologist conceded, delaying the administration of pain medications has a "racial undertone."

It is a standard example in introductory genetics courses, but rarely do students get to see the world behind the textbooks. The article mentions that Jacobs may have survived longer than typical because she also carries the beta thalassemia variant, which tends to reduce the severity of her sickle cell.

In a paper in press in the Journal of Theoretical Biology, Randal Bollinger and colleagues suggest that the human vermiform appendix functions as a "safe house" for bacteria:

The observations described above, in conjunction with the survival advantages afforded to bacteria by biofilms(Costerton, 1995; Costerton, 1999; Costerton et al., 1995) and the architecture of the human large bowel, give rise to the idea that the appendix is a compartment well suited for maintaining beneficial or commensal microorganisms, being well positioned to avoid contamination by pathogenic organisms present transiently in the fecal stream. Indeed, the narrow lumen of the appendix as well as its location at the lower end of the cecum are both factors that afford relative protection from the fecal stream as it is propelled by peristalsis. Given the metabolic advantages (Bradshaw et al., 1994; Bradshaw et al., 1997) and other advantages (Costerton, 1995; Costerton, 1999; Costerton et al., 1995) that biofilms are known to afford bacteria, biofilm formation in the appendix is expected to be a relatively effective means of preserving and protecting commensal bacteria. In essence, the structure of the appendix is expected to enhance the protective effect of biofilm formation for commensal bacteria. Effective biofilm formation by commensal bacteria in the appendix is expected to facilitate not only the exclusion of pathogens, but also the adherence of the non-pathogenic commensal organisms within that cavity. Regular shedding and regeneration of biofilms within the appendix would be expected to re-inoculate the large bowel with commensal organisms in the event that the large bowel became infected by a pathogen and was flushed out as a defensive response to that infection (Bollinger et al. 2007:7-8).

So in other words, the appendix supposedly facilitates the use of diarrhea as a pathogen-shedding mechanism, because it would preserve the beneficial gut flora when the body sheds the biofilm coating the rest of the colon.

It's a hypothesis.

So here's a problem: The authors note that the appendix may now be relatively useless because of the lower importance of fecal-borne diseases "in the face of modern medicine and sanitation practices." But before people started living in sedentary settlements, with high population densities, fecal-borne diseases must have been vastly less important than they have been historically, when people regularly have drunk from contaminated water supplies. Throughout human evolution up until the Holocene, diarrheal diseases would not have been absent (food poisoning and incidental contact with fecal-borne disease from other species always being possible), but they must have been vastly less important than they have been recently.

Indeed, maintenance of a reserve supply of commensal bacteria in the event of infection by pathogens may be unnecessary in areas where outbreaks of enteric pathogens do not affect the vast majority of the population at any one time. Certainly this idea is consistent with the well-known observation that appendectomy is without currently discernable long-term side effects in societies with modern medical and sanitation practices (ibid.:9).

If it's adaptive, it must be not to the recent environment of high enteric pathogen load, but the ancestral environment. And not just to meat-eating: the apes have appendices, too. In fact, Fisher (2000) points out that many primates, including non-anthropoids, have similar structures. Others have thickened "biofilm"-like mucosal layers in the cecum that would seem to approximate this microbe-harboring function. Since this includes primarily fruit-eating and leaf-eating species, there is no reason why contact with meats, bacteria from spoiled meats, or enteric bacteria from consumed animals should necessarily be involved. I'm not sure why the current paper (Bollinger et al. 2007) didn't cite any of this comparative work; it certainly seems relevant to their hypothesis.

The appendix looks functional to me, I'm just not sure that it is specifically a "safe harbor" in the face of enteric pathogens. It may just be a "safe harbor" in the face of normal elimination.

I guess that last is an unfortunate turn of phrase...

