Genetics

Sparks flew at a symposium hosted by the Stanford Center for Health Research on Women & Sex Differences in Medicine, which I attended yesterday. One invited speaker -Louann Brizendine, MD, of the University of California at San Francisco – is the author of a couple of books titled The Male Brain and The Female Brain. Another invited speaker – neuroscientist Daphna Joel, PhD, who’d flown in from the University of Tel Aviv, in Israel – emphatically maintained that there is no such thing as a “male” brain or a “female” brain. “What we know,” she said bluntly, “is that males have brains and females have brains.”

Whatever the semantics of that debate, two things are pretty clear any way you slice it. First, male and female brains are mostly alike. Second, there are measurable and meaningful differences in what goes on inside male versus female brains. As another neuroscientist, UCLA’s Art Arnold, PhD, put it: “Every cell in a female’s brain expresses a set of genes that the cells in a male’s brain express at much lower levels, if at all.”

Adding heft to Arnold’s comment was a presentation by Nirao Shah, MD, PhD, of UCSF. The neuroanatomist showcased research in his lab that had pinpointed specific genes whose activity levels differed significantly in the brains of male and female mice. Many of these genes, he noted, have human analogs that have been implicated in alcoholism, autism, breast and prostate cancers, and more. By conducting rigorous experiments with mice in which one or another of such genes had been put out of commission, Shah and his colleagues were able to tease out the behavioral consequences of specific genes’ inactivation. For example, knocking out a particular gene in female mouse moms results in a massive dimunition in their willingness to defend their nests from intruders – a maternal mandate that normal female mice observe rigorously – yet has no other observable effect on their maternal or sexual behavior. Torpedoing a different gene radically reduces Minnie Mouse’s mating mood; but the Mickeys in which this gene has been trashed “are completely normal, as far as we can tell,” Shah said.

The upshot: Yes, there are significant differences in behavior (and therefore in brain action) and in gene activity in the brain cells of males and females. Those of male and female mice, that is. What about humans’?

Well, nobody was talking about knocking any genes out of people to see if the men indulge in fewer barroom brawls and the women start laughing off their babies’ cries of distress. But there are certainly some strong hints of medically significant differences: The ratio of men to women with autism run somewhere in the neighborhood of 8:1 or even 16:1. Depression is twice as common among women as among men – but only between menarche and menopause. Alzheimer’s disease abounds more in women, even after taking into consideration women’s greater longevity (itself a medically important difference), as does autoimmunity. On the other hand, Parkinson’s and schizophrenia preferentially affect men. There seems to be more at work here than the simple “absorption of gender stereotypes,” and it’s good to see hardcore biologists attacking the problem with all the scientific rigor at their disposal.

Let’s not call the whole thing off.

Previously: A call to advance research on women’s health issues
Photo by namuit

Research recently published in PLOS ONE suggests that genetics may be a primary factor in shaping individuals’ financial decisions. In the paper, Brian Knutson, PhD, associate professor of psychology at Stanford, and colleagues examined how a serotonin gene, known as 5-HTTLPR, influenced participants’ willingness to take risks when investing their money.

As explained in a Stanford Report article published today, we all have two copies, known as alleles, of the 5-HTTLPR gene. Individual combinations can include two short, two long or one short and one long allele. Researchers found that those with two short alleles displayed more neurotic traits and were more risk adverse. Paul Gabrielsen writes:

The researchers asked 60 volunteers from the Bay Area to divvy up $10,000 among three investment options: stocks, bonds or cash. On average, study participants with two short 5-HTTLPR alleles kept 24 percent more of that money in cash than did the two-long-allele carriers, who put more money in stocks.

Knutson and his colleagues had previously measured participants’ financial literacy, cognition and income level, but those factors didn’t explain the variation in investment strategy. Could the gene explain the variation?

“We found that it did,” Knutson said.

Given neurotic participants’ propensity to avoid risk, [Kellogg School of Management professor Camelia Kuhnen, PhD,] hypothesized that they would react just as strongly to a negative outcome. In unpublished research, Kuhnen watched how participants’ brains reacted during a game in which they learned, by trial-and-error, which of two options carried greater financial risk. Short-allele carriers displayed heightened anxiety before making a decision, but reacted no differently than long-allele carriers when they saw a negative outcome.

