Archive for the ‘NIH’ Category

Because Kent Brantly is a physician who has watched people die of Ebola, there was an especially chilling prescience to his assessment last week, between labored breaths: “I am going to die.”

His condition was grave. But then on Saturday, we saw images of Brantly’s heroic return to U.S. soil, walking with minimal assistance from an ambulance into an isolation unit at Emory University Hospital.

“One of the doctors called it ‘miraculous,'” Dr. Sanjay Gupta reported from Emory this morning, of Brantly’s turnaround within hours of receiving a treatment delivered from the U.S. National Institutes of Health. “Not a term we scientists like to throw around.”

“The outbreak is moving faster than our efforts to control it,” Dr. Margaret Chan, director of the World Health Organization, said on Friday in a plea for international help containing the virus. “If the situation continues to deteriorate, the consequences can be catastrophic in terms of lost lives, but also severe socioeconomic disruption and a high risk of spread to other countries.”

In that light, and because Ebola is notoriously incurable (and the strain at large its most lethal), it is overwhelming to hear that “Secret Serum Likely Saved Ebola Patients,” as we do this morning from Gupta’s every-20-minute CNN reports. He writes:

Three top secret, experimental vials stored at subzero temperatures were flown into Liberia last week in a last-ditch effort to save two American missionary workers [Dr. Kent Brantly and Nancy Writebol] who had contracted Ebola, according to a source familiar with details of the treatment.

Brantly had been working for the Christian aid organization Samaritan’s Purse as medical director of the Ebola Consolidation Case Management Center in Monrovia, Liberia. The group yesterday confirmed that he received a dose of an experimental serum before leaving the country.

In Gupta’s optimistic assessment, Brantly’s “near complete recovery” began within hours of receiving the treatment that “likely saved his life.” Writebol is also reportedly improved since receiving the treatment, known as zMapp. But to say that it was a secret implies a frigid American exceptionalism; that the people of West Africa are dying in droves while a classified cure lies in wait.

The “top-secret serum” is a monoclonal antibody. Administration of monoclonal antibodies is an increasingly common but time-tested approach to eradicating interlopers in the human body. In a basic monoclonal antibody paradigm, scientists infect animals (in this case mice) with a disease, the mice mount an immune response (antibodies to fight the disease), and then the scientists harvest those antibodies and give them to infected humans. It’s an especially promising area in cancer treatment.

In this case, the proprietary blend of three monoclonal antibodies known as zMapp had never been tested in humans. It had previously been tested in eight monkeys with Ebola who survived—though all received treatment within 48 hours of being infected. A monkey treated outside of that exposure window did not survive. That means very little is known about the safety and effectiveness of this treatment—so little that outside of extreme circumstances like this, it would not be legal to use. Gupta speculates that the FDA may have allowed it under the compassionate use exemption.

A small 2012 study of monoclonal antibody therapy against Ebola found that it was only effective when administered before or just after exposure to the virus. A 2013 study found that rhesus macaques given an antibody mix called MB-003 within the 48-hour window had a 43 percent chance of surviving—as opposed to their untreated counterparts, whose survival rate was zero.

This Ebola outbreak is the largest in the history of the disease, in terms of both cases and deaths, 729 887 known so far. As Chan warned in her call for urgent international action, the outbreak is geographically the largest, already in four countries with fluid population movement across porous borders and a demonstrated ability to spread by air travel. The outbreak will be stopped by strategic quarantines and preventive education, primarily proper handling of corpses. More than 60 aid workers have become infected, but many more will be needed to stem the tide.

Dr. Anthony Fauci, director of the U.S. National Institute of Allergy and Infectious Disease (NIAID), is encouraged by the antibody treatment.

“Obviously there are plans and enthusiasm to expand this,” Fauci told me. “The limiting factor is the extraordinary paucity of treatment regimens.” Right now the total amount available, to Fauci’s knowledge, is three treatment courses (in addition to what was given to Brantly and Writebol).

NIAID did some of the original research that led to the development, but this is owned by Mapp Biopharmaceuticals. “They are certainly trying to scale up,” Fauci said, “but I’ve heard that their capability is such that it’s going to be months before they have a substantial number of doses, and even then they’re going to be limited.”

“We’re hearing that the administration of this cocktail of antibodies improved both Dr. Brantly and Ms. Writebol, but you know, we don’t know that,” Fauci said, noting the sample size (two) of this small, ad hoc study. Proving effectiveness would require a much larger group of patients being compared to an untreated group. “And we don’t know that they weren’t getting better anyway.”

Thanks to Kebmodee for bringing this to the attention of the It’s Interesting community.

By Jeannie Baumann

Many scientists now spend more time scrambling to raise money for their work than actually doing the research because of the erosion of NIH funding over the last decade, the president of a biomedical research university said during a June 18 congressional briefing.

Mark Tessier-Lavigne said the 25 percent decline in the National Institutes of Health’s purchasing power has led to grants being funded at historically low rates, causing promising young scientists to leave the field altogether and threatening the future of the biomedical research workforce.

“The financial squeeze has triggered a crisis in the biomedical research enterprise,” according to Tessier-Lavigne, who is president of the Rockefeller University in New York and investigates how neural circuits in the brain form during embryonic development. “Renewing NIH funding is an essential investment, not just for our health, but also for our economy.”

Tessier-Lavigne was the main speaker at the Capitol Hill briefing, “Paying Dividends: How Federally Funded Biomedical Research Fuels the Pharmaceutical Industry in the U.S.,” which was organized by the Coalition for the Life Sciences and theCongressional Biomedical Research Caucus as part of the 2014 caucus briefing series.

The key point of Tessier-Lavigne’s presentation—that scientific opportunity has never been greater while federal funding for basic research is at a low—has been echoed, especially by NIH Director Francis S. Collins when testifying before lawmakers in both the House and the Senate.

“We live in a golden age of biological research, of disease research, and of drug discovery that’s been enabled by a revolution in the biosciences that’s occurred over the past 40 years, thanks to the development of very powerful technologies,” said Tessier-Lavigne, citing as examples recombinant DNA, gene sequencing, human genetics and imaging. “We can now tackle disease systematically and that is enabling systematic drug discovery.”

The research ecosystem requires early investment through NIH funding to academia to yield the treatments and cures from the pharmaceutical industry, Tessier-Lavigne said.

“There’s a division of labor,” he said. “Most of the scientific discovery that leads to the insights that are built upon are made in academia, in research labs, in research institutes, in universities supported by the NIH. At the other end of the spectrum, industry—mostly large pharmaceutical companies and large biotech companies—are responsible for making the drugs and taking them through human clinical trials.”

Tessier-Lavigne has worked at both ends of the spectrum, serving as chief scientific officer at biotechnology company Genentech before taking over at Rockefeller. He rejected the idea that drug companies could take on funding the basic research. The cost and time lines of drug discovery and development are already too great, he said.

“To make a drug, to get a drug approved there’s huge attritions,” he said. The process starts with targeting 24 projects, and scientists try to make drugs to fight them that yields on average about nine drug candidates that make it into clinical trials.

“But of those nine, only a single one will make it over the finish line as an approved drug,” he said.

That drug-making process takes an average of 13 years, including five years to make the drug candidates and eight years to get to clinical approval. Including failures, he estimated those costs at anywhere between $2 billion to $4 billion per drug.

“So companies that do this are already struggling to succeed just at this. There are no more resources to fund the ferment back here that leads to the identification of new knowledge. The companies can’t do it and they won’t do it,” he said.

“Couldn’t we just rely on other nations to generate the basic knowledge and then industry here could continue to do the translational work?” Tessier-Lavigne asked rhetorically.

“Well, that’s not how it works. Industry wants its R&D [research and development] sites to be located next to the sites of innovation. It’s as simple as that,” he said.

Over the past 30 years, Tessier-Lavigne said, there has been a “massive” transfer of industry from Europe to the U.S. because of the prominence of the U.S. biomedical enterprise.

“If we don’t maintain, sustain our investment in our basic biomedical enterprise, industry will pick up and move to the other sites,” he said, adding that countries like China are where these companies will move, taking jobs with them.
Rep. Jackie Speier (D-Calif.), co-chairman of the Congressional Biomedical Research Caucus, also mentioned that the U.S. may lose its position as the leader in R&D.

“We still lead in terms of patents and overall research, but China is about to eat our lunch,” said Speier, whose district includes the Bay Area and Genentech’s headquarters. “In fact, China has just about eclipsed Japan now in terms of research and within the next 10 years, it is anticipated that they will indeed overcome us in terms of research and development. And that would indeed be a tragic set of circumstances.”
Action Plan

Tessier-Lavigne proposed an action plan that primarily involves gradually restoring NIH funding in absolute dollars to its 2003 level—the final year of a five-year doubling. Since the 2003 doubling, the NIH’s budget has remained flat at about $30 billion. Collins has said that his agency would have about a $40 billion annual budget if the NIH had continued to receive the steady, 3 percent increases it received from the 1970s onward.

Restoring funding to the 2003 levels would relieve the squeeze on existing programs so scientists can focus on their work as well as stimulate new initiatives to accelerate progress and open new areas of discovery, Tessier-Lavigne said.

At the same time, the academic sector has a responsibility to make sure it spends these dollars effectively while developing a pipeline of new talent. And all stakeholders—academia, the NIH, disease foundations and the private sector—must ensure research discoveries are effectively translated into new therapies and cures.

The next congressional briefing is scheduled for July 16 on the advances and potential of embryonic stem cell research, withLawrence Goldstein, director of the University of California, San Diego, Stem Cell Program.

Thanks to Pete Cuomo for bringing this to the attention of the It’s Interesting community.

Recently the mainstream has come to embrace the fact that the job market for Ph.D. biomedical researchers is overcrowded. According to a new report from a working group of the National Institutes of Health (NIH) Advisory Committee to the Director (ACD), the job market looks very different for physician-scientists. In fact, “[t]here may not be enough [physician-scientists] to replace those preparing to retire,” Jocelyn Kaiser reports in a ScienceInsider.

The working group analyzed data on “M.D.-Ph.D.s, M.D.s, nurses, and other researchers with clinical training” collected from an American Medical Association (AMA) survey, finding—in stark contrast to trends in the number of biomedical Ph.D. graduates—that “[t]he number of physicians conducting research has declined 5.5% since 2003 to about 13,700 in 2012.” The working group also analyzed data from NIH and AMA and found that many NIH-funded principal investigators (PIs) are in their 60s and 70s, and that the number of PIs under 60 is declining.

The data have fueled concern for the future of the physician-scientist population. The need for younger physician-scientists is getting more attention because “we’re worried that they’re [physician-scientists are] going to dry up and this is going to be a serious problem,” said working group co-chair David Ginsburg of the University of Michigan, Ann Arbor, in a call with reporters, as quoted by Kaiser.

Kaiser notes that some of the working group’s recommendations for fixing these problems echo those of the 2012 Biomedical Workforce Working Group of the ACD, led by Princeton University molecular biologist Shirley Tilghman: Enrich training programs, and give more weight to proposals from young researchers. “It also recommends creating a category for physician-scientists within the so-called kangaroo, or K99/R00, awards—two-stage awards that include a training grant and research support,” Kaiser writes.

Thanks to Dr. Lutter for bringing this to the attention of the It’s Interesting community.

A placenta sustained you and every person ever born for 9 months, serving as your lungs and kidneys and pumping out hormones while you developed in the womb. Problems with this disk-shaped mass of tissue can contribute to everything from preterm births to diseases of middle age. Yet when a baby is born, hospitals usually throw the placenta away.

“It’s the least understood human organ,” says Alan Guttmacher, director of the National Institute of Child Health and Human Development (NICHD) in Bethesda, Maryland. “A large part of the scientific community never thinks about the placenta at all.” He and others hope to change that, however, by rallying researchers and funders, including other parts of the National Institutes of Health (NIH), around an effort to better understand the underappreciated organ. At an NICHD-sponsored workshop last week, some 70 researchers laid out their ideas for what NICHD calls the Human Placenta Project, including ways to better monitor the placenta during a pregnancy, and drugs to bolster it when it falters.

The human placenta forms primarily from cells that develop from the outer layer of fetal cells that surround an early embryo. Early in pregnancy, these trophoblasts invade the uterine wall and later develop a complex network of tiny projections called villi, which contain fetal blood vessels. This treelike structure of villi absorbs oxygen and nutrients from maternal blood; fetal waste and carbon dioxide meanwhile diffuse into the maternal bloodstream. Other specialized cells link the developing placenta to the umbilical cord. To avoid rejection by the mother’s immune system, the placenta employs various tricks, such as not expressing certain proteins. The placenta’s role during pregnancy is “an incredibly interesting biological time” that offers lessons for everything from cancer to organ transplantation, says physician-scientist Kimberly Leslie of the University of Iowa in Iowa City.

A malfunctioning, too small, or weakly attached placenta can starve the fetus, stunting its growth, and can also contribute to preeclampsia, or pregnancy-related high blood pressure, a condition that occurs in up to 6% of pregnancies and can require premature delivery of a baby. Adult diseases, too, ranging from cardiovascular disease to insulin resistance, seem to be linked to abnormal placenta morphology for poorly understood reasons.

During recent strategic planning at NICHD, researchers concluded that the placenta deserved closer study. “It came up repeatedly,” Guttmacher says. He expects that the Human Placenta Project will focus on understanding both the normal and abnormal placenta in real time during the course of pregnancy. It will also look for possible interventions—for example, a drug that would spur the growth of an abnormally small placenta.

Some at the workshop hope to adapt ultrasound and magnetic resonance imaging techniques now used to study the heart and brain to measure blood flow and oxygenation in the placenta. Injecting tracers, however, may be sensitive ethical territory. “People are very scared of doing things to pregnant women,” said placenta researcher Nicholas Illsley, of Hackensack University Medical Center in New Jersey, at the meeting. Another idea is to probe the mother’s bloodstream for cells and nucleic acids shed by the placenta as a window into the function of the organ.

Researchers also mused about creating a “placenta on a chip” that would mimic the tissue in the lab or developing molecular sensors that could monitor the placenta throughout pregnancy. “This sounds like science fiction, but if you showed me an iPhone 20 years ago, I would have said this was science fiction,” said Yoel Sadovsky, of the Magee-Womens Research Institute in Pittsburgh, Pennsylvania, at the meeting.

Attendees described a few immediate goals. One is to come up with standard definitions of a normal and abnormal placenta. Placenta morphology varies widely, and those from a healthy pregnancy can still have visible abnormalities, whereas those from sick babies often look completely normal, says systems biologist Brian Cox of the University of Toronto in Canada. Even before the NICHD meeting, the international community of placenta researchers had begun to coordinate their efforts by planning a website that will list existing placenta biobanks and help match collaborators.

At a time when NICHD’s budget is flat, money could be a limiting factor for the Human Placenta Project, which Guttmacher hopes will fund its first grants in 2016 and go for a decade or more. He expects that in addition to setting aside new money for the project, NICHD may give extra weight to high-quality grant applications focusing on the placenta. NICHD’s own contribution may be only “in the millions” of dollars, Guttmacher says. But he says eight other NIH institutes have expressed interest in contributing, as has the March of Dimes, an organization long focused on maternal and infant health. At long last, a throwaway organ may get the attention it deserves.

Thanks to Kebmodee for bringing this to the attention of the It’s Interesting community.

Sol Snyder, Distinguished Service Professor of Neuroscience, Pharmacology and Psychiatry, School of Medicine

Growing up, I never had any strong interest in science. I did well in lots of things in high school. I liked reading philosophy and things like that, but being a philosopher is not a fit job for a nice Jewish boy.

This was in the mid-1950s, and many of my friends were going into engineering, preparatory to joining the then prominent military industrial complex. Others were going to be doctors, so I got the idea that maybe I’d be a psychiatrist. I didn’t have any special affinity for medicine or desire to cast out the lepers or heal mankind.

I was always reading things. My father valued education. He wasn’t a big advice giver, but he … had a lot of integrity. What was important to him was doing the right thing. And he had great respect for the intellectual life and science.

My father’s professional life commenced in 1935 as the 10th employee of what became the NSA. He led a team that broke one of the principal Japanese codes. At the end of World War II, computers were invented, and, if you think about it, what could be the best entity to take advantage of computers than NSA, with its mission of sorting gibberish and looking for patterns. So my father was assigned to look at these new machines and see if they would be helpful. He led the computer installations at NSA.

Summers in college I worked in the NSA. My father taught me to program computers in machine language. Computers were a big influence on me.

I learned at the NSA about keeping secrets. What is top secret, what is need-to-know—that is one of the things you learn in the business. You don’t talk to the guy at the next desk even if you’re working on the same project. If that person doesn’t need to know, you just shut up.

In medical school, I started working at the NIH in Bethesda during the summers and elective periods, largely because the only thing I really did well up to that time was play the classical guitar and one of my guitar students was an NIH researcher. In high school I thought I might go the conservatory route, but that’s even less fitting for a nice Jewish boy than being a philosopher.

It was through my contacts at NIH that I was able to get a position working with future Nobel Prize winner Julius Axelrod. Julie was a wonderful mentor who did research on drugs and neurotransmitters. Working with him was inspirational. I just adored it.

What was notable about Julie was his great creativity, always coming up with original ideas. Even though he was an eminent scientist, he didn’t have a regular office. He just had a desk in a lab. He did experiments with his own two hands every day.

Philosophically, Julie emphasized you go where the data takes you. Don’t worry that you’re an expert in enzyme X and so should focus on that. If the data point to enzyme Y, go for it. Do what’s exciting.

My very first project with Julie was studying the disposition of histamine. I thought I had found that histamine had been converted into a novel product that looked really interesting, and I was wrong. I missed the true product because we separated the chemicals on paper and discarded the radioactivity at the bottom, throwing away the real McCoy. Another lab at Yale found it, led, remarkably, by a close friend since kindergarten. My humiliation didn’t last very long. I learned not to be so sloppy, to take greater care, and, most important, to explore peculiar results.

How does one pick research directions? You can go where it’s “hot,” but there you’re competing with 300 other people, and everyone can make only incremental changes. But if you follow Julie Axelrod’s rules and you don’t worry about what’s hot, or what other people are doing—just go where your data are taking you—then you have a better chance of finding something that nobody else had found before.

With the discovery of the opiate receptor, I was fortunate to launch a new field: molecular identification of neurotransmitter receptors. Later we discovered that the gas nitrous oxide is a neurotransmitter.

I’m a klutz. I can’t hammer a nail. So for the technical side, like dissecting brains to look at different regions, I enlisted friends. I learned to collaborate, a key element in so many discoveries.

Johns Hopkins has always been a collegial place. People are just friendly and interact with each other. This tradition goes back to the founding of the medical school, permeating the school’s governance as well as research. We tend to be more productive than faculty at other schools, where one gets ahead by sticking an ice pick in the backs of colleagues.

One of my heroes was my guitar teacher, Sophocles Papas, Andrés Segovia’s best friend. Sophocles was an important influence in my life, and we stayed close until he died in his 90s. In a couple of years after commencing lessons, I was giving recitals, all thanks to him. Like Julie, Sophocles emphasized innovative short cuts to creativity.

I’ve remained involved with music. I’m the longest-serving trustee on the Baltimore Symphony Orchestra, chairing for many years its music committee. Trustees of arts organizations are typically businesspeople selected for their fundraising acumen. But the person who nominated me reportedly commented, I’d like to propose something radical: I’d like to propose a trustee who cares about music.

Most notable about psychiatry is that the major drugs—antipsychotics for schizophrenia, antidepressants, and anti-anxiety drugs—were all discovered in the mid-1950s. Subsequent tweaking has enhanced potency and diminished side effects, but there have been no major breakthroughs. No new class of drugs since 1958—rather frustrating.

As biomedical science advances, especially with the dawn of molecular biology, our power to innovate is just dazzling. Today’s students take all of this for granted, but those of us who have been doing research for several decades are daily amazed by our abilities to probe the mysteries of life.

The logic of nature is elegant and straightforward. The more we learn about how the body works, the more we are amazed by its beauty and inherent simplicity.

One of my pet peeves is that the very power of modern science leads journal and grant reviewers to expect every “i” dotted and every “t” crossed. Because of this, four years or more of work go into each scientific manuscript. Then, editors and reviewers of journals are so picayune that revising a paper consumes another year.

Now let’s consider the poor post­doctoral fellow or graduate student. To move forward in his or her career requires at least one major publication—a five-year enterprise. If you only have one shot on goal, one paper in five years, your chances of success shrivel. The duration of PhD training and postdoctoral training is getting so long that from the entry point at graduate school to the time you’re out looking for a job as an assistant professor is easily 12, 15 years. Well, that is ridiculous. If you got paid $10 million at the end of this road, that would be one thing, but scientists earn less than most other professionals. We’re deterring the young smart people from going into science.

Biomedical researchers don’t work in a vacuum. They work with grad students and postdoctoral fellows, so being a good mentor is key to being a good scientist. Keep your students well motivated and happy. Have them feel that they are good human beings, and they will do better science.

The most important thing is that you value the integrity of each person. I ask my students all the time, What do you think? And this discussion turns into minor league psychotherapy. Ah, you think that? Tell me more. Tell me more.

The “stupidest” of the students here are smarter than me. It’s a pleasure to watch them emerge.

I see my life as taking care of other people. Although I didn’t go to medical school with any intelligent motivation, once I did, I loved being a doctor and trying to help people. And I love being a psychiatrist and trying to understand people, and I try to carry that into everything I do.

In medical research, all of us want to find the causes and cures for diseases. I haven’t found the cause of any disease, although with Huntington’s disease, we are making inroads. And, of course, being a pharmacologist, my métier is discovering drugs and better treatments.

My secret? I come to work every day, and I keep my own calendar. That way I have free time to just wander around the lab and talk to the boys and girls and ask them how it’s going. That’s what makes me happy.

Sol Snyder joined Johns Hopkins in 1965 as an assistant resident in Psychiatry and would later become the youngest full professor in JHU history. In 1978, he received the Albert Lasker Basic Medical Research Award for his