GREs don't predict grad school success. What does?

Summer is just beginning, but before we know it, the graduate school application and admission season will be upon us again. The ostensible goal of that arduous and anxiety-fraught procedure—and of the even more involved process of hiring and promoting faculty members at research universities—is to identify the next generation of productive scientists. But how can the relevant committees accomplish this when no one can really specify the qualities of mind, heart, character, spirit, and background that combine to produce great research?

This long-standing question has been bothering me since I read a pair of studies about grad school admissions practices, one from the University of North Carolina (UNC) in Chapel Hill and the other from Vanderbilt University in Nashville. (My colleague Maggie Kuo wrote about them when they were published in January.) These papers add to a growing body of information suggesting that widely used “objective” admissions measures, such as GRE test scores and GPA, are exactly the wrong way to go about picking future contributors to scientific progress. Yet, they continue to strongly influence admissions committees—probably to the detriment of individual aspiring scientists who, despite their brilliance, may not look good on paper, and of the entire scientific enterprise.

Objective failure

Top graduate programs, which receive many more applications than they can accept, often use “objective” numerical criteria as screening devices to shorten their lists of “serious” candidates, explained education researcher Julie Posselt of the University of Southern California in Los Angeles in Inside Graduate Admissions: Merit, Diversity, and Faculty Gatekeeping. (These criteria also happen to be especially effective at knocking women and members of underrepresented minority groups out of applicant pools.) As the authors of the new UNC study write, admissions committees often assume that “[t]ypical selection criteria [such as] standardized test scores, undergraduate GPA, letters of recommendation, a resume and/or personal statement highlighting relevant research or professional experience, and feedback from interviews with training faculty … correlate with research success in graduate school.”

Yet, both the UNC and Vanderbilt studies found that none of the supposedly objective credentials predicted anything recognizable as scientific productivity—not first-author publications, conference presentations, fellowships or grants won, completing the Ph.D., passing the qualifying exam, or proceeding swiftly to dissertation defense or to the degree. Among the Vanderbilt sample, GRE scores turned out to be only “moderate predictors of first semester grades” and “weak to moderate predictors of graduate GPA,” the authors report. There is no convincing evidence of a “relationship between general GRE scores and graduate student success in biomedical research,” they write. At UNC, grades, amount of previous research experience (among students who all had at least some research experience), and faculty interview ratings all failed to foretell grad school productivity.

Another supposedly objective criterion that Posselt found to be influential during the screening process, especially with elite graduate departments, is the standing of an applicant’s undergraduate school. But a 2014 study from a professor at the University of California (UC), San Francisco, found that this metric also washed out as a predictor of grad school performance. Even a bachelor’s degree from one of the U.S. News & World Report “top 10 life sciences universities” made no discernible difference.

How to spot talent

If these widely used measures don’t work, what does? A group of researchers who devise and study metrics of research productivity and success wrote in 2012 that “the best way of predicting a scientist’s future success is for peers to evaluate scientific contributions and research depth.” They see the statistical method they developed as “useful” to “funding agencies, peer reviewers and hiring committees.” But even so, they make clear that, to ferret out that je ne sais quoi that foreshadows outstanding scientific performance, nothing compares to subjective judgments of quality by experienced researchers.

This emphasis on expert opinion also happens to align with the conclusions of the studies. The predictor that emerged as most powerful in both the UNC study and the UC San Francisco analysis was letters of recommendation from applicants’ undergraduate teachers—in other words, subjective assessments from people who presumably knew both them and their subjects well. Students who received top recommendations, the UNC co-authors suggest, show a “constellation of characteristics that typically correlate with research success [such as ability to] persevere and maintain focus and optimism in the face of regular challenges.”

And if objective measures such as scores and grades don’t work in predicting students’ scientific promise, can objective measures such as numbers of publications do any better at spotting true intellectual promise among faculty candidates? Not according to physicist Peter Higgs, whose work on subatomic particles in the 1960s inspired the long but ultimately successful hunt for the eponymous Higgs boson. As he told The Guardian in 2013, while traveling to Stockholm to receive the Nobel Prize in Physics, for years he had been “an embarrassment to [his] department when they did research assessment exercises.” With fewer than 10 papers published since this 1964 breakthrough, he often responded to departmental requests for lists of recent publications with a simple reply: “None.” Given today’s requirement to publish frequently, he added, “It’s difficult to imagine how I would ever have enough peace and quiet in the present sort of climate to do what I did in 1964. … Today I wouldn’t get an academic job. It’s as simple as that. I don’t think I would be regarded as productive enough.”

Then there’s mathematician Yitang “Tom” Zhang, who was completely unknown—as in zero peer-reviewed publications and an adjunct teaching job—when, in 2013, at the age of 57 and 12 years out from receiving his Ph.D., he submitted a paper that astounded the mathematical world by solving a long-standing problem in number theory. Now hailed as a “genius” and a “celebrity,” he has since that triumph received numerous major prizes and appointments to two professorships, first at the University of New Hampshire and then UC Santa Barbara.

None of this is meant to suggest that every scanty publication list or so-so GRE score conceals hidden brilliance. But it does suggest a more reliable formula for spotting exceptional talent among people who appear not to possess it according to supposedly objective measures of scientific promise. It seems pretty likely that at least some of the people who knew and worked with Higgs and Zhang in their pre-fame days were aware of their abilities. It thus stands to reason that committees evaluating scientific potential, whether in grad school applicants or would-be faculty members, might benefit from paying more attention to what the scientists who know the candidates think of their minds and characters. Reading and considering such testimony would undoubtedly take more time and effort and could feel less “scientific” than looking at numbers, whether test scores, GPAs, or tallies of publications. But it appears more likely to pay off.



This article was originally published in Science. Read the original article.

How a Galápagos Bird Lost the Ability to Fly

The birds of the Galápagos Islands are still playing a role in helping us understand evolution.

When Darwin visited the islands, it was the wide variety of finch beaks that helped him understand how one species could evolve into many.