“The difference between these people is not about how they react to outcomes,” Kuhnen said. “It’s about how, before the choice, they think about the decision.”

The findings, says Knutson, can help in understanding how emotions affect decision making. “You’re not a slave to your genotype,” he notes in the story “If you understand how it’s influencing your behavior, then you have a shot at changing that behavior.”

Photo by Alan Cleaver

There’s an interesting piece in Wired today about how shifts in the genomics industry could ultimately result in the “emergence of personalized medicine as the new standard of care.”

In the article, Daniela Hernandez outlines some of the driving forces behind the industry’s evolution and why such changes could make genetic testing more affordable and accessible for the general public. She writes:

Right now, most genetic testing happens in top-tier hospitals for conditions like cancer or rare genetic diseases and to test whether patients might have adverse reactions to certain medications. But it will likely become more mainstream as scientists and doctors learn more about the genome and genetic interpretation gets better and cheaper. Entrepreneurs are counting on it, and startups aiming to make genomic medicine as routine as having a blood test or getting an EKG are launching all the time.

…

With big and small companies duking it out to make it big in this space, patients may stand to benefit. Whoever the top players in the industry end up being, they’ll likely compete on price and speed, which should not only decrease the strain on patients’ wallets but also on the anxiety they may feel while they await a diagnosis. Many genomic startups and even larger companies like Illumina are storing genetic data up in the Amazon cloud and making that data available through the web. Soon that data will be integrated with medical records and people will have 24/7 access to their whole genomes through mobile devices, like they do for their financial information today, says Stanford’s Dr. Euan Ashley, co-founder of another genomics startup, Personalis. “That future is not so far away.”

Previously: Stanford geneticist talks tracking biological data points and personalized medicine, When it comes to your genetic data, 23andMe’s Anne Wojcicki says: Just own it, Scientists announce the completion of the ENCODE project, a massive genome encyclopedia and Ask Stanford Med: Genetics chair answers your questions on genomics and personalized medicine
Photo by Spanish Flea

Estrogen-based hormone therapy has had its ups and downs. In 2002, one arm of the Women’s Health Initiative, a large-scale longitudinal trial of women examining hormone therapy, was halted due to an unexpected increase in adverse cardiovascular events among women on the therapy. The ensuing publicity resulted in many women ditching their regimens. But subsequent research (see for example this study, and this one) has shown that women who start treatment at menopause or soon afterward can benefit.

Now, a new study conducted by researchers based at Stanford and the University of California-San Francisco suggests that for women who are carriers of a well-known genetic risk factor for cognitive decline in general and Alzheimer’s disease in particular, beginning an estrogen regimen at menopause may be a good idea.

As I wrote in my news release about the study, which was just published in the open-access online journal PLOS ONE and led by Stanford psychopharmacologist Natalie Rasgon, MD, PhD:

All people carry two copies of a gene called ApoE. (One copy is inherited from each parent). Like genes for eye or hair color, ApoE comes in more than one version. Some 15 to 20 percent of Americans carry at least one copy of ApoE4, a version that puts them at substantially increased risk for late-onset Alzheimer’s disease in comparison with people who are not ApoE4 carriers.

For their work, the researchers recruited 70 healthy, high-functioning middle-aged women who had all been on hormone therapy since menopause and divided them into two groups: One group stayed on their regimen, the others dropped it.

An analysis of blood samples drawn from the volunteers when they first started on the study and again two years later showed significant differences between the two groups. In those women with one or more copies of ApoE4, a molecular measure of cellular aging called telomere shortening was greatly accelerated compared with its speed in women not carrying ApoE4. In other words, the cells of women carrying ApoE4 seemed to be aging at a faster rate than was seen in the cells of non-carriers.

Interestingly, though, carriers who stayed on the regimen throughout the two-year duration of the study showed no such signs of accelerated biological aging.

“Our take-home findings from this study were, first, that ApoE4 carriers are at greater risk of biological aging, which is associated with negative health outcomes and, second, that if you were a postmenopausal ApoE4 carrier, being on estrogen therapy was a good thing for telomere length, an established measure of biological aging at the cellular level,” Rasgon told me during an interview. “This brings us a step closer to being able to identify which women will benefit the most from estrogen replacement therapy.”

