Last night I listened squeamishly to my 13-year-old daughter and her friends compete in a (loud!) Fear-Factor-type eating contest in the other room (a sample dish: gummi worms covered in coleslaw – shudder). Fortunately for her (and all of us, really), the old adage “you are what you eat” is a vast oversimplification of nutrition science; many factors actually influence our overall health and body composition.

A similar simplification existed at one time in genetics, when it was believed that the DNA sequence of our genes determined our biological destiny. But over time scientists have learned that many variables affect how, when and even to what degree these genes are expressed, or transformed, into proteins. For instance, I may have the same DNA sequence for gene A as my friend, but I may make more, or fewer, molecules of protein A than she does, and therefore have a significantly different biological outcome. Unfortunately, it’s been difficult to accurately quantify and compare protein levels among individuals and groups.

Now research led by Stanford geneticists Hua Tang, PhD, and Michael Snyder, PhD, published yesterday in Nature (subscription required), has shown that these variations in gene expression levels are inherited over generations. In other words, your levels of expression of individual genes is likely to be similar to that of your parents. What’s more, genes involved in common processes tend to vary in similar ways – indicating a high degree of coordination of expression. As Tang explained in an e-mail to me:

We’ve found that the abundance of many proteins varies considerably among individuals, and we have identified numerous DNA variants that may influence the protein expression of a neighboring gene. We also showed that proteins that co-vary tend to have related biological functions or physical interactions.

The researchers used a sophisticated variation of a technique called quantitative mass spectrometry to determine the relative level of nearly 6,000 proteins in cells from 95 people from around the world. Until recently, most researchers relied on an indirect, and inexact, method that estimated protein levels within a cell based on the prevalence of RNA messages encoding that protein. Co-first author and research associate Sophie Candille, PhD, (who co-authored the research with postdoctoral scholar Linfeng Wu, PhD) explained:

RNA is in fact an intermediary molecule in the expression of the protein-coding genome. Proteins are the end product and active agents of the cell but their quantification has been challenging and therefore has lagged behind that of RNA.

By analyzing which proteins co-vary, the researchers were able to identify new functional groups that hint at previously unknown protein networks and interactions. Postdoctoral scholar and co-first author Linfeng Wu, PhD, concluded:

This research is important because many proteins are involved in the human immune response and diseases such as cancer. Therefore, the DNA variants that influence gene expression at the protein level are likely to be associated with disease phenotypes.

As Wu explained, the researchers are particularly interested in understanding how variation in protein expression levels affects disease risk or physical attributes. In my case, I can’t help wondering whether I have a genetic predisposition to nausea when I hear talk of eating bananas with Baconnaise or Spam with chocolate sauce (gag). But maybe, my reaction isn’t all that unusual?

Previously: Stanford geneticist talks tracking biological data points and personalized medicine

What if it were possible, when faced with a devastating neurological disease like multiple sclerosis, to coax the brain to heal itself? Unfortunately, we’re probably still years away from any kind of quick fix for these conditions (if, in fact, one exists at all). But recent research by Stanford geneticist Anne Brunet, PhD, describes an intriguing way to delay the onset of a multiple-sclerosis-like disease in laboratory mice. The study is published in the most recent issue of Nature Cell Biology.

We’re excited by the potential implications our study has on demyelinating diseases and injuries

Specifically, the researchers created a type of mouse in which they could turn the expression of a protein called SIRT1 on and off in the neural stem cells in the animals’ brains. (They wanted to investigate SIRT1′s involvement in the disease because it appears to be highly expressed in the brains of mice with multiple sclerosis.) They found that animals in which the protein’s expression was blocked developed the characteristic paralysis of the disorder more slowly than their peers with normal levels of SIRT1 expression.

From our article:

Blocking SIRT1 expression appears to work by promoting the development of neural stem cells in the brain into a type of cell called an oligodendrocyte precursor. These cells, in turn, become the mature oligodendrocytes that wrap the long arms of neurons with myelin — a fatty material necessary to facilitate the transmission of the electrical impulses from one nerve cell to another. In humans, most myelination occurs during infancy and adolescence.