Now the Galápagos cormorants, the only species of cormorant to have lost the ability to fly, have enabled scientists to pin down the genes that led to this species’ split from all other cormorants about two million years ago.

They are genes that are present in birds, mammals and most animals, including even the worm often studied in laboratories: C. elegans. In fact, they are even present in some algae. Their ultimate effect varies, however. In humans and in the cormorants, the genes affect bone growth. But mutations in humans can cause some dreadful diseases; in the birds, they caused smaller wings, which were not effective for flight, and a weaker breastbone.

Alejandro Burga, who analyzed the DNA of these and other cormorants with his colleagues, is a researcher in the lab of Leonid Kruglyak, the chairman of human genetics at U.C.L.A.’s medical school. He said he and Dr. Kruglyak were discussing how they might use the increasing power of modern genetics to investigate how new species develop. “We have very little idea how these things happen in nature,” he said.

On a trip to the Galápagos, Dr. Kruglyak viewed cormorants as an ideal subject, partly because of their relatively recent evolution as a species and their obvious difference from all their kin.

Other flightless birds like ostriches and kiwis do not have close relatives among flying birds, since their split from flying birds occurred 50 million years ago or more. But the Galápagos cormorants are closely related to neo-tropical cormorants and double-crested cormorants, both common birds.

Patricia Parker, a behavioral ecologist at the University of Missouri, St. Louis, who studies bird diseases in the Galápagos, provided tissue samples for DNA of the flightless cormorants.

“She had in her freezer over 200 samples of this bird,” Dr. Burga said. He and the other researchers on the team gathered samples from the living cormorants and began an exhaustive comparison of the different genomes. They narrowed their focus down to genes that affect bone growth.

They found that a gene called Cux1 and some others were involved in the growth of cilia. These whip-like structures on the surface of cells can function in movement in single-celled animals. But in birds and humans and other complex organisms they work like antennas, and one of their jobs is to pick up biochemical signals for bone growth.

The end result of mutations in Cux1 in humans can be terrible diseases, called ciliopathies. In the cormorants, however, the result seems to have been to prematurely stop bone growth in the wings, resulting in the loss of flight, but leaving the birds to thrive in the water and on land.

The researchers tried inserting some of the mutations they found in the worm, C. elegans, and in mouse tissue. In the worm it caused a change in behavior related to the cilia, and in the mouse tissue it interfered with bone growth.

That doesn’t prove they have the right genes, but it is further supporting evidence.

Loss of flight was an evolutionary process that interested Darwin, but it seems he never saw the flightless cormorants. They are found around only two islands in the Galápagos, and he never mentions the birds in his account of his Galápagos visit in “The Voyage of the Beagle.”

Without a knowledge of DNA and the tools of modern genomics, he could not have come up with the conclusions of the current study, published in Science on Thursday.

But he certainly would have had something to say.


This article was originally published in The New York Times.  Read the original article.

New Electrical Brain Stimulation Technique Shows Promise in Mice

Pulses of electricity delivered to the brain can help patients with Parkinson’s disease, depression, obsessive-compulsive disorder and possibly other conditions. But the available methods all have shortcomings: They either involve the risks of surgery, from implanting electrodes deep within the brain, or they stimulate from the skull’s surface, limiting the ability to target electricity to the right brain areas.

Now, a team of neuroscientists and engineers has devised a method that might achieve the best of both worlds: skipping the surgery while reaching deep brain areas. The research, published Thursday in the journal Cell and led by a prominent neurobiologist at the Massachusetts Institute of Technology, was conducted in mice, and many questions remain about its potential application to people. But experts say if the method proves effective and safe, it could help a range of neurological and psychiatric disorders more cheaply and safely than current approaches.

“They have this clever new way to deliver current to a spot of interest deep in the brain and do it without invading the brain,” said Dr. Helen Mayberg, a professor of psychiatry, neurology and radiology at Emory University, who was not involved in the study and who pioneered the still-experimental treatment of deep brain stimulation for depression. “If you didn’t have to actually open up somebody’s brain and put something in it, if it could do what we’re doing now just as well — sign me up.”

Edward S. Boyden, the study’s senior author and co-director of the M.I.T. Center for Neurobiological Engineering, said he and his colleagues are already testing the method on people without disorders to see if it works in human brains. If those results are promising, at least one clinician, Dr. Alexander Rotenberg, a neurologist who directs the neuromodulation program at Boston Children’s Hospital and Harvard Medical School, said he would collaborate with the team to evaluate the technique for epilepsy.

“This is something that many of us in the field have wished for for a long time,” said Dr. Rotenberg, who said it might also eventually help tens of thousands of epilepsy patients for whom medications fail. Dr. Rotenberg and Dr. Mayberg said they could also envision the technique as a diagnostic tool to pinpoint the best brain location to target for electrical stimulation before surgically implanting electrodes for deep brain stimulation.

At a time when scientists are developing sophisticated technological approaches to look inside the brain and manipulate brain cells — including a celebrated technique called optogenetics that was created in part by Dr. Boyden — the new study uses a basic and long-established tool: electricity. But it adds a brand new twist.

“Rather than try to prove another way to modulate the brain, they take a very simple technology and are using it in a unique way,” said Dr. Casey Harrison Halpern, an assistant professor of neurosurgery at Stanford University who uses deep brain stimulation for Parkinson’s and O.C.D. and was not involved in the study. “Now we just have to see where it plays out best in the clinical arena. I could rattle off 10 potential ways that it could and should be tested.”

The method, called temporal interference, involves beaming different electric frequencies, too high for neurons to respond to, from electrodes on the skull’s surface. The team found that where the currents intersected inside the brain, the frequencies interfered with each other, essentially canceling out all but the difference between them and leaving a low-frequency current that neurons in that location responded to, Dr. Boyden said.

“Very high frequency electronic fields are much faster than the brain can actually follow for the same reasons that you and I can’t hear sonar,” he said. “But if you deliver 1,000 hertz and 1,001 hertz to the brain, the neuron will react as if you were delivering 1 hertz. And only the region where the two interfere is where you get the signal.”