References:

Bollinger RR, Barbas AS, Bush EL, Lin SS, Parker W. 2007. Biofilms in the large bowel suggest an apparent function of the human vermiform appendix. J Theor Biol (in press) doi:10.1016/j.jtbi.2007.08.032

Fisher RE. 2000. The primate appendix: a reassessment. Anat Rec B 261:228-236. doi:10.1002/1097-0185(20001215)261:6<228::AID-AR1005>3.0.CO;2-O

A new whole-genome association study has found more genetic variants protective against HIV. The course of HIV infection is variable, even in the absence of medication, and it has been known for some time that some of the variation in disease progress is attributable to genetic variation among people. One gene variant (CCR5Δ32) is strongly protective against HIV-1; this is because the virus exploits the CCR5 chemokine receptor to infect T cells, and homozygotes for the Δ32 allele do not have this vulnerability.

The new research looked through the entire genome to find single nucleotide polymorphisms (SNPs) associated with variant disease phenotypes:

Understanding why some people establish and maintain effective control of HIV-1 and others do is a priority in the effort to develop new treatments for HIV/AIDS. Using a whole-genome association strategy we identified polymorphisms that explain nearly 15% of the variation among individuals in viral load during the asymptomatic set point period of infection. One of these is found within an endogenous retroviral element and is associated with major histocompatibility allele HLA-B*5701, while a second is located near the HLA-C gene. An additional analysis of the time to HIV disease progression implicated a third locus encoding a RNA polymerase subunit. These findings emphasize the importance of studying human genetic variation as a guide to combating infectious agents.

From a very large study population of infected patients, the authors were able to identify a subset for whom recurrent measurements of viral load and other essential data were available. This allowed them to find genes that associate with the temporal progression of the disease, not just its presence or absence. An article on ScienceNOW by Jon Cohen describes the setup:

The team studied 486 patients infected with HIV who had not received treatment and had known dates of infection and accurate set points. Then they checked blood samples against half a million known variations in DNA sequences, or single-nucleotide polymorphisms, which recently were identified by the International HapMap Project that looked for differences in the genomes of people from many populations. "We've approached this as a straight, quantitative genetic problem," explains David Goldstein, a geneticist at Duke University in Durham, North Carolina, who led the study. The researchers say this is the first study to ever do such a genome-wide association analysis for an infectious disease.

The study identifies a number of other candidates besides the three significant ones that receive most of the discussion. It's tricky to test for significance in genome-wide surveys because the genome is so large and there are potentially many genes with small effects on disease phenotype. Still, genes with small effect (unless rare and highly protective) are not particularly good candidates for therapeutic treatments, so the major ones are the main story.

References:

Fellay J and 26 others. A whole-genome association study of major determinants for host control of HIV-1. Science (online early) doi:10.1126/science.1143767

I couldn't help but wonder after reading this story:

Bacterial biofilms can form almost anywhere, even on your teeth if you don't brush for a day or two. When they accumulate in hard to reach places such as the insides of food processing machines or medical catheters, however, they become persistent sources of infection.

These bacteria excrete a variety of proteins, polysaccharides, and nucleic acids that together with other accumulating materials form an extracellular matrix, or in Lu's words, a "slimy layer," that encases the bacteria. Traditional remedies such as antibiotics are not as effective on these bacterial biofilms as they are on free-floating bacteria. In some cases, antibiotics even encourage bacterial biofilms to form.

Lu and senior author James Collins, professor of biomedical engineering at BU, aim to eradicate these biofilms using bacteriophage, tiny viruses that attack bacteria. Phage have long been used in Eastern Europe and Russia to treat infection.

The story describes research that built a sort of "phage toolkit", for those times when you don't "want to dig through sewage to find these phages."

Another reason to avoid inbreeding:

The twin border communities of Hildale, Utah, and Colorado City, Ariz., have the world's highest known prevalence of fumarase deficiency, an enzyme irregularity that causes severe mental retardation brought on by cousin marriage, doctors say.

"Arizona has about half the world's population of known fumarase deficiency patients," said Dr. Theodore Tarby, a pediatric neurologist who has treated many of the children at Arizona clinics under contracts with the state.

