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Education, Evolution, Global Health, Research, Stanford News

Stanford med student/HHMI fellow investigates bacteriophage therapy as an alternative to antibiotics

Stanford med student/HHMI fellow investigates bacteriophage therapy as an alternative to antibiotics

IMG_5145 croppedSecond-year medical student Eric Trac isn’t one to shy away from a challenge. Trac’s family is from Vietnam and he didn’t speak much English as a child, but Trac and his mother overcame this hurdle by practicing English and studying together every night until the early morning hours so he could do well at school. Now, just 12 years later, Trac is a Howard Hughes Medical Institute (HHMI) fellow taking on a new kind of challenge: investigating an alternative to antibiotics.

Many people think that antibiotics are the only way to kill bacteria, but this isn’t true. “Before we used antibiotics, we used bacteriophages,” Trac said. “Just like viruses attack people, bacteriophages attack bacteria. In other words, bacteria can get sick as well.”

Bacteriophages have been used since the early 1900s in countries like France, Poland and the U.S. to treat diseases such as cholera and dysentery. But interest in bacteriophage therapy, and its use, declined in the West after antibiotics were discovered in the 1920s. Now that bacteria are becoming increasingly resistant to antibiotics, researchers in the West are taking interest in the decades of bacteriophage research that continued in Eastern Europe and the former Soviet Union long after antibiotics became popular elsewhere. Unfortunately, many of these studies don’t meet the scientific standards (e.g., double blind studies, experimental controls) that Western drug research requires.

So, for his year-long HHMI project, Trac and his mentors, bioengineer and physicist Stephen Quake, PhD, and pediatric pulmonary expert David Cornfield, MD, will test bacteriophage therapy — with the required scientific protocols — to see if it could be a viable, and safe alternative to antibiotics. His project will focus on two common bacteria, Pseudomonas aeruginosa and Staphylococcus aureus, that can cause life-threatening infections, especially in people with cystic fibrosis. “The need for alternative ways to kill these two bacteria is great,” Trac said.

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Evolution, Genetics, HIV/AIDS, Immunology, Infectious Disease, Research, Stanford News

Study: Chimps teach people a thing or two about HIV resistance

Study: Chimps teach people a thing or two about HIV resistance

I, personally, have never had trouble distinguishing a human being from a chimp. I look, and I know.

But I’m not a molecular biologist. Today’s sophisticated DNA-sequencing technologies show that the genetic materials of the two species, which diverged only 5 million or so years ago (an eye-blink in evolutionary time), are about 98 percent identical. Think about that next time you eat a banana.

One major exception to that parallelism: a set of three genes collectively called the major histocompatibility complex, or MHC. These genes code for proteins that sit on the surfaces of each cell in your body, where they serve as jewel cases that display bits of proteins that were once inside that cell but have since been chopped into pieces by molecular garbage disposals, transported to the cell surface and encased in one or another of the MHC proteins. That makes the protein bits highly visible to roving immune cells patrolling our tissues to see if any of the cells within are harboring any funny-looking proteins. If those roving sentry cells spot a foreign-looking protein bit, they flag the cell on whose surface it’s displayed as possibly having been infected by a virus or begun to become cancerous.

Viruses replicate frequently and furiously, so they evolve super-rapidly. If they can evade immune detection, that’s groovy from their perspective. So our MHC has to evolve rapidly, too, and as a result, different species’ MHC genes  diverge relatively quickly.  To the extent they don’t, there’s probably a good reason.

Stanford immunologist and evolutionary theorist Peter Parham, PhD, pays a lot of attention to the MHC genes. In a new study in PLOS Biology, he and his colleagues have made a discovery that may prove relevant to AIDS research, by analyzing genetic material found in chimp feces. Not zoo chimps. Wild Tanzanian chimps. As I noted in a news release about the study:

The wild chimps inhabit Gombe Stream National Park, a 13.5-square-mile preserve where they have been continuously observed from afar since famed primatologist Jane Goodall, PhD, began monitoring them more than 50 years ago.