That means other regions would be unaffected by the electricity, in contrast to what happens with other surface techniques, like transcranial magnetic stimulation, a federally approved treatment for depression.


When the team used electricity to stimulate the hippocampus in mice, “there’s no evidence whatsoever that the neurons were activated,” in the cortex and other structures closer to the surface, said Li-Huei Tsai, director of M.I.T.’s Picower Institute for Learning and Memory, who led the mouse experiments.

“Before you see the results, you’re like ‘really?’ ” she said. “But we saw the extremely precise localized signal only in the region we stimulated.”

To further test whether they could target the electricity, the researchers aimed at certain spots in the motor cortex causing mice to move forepaws, whiskers or ears. The technique caused no safety problems, Dr. Tsai said.

Several experts raised potential limitations and questions. Dr. Mayberg said it would have to deliver frequencies like 130 hertz, higher than those in the study, and would need to work among complex brain circuitry, like the white matter bundles her work involves.

Dr. Michael Okun, a neurologist at the University of Florida and medical director for the Parkinson’s Foundation, said delivering electricity to people who need it occasionally or even once a day seemed more feasible than for people with “complex diseases like Parkinson’s who have a need for near-continuous stimulation.”

All the experts wondered about logistics: Would patients use a portable, wearable electricity-delivery device? And they emphasized a need to direct electricity to smaller, more precise brain locations, a limitation Dr. Boyden said he hoped could be addressed by using more electrodes.

“We’ve got to avoid areas of the brain that might cause motor contractions or weakness or problems with speech or vision,” Dr. Okun said. “A couple of millimeters in brain space could be the distance between Florida and Australia.”

Still, he said, so far “they’ve accomplished something that’s fairly remarkable.”

This article was originally published in The New York Times.  Read the original article.

Cancer therapy may work in unexpected way

Antibodies to the proteins PD-1 and PD-L1 have been shown to fight cancer by unleashing the body’s T cells, a type of immune cell. Now, researchers at the Stanford University School of Medicine have shown that the therapy also fights cancer in a completely different way, by prompting immune cells called macrophages to engulf and devour cancer cells.

The finding may have important implications for improving and expanding the use of this cancer treatment, the researchers said.

A study describing the work, which was done in mice, was published online May 17 in Nature. The senior author is Irving Weissman, MD, professor of pathology and of developmental biology. The lead author is graduate student Sydney Gordon.

PD-1 is a cell receptor that plays an important role in protecting the body from an overactive immune system. T cells, which are immune cells that learn to detect and destroy damaged or diseased cells, can at times mistakenly attack healthy cells, producing autoimmune disorders like lupus or multiple sclerosis. PD-1 is what’s called an “immune checkpoint,” a protein receptor that tamps down highly active T cells so that they are less likely to attack healthy tissue.

How cancer hijacks PD-1

About 10 years ago, researchers discovered that cancer cells learn to use this immune safeguard for their own purposes. Tumor cells crank up the production of PD-L1 proteins, which are detected by the PD-1 receptor, inhibiting T cells from attacking the tumors. In effect, the proteins are a “don’t kill me” signal to the immune system, the Stanford researchers said. Cancer patients are now being treated with antibodies that block the PD-1 receptor or latch onto its binding partner, PD-L1, to turn off this “don’t kill me” signal and enable the T cells’ attack.


“Using antibodies to PD-1 or PD-L1 is one of the major advances in cancer immunotherapy,” said Weissman, who is also the Virginia and D.K. Ludwig Professor for Clinical Investigation in Cancer Research, director of the Stanford Institute for Stem Cell Biology and Regenerative Medicine and director of the Ludwig Center for Cancer Stem Cell Research and Medicine at Stanford. “While most investigators accept the idea that anti-PD-1 and PD-L1 antibodies work by taking the brakes off of the T-cell attack on cancer cells, we have shown that there is a second mechanism that is also involved.”

What Weissman and his colleagues discovered is that PD-1 activation also inhibits the anti-cancer activity of other immune cells called macrophages. “Macrophages that infiltrate tumors are induced to create the PD-1 receptor on their surface, and when PD-1 or PD-L1 is blocked with antibodies, it prompts those macrophage cells to attack the cancer,” Gordon said.

Similar to anti-CD47 antibody

This mechanism is similar to that of another antibody studied in the Weissman lab: the antibody that blocks the protein CD47. Weissman and his colleagues showed that using anti-CD47 antibodies prompted macrophages to destroy cancer cells. The approach is now the subject of a small clinical trial in human patients.

As it stands, it’s unclear to what degree macrophages are responsible for the therapeutic success of the anti-PD-1 and anti-PD-L1 antibodies.

The practical implications of the discovery could be important, the researchers said. “This could lead to novel therapies that are aimed at promoting either the T-cell component of the attack on cancer or promoting the macrophage component,” Gordon said.

Another implication is that antibodies to PD-1 or PD-L1 may be more potent and broadly effective than previously thought. “In order for T cells to attack cancer when you take the brakes off with antibodies, you need to start with a population of T cells that have learned to recognize specific cancer cells in the first place,” Weissman said. “Macrophage cells are part of the innate immune system, which means they should be able to recognize every kind of cancer in every patient.”


This article was originally published in NIH. Read the original article.

Study Identifies Genetic Mutations in Tumors From 10,000 Patients with Metastatic Cance

Researchers at Memorial Sloan Kettering Cancer Center (MSK) have reported the results of an initiative to characterize the genetic mutations in tumors from more than 10,000 patients with advanced cancer who were treated at the center.

The research team used a DNA sequencing test called MSK-IMPACT to characterize the genetic mutations in the patients’ tumors and used that information to match hundreds of patients to existing targeted therapies or to clinical trials. The researchers are continuing to follow up with participants to assess their long-term outcomes.

They also identified new cancer-related genetic mutations and found well-known mutations in cancer types where the mutations had not been observed previously. All of the data from the study have been made publicly available in a way that protects patient privacy, allowing researchers across the world to access and analyze them.