Colorado City, AZ and adjacent Hilldale, UT form a closed community housing a formerly LDS splinter sect:

Local historian Benjamin Bistline said 75 to 80 percent of people in the area are blood relatives of two men — John Y. Barlow and Joseph Smith Jessop — who founded the sect on the remote desert plateau in the early 1930s.

"There aren't any new people coming in. It's a closed door and that gene just keeps getting passed around," said Bruce Wisan, a court-appointed accountant overseeing a trust of the sect's assets.

Everybody carries some deleterious recessives; mating with close relatives produces the chance that a child will have the homozygote recessive genotype. But a lot of discussion of inbreeding neglects the community or cultural aspect -- in examples like this one, the fact that an entire community has adopted the practice of close relative marriage creates a pool of potential sufferers of the disorder. In a sense, the allele becomes emblematic of the group: here, fifty percent of cases of fumarase deficiency in the world belong to this one community of 10,000 people.

Alfred Crosby gives a short quote from chapter 19 of Darwin's The Voyage of the Beagle, and I found it interesting enough to look for the full context. Voyage is online free at several places. Because it's online I don't have ready page numbers for the quotes below, they are all from chapter 19.

The passage is part of Darwin's description of Australia, which he finds "in all respects there was a close resemblance to England: perhaps the alehouses here were more numerous." Then he takes up the subject of the aboriginals:

The number of aborigines is rapidly decreasing. In my whole ride, with the exception of some boys brought up by Englishmen, I saw only one other party. This decrease, no doubt, must be partly owing to the introduction of spirits, to European diseases (even the milder ones of which, such as the measles, [1] prove very destructive), and to the gradual extinction of the wild animals. It is said that numbers of their children invariably perish in very early infancy from the effects of their wandering life; and as the difficulty of procuring food increases, so must their wandering habits increase; and hence the population, without any apparent deaths from famine, is repressed in a manner extremely sudden compared to what happens in civilized countries, where the father, though in adding to his labour he may injure himself, does not destroy his offspring.

Besides the several evident causes of destruction, there appears to be some more mysterious agency generally at work. Wherever the European has trod, death seems to pursue the aboriginal. We may look to the wide extent of the Americas, Polynesia, the Cape of Good Hope, and Australia, and we find the same result.

The last passage (from "Wherever" to "result") was quoted by Crosby. I think the preceding paragraph gives important context to Darwin's thinking on the matter; he had the main elements (which would probably have been common knowledge), although his attribution of juvenile mortality to a "wandering life" probably would be more correctly directed toward disease as well.

But that doesn't give the after context, either. Here's what follows in the same paragraph:

Nor is it the white man alone that thus acts the destroyer; the Polynesian of Malay extraction has in parts of the East Indian archipelago, thus driven before him the dark-coloured native. The varieties of man seem to act on each other in the same way as different species of animals -- the stronger always extirpating the weaker. It was melancholy at New Zealand to hear the fine energetic natives saying that they knew the land was doomed to pass from their children. Every one has heard of the inexplicable reduction of the population in the beautiful and healthy island of Tahiti since the date of Captain Cook's voyages: although in that case we might have expected that it would have been increased; for infanticide, which formerly prevailed to so extraordinary a degree, has ceased; profligacy has greatly diminished, and the murderous wars become less frequent.

He finishes this section with some discussion of the mechanism of disease spreading by ship -- even when no symptoms were found among the crew. This idea, which Darwin attributes to Williams' Narrative of Missionary Enterprise, has become important to explain certain New World epidemics as well as those in Polynesia.

This is a great quote for Crosby to have used because it shows that many educated people were aware that disease had decimated (and was still decimating) indigenous peoples, even as historians ignored disease as a factor in their narratives of New World conquest and colonization.

But then Darwin goes straight on: for him, disease susceptibility in aboriginal peoples is not mere happenstance, but a symptom of European superiority!

Still, that's nothing compared to the final line of the chapter:

Farewell, Australia! you are a rising child, and doubtless some day will reign a great princess in the South: but you are too great and ambitious for affection, yet not great enough for respect. I leave your shores without sorrow or regret.