Previously: Hormone therapy soon after menopause onset may reduce Alzheimer’s risk and Study shows common genetic risk factor for Alzheimer’s disrupts brain function in healthy older women, but not men
Photo by FishTech

Nearly a year ago, Stanford geneticist Michael Snyder, PhD, and colleagues published an analysis of some of his body’s most intimate secrets: the sequence of his DNA, the RNA and proteins produced by his cells and the metabolites and signaling molecules flowing through his blood. During the course of the study, Snyder not only discovered that he was predisposed to diabetes, but he also watched himself develop the disease.

In this Mendelspod video Q&A, Snyder discusses how his research is progressing, his decision to begin self-tracking nutritional and exercise information, and the expansion of his project to include another ten individuals. He also comments on the potential of using an integrative Personal “Omics” Profile (iPoP) – the approach of collecting and analyzing billions of individual bits of data - in a clinical setting. For those who have always desired to spy on the biological interworkings of their own bodies, it’s fascinating stuff.

Previously: NPR explores the pros and cons of scientists sequencing their own genes, Ask Stanford Med: Genetics chair answers your questions on genomics and personalized medicine, How genome testing can help guide preventative medicine and ‘Omics’ profiling coming soon to a doctor’s office near you?

I’ve been fascinated by the placenta ever since I wrote about Lucile Packard Children’s Hospital neonataologist Anna Penn, MD, PhD, and her quest to find out more about this ‘most mysterious organ.’ The recent work of Penn and others have shown that the placenta is much more than a mere housekeeper moderating the ongoing biological conversation between mother and fetus. It also differs markedly among species, which suggests a history of rapid evolution.

Now, geneticist Julie Baker, PhD, and graduate student Edward Chuong have published an intriguing article (.pdf) in Nature Genetics suggesting that species-specific differences are due to the activity of viral sequences that have been incorporated into the mammalian genome over time. (My colleague, Bruce Goldman, has written an elegant description of how these sequences, called endogenous retroviruses, are constantly accumulating in our DNA.) As Chuong explained in an e-mail to me:

Endogenous retroviruses, or ERVs, are genomic “parasites” that occupy 8 to 10 percent of mammalian genomes. They must be aggressively silenced for the embryo to develop properly. In contrast, ERVs are highly active in the placenta, although their functional role – if any – has largely remained a mystery. In this study, we show that these ERVs function as a genome-wide source of enhancers in the placenta. Our findings point to ERV enhancer activity as a potentially significant evolutionary mechanism driving the rapid evolution of the placenta.

Why might the placenta need to evolve so quickly? Well, as any pregnant woman will tell you, with pregnancy comes many indignities. Some are purely physical in nature, others are less obvious. Specifically, the maternal immune system has to be kept from recognizing the fetal cells as foreign and mounting a fatal attack. The placenta protects the fetus by, among other things, secreting molecules to dampen the mother’s immune response; the immune system, conversely, tries to evade this suppression. Says Chuong:

Intriguingly, the fact that the placenta is remarkably different across species may reflect an ongoing co-evolutionary arms races between parent and offspring.

Previously: The placenta sacrifices itself to keep baby healthy in case of starvation, research shows, Program focuses on the treatment of placental disorders and Viruses can cause warts on your DNA

An article in today’s New York Times highlights just-published work by Massachusetts General Hospital researchers and Stanford genomics expert Ron Davis, PhD, in which the scientists presented “stunning evidence that the mouse model has been totally misleading for at least three major killers – sepsis, burns and trauma.” As a result, according to the Times article, “years and billions of dollars have been wasted following false leads.”

The newspaper story is referring to a Proceedings of the National Academy of Sciences study that writer Gina Kolata says may help explain why every one of nearly 150 drugs tested at huge expense in patients with sepsis has failed.

This work goes back several years, with Davis and his associates finding patterns of gene activity that seemed to predict which sepsis victims will live and which will die. The researchers tried to publish their results in several journals but were initially rebuffed because they hadn’t tested their findings in mice to see if the same things happened, according to the article:

“They were so used to doing mouse studies that they thought that was how you validate things,” [Davis] said. “They are so ingrained in trying to cure mice that they forget we are trying to cure humans.”