Diseases such as multiple sclerosis wreak havoc in the central nervous system by damaging this protective myelin coating and impeding communication between nerve cells.

Brunet, who last year received a Pioneer Award from the National Institutes of Health for her work in studying the inheritance of longevity, worked with Stanford neurologist and noted multiple sclerosis researcher Lawrence Steinman, MD, to conduct the study. She told me:

We are excited by the potential implications our study has on demyelinating diseases and injuries… It’s intriguing because activating SIRT1 is typically considered to be beneficial for metabolism and health, but in this case, inactivating SIRT1 can provide protection against a demyelinating injury.

Previously: NIH awards nine Stanford faculty funding for innovative research, Black hat in Alzheimer’s, white hat in multiple sclerosis? and Amyloid, schmamaloid: Stanford MS expert finds dreaded proteins may not be all bad.

I wrote yesterday about the Twitter stream launched by NIH Director Francis Collins, MD, PhD, to call attention to the real-world effects of the budget sequestration on biological research in labs across the country. Today the agency detailed for the first time the way it plans to carry out the mandatory cuts, including funding fewer new and competing grants and trimming the budget of existing awards. From an article in Science Insider:

As a result, NIH expects to fund 8283 new and competing research grants this year, a drop of 703, according to this table. That number firms up the “hundreds fewer” awards that NIH officials warned of earlier this year. Including ongoing (already awarded) grants that are ending, the total number of research grants will drop by 1357 to 34,902 awards. The decline “reflects the fact that NIH’s budget is being shrunk due to the new budget and political reality, which is bad news for researchers and the patients they are trying to help,” says Tony Mazzaschi of the Association of American Medical Colleges in Washington, D.C.

Individual institutes are also announcing their plans for cuts, the article says.

Previously: NIH director polls Twitter for real-world responses to budget cutbacks and As budget sequester nears, a call for Congress to protect funding for scientific and medical research

Here’s a developing social media story of interest to scientists, clinicians and the general public. National Institutes of Health Director Francis Collins, MD, PhD, kicked a hornets’ nest on Twitter earlier today with a tweet asking researchers to describe the direct impact of the U.S. budget sequestration, which began in March, on their research and lives. He asked respondents to use the hashtag #NIHSequesterImpact. The responses (some of which I’ve included below) are fascinating and depressing:

“I am no longer encouraging undergraduates to consider graduate school. No future in it.”

“The NIH training grant I’m on was canceled”

“Watching top notch science go unfunded; bright, young investigators forced to close labs, it’s heartbreaking.”

“I know a lot of very smart USA young researchers that are seriously considering China”

“Nothing will impact treating patients more in the long term than poorly funded basic science. Nothing“

Check it out if you’d like to hear a real-time conversation about what it’s like to be a researcher today, and join in if you have anecdotes to share.

Previously: As budget sequester nears, a call for Congress to protect funding for scientific and medical research, Director of NIH discusses accelerating translation of biomedical research into clinical applications and Francis Collins profiled in New Yorker

In a novel combination of biochemical experimentation and data mining, Stanford researchers and postdoctoral scholars Cigall Kadoch, PhD, and Diana Hargreaves, PhD, have identified a large protein complex that appears to be significantly involved in cancer development in humans.

The multisubunit is a member of a family of chromatin-regulatory complexes that keep DNA tightly packed in a cell’s nucleus. Originally thought of as a kind of housekeeping, or maintenance, protein in the cell, it’s now becoming apparent that these complexes are really important in development and cancer.

Kadoch, working in the laboratory of developmental biologist  Gerald Crabtree, MD, used biochemical techniques to identify seven previously unidentified members of the complex, which is called BAF (or mSWI/SNF). She and Hargreaves then analyzed 44 pre-existing studies that detailed the DNA sequences of primary human tumors of all types. They calculated the likelihood that any protein component of the large group was mutated. (The approach varies from others that analyze the mutation rates of individual proteins.)