A second Darwin passage quoted by Crosby (1994) is from the Descent of Man, where Darwin wrote once more about the population growth in European colonies:

The remarkable success of the English as colonists over other European nations, which is well illustrated by comparing the progress of the Canadians of English and French extraction, has been ascribed to their "daring and persistent energy;" but who can say how the English gained their energy. There is apparently much truth in the belief that the wonderful progress of the United States, as well as the character of the people, are the results of natural selection; the more energetic, restless, and courageous men from all parts of Europe having emigrated during the last ten or twelve generations to that great country, and having there succeeded best.²⁷ Looking to the distant future, I do not think that the Rev. Mr. Zincke takes an exaggerated view when he says:²⁸ "All other series of events — as that which resulted in the culture of mind in Greece, and that which resulted in the empire of Rome — only appear to have purpose and value when viewed in connection with, or rather as subsidiary to .... the great stream of Anglo-Saxon emigration to the west."

Obscure as is the problem of the advance of civilisation, we can at least see that a nation which produced during a lengthened period the greatest number of highly intellectual, energetic, brave, patriotic, and benevolent men, would generally prevail over less favoured nations (Darwin 1871:179-180).

This serves as introduction to a section about the means by which natural selection led to the origin of mankind from animals, and civilized societies from barbarous ones. Darwin describes a kind of race-level or nation-level selection, using his "struggle for existence" metaphor. Then he returns to the topic of the Fuegans, upon whom he had spent such consideration in Voyage of the Beagle, to suggest they had been "compelled by other conquering hordes to settle in their inhospitable country, and they may have become in conseqeunce somewhat more degraded."

This raises a question for Darwin: if people can become "degraded" as a consequence of inhabiting an "inhospitable" place, perhaps it is possible that all of the "barbarous" peoples have suffered this fate sometime in the past, explaining their current states?

He spends only a couple of paragraphs on this question, with a brief statement that "civilized" peoples carry customs that link them to barbarous peoples, referring the reader to Tylor for details. I find this interesting as a reminder that Darwin operated in parallel with the beginnings of real ethnology. The section concludes with this remark, which concerns what a cladist would call the "character polarity" of civilization:

[T]here can hardly be a doubt that the inhabitants of these many countries, which include nearly the whole civilised world, were once in a barbarous condition. To believe that man was aboriginally civilised and then suffered utter degradation in so many regions, is to take a pitiably low view of human nature. It is apparently a truer and more cheerful view that progress has been much more general than retrogression; that man has risen, though by slow and interrupted steps, from a lowly condition to the highest standard as yet attained by him in knowledge, morals, and religion (Darwin 1871:183-184).

It is one of Crosby's themes that disease itself was a factor driving formerly vibrant indigenous societies into a state of collapse just prior to European colonization. The seeds of that hypothesis are there in facts that Darwin (and others) knew, but they had very different interpretations.

References:

Crosby AW. 1994. Germs, Seeds and Animals: Studies in Ecological History. M. E. Sharpe, Armonk, NY.

Darwin C. 1860. The Voyage of the Beagle. Revised edition. Online free text.

Darwin C. 1871. The Descent of Man, and Selection in Relation to Sex. Vol. 1. John Murray, London.

Here's an interesting abstract from a 2005 review paper by Ann Gardner and Richard Boles:

Is a "Mitochondrial Psychiatry" in the Future? A Review

The field of "mitochondrial medicine" has advanced rapidly since the first patient with a mitochondrial disorder, a concept primarily used for defects of the respiratory chain, was described in 1962 and the first mitochondrial DNA (mtDNA) mutations were described in 1988. Because of the ubiquitous requirement for energy and unique aspects of mtDNA genetics, mtDNA mutations are known to cause a bewildering spectrum of clinical manifestations. However, because of its high-energy requirement, brain is the primary tissue affected in mitochondrial disorders. Using a variety of approaches, mitochondrial function has been shown in numerous studies to be abnormal in patients with schizophrenia and depression. Although less studied, an increase of psychiatric symptoms and disorders, in particular depression, are likely present in patients with mitochondrial disorders. The major categories of drugs used to treat schizophrenia and depression have been demonstrated to exert effects on mitochondria. The authors conclude that an association between energy metabolism and the mental disorders of schizophrenia and depression has been well documented, but that no conclusive evidence as yet demonstrates a causal relationship. A "mitochondrial psychiatry" model is proposed in which a moderate reduction in mitochondrial energy metabolism, genetically determined and/or acquired, is one predisposing factor in the multi-factorial development of certain chronic mental disorders. Clinical implications of our hypothesis, present and future, include the presence of co-morbid somatic symptoms/conditions, and specific treatment at least in highly-selected cases.

The association studies linking certain mtDNA polymorphisms to mental disorders like schizophrenia or Alzheimer's are potentially confounded by population history, which has spread some initially rare mtDNA variants far from their points of origin and to relatively high frequencies (see exchange between Kato 2001b and McMahon et al. 2001). Two problems make mtDNA-disease linkage difficult. First, mtDNA is nonspecific in its activity -- expressed in all cell types -- so that it is hard to establish clear biochemical pathways leading to particular neurophysiological disorders. Second, there is no possibility of localizing mtDNA variants by LD, since it is entirely linked.

Another issue is that mtDNA coding polymorphisms in humans often vary among other primate species. There is an argument (employed by McMahon et al. 2001) that coding variation found naturally among different primate lineages is unlikely to be functionally relevant in humans -- in other words, such variations are likely to be functionally neutral. But given the extensive behavioral variability of other primates, this argument by itself seems weak -- there is no reason why a variant allele associated with neurophysiological variation in humans should not also vary amont primate lineages. It seems just as likely that such variants may be especially variable among other primates, because they may provide targets for selection on behavior outside of the human context.

Some of these problems and some other work were reviewed by Tadafumi Kato in a 2001 Molecular Psychiatry review:

The other, forgotten genome: mitochondrial DNA and mental disorders

This paper summarizes recent research on mitochondrial DNA (mtDNA) which might be described as the 'other, forgotten genome'. Recent studies suggest the possible pathophysiological significance of mtDNA in schizophrenia and neurodegenerative and mood disorders. Decreased activity of the mitochondrial electron transport chain has been implicated in both Parkinson's and Alzheimer's disease and while age-related accumulation of mtDNA deletions has been suggested as a possible cause, there is no concrete evidence that particular mtDNA polymorphisms are responsible. In schizophrenia, the activity and/or mRNA expression of complex IV are involved, but the direction of the alteration is not the same and there is no evidence linking schizophrenia with mtDNA. In bipolar disorder, there is some evidence of parent-of-origin effects and association with mtDNA polymorphisms but further investigation is needed to elucidate the role of mtDNA in mental disorders.

Later research has employed whole-mtDNA screening to try to resolve such problems. For example, Martorell and colleagues (2006) screened maternal-offspring pairs affected by schizophrenia to find candidate mtDNA polymorphisms that contribute to the disorder:

New variants in the mitochondrial genomes of schizophrenic patients

The impaired mitochondrial function hypothesis in schizophrenia is based on evidence of altered brain metabolism, morphology, biochemistry and gene expression. Mitochondria have their own genome, which is needed to synthesize some of the subunits of the respiratory chain enzymes. Mitochondrial DNA (mtDNA) is maternally inherited and we observed an excess of maternal transmission of schizophrenia in a set of parent-offspring affected pairs. We therefore hypothesized that mutations in the mtDNA may contribute to the complex genetic basis of schizophrenia. The entire mtDNA of six schizophrenic patients with an apparent maternal transmission of the disease was sequenced and compared to the reference sequence. We have identified 50 variants and among these six have not been previously reported. Three of them were missense variants: MTCO2 7750C>A, MTATP6 8857G>A and MTND4 12096T>A. These were maternally inherited because they were also present in the mtDNA of their respective schizophrenic mothers and none of them were found in 95 control individuals. The MTND4 12096T>A (Leu446His) is a heteroplasmic variant present in five of the six mother-offspring patient pairs that triggers a non-conservative substitution in the ND4 subunit of complex I. Sequence alignment of 110 ND4 peptides from all eukaryotic kingdoms shows that only hydrophobic amino acids are found in this position. Moreover, leucine was conserved or substituted by an isoleucine in all mammalian species. This indicates that the presence of histidine could affect complex I activity in patients with schizophrenia.