“That started us thinking,” he continued. “Is it the same in the mouse or not?” The group decided to look, expecting to find some similarities…

But when the investigators looked, there were none at all. In fact, some genes that were “turned on” by sepsis in mice were “turned off” in humans. Further, in humans, similar genes were activated by sepsis, trauma and burns – three conditions in which the immune system overreacts and inflicts more damage to the body than the bacteria, knock to the head or house fire, respectively, that originally caused the problem. But in mice, these three different types of stimuli trigger three quite different gene-activation patterns.

So, a drug that might work in a human could have the opposite effect in a mouse. And vice versa.

The man/mouse mismatch, intriguingly, shows up in other places, too. For instance, a recent study led by Stanford immunologist Mark Davis, PhD, suggests that experimental mice – who spend their entire lives in artificial, ultra-germ-free environments – may be a poor model for adult humans’ more battle-hardened immune systems, which have acquired quite a bit of savoir faire.

And in another study a few months back, Stanford drug-development expert Gary Peltz, MD, PhD, developed mice with humanized livers, explicitly to address another disparity that can easily result in costly failures of new drugs in clinical trials: Mice’s livers, being different from ours, often metabolize new experimental drugs quite differently from the way ours would.

Previously: Professor Ronald Davis wins 2011 genetics prize from the Gruber Foundation, Deja vu: Adults’ immune systems “remember” microscopic monsters they’ve never seen before and Fortune teller: Mice with “humanized” livers predict HCV drug candidate’s behavior in humans
Photo by gliuoo

Nature and nurture have long been the ‘tomayto’ and ‘tomahto’ of lengthy arguments in both psychology and medicine. At the end of the day, of course, disease is caused neither strictly by genes nor strictly by the environment, but by the interactions between them.

In a new study published in Nature Genetics, Stanford medical-systems expert Atul Butte, MD, PhD (whom I’ve written about at length in the past), has figured out a sophisticated way to crunch massive amounts of genetic and environmental data and pull faint but important signals out of the noise. Sifting through mountains of data gathered in biennial health-and-nutrition surveys run by the federal government’s Centers for Disease Control and Prevention, Butte teased out a gene/environment relationship that may make you want to eat a carrot.

Just over half of us, it’s already known, are walking around with two copies – one from dad, one from mom – of a particular version of a gene that seems to very slightly predispose us to developing type 2 diabetes at some point in our lives. Nothing much we can do about that.

Unlike genes, however, our environment is something we can sometimes do something about. The Butte team’s new work suggests that in people carrying a double dose of the gene version in question, low blood levels of the micronutrient beta-carotene (a vitamin A precursor found copiously in carrots and many other red, orange and yellow vegetables as well as in many vitamin supplements) are associated with not just a slight risk but a significantly increased risk for type 2 diabetes, whereas in those with high blood levels of the substance, that risk appears to be substantially mitigated.

A bit more offbeat is Butte et al.’s finding that another micronutrient – gamma-tocopherol, one of the eight forms of vitamin E – has the opposite interaction with the exact same gene: High levels of it, in people with two copies of the diabetes-related gene version, substantially boost the risk, while low levels reduce it. Nobody knows yet why that’s true, as I explain in our press release:

“We can’t say, based on just this study, that ‘vitamin E is bad for you,’” said [the Human Genetics paper's first author, postdoctoral researcher Chirag Patel, PhD]. He noted that blood levels of alpha-tocopherol - another form of vitamin E that predominates in most supplements - showed no deleterious interaction with the predisposing gene variant in the new study.

But it’s not too early to recommend that people who like carrots keep on eating them. And, the authors speculate, it could be that gamma-tocopherol, rather than being bad in itself, may instead just be a marker of a diet rich in the things where vitamin E is found. This includes soybean, corn, or canola oils (which are, unfortunately, ingredients in many processed and fried foods) and trans-fatty-acid-loaded margarine.

Previously: Mining medical discoveries from a mountain of ones and zeroes, Newly identified type-2 diabetes gene’s odds of being a false finding equal one in 1 followed by 10 zeroes and Cheap data! Stanford scientists’ “opposites attract” algorithm plunders public databases, scores surprising drug-disease hook-ups
Photo by color line

People with HIV have to take a cocktail of drugs daily to keep the lethal virus in check. But a novel gene therapy approach, now under development at Stanford, could make patients resistant to the virus and free them from this lifelong dependence on drugs, which have adverse side-effects.