As described in our release:

The results, once the newly discovered members were included, were surprising: 19.6 percent of all human tumors displayed a mutation in at least one of the complex’s subunits. In addition, for some types of cancers (such as synovial sarcoma), every individual tumor sample examined had a mutation in a BAF subunit. The results suggest that the BAF complex, when unmutated, plays an important protective role against the development of cancer in many different tissues.

Crabtree, who is also a Howard Hughes Medical Institute investigator, described his lab’s long-standing interest in BAF and other similar protein complexes:

Somehow these chromatin-regulatory complexes manage to compress nearly two yards of DNA into a nucleus about one one-thousandth the size of a pinhead. And they do this without compromising the ability of the DNA to be replicated and selectively expressed in different tissues – all without tangling. In 1994 we reported that complexes of this type were likely to be tumor suppressors. Here we show that they are mutated in nearly 20 percent of all human malignancies thus far examined.

The work was published yesterday in Nature Genetics. The researchers are now working to understand exactly how the mutations they’ve observed affect the function of the BAF complex.

Previously: Dumb, dumber and dumbest? Stanford biologist suggests humans on a downward slide and New clues arise in pancreatic cancer from Stanford researchers
Photo of (left to right) Cigall Kadoch, Gerald Crabtree and Diana Hargreaves, by Nathaniel Hathaway

I was so happy to learn that Stanford stem cell researcher Marius Wernig, MD, (here describing his research as part of the California Institute for Regenerative Medicine’s recent Elevator Pitch competition) has been selected by the International Society for Stem Cell Research to receive its Outstanding Young Investigator of the year at the organization’s annual meeting in June in Boston.

My colleagues at CIRM beat me to the punch yesterday (Wernig is a CIRM grant recipient) with a nice blog post about the award.

I’ve written several times (here and elsewhere) about Wernig’s research as part of Stanford’s Institute for Stem Cell Biology and Regenerative Medicine. Essentially, he’s shown that it’s possible to directly convert adult, terminally differentiated cells directly into other types of cells like neurons, without first having to force the cells through a stage called induced pluripotency. It’s exciting stuff.

Wernig, who was in a former life a composer of classical music,  joins Stanford researcher Joanna Wysocka, PhD, in the ISSCR hall of fame. She won the award in 2010.

Previously: Stanford scientists turn human skin cells directly into neurons, skipping iPS stage, The end of iPS? Stanford scientists directly convert mouse skin cells to neural precursors and Stanford researcher wins Outstanding Young Investigator Award from international stem cell society.
Video courtesy of the California Institute for Regenerative Medicine

I was excited last week to find myself writing about an entirely new way that cells communicate in the developing embryo. The work happened like this: Geneticist and developmental biologist Maria Barna, PhD, and her colleagues wanted to use advanced, high-resolution microscopy to investigate how cells in developing chick and mouse embryos send signals to one another across relatively large distances. When they looked at individual cells, they stumbled upon a previously invisible structure that resembles long, very thin fingers that burrow through densely packed cells to reach neighbors several cell-lengths away. (Conventional fixation and imaging techniques destroy these ‘specialized filopodia’.) They then watched as the cells used these structures to deliver and receive payloads of signaling molecules to one another. Their research is published in the current issue of Nature.

From our release:

The seeming specificity of the interaction contrasts starkly with the commonly held notion that signaling molecules are released from one cell and float, or diffuse, through the intercellular space to their targets. While this finding does not preclude the use of diffusion as a signaling method, it identifies another new, surprising avenue of long-distance cellular communication.

I can’t stop marveling at how scientists are still discovering entirely new unique parts of a cell. Apparently others feel the same: The work was featured this week on the Los Angeles Times’ health and science blog (including a cool video of the filopodia grasping one another) and by the California Institute for Regenerative Medicine. Because the work was conducted while Barna was a faculty member at the University of California-San Francisco, they also wrote about the work.

Photoof filopodia by Esther Llagostera

A million years ago (all the way back in 2006!) I wrote an article for Stanford Medicine magazine about genetic technologies and the eugenics movement in this country during the first part of the 1900s. I still remember it as one of the most fascinating of my articles to research, demanding as it did that I speak with a variety of geneticists and ethicists about the increasing control that humans have over their genetic destiny.