One thing that sets the Gombe chimps apart from captive chimps, unfortunately, is a high rate of infection by the simian equivalent of HIV, the virus responsible for AIDS.

The study’s lead author, postdoc Emily Wroblewski, PhD, set up shop in a corner of Parham’s lab and extracted DNA from fecal samples legally obtained by other researchers (close contact with the animals is prohibited). Each sample could be tied to a particular Gombe-resident chimp. RNA extracted from the same sample indicated that chimp’s infection status.

Parham, Wroblewski and their colleagues found that one particular MHC gene came in 11 different varieties – astounding diversity for such a small collection of chimps (fewer than 125 of them in the entire Gombe). Surprisingly, one small part of one of those 11 gene variants was nearly identical to a piece of a protective version of its human counterpart gene, a version that seems to protect HIV- infected people slowing HIV progression to full-blown AIDS.

Why is that important? Because any piece of an MHC gene that has maintained its sequence in the face of 5 million years of intense evolutionary pressure must be worth something.

Sure enough, fecal samples from chimps with that MHC gene variant, so strikingly analogous to the protective human variant, had lower counts of virus that those from infected chimps carrying other versions of the gene.

You can believe that scientists will be closely examining the DNA sequence contained in both the human and chimp gene variant, as well as the part of the MHC protein that DNA sequence codes for. Because it must be doing something right.

Previously: Revealed: Epic evolutionary struggle between reproduction and immunity to infectious disease, Our species’ twisted family tree and Humans share history – and a fair amount of genetic material – with Neanderthals
Photo by Emily Wroblewski

Evolution, Parenting, Pediatrics, Research, Women's Health

Just when did it begin to “take a village to raise a child”?

9640826608_e65589c650_zImagine a prehistoric human mother raising her baby outside of any community or family structure, with no help from others. It sure doesn’t fit with my idea of the “village” that raises a child, a phrase I often associate with romantic notions of pre-modern lifestyles. But according to a study done by University of Utah anthropologist Karen Kramer, PhD, if you go far back enough in human evolution, mothers raised their young alone and didn’t feed or care for them past weaning (which happened around 5 or 6 years of age!).

The study, published in the Journal of Human Evolution and interestingly titled “When mothers need others: The impact of hominin life history evolution on cooperative breeding,” examines how humans transitioned into family and community patterns of child rearing. It suggests that the earliest cooperative groups were formed by a mother and many of her children, with older ones helping rear younger siblings; after this was established, other adults were incorporated, probably when bands of mothers with their offspring teamed up. As women became better at reproducing, they needed the extra help.

As noted in a University of Utah press release, this is different from the predominating theories among anthropologists, which point to cooperation among adults. Kramer also comments:

Human mothers are interesting. They’re unlike mothers of many other species because they feed their children after weaning and others help them raise their children. As an anthropologist, I live and work in traditional societies where, like other researchers, I have observed many times that it takes a village to raise a child. Not only do mothers work hard to care for their young, but so do her older children, grandmothers, fathers and other relatives. But this wasn’t always the case.

The consequences for health likely factored into the “economic decision making” that Kramer modeled in her study – children reared cooperatively were more likely to survive, and I imagine mothers garnered more than a few benefits from extra pairs of eyes, ears, hands, and feet, as well.

And another thing this study shows us: Some of the same decisions that parents weigh today – how many children to have, which kind of help to recruit in raising them, and what kind of balance between kids and other pursuits will optimize health – are really not so novel.

Previously: Computing our evolution and Revealed: Epic evolutionary struggle between reproduction and immunity to infectious disease
Photo by Jaroslav A. Polak

Evolution, Genetics, Microbiology, Pregnancy, Research, Science, Stanford News, Stem Cells

My baby, my… virus? Stanford researchers find viral proteins in human embryonic cells

My baby, my... virus? Stanford researchers find viral proteins in human embryonic cells

Wysocka - 560

One thing I really enjoy about my job is the opportunity to constantly be learning something new. For example, I hadn’t realized that about eight percent of human DNA is actually left-behind detritus from ancient viral infections. I knew they were there, but eight percent? That’s a lot of genetic baggage.