In a new study, the researchers describe their technique of using “genome editing” to make T cells, key cells of the immune system, resistant to the virus. In studies done in the lab, the technique effectively blocked the virus from entering the cells through one of two receptors, known as CCR5 and CXCR4. These are the two common entry points for the virus.

In one instance, the researchers used genetic manipulation to deactivate the CCR5 receptor gene. And for added protection, they were able to introduce three known anti-HIV genes into the receptor genes. This blocked both CCR5 and CXCR4. These modified T cells had more than 1,200-fold protection, and in some instances more than 1,700-fold protection, against HIV; unmodified cells succumbed to infection in a matter of weeks, the researchers reported.

The research is still in the early stages and has to go through animal testing, as well as clinical trials. But it is a very encouraging step forward in the field of gene therapy for HIV, Matt Porteus, MD, the lead investigator told me.

“I feel this is a significant improvement in the first generation application. So I’m very excited,” he said.

Interestingly, as I left Porteus’ lab, located in the Lorry I. Lokey Stem Cell Research Building, I ran into another HIV researcher and mentioned the work, which was entirely new to him. That’s how innovative this technique is.

Porteus, a pediatrician, is interested is using the approach to treat other diseases as well. A hematologist and cancer biologist, he treats children at Lucile Packard Children’s Hospital and is hoping some of his patients, such as those with sickle cell anemia, might someday benefit from a gene therapy approach along these lines.

Can’t blame us if our feet hurt. We humans have been walking erect for well over 3 million years. 

That new style of locomotion necessitated “considerable anatomical changes that altered the size and shape of the human female pelvis and the dimensions of the birth canal,” write Stanford and evolutionary theorist Peter Parham, PhD, and pathologist Ashley Moffitt, MD, of the University of Cambridge, in a just-released review article in Nature Reviews Immunology.

Walking upright, along with the development of our bigger brains, allowed us to head out out of Africa into Eurasia. Successive migration events of this nature have occurred a number of times since – leading to the emergence of Neanderthals in Europe around 600,000 years ago and the arrival there of anatomically modern humans (that’s us) a scant 67,000 years ago, give or take a few weeks.

But those bigger brains caused problems, too, the authors write:

The size of the human baby’s head increased until it reached the limit defined by the birth canal… [A]t full term, a modern human baby’s head just fits into the birth canal… [I]n the course of human evolution, birthing became a difficult, dangerous and frequently fatal process…

Bigger brains need more nourishment in utero, putting greater demands on the blood supply to the placenta. Plus, insufficient blood supply to the placenta can lead to pre-eclampsia, stillbirth or low birth weight. But if an emerging baby’s head is too big, it could kill both mother and child on the way out of the womb. It’s a delicate balancing act.

To the rescue come specialized immune cells called natural killer (or NK) cells, which play an important role in our front-line defense against infectious pathogens. NK cells play a key role in reproduction, too, by carefully regulating the development of placental blood vessels. This keeps fetal growth in bounds.

NK cells feature a particular surface molecule that comes in two versions. One of these versions turns out to be somewhat better suited for the task of managing fetal growth, the other for fighting infectious pathogens. Both of these versions are found in every human population ever studied, suggesting that a group’s survival over evolutionary time is favored by some optimal balance between the two.

Parham and Moffett conjure up a vision of just how such a compromise between these two versions might arise:

When an epidemic infection passed through a population, causing disease, death (particularly of the young) and social disruption, selection favored [one version]. When the epidemic subsided, the surviving and now smaller population was immune to further infection and enriched for [that version]. At this juncture, survival of the current generation was no longer the issue, and the priority became production of the next generation. [This favored the evolutionary selection of] factors that enhance the generation of larger and more robust progeny… [H]uman history has always involved successive cycles of [this] type…

Thus, all human populations maintain a mix of both surface-molecule versions. Any distinction between safe, efficient reproduction and vulnerability to infectious disease may seem nonexistent to people who consider babies to be invading organisms – which I suppose they are, in a way. (But cute, too.)

Previously: Our species’ twisted family tree, Humans owe important disease-fighting genes to trysts with cavemen and Humans share history – and a fair amount of genetic material – with Neanderthals
Photo by Lord Jim

Scope will be on a limited publishing schedule in honor of Martin Luther King, Jr. Day. We’ll resume our normal schedule tomorrow.