When, last year, I had the privilege of writing about Stanford biophysicist Stephen Quake, PhD, and his work on whole-genome sequencing of fetuses before birth, I couldn’t help but remember that article of yore. What are we getting ourselves into?

Now MIT Technology Review has recognized whole-genome fetal sequencing as one of its “10 Breakthrough Technologies 2013.” Accompanying the designation is an in-depth review of the technology and its implications – which are far more complex than I could have imagined six years ago. The article contains comments from several experts, including Stanford law professor and bioethicist Hank Greely, JD, and Quake:

Quake says proving that a full genome readout is possible was the “logical extension” of the underlying technology. Yet what’s much less clear to Quake and others is whether a universal DNA test will ever become important or routine in medicine, as the more targeted test for Down syndrome has become. “We did it as an academic exercise, just for the hell of it,” he says. “But if you ask me, ‘Are we going to know the genomes of children at birth?’ I’d ask you, ‘Why?’ I get stuck on the why.” Quake says he’s now refining the technology so that it could be used to inexpensively pull out information on just the most medically important genes.

In my opinion, experts are right to consider the impact of this type of technology before it becomes commonplace. The ethical implications of parents learning their child’s genome sequence within a few weeks of conception – and of possibly using that information to make decisions about the pregnancy’s outcome – are substantial. Thankfully, some really smart people have been asking these questions in one form or another for years, even though the answers seem to end up more grey than black and white. From that ancient article I wrote six years ago:

For example, even though sex selection of embryos fertilized in vitro has many people up in arms, there’s no evidence that it’s on track to alter the gender balance in this country: Boys and girls are nearly equally sought after, says [medical geneticist and associate chair of pediatrics Eugene Hoyme, MD]. And although some parents will terminate a pregnancy if the fetus has a genetic or developmental problem that they feel isn’t compatible with a meaningful life, different families draw this line at dramatically different points in the sand. For some, it’s too much to consider having a child with Down syndrome. For others it’s important to sustain life as long as possible regardless of the severity of the condition. Still others might choose to have a child as similar to them as possible, down to sharing disabilities such as deafness.

“Eugenics is here now,” says Stanford bioethicist David Magnus, PhD. “So what? We allow parents to have virtually unlimited control over what school their child attends, what church they go to and how much exercise they get. All of these things have a much bigger impact on a child’s future than the limited genetic choices available to us now. As long as these are safe and effective, why not give parents this option as well?”

Previously: New techniques to diagnose disease in a fetus, Better know a bioengineer: Stephen Quake and Stanford bioethicists discuss pro, cons of biotech patents
Photo by paparutzi

Really. Come on. Who isn’t interested in hair? Hair growth, hair loss, hair thickness, hair shape, hair location. I’d bet that everyone of us spends at least a minute or two each day thinking about (or, if you’re like me, futilely plucking and prodding at) the state of our locks.

Now Stanford researchers have delved deep into the cells surrounding our hair follicles to better understand what makes them grow and maintain hair. Perhaps not surprisingly, the answer lies in the stem cells (here, called ‘bulge cells’) within the follicle.

Specifically, research associate Yiqin Xiong, PhD, and associate professor of medicine Ching-Pin Chang, MD, PhD, have identified a signaling circuit that controls the cells’ activity. The research was published yesterday in Developmental Cell (subscription required). As Chang explained in an e-mail to me:

By promoting self-renewal of stem cells, this circuit maintains a healthy pool of bulge cells for repeated cycles of hair growth and regeneration. Each cycle of hair regeneration is initiated by the activation of this circuit in those bulge cells, and subsequent growth of the hair is sustained by the circuit in hair matrix cells.  Besides hair regeneration, the circuit is triggered by skin injury to stimulate migration of the bulge cells to the wounded area to differentiate into epidermal cells, thereby regenerating epidermis over the wounded skin.