These sequences are often inactive in mature cells, but recent research has shown they can become activated in some tumor cells or in human embryonic stem cells. Now developmental biologist Joanna Wysocka, PhD, and graduate student Edward Grow, have shown that some of these viral bits and pieces spring back to life in early human embryos and may even affect their development.

Their research was published today in Nature. As I describe in our press release:

Retroviruses are a class of virus that insert their DNA into the genome of the host cell for later reactivation. In this stealth mode, the virus bides its time, taking advantage of cellular DNA replication to spread to each of an infected cell’s progeny every time the cell divides. HIV is one well-known example of a retrovirus that infects humans.

When a retrovirus infects a germ cell, which makes sperm and eggs, or infects a very early-stage embryo before the germ cells have arisen, the viral DNA is passed along to future generations. Over evolutionary time, however, these viral genomes often become mutated and inactivated. About 8 percent of the human genome is made up of viral sequences left behind during past infections. One retrovirus, HERVK, however, infected humans repeatedly relatively recently — within about 200,000 years. Much of HERVK’s genome is still snuggled, intact, in each of our cells.

Wysocka and Grow found that human embryonic cells begin making viral proteins from these HERVK sequences within just a few days after conception. What’s more, the non-human proteins have a noticeable effect on the cells, increasing the expression of a cell surface protein that makes them less susceptible to subsequent viral infection and also modulating human gene expression.

More from our release:

But it’s not clear whether this sequence of events is the result of thousands of years of co-existence, a kind of evolutionary symbiosis, or if it represents an ongoing battle between humans and viruses.

“Does the virus selfishly benefit by switching itself on in these early embryonic cells?” said Grow. “Or is the embryo instead commandeering the viral proteins to protect itself? Can they both benefit? That’s possible, but we don’t really know.”

Wysocka describes the findings as “fascinating, but a little creepy.” I agree. But I can’t wait to hear what they discover next.

Previously: Viruses can cause warts on your DNA, Stanford researcher wins Vilcek Prize for Creative Promise in Biomedical Science and Species-specific differences among placentas due to long-ago viral infection, say Stanford researchers
Photo of Joanna Wysocka by Steve Fisch

Evolution, In the News, Research, Science

Chins make us human; new study examines why

Chins make us human; new study examines why

il-150226-ts-08When we think of what makes us human, it’s common to think of something like language or tool-making. Something that likely doesn’t pop into mind is the chin – but humans are the only species to have one! The bony prominence is missing from the skulls of Neanderthals, archaic humans, primates, and indeed all other animals. (In the photo, the skull on the left is human, and the one on the right is Neanderthal).

Scientists have puzzled for more than a century over why chins developed, and the dominant theory has been that they resulted from mechanical forces like chewing. Bones under pressure sustain tiny tears that then enable new bone to grow, much like weight lifting does to muscles. But a new study conducted by University of Iowa researchers suggests that mechanical forces have nothing to do with it: It’s more likely that chins resulted from shifting social dynamics.

The study, published in the Journal of Anatomy, capitalized on the fact that children don’t have chins either – the bone underneath their lower lip is smooth, and the prominence develops with age. The study examined nearly 40 people ranging from 3-20 years old, correlating their chin development with various forces exerted by their cranio-facial anatomy (during chewing, for example), and concluded that mechanical forces don’t play a role in chin development. In fact, those with the most mechanical force had the smallest chins.

Nathan Colton, PhD, professor of orthodontics at the UI College of Dentistry and lead author of the study, is quoted in a UI press release:

In short, we do not find any evidence that chins are tied to mechanical function and in some cases we find that chins are worse at resisting mechanical forces as we grow. Overall, this suggests that chins are unlikely related to the need to dissipate stresses and strains and that other explanations are more likely to be correct.

Instead, the researchers think that the chin results from the facial structure being rearranged as faces got smaller – human faces are 15 percent smaller than those of Neanderthals. This reduction resulted from a decrease in testosterone levels, which happened as males of the species benefitted more from interacting socially with other groups rather than fighting other males.