Well, there's an example of a change not found in other lineages, and putatively under recurrent mutation as a rare disease-associated variant in humans.

Most disease-associated mitochondrial variants presumably do result from recurrent mutations under purifying selection. Different from nuclear genes, the mtDNA has a very high rate of mutations. This means that somatic mosaicism (i.e., different mtDNA mutations accumulating in different parts of the body over time) or heteroplasmy (i.e., different mtDNA sequences within given cells) play a role in some of the disorders of aging and senescence, such as Parkinson's disease.

There is now a substantial literature linking the common mtDNA haplogroups with longevity. For example, De Benedictis et al. (1999) found that Italian centenarians were significantly more likely to carry mtDNA haplogroup J than a set of younger individuals. Interestingly, Rose et al. (2001) found that the haplogroup J mutations were also associated with some complex diseases, concluding:

The general picture that emerges from the study is that the J haplogroup of centenarians is surprisingly similar to that found in complex diseases, as well as in Leber Hereditary Optic Neuropathy. This finding implies that the same mutations could predispose to disease or longevity, probably according to individual-specific genetic backgrounds and stochastic events. This data reveals another paradox of centenarians and confirms the complexity of the longevity trait.

The specificity of genetic background was also suggested by Dato et al. (2004), who found no evidence of an increase of haplogroup J with age cohorts in their southern European sample. Population-specific effects due to allelic background have the potential to confound many kinds of association studies, particularly those related to longevity -- for which frequency changes over time in one or more genes are also a consideration.

All this is a bit of a prologue to a new paper, "An enhanced MITOMAP with a global mtDNA mutational phylogeny", by Eduardo Ruiz-Pesini and colleagues from Doug Wallace's lab:

The MITOMAP (http://www.mitomap.org) data system for the human mitochondrial genome has been greatly enhanced by the addition of a navigable mutational mitochondrial DNA (mtDNA) phylogenetic tree of 3000 mtDNA coding region sequences plus expanded pathogenic mutation tables and a nuclear-mtDNA pseudogene (NUMT) data base. The phylogeny reconstructs the entire mutational history of the human mtDNA, thus defining the mtDNA haplogroups and differentiating ancient from recent mtDNA mutations. Pathogenic mutations are classified by both genotype and phenotype, and the NUMT sequences permits detection of spurious inclusion of pseudogene variants during mutation analysis. These additions position MITOMAP for the implementation of our automated mtDNA sequence analysis system, Mitomaster.

The map characterizes apparent disease-linked mutations, which anyone can cruise to her heart's content. The paper also provides a brief account of the way that different haplogroups got their names, and their geographical distributions.

That paper is part of a special database issue of Nucleic Acids Research, which has short articles on the latest and greatest versions of many publicly accessible databases in molecular biology and genetics. All the papers are free, and it is a tremendous opportunity to learn about the fundamental data of genomics.

References:

Dato S, Passarino G, Rose G, Altomare K, Bellizi D, Mari V, Feraco E, Franceschi C, De Benedictis G. 2004. Association of the mitochondrial DNA haplogroup J with longevity is population specific. Eur J Hum Genet 12:1080-1282. doi:10.1038/sj.ejhg.5201278

De Benedictis G, Rose G, Carrieri G, De Luca M, Falcone E, Passarino G, Bonafé M, Monti D, Baggio G, Bertolini S, Mari D, Mattace R, Franceschi C. 1999. Mitochondrial DNA inherited variants are associated with successful aging and longevity in humans. FASEB Journal 13:1532-1536.