In the past, news about hair growth (and how to stimulate it) has been a trigger for a deluge of interest from media and individuals struggling with… (how shall we say it?) ‘hair problems.’ But the research has many implications beyond hair, or the lack thereof. For example, the presence or absence of hair follicles on the skin affect how the skin heals after a wound, and whether a scar remains. According to Chang:

This molecular circuit in the hair follicle can be targeted for therapeutic purposes. Because of its activity in hair regeneration, inhibition of this circuit can reduce hair growth in patients with excessive hairiness (hirsutism), whereas activation of this pathway can promote hair growth for people with baldness (alopecia). Also, for its activity during epidermal regeneration, activation of the circuit can facilitate wound healing for patients receiving surgery and for diabetic patients who have wounds that are difficult to treat. The activity of the circuit in both hair follicle and epidermal regeneration may have additional therapeutic benefit. Lack of hair follicles in a wounded area is a hallmark of scar formation. Targeting this pathway has the advantage of promoting both hair follicle formation and wound repair, thus reducing scar formation in the wound.

Interestingly, one of the key molecules, called Brg1, involved in this regulatory circuit has also been implicated in previous work from Chang’s lab in the enlargement of the heart and in fetal heart development. It’s apparent this story has many layers, some more than skin deep.

Previously:  Examining the role of genetics in hair loss and Epigenetics: the hoops genes jump through,
Photo by Furryscaly

I’m ashamed to admit that the study of statistics was regarded (at least by me) as a necessary evil when I was in graduate school. I vaguely remember one course that attempted to teach a lecture hall of sleepy, stressed-out students how to calculate p values, the differences between retrospective, prospective and case-control studies, and the nuances between sensitivity and specificity. And don’t even get me started on odds ratios. Can you tell I’m still a bit fuzzy? In fact, I keep a reference guide at my desk for help (which I have to consult embarrassingly often).

Statistics might be dull, but there’s no denying its importance in scientific research – and the fallout when scientists fail to appreciate its power. Now, Stanford researcher John Ioannidis, MD, DSci, (of the “Why most published research findings are false” fame) has joined forces with Marcus Munafo, PhD, and others at the University of Bristol to publish a new study in in Nature Reviews Neuroscience (subscription required) delineating the statistical flaws in many published neuroscience studies. Essentially, the researchers found that, although many scientists realize that an under-powered study (for example, one with too few study subjects to adequately capture the phenomena being investigated) is less likely to find statistically significant results, they don’t necessary realize the converse: that any statistically significant finding from such a study is less likely to represent a true effect.

Stellar science blogger Ed Yong explains the sobering implications in an excellent post today:

Statistical power refers to the odds that a study will find an effect—say, whether antipsychotic drugs affect schizophrenia symptoms, or whether impulsivity is linked to addiction—assuming those effects exist. Most scientists regard a power of 80 percent as adequate—that gives you a 4 in 5 chance of finding an effect if there’s one to be found. But the studies that Munafo’s team examined tended to be so small that they had an average (median) power of just 21 percent. At that level, if you ran the same experiment five times, you’d only find an effect on one of those. The other four tries would be wasted.

But if studies are generally underpowered, there are more worrying connotations beyond missed opportunities. It means that when scientists do claim to have found effects—that is, if experiments seem to “work”—the results are less likely to be real. And it means that if the results are actually real, they’re probably bigger than they should be. As the team writes, this so-called “winner’s curse” means that “a ‘lucky’ scientist who makes the discovery in a small study is cursed by finding an inflated effect.”

I encourage you to read all of Ed’s post, which includes multiple comments from Ioannidis, Munafo and other researchers uninvolved in the study. It’s a fascinating analysis of why many studies are designed as they are, and it discusses some of the obstacles that must be overcome to improve their fidelity. And don’t overlook the comment stream, which is currently hosting a rich discussion among scientists in the field.

Previously: NIH funding mechanism “totally broken” says Stanford researcher, Research shows small studies may overestimate the effects of many medical interventions and Animal studies: necessary but often flawed, says Stanford’s Ioannidis
Photo by futureshape