Robert Franciscus, PhD, professor of anthropology at UI and a contributing author on the study, also comments:

What we’re arguing is that modern humans had an advantage at some point to have a well-connected social network, they can exchange information, and mates, more readily, there’s innovation. And for that to happen, males have to tolerate each other. There had to be more curiosity and inquisitiveness than aggression, and the evidence of that lies in facial architecture.

Previously: Humans share history – and a fair amount of genetic material – with Neanderthals
Photo by Tim Schoon, University of Iowa

Evolution, Global Health, In the News, Microbiology, Nutrition, Research

A key bacteria from hunter gatherers’ guts is missing in industrial societies, study shows

392924423_860dafa0a4_oTrends like the paleo diet and probiotic supplements attest to the popular idea that in industrial societies, our digestion has taken a turn for the worse. The scientific community is gathering evidence on how the overuse of antibiotics affects our microbiome, and on what might be causing the increasing incidence gastrointestinal inflammatory disorders like Crohn’s disease and colitis. Scientists are now one step closer to knowing exactly what has changed since the majority of humans were hunter-gatherers.

Yesterday, a paper published in Nature Communications found that an entire genus of bacteria has gone missing from industrialized guts. Treponema are common in all hunter-gatherer societies that have been studied, as well as in non-human primates and other mammals. Treponema have primarily been known as pathogens responsible for diseases like syphilis, but the numerous strains found in the study are non-pathenogenic and closely resemble carbohydrate-digesting bacteria in pigs, whose digestive system is notably similar to that of humans. The genus is undetectable in humans from urban-industrial societies.

The study, led by anthropologists from the University of Oklahoma and the Universidad Científica del Sur in Peru, used genomic reconstruction to compare microbes in stool samples from two groups in Peru, one of hunter-gatherers and one of traditional farmers, with samples from people in Oklahoma. Each group comprised around 25 people. This is the first comprehensive study of the full-spectrum of microbial diversity in the guts of a group of hunter-gatherers – in this case, the Amazonian Matses people.

The researchers also sought to understand how diet affects gut health: The hunter-gatherers ate game and wild tubers, the traditional farmers ate potatoes and domestic mammals, and the Oklahomans ate primarily processed, canned, and pre-packaged food, with some additional meat and cheese.

Science published a news report discussing the findings, in which co-author Christina Warinner, PhD, an anthropologist at the University of Oklahoma, is quoted as saying:

Suddenly a picture is emerging that Treponema was part of core ancestral biome. What’s really striking is it is absolutely absent, not detectable in industrialized human populations… What’s starting to come into focus is that having a diverse gut microbiome is critical to maintaining versatility and resiliency in the gut. Once you start to lose the diversity, it may be a risk factor of inflammation and other problems.

Further research is needed to answer the next question: Is there a direct link between the absence of Treponema and the digestive health and prevalence of certain diseases (like colitis and Crohn’s) in industrialized humans? If so, this could be a valuable key to increasing our digestive health. It would also indicate that imitating a paleo diet is not enough to achieve a real “paleo gut.”

Previously: Drugs for bugs: industry seeks small molecules to target, tweak, and tune-up our gut microbes, Tiny hitchhikers, big impact: studying the microbiome to learn about disease, Civilization and its dietary (dis)contents: Do modern diets starve our gut-microbial community?, Stanford team awarded NIH Human Microbiome Project grant, and Contemplating how our human microbiome influences personal health
Photo by AJC1

Applied Biotechnology, Cancer, Evolution, Immunology, Research, Stanford News

Corrective braces adjust cell-surface molecules’ positions, fix defective activities within cells

Corrective braces adjust cell-surface molecules' positions, fix defective activities within cells

bracesStanford molecular and cellular physiologist and structural biologist Chris Garcia, PhD, and his fellow scientists have tweaked together a set of molecular tools that work like braces of varying lengths and torque to fix things several orders of magnitude too small to see with the naked eye.

Like faulty cell-surface receptors, for instance, whose aberrant signaling can cause all kinds of medical problems, including cancer.