Gardner A, Boles RG. 2005. Is a "Mitochondrial Psychiatry" in the future? A review. Curr Psychiatry Rev 1:255-251. doi:10.2174/157340005774575064

Kato T. 2001a. The other, forgotten genome. mitochondrial DNA and mental disorders. Mol Psychiatry 6:625-633. Abstract

Kato T. 2001b. DNA Polymorphisms and bipolar disorder (letter). Am J Psychiatry 158:1169-1170.

Martorell L, Segués T, Folch G, Valero J, Joven J, Labad A, Vilella E. 2006. New variants in the mitochondrial genomes of schizophrenic patients. Eur J Hum Genet 14:520-528. doi:10.1038/sj.ejhg.5201606

McMahon FJ, Chen Y, Torroni A. 2001. Dr. McMahon and colleagues reply to "DNA Polymorphisms and bipolar disorder." Am J Psychiatry 158:1170.

Rose G, Passarino G, Carrieri G, Altomare K, Greco V, Bertolini S, Bonafè M, Franceschi C, De Benedictis G. 2001. Paradoxes in longevity: sequence analysis of mtDNA haplogroup J in centenarians. Eur J Hum Genet 9:701-707. Abstract

Ruiz-Pesini E, Lott MT, Procaccio V, Poole JC, Brandon MC, Mishmar D, Yi C, Kreuzinger J, Baldi P, Wallace DC. 2007. An enhanced MITOMAP with a global mtDNA mutational phylogeny. Nucleic Acids Res 35:D823-D828. doi:10.1093/nar/gkl927

Nick Wade has an article about progress toward a treatment for Rett syndrome, a form of autism that almost exclusively affects females.

Researchers have found that Rett syndrome, a severe form of autism, may not be so entirely beyond repair as supposed. In mice that carry the same genetic defect as human patients and have similar symptoms, the disease can be substantially reversed, even in adult mice, by correcting the errant gene.

That's great news, if it pans out as a treatment. A survey of the literature shows that Rett syndrome is associated with mutations of MECP2, and the mutations are essentially sporadic single-family events. MECP2 is an X-linked gene, and most mutations occur on the paternal X chromosome. Males with an affected allele apparently do not survive beyond a year, unless they have an extra X chromosome.

Anyway, all those details are in OMIM. I'm looking for genes with recurrent sporadic mutations beyond the well-known examples like neurofibromatosis and myotonic dystrophy.

Nature has a little article this week by Fran Van Heuverswyn et al. announcing that SIV (the primate relative of HIV) has been found in wild populations of Western lowland gorillas.

The finding of distinct but related SIVgor strains in gorillas living nearly 400 km apart suggests that, as in chimpanzees, SIV infection is endemic in gorillas. An alternative explanation could be that gorillas acquire SIV sporadically from chimpanzees, but this seems unlikely as no chimpanzee community surveyed so far, including several from habitats that overlap with those of the SIVgor-positive gorillas, harbour group O-like viruses (see supplementary information). The phylogenetic relationships shown in Fig. 1b argue that chimpanzees were the original reservoir of SIVs now found in chimpanzees, gorillas and humans; that distinct chimpanzee communities in southern Cameroon transmitted divergent SIVcpz to humans, giving rise to HIV-1 groups M and N1; and that chimpanzees transmitted HIV-1 group O-like viruses either to gorillas and humans independently, or to gorillas that then transmitted the virus to humans (Van Heurverswyn et al. 2006:164).

OK, here's what I want to know: If the virus originated in chimpanzees, I can understand that it might have moved to humans by bushmeat consumption. But how did it move to gorillas?

The article suggests it may have crossed from humans to gorillas through hunting, and the gorilla lineages do cluster phylogenetically with some human HIV lineages, so it's not impossible. But it's hard to figure just how this is supposed to work in practice. Well, it's a stumper!

References:

Van Heuverswyn F and 15 others. 2006. Human immunodeficiency viruses: SIV infection in wild gorillas. Nature 444:164. DOI link