The results demonstrate that a comprehensive, enterprise-wide effort to map the genetic alterations of patients’ tumors is feasible, can provide important information for timely patient care, and may help shape the future of cancer therapy, the researchers wrote.

Already “the data have been used by the research labs here at Sloan Kettering and are utilized and discussed as part of routine clinical care,” said the study’s lead investigator, Michael Berger, Ph.D.

The results of the study were reported May 8 in Nature Medicine.

Next-Generation Sequencing

DNA sequencing tests can identify genetic mutations that drive an individual patient’s cancer growth or development, which can help clinicians determine the most appropriate treatment.

The MSK-IMPACT test uses next-generation sequencing, a technology that allows several portions of DNA to be sequenced hundreds of times simultaneously, producing a genetic mutation profile quickly and with high accuracy. The researchers designed the test to identify different types of genetic alterations, including point mutations inside and outside of genes, alterations in the number of copies of a gene, and DNA rearrangements.

During the study period, MSK-IMPACT originally tested for alterations in 341 genes and was later expanded to include a total of 410 genes. The alterations covered by the test are constantly reviewed and revised by a team of clinicians, researchers, and clinical bioinformatics experts, explained Dr. Berger, allowing them to add newly discovered cancer-related genes or genes that are under lab or clinical study at MSK.

Some sequencing tests only focus on alterations typically found in one cancer type. But because the MSK-IMPACT test covers alterations in hundreds of genes, it is a broader approach that can be applied to any person with a solid tumor.

The researchers tested DNA from a biopsy  sample of each patient’s primary or metastatic tumor and, for comparison, normal DNA from the patient’s blood cells. This allowed them to separate inherited from noninherited, or somatic, mutations. Testing and analysis were typically completed in less than 3 weeks.

Over a period of 2 years, the investigators tested 10,945 tumor samples from 10,336 patients with 62 types of advanced or metastatic cancer who had typically undergone several rounds of cancer treatment.

Overall they found 78,066 mutations, 22,989 alterations in gene copy number, and 1,875 DNA rear­rangements. The majority of these alterations had not been previously identified. They estimated that 81% of the alterations would have been missed by other sequencing tests that only read frequently-mutated areas of genes, known as hotspots.

The researchers compared the mutations identified by MSK-IMPACT with those found via The Cancer Genome Atlas (TCGA), an initiative supported by NCI and the National Human Genome Research Institute that sequenced and analyzed untreated primary tumors from more than 11,000 patients with several types of cancer.

In general, the results of MSK-IMPACT and TCGA were highly consistent. However, they found many mutations at a higher frequency in the MSK study, which may reflect genetic differences between primary and advanced or metastatic tumors, Dr. Berger explained.

They also found some mutations that have been linked to treatment resistance that were not seen—and not expected to be seen—in the TCGA study, such as mutations in the androgen receptor gene that drive resistance to drugs that block the androgen receptor.

“Overall, things are pretty similar, but we do see expected differences,” Dr. Berger said. “We will continue to mine the data to look for acquired mutations associated with tumor progression.”

In addition, the investigators found several well-studied genetic alterations in unexpected cancer types. For example, certain DNA rearrangements that lead to fusion genes, including those involving the ALK gene, are typically present in lung tumors. However, the MSK researchers found these same fusion genes in 11 other cancer types.

Knowledge of genetic alterations that drive a patient’s cancer growth can be used to guide their treatment. In nearly 90% of patients, the researchers identified at least one genetic alteration that drives the cancer’s growth or development.

However, not every “driver” alteration is clinically actionable, meaning predictive of patient response to a Food and Drug Administration-approved or investigational therapy. An alteration may be a cancer “driver,” but it may not be actionable if there is no existing therapy that targets it. Using a database that catalogs clinically actionable mutations, they found that 37% of patients had at least one clinically actionable mutation.

In addition, some patients did not have a single actionable mutation, but rather, a group of mutations that are clinically actionable when present together. These groups, known as mutation signatures, can also be predictive of patient response to an approved or investigational therapy.

For example, a mutation signature known as microsatellite instability is predictive of patient response to treatment with immune checkpoint inhibitors. Hundreds of patients with this signature were subsequently enrolled in clinical trials and responded well to treatment with an immune checkpoint inhibitor.

The Impact of MSK-IMPACT

The MSK-IMPACT program “has been a huge team effort,” Dr. Berger said. “Hundreds of people are involved,” including teams of clinicians, researchers, clinical bioinformatics specialists, and software engineers. These teams also had to maintain tight coordination with the hospital’s medical records system, he added.

In addition to serving as a resource to guide treatment for individual patients, the data accrued from these tests also serve as an immediate investigative resource for the cancer research community. Researchers can carry out experiments to explore the biological functions of mutations identified by the study, which could potentially help clinicians interpret patients’ genetic sequencing results, Dr. Berger explained.

The data have also helped clinical researchers identify patients who qualify for open clinical trials at MSK. Some trials, called basket trials, recruit patients based on their tumor’s genetic alterations, rather than the organ where the patient’s cancer originated.

“If a new clinical trial were to open, we can identify the patients most likely to benefit all at once and enroll them very quickly,” Dr. Berger explained.

MSK-IMPACT is considered a “targeted panel” test because it sequences selected areas of DNA. Comprehensive sequencing approaches like whole-genome or whole-exome sequencing—which sequence the entire genome or large parts of it—may further enhance clinical sequencing efforts, said Jean Claude Zenklusen, Ph.D., director of NCI’s TCGA program office.

“Panels are [biased] by default because you are choosing” what DNA areas to sequence, he explained. “We can tell so much more from whole-exome and whole-genome sequencing.”

But given the limits to our current understanding of cancer genetics, the additional information gathered from these comprehensive tests may not be useful in the clinic right now, explained Dr. Berger. “By utilizing a targeted approach we were able to influence the treatment of a larger number of patients and identify more candidates for clinical trials,” he said.

Moving forward, Dr. Zenklusen believes that could change.