Cell-surface receptors transmit naturally occurring signals from outside cells to the insides of cells. Molecular messengers circulating in the blood stumble on receptors for which they’re a good fit, bind to them, and accelerate or diminish particular internal activities of cells, allowing the body to adjust to the needs of the minute.

Things sometimes go wrong. One or another of the body’s various circulating molecular messengers (for example, regulatory proteins called cytokines) may be too abundant or scarce. Alternatively, a genetic mutation may render a particular receptor type overly sluggish, or too efficient. One such mutation causes receptors for erythropoietin – a cytokine that stimulates production of certain blood-cell types – to be in constant overdrive, resulting in myeloproliferative disorders. Existing drugs for this condition sometimes overshoot, bringing the generation of needed blood-cell types to a screeching halt.

Garcia’s team took advantage of the fact that many receptors – erythropoietin receptors, for example – don’t perform solo, but instead work in pairs. In a proof-of-principle study in Cell, Garcia and his colleagues made brace-like molecular tools composed of stitched-together antibody fragments (known in the trade as diabodies). They then showed that these “two-headed beasts” can selectively grab on to two members of a mutated receptor pair and force the amped-up erythropoietin receptors into positions just far enough apart from, and at just the right angles to, one another to slow down their hyperactive signaling and act like normal ones.

That’s a whole new kind of therapeutic approach. Call it “cellular orthopedics.”

Previously: Souped-up super-version of IL-2 offers promise in cancer treatment and Minuscule DNA ring tricks tumors into revealing their presence
Photo by Zoe

Cancer, Evolution, Genetics, Infectious Disease, Microbiology, Research, Stanford News

Bubble, bubble, toil and trouble – yeast dynasties give up their secrets

Bubble, bubble, toil and trouble - yeast dynasties give up their secrets

yeasty brew

Apologies to Shakespeare for the misquote (I’ve just learned to my surprise that it’s actually “Double, double, toil and trouble“), but it’s a too-perfect lead-in to geneticist Gavin Sherlock’s recent study on yeast population dynamics for me to be bothered by facts.

Sherlock, PhD, and his colleagues devised a way to label and track the fate of individual yeast cells and their progeny in a population using heritable DNA “barcodes” inserted into their genomes. In this way, they could track the rise and fall of dynasties as the yeast battled for ever more scarce resources (in this case, the sugar glucose), much like what happens in the gentle bubbling of a sourdough starter or a new batch of beer.

Their research was published today in Nature.

From our release:

Dividing yeast naturally accumulate mutations as they repeatedly copy their DNA. Some of these mutations may allow cells to gobble up the sugar in the broth more quickly than others, or perhaps give them an extra push to squeeze in just one more cell division than their competitors.

Sherlock and his colleagues found that about one percent of all randomly acquired mutations conferred a fitness benefit that allowed the progeny of one cell to increase in numbers more rapidly than their peers. They also learned that the growth of the population is driven at first by many mutations of modest benefit. Later generations see the rise of the big guns – a few mutations that give carriers a substantial advantage.

This type of clonal evolution mirrors how a bacterium or virus spreads through the human body, or how a cancer cell develops mutations that allow it to evade treatment. It is also somewhat similar to a problem that kept some snooty 19th century English scientists up at night, worried that aristocratic surnames would die out because rich and socially successful families were having fewer children than the working poor. As a result, these scientists developed what’s known as the “science of branching theory.” They described the research in a paper in 1875 called “On the probability of extinction of families,” and Sherlock and his colleagues used some of the mathematical principles described in the paper to conduct their analysis.

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Evolution, In the News, Research, Stanford News

Blond ambition: Delving into the work of Stanford biologist David Kingsley

Blond ambition: Delving into the work of Stanford biologist David Kingsley

Thanks to a tiny fish called the stickleback, Stanford developmental biologist David Kingsley, PhD, and his team uncovered the genetic basis for blond hair earlier this year.