“I think at some point targeted panels are going to be a thing of the past because a more complete read gives you more information that helps you understand the picture,” he said. “Why use the CliffsNotes instead of reading the actual Shakespeare play?”



This article was originally published in NIH. Read the original article.

A Traumatic Experience Can Reshape Your Microbiome

I’m not disputing the scientific soundness of the whole brain-gut connection, but it really does sound a little bit like something out of a science-fiction story. I mean, you’re telling me that the trillions of tiny organisms that live in my gut, chomping up my food for me and maintaining my digestive system, have an impact on what I think and do and say? That the content of my thoughts might be at least partially determined by the eggs I had for breakfast, or the vitamin C I haven’t consumed enough of? It boggles the mind (at least, a mind influenced by my microbiome, fueled almost exclusively by Sour Patch Kids).

Strange as it may seem, though, it’s also a case of our science finally catching up to our idioms. Without realizing it, we’ve been talking about the link between brain and gut for a long time: Ever had a gut-wrenching car ride, or a gut instinct about someone, or butterflies in your stomach? In less colorful terms, the stomach and the mind really do talk to one another; in one study, for example, tentative mice that received gut bacteria transplants from braver ones became more fearless, exploring a maze with less hesitation. So strong is the microbiome’s impact that some have deemed it the “second brain.” And recently, a team of researchers found that our guts may harbor evidence of difficult life experiences many years after the fact, changing everything from how we digest food to how we process stress. In fact, these changes in our “second brain” may substantially alter the structure of our first, creating a feedback loop between the two.

For the study, published last month in the journal Microbiome, the authors analyzed the microbiomes of a group of students with irritable bowel syndrome, or IBS, a fairly common chronic condition marked by pain in the stomach, gas, and indigestion. (Though there are ways to manage IBS, many of which involve reducing stress, we don’t know what causes the syndrome.) They did the same for a control group of healthy volunteers, and also collected brain scans, stool samples, and behavioral and biographical information from participants in both categories.

The results were startling: Across the board, those in the IBS group were far more likely to exhibit anxiety and depression. When the researchers further divided IBS-afflicted subjects into two smaller groups — those with a microbiome undistinguishable from that of a healthy control, and those with noticeable differences — they found that the subgroup with different microbiomes also had more history of early life trauma, and their IBS symptoms lasted longer. “It is possible,” the authors wrote, “that the signals the gut and its microbes get from the brain of an individual with a history of childhood trauma may lead to lifelong changes in the gut microbiome.”

It’s also possible — or even probable — that the relationship isn’t uni-directional. The researchers noticed that the people with altered microbiomes had differently shaped brains, too, suggesting that the impacted gut may have doubled back and impacted certain brain regions — though they noted in the study that they don’t have enough information to be sure that’s the case, and cautioned against leaping to conclusions. Even more than the science of the gut on its own, the science of what how it affects the brain is still in its infancy; rather than arriving at any firm conclusions, this study is meant to open up the field more, laying a foundation for future researchers to build on.

If it’s true that the gut influences the brain just as the brain impacts the gut, though, then these findings may have tremendous implications for both mental and physical health. It might be a stretch to say that anxiety meds could one day be supplemented with kombucha, but it’s not too wild to imagine a future where treating ailments of the mind also involves treating the digestive system, or vice versa (already, some people are using talk therapy to ease IBS). For now, it can’t hurt to remember the connection between the two, and do everything in your power to live a life that gives you peace of mind — because it’ll give you peace of stomach, too.

This article was originally published in The Atlantic. Read the original article.

The Making of Space Mice

Mouse sperm exposed to cosmic radiation on the International Space Station for nearly 300 days has been used to produce healthy offspring back on Earth, according to new research.

In August 2013, Japanese researchers sent samples of freeze-dried mouse spermatozoa to the space station on cargo launched by JAXA, Japan’s space agency. Researchers used freeze-dried sperm because the samples can survive in room temperature for up to two years, and be easily rehydrated back on Earth, sperm intact. They’re also cheaper to transport; cryogenically preserved cells would have required a freezer, and more weight on rockets makes the ride more expensive.

Once the sperm arrived on the ISS, the samples were stored at about minus 95 degrees Celsius, or minus 139 degrees Fahrenheit. For 288 days, they were exposed to the microgravity environment on the ISS, where the inhabitants, mouse sperm and astronauts alike, receive cosmic radiation about 100 times stronger than that on Earth.

The samples returned on a rocket in May 2014. Back in Japan, researchers compared the space spermatozoa to control samples that had been kept under similar conditions in a lab on Earth. They used to the sperm to fertilize the eggs of lab mice in vitro, and then implanted the embryos. After about 19 days of gestation, the researchers carried out c-sections and delivered healthy pups.

The research is described in a study published Monday in Proceedings of the National Academy of Sciences. The researchers had hoped, of course, for healthy offspring, said Teruhiko Wakayama, the lead author and professor at the University of Yamanshi in Kofu, who had watched along with his colleagues as the mouse sperm blasted off into the night sky from an island in Japan’s Kagoshima prefecture. The number of pups and the gender breakdown from births resulting from the space sperm was comparable to births that occurred in the lab using sperm from Earth. Examination of their brain tissue and organs, as well as genetic testing, showed only minor differences between the two groups. The researchers mated the space mice after they became adults and all had healthy offspring, suggesting that exposure to space hadn’t negatively affected fertility.

But even though the offspring were healthy, the sperm DNA was damaged after about nine months in space, Wakayama told me over email. In his earlier ground experiments simulating the space environment, DNA seemed to be affected only after much higher levels of exposure to radiation, higher than what’s found on the ISS. The researchers had expected any negative effect from this experiment to be unnoticeable. “Fortunately, those DNA damage did not affect the offspring,” Wakayama said. The presence of healthy offspring suggests that the DNA was somehow repaired during the embryonic stage.

Wakayama’s work builds on a growing body of research on reproduction of living organisms in space. Other scientists have studied the effects of spaceflight on salamanders, fish, sea urchins, and frogs. The results have been mixed. Some female mice brought to the ISS in 2010 and 2011 stopped ovulating, and others lost a key structure that forms inside the ovary to help maintain pregnancy in its early stages. Last year, a Chinese spacecraft took thousands of fertilized mouse embryos for a 12-day trip into space. When they returned, they had formed into blastocysts, clusters of different types of cells, and hit the same developmental milestones as embryos on Earth.

Mice are common stand-ins for humans in scientific and medical research, but space-related challenges like figuring out how to colonize Mars are slightly more complicated than, say, determining the side effects of cholesterol drugs. Scientists suspect the lack of gravity would negatively affect a human pregnancy, starting at its ability to even take hold in the uterus. They know some things, like that radiation exposure can increase the risk of cancer in astronauts, including in reproductive organs, and that men who’ve spent time in space seem to father more female children than male.

The damaged sustained by the mouse sperm DNA in the Japanese study illustrates the risks of long-duration space travel. The ISS orbits just inside Earth’s magnetic field, which blocks out the worst of cosmic radiation. If humans want to live beyond that bubble, the researchers note, they’ll need reproductive technology capable of preserving and protecting cells from the harsh environment of space, for themselves and the animals they might bring with them.

This article was originally published in The Atlantic. Read the original article.

Fitness trackers accurately measure heart rate but not calories burned

Millions of people wear some kind of wristband activity tracker and use the device to monitor their own exercise and health, often sharing the data with their physician. But is the data accurate?

Such people can take heart in knowing that if the device measures heart rate, it’s probably doing a good job, a team of researchers at the Stanford University School of Medicine reports. But if it measures energy expenditure, it’s probably off by a significant amount.

An evaluation of seven devices in a diverse group of 60 volunteers showed that six of the devices measured heart rate with an error rate of less than 5 percent. The team evaluated the Apple Watch, Basis Peak, Fitbit Surge, Microsoft Band, Mio Alpha 2, PulseOn and the Samsung Gear S2. Some devices were more accurate than others, and factors such as skin color and body mass index affected the measurements.

In contrast, none of the seven devices measured energy expenditure accurately, the study found. Even the most accurate device was off by an average of 27 percent. And the least accurate was off by 93 percent.

“People are basing life decisions on the data provided by these devices,” said Euan Ashley, DPhil, FRCP, professor of cardiovascular medicine, of genetics and of biomedical data science at Stanford. But consumer devices aren’t held to the same standards as medical-grade devices, and it’s hard for doctors to know what to make of heart-rate data and other data from a patient’s wearable device, he said.

A paper reporting the researchers’ findings was published online May 24 in the Journal of Personalized Medicine. Ashley is the senior author. Lead authorship is shared by graduate student Anna Shcherbina, visiting assistant professor Mikael Mattsson, PhD, and senior research scientist Daryl Waggott.

Hard for consumers to know device accuracy

Manufacturers may test the accuracy of activity devices extensively, said Ashley, but it’s hard for consumers to know how accurate such information is or the process that the manufacturers used in testing the devices. So Ashley and his colleagues set out to independently evaluate activity trackers that met criteria such as measuring both heart rate and energy expenditure and being commercially available.


“For a lay user, in a non-medical setting, we want to keep that error under 10 percent,” Shcherbina said.

Sixty volunteers, including 31 women and 29 men, wore the seven devices while walking or running on treadmills or using stationary bicycles. Each volunteer’s heart was measured with a medical-grade electrocardiograph. Metabolic rate was estimated with an instrument for measuring the oxygen and carbon dioxide in breath — a good proxy for metabolism and energy expenditure. Results from the wearable devices were then compared to the measurements from the two “gold standard” instruments.

“The heart rate measurements performed far better than we expected,” said Ashley, “but the energy expenditure measures were way off the mark. The magnitude of just how bad they were surprised me.”

Heart-rate data reliable

The take-home message, he said, is that a user can pretty much rely on a fitness tracker’s heart rate measurements. But basing the number of doughnuts you eat on how many calories your device says you burned is a really bad idea, he said.

Neither Ashley nor Shcherbina could be sure why energy-expenditure measures were so far off. Each device uses its own proprietary algorithm for calculating energy expenditure, they said. It’s likely the algorithms are making assumptions that don’t fit individuals very well, said Shcherbina. “All we can do is see how the devices perform against the gold-standard clinical measures,” she said. “My take on this is that it’s very hard to train an algorithm that would be accurate across a wide variety of people because energy expenditure is variable based on someone’s fitness level, height and weight, etc.” Heart rate, she said, is measured directly, whereas energy expenditure must be measured indirectly through proxy calculations.

People are basing life decisions on the data provided by these devices.

Ashley’s team saw a need to make their evaluations of wearable devices open to the research community, so they created a website that shows their own data. They welcome others to upload data related to device performance.

The team is already working on the next iteration of their study, in which they are evaluating the devices while volunteers wear them as they go about a normal day, including exercising in the open, instead of walking or running on a laboratory treadmill. “In phase two,” said Shcherbina, “we actually want a fully portable study. So volunteers’ ECG will be portable and their energy calculation will also be done with a portable machine.”



This article was originally published in NIH. Read the original article.

A Vital Drug Runs Low, Though Its Base Ingredient Is in Many Kitchens

Hospitals around the country are scrambling to stockpile vials of a critical drug — even postponing operations or putting off chemotherapy treatments — because the country’s only two suppliers have run out.

The medicine? Sodium bicarbonate solution. Yes, baking soda.

Sodium bicarbonate is the simplest of drugs — its base ingredient, after all, is found in most kitchen cabinets — but it is vitally important for all kinds of patients whose blood has become too acidic. It is found on emergency crash carts and is used in open-heart surgery and as an antidote to certain poisons. Patients whose organs are failing are given the drug, and it is used in some types of chemotherapy. A little sodium bicarbonate can even take the sting out of getting stitches.

“As I talk to colleagues around the country, this is really a problem we’re all struggling with right now,” said Mark Sullivan, the head of pharmacy operations at Vanderbilt University Hospital and Clinics in Nashville.