Kingsley’s research caught the eye of the team at HHMI Bulletin, which featured his discovery in their fall issue. As described in the piece, Kingsley and fellow researcher Catherine Guenther, PhD, discovered the change in a single point in the genetic sequence outside the gene itself. The discovery prompted a question because the gene, known as KITLG, is involved in many other key processes in developing organisms. Yet Kingsley found the control for hair color acted alone.

“The genetic mechanism that controls blond hair doesn’t alter the biology of any other part of the body. It’s a trait that’s skin deep, and only skin deep,” Kingsley told HHMI.

The HHMI feature also includes a video of Kingsley – above – that provides glimpses into his lab and reveals the sources of his inspiration (as well as his penchant for purchasing telescopes).

And for a Friday giggle, check out his lab members spelling his name with their bodies here.

Becky Bach is a science-writing intern at the Office of Communications and Public Affairs. 

Previously: It’s a blond thing: Stanford researchers suss out molecular basis of hair color, Something fishy: Threespine stickleback genome published by Stanford researchers and Hey guys, sometimes less is really more

Behavioral Science, Evolution, Imaging, Neuroscience, Research, Stanford News, Surgery

In a human brain, knowing a face and naming it are separate worries

In a human brain, knowing a face and naming it are separate worries

Alfred E. Neuman (small)Viewed from the outside, the brain’s two hemispheres look like mirror images of one another. But they’re not. For example, two bilateral brain structures called Wernicke’s area and Broca’s area are essential to language processing in the human brain – but only the ones  in the left hemisphere (at least in the great majority of right-handers’ brains; with lefties it’s a toss-up), although both sides of the brain house those structures.

Now it looks as though that right-left division of labor in our brains applies to face perception, too.

A couple of years ago I wrote and blogged about a startling study by Stanford neuroscientists Josef Parvizi, MD, PhD, and Kalanit Grill-Spector, PhD. The researchers recorded brain activity in epileptic patients who, because their seizures were unresponsive to drug therapy, had undergone a procedure in which a small section of the skulls was removed and plastic packets containing electrodes placed at the surface of the exposed brain. This was done so that, when seizures inevitably occurred, their exact point of origination could be identified. While  patients waited for this to happen, they gave the scientists consent to perform  an experiment.

In that experiment, selective electrical stimulation of another structure in the human brain, the fusiform gyrus, instantly caused a distortion in an experimental subjects’ perception of Parvizi’s face. So much so, in fact, that the subject exclaimed, “You just turned into somebody else. Your face metamorphosed!”

Like Wernicke’s and Broca’s area, the fusiform gyrus is found on each side of the brain. In animal species with brains fairly similar to our own, such as monkeys, stimulation of either the left or right fusiform gyrus appears to induce distorted face perception.

Yet, in a new study of ten such patients, conducted by Parvizi and colleagues and published in the Journal of Neuroscience,  face distortion occurred only when the right fusiform gyrus was stimulated. Other behavioral studies and clinical reports on patients suffering brain damage have shown a relative right-brain advantage in face recognition as well as a predominance of right-side brain lesions in patients with prosopagnosia, or face blindness.

Apparently, the left fusiform gyrus’s job description has changed in the course of our species’ evolution. Humans’ acquisition of language over evolutionary time, the Stanford investigators note, required the redirection of some brain regions’ roles toward speech processing. It seems one piece of that co-opted real estate was the left fusiform gyrus. The scientists suggest (and other studies hint) that along with the lateralization of language processing to the brain’s left hemisphere, face-recognition sites in that hemisphere may have been reassigned to new, language-related functions that nonetheless carry a face-processing connection: for example, retrieving the name of a person whose face you’re looking at, leaving the visual perception of that face to the right hemisphere.

My own right fusiform gyrus has been doing a bang-up job all my life and continues to do so. I wish I could say the same for my left side.

Previously: Metamorphosis: At the push of a button, a familiar face becomes a strange one, Mind-reading in real life: Study shows it can be done (but they’ll have to catch you first), We’ve got your number: Exact spot in brain where numeral recognition takes place revealed and Why memory and  math don’t mix: They require opposing states of the same brain circuitry
Photo by AlienGraffiti

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