Hospitals have been struggling with a dwindling supply of the medicine for months — one of the suppliers, Pfizer, has said that it had a problem with an outside supplier but that the situation worsened a few weeks ago. Pfizer and the other manufacturer, Amphastar, have said they don’t know precisely when the problem will be fixed, but it will not be before June for some forms of the drug, and in August or later for other formulations.

Continue reading the main story

The shortage of sodium bicarbonate solution is only the latest example of an inexpensive hospital staple’s supply dwindling to a critical level. In recent years, hundreds of generic injectable drugs have become scarce, vexing hospital administrators and government officials, who have called on the manufacturers to give better notice when they are about to run short.

Without an abundant supply of sodium bicarbonate, some hospitals are postponing elective procedures or making difficult decisions about which patients merit the drug. At Providence Hospital in Mobile, Ala., supplies ran so low a few weeks ago that Gino Agnelly, the head pharmacist, embarked on a desperate scavenger hunt, culling vials from the 50 crash carts that were stowed around the hospital.

Mr. Agnelly said he had been getting by with a supply of about 175 vials when a patient with a heart problem suddenly needed 35 of them.

He called a meeting of doctors and administrators, and they came to a difficult conclusion: They would need to postpone the seven open-heart operations that were scheduled for the next week. One critically ill patient was sent to a hospital across town because his surgery could not be delayed, Mr. Agnelly said.

Pfizer sent an emergency shipment a few days later, but the continuing shortage has forced Mr. Agnelly to make hard choices.

“Does the immediate need of a patient outweigh the expected need of a patient?” he asked. “It’s a medical and ethical question that goes beyond anything I’ve had to experience before.”

Erin Fox, a drug shortage expert at the University of Utah, said unexpected shortfalls of critical medicines had become routine. In 2014, a shortage of saline solution — salt water — sent hospitals into a similar panic. This is not even the first time that the supply of sodium bicarbonate has run out. The last shortage occurred in 2012.

“It is unbelievably frustrating,” Ms. Fox said. “It makes me so mad that we are out of these really basic lifesaving medications.”

Mr. Sullivan, of Vanderbilt, said the shortages typically occurred with cheaper, “bread-and-butter” hospital drugs, leading him to question whether manufacturers were investing enough in the production process needed to make a reliable supply.

“The specialty, high-dollar medicines — I don’t ever seem to see them experiencing shortages with those products,” he said.

The situation with sodium bicarbonate solution appears to have begun in February when Pfizer, the main supplier, announced it was in short supply, Ms. Fox said. A spike in demand then led Amphastar to run low. Now, even less-than-ideal alternatives to sodium bicarbonate, such as sodium acetate, are difficult to obtain.

Kuldip Patel, the associate chief pharmacy officer at Duke University Hospital in North Carolina, said he had become accustomed to the juggling act required when an old standby was suddenly unavailable.

“It’s not like we haven’t been here before,” he said.

Mr. Patel said the problem had worsened just after Pfizer went from shipping its generic injectable products from five regional warehouses to one national distribution center, part of a reorganization after its acquisition of the drugmaker Hospira.


“That’s when it all derailed,” he said.

A spokesman for Pfizer said the shortage of sodium bicarbonate was not related to the change in distribution, but was due to a manufacturing delay caused by an outside supplier. The spokesman, Thomas Biegi, said the delay had not been caused by a problem with the supplier of the raw ingredient, sodium bicarbonate, but he added that he could not divulge further details, citing confidentiality agreements.

Regardless of the reason, Mr. Patel said, drug companies should do a better job of creating contingency plans for keeping vital drugs in supply, especially during transitions.

“In situations like this, where a major manufacturer is buying out another major manufacturer of critically needed drugs, there has to be a detailed backup plan in case things don’t go smoothly,” Mr. Patel said.

Mr. Biegi said Pfizer was working hard to fix the problem. “Pfizer has a dedicated team focused on working with suppliers to address this and have already taken several steps to expedite supply recovery of this drug,” he said.

Andrea Fischer, a spokeswoman for the Food and Drug Administration, said companies were asked to notify the agency of problems, but “there are no requirements that firms keep emergency supplies or that they stock up prior to any changes they make.”

She said the agency was in close contact with the companies and “exploring all possible solutions to this critical shortage, including temporary importation, to help with this shortage until it’s resolved.”

Ms. Fischer said the agency had recently made progress in preventing supply problems. In 2011, it tracked 251 new shortages, an all-time high. But by 2016, she said, there were only 23 new shortages. Currently, more than 50 drugs are classified as being in shortage on the F.D.A. website.

“Unfortunately,” she said, “not all shortages can be prevented.”

The shortage problem has been traced to a confluence of factors, ranging from problems with suppliers of the raw ingredients to trouble at the aging facilities where many of the most inexpensive generics are made. Consolidation in the industry has also reduced the number of companies producing certain drugs, so that when one company has a problem, the other quickly runs out as well.

Ms. Fischer said the F.D.A. gave the approval process a priority status when a company wanted to enter a market that was in short supply.

Some large hospitals, such as Duke, house so-called compounding pharmacies, which can make custom batches of generics like sodium bicarbonate. Mr. Patel said that Duke was in the process of doing just that, but that setting up the process took time. The solution must be pure and sterile because it is injected into the bloodstream.

At Providence Hospital in Mobile, Mr. Agnelly said he was so desperate that he had done an internet search to investigate if he could safely mix his own batch with some baking soda and water. The hospital does not have a compounding pharmacy.

He discovered just one research paper, dating to 1947, when doctors did exactly that during World War II.

“This is not new technology. These are not expensive materials,” Mr. Agnelly said, adding that he quickly abandoned the idea. “It’s not what you would expect in the First World.”

This article was originally published in The New York Times.  Read the original article.

Ditch the Gluten, Improve Your Health?

This just in: A new health myth has been taking the country by storm.

Perhaps I’m exaggerating a bit. After all, health fads — especially diet fads — have come and gone for decades. Some are more worthy than others. For example, I am impressed by the evidence supporting the Mediterranean diet as a healthy option. As each one of us is different, the “ideal diet” may not be the same for each person. But the interest and enthusiasm surrounding the gluten-free food movement in recent years has been remarkable. Just a few years ago, relatively few people had ever heard of gluten. And it certainly wasn’t the “food movement” it has recently become.

If you’re considering limiting your consumption of gluten, you’re certainly not alone. But, the question is: Will restricting the gluten you eat improve your health? And will it make you feel better? It’s appealing to think so.

What Is Gluten?

Gluten is a protein found in many grains, including wheat, barley and rye. It’s common in foods such as bread, pasta, pizza and cereal. Gluten provides no essential nutrients. People with celiac disease have an immune reaction that is triggered by eating gluten. They develop inflammation and damage in their intestinal tracts and other parts of the body when they eat foods containing gluten. Current estimates suggest that up to 1% of the population has this condition. A gluten-free diet is necessary to eliminate the inflammation, as well as the symptoms. Grocery stores and restaurants now offer gluten-free options that rival conventional foods in taste and quality; only a few years ago, it was much harder to maintain a gluten-free diet.

So, maybe it should come as no surprise that people would embrace the gluten-free mantra. And embrace it they have. According to a survey by the Consumer Reports National Research Center a full 63% of Americans believe that a gluten-free diet could improve their mental or physical health. And up to a third of Americans are cutting back on it in the hope that it will improve their health or prevent disease.

Is This Really a Myth?

To call something a myth, it’s important to define the term. My non-scientific definition of a health myth requires most of the following:

Many people believe it.
There is no compelling scientific evidence to support it.
There is at least some scientific evidence against it.
There is a pseudo-scientific explanation that may have intuitive appeal (for example, enemas to “detoxify” the colon).
The idea defies standard understanding of biology or has no reasonable biologic explanation. An example is a diet that is said to help you lose weight despite increasing your caloric intake and reducing exercise.
Three other features of many popular health myths include:

The possibility that it can actually harm you
A profit motive (by those promoting the myth)
Celebrity endorsement
From this definition, the notion that a gluten-free diet will improve health is a certifiable health myth for most people.

Who Should Avoid Gluten?

There is at least some truth to the idea that gluten can be harmful. As mentioned, people with celiac disease avoid sickness and maintain much better health if they follow a gluten-free diet. For them, a gluten-free diet is nothing short of essential.

And then there are people described as “gluten-sensitive.” Their tests for celiac disease are negative (normal) and yet they get symptoms (including bloating, diarrhea or crampy abdominal pain) whenever they eat foods that contain gluten. One cause is wheat allergy, a disorder that can be diagnosed by skin testing. But for many, the diagnosis remains uncertain. Some have begun calling this “non-celiac gluten hypersensitivity,” a poorly defined condition about which we have much to learn.

Avoiding gluten makes sense for people with celiac disease, wheat allergy or those who feel unwell when they consume gluten.

What About Everyone Else?

There is no compelling evidence that a gluten-free diet will improve health if you don’t have celiac disease. The same is true if you can eat gluten without trouble. Of course, future research could change this. We may someday learn that at least some people without celiac disease or symptoms of intestinal disease are better off avoiding gluten.

So Why Are Gluten-Free Diets So Popular?

I suspect the popularity relates to a combination of factors, including:

Intuition – It just seems like a good idea.
Logic – If gluten is bad for people with celiac disease, maybe it’s bad for me.
Celebrity endorsement – If eliminating gluten is encouraged by someone I admire, maybe I should give it a try.
Anecdote – Testimonials can be powerful. Hearing about someone with bothersome symptoms that finally went away after eliminating gluten is difficult to ignore.
Marketing – Never underestimate the power of persuasion. Those selling gluten-free products or books about gluten-free diets can be convincing even if there’s little science to back it up.
What’s the Downside?

Actually, just about any health intervention comes with some risk. Eliminating gluten is no exception. Before you buy into the gluten-free life, buyer beware! It may not help, may cause trouble, and it’ll likely cost you more.

While many people in the Consumer Reports survey thought gluten-free diets were more nutritious and contained more minerals and vitamins than conventional foods, the opposite is often true. Gluten-free foods are commonly less fortified with folic acid, iron and other nutrients than regular, gluten-containing foods. And gluten-free foods tend to have more sugar and fat. Several studies have found a trend toward weight gain and obesity among those who follow a gluten-free diet (including those with celiac disease).

Meanwhile, gluten-free foods tend to be more expensive than conventional foods. It reminds me of the organic food option: People are often willing to pay higher prices for foods they think are healthier. The problem is that there is little or no proof that these foods are actually better for you.

What’s a Gluten-Conscious Person To Do?

If you feel well and have no digestive symptoms, enjoy your good health! And stop worrying so much about gluten.

But if you have symptoms that might be related to gluten, or if you have significant and unexplained symptoms, talk to your doctor. Symptoms of celiac disease or gluten sensitivity include:

Abdominal pain
Weight loss and poor appetite
Bloating or feeling full
An itchy rash
Growth delay (in children)
There are reliable tests to diagnose celiac disease. These include blood tests that detect certain antibodies, genetic tests and intestinal biopsies. The results can help you understand which, if any foods, you should avoid. You may learn that you can eat anything you like. Or, you may learn that it’s lactose (the sugar in milk), not gluten, that’s causing you trouble. Or, you may turn out to have another common condition that’s unrelated to gluten, such as Crohn’s disease, an ulcer or irritable bowel disease.

The Bottem Line

We are undoubtedly in a time of heightened gluten awareness. Is that a good thing? It is if you have celiac disease. I think it’s a major step forward that people who truly need to avoid gluten can do so more easily than in the past as more gluten-free foods are now available and labels are more clearly identifying foods with or without gluten. But the “dangers” of gluten have probably been overstated — and oversold. Don’t be swayed by an elite athlete or movie star to restrict your diet when there’s no medical reason to do so. It’s up to you and your doctor – not a celebrity or a book author – to take care of your health.



This article was originally published in NIH. Read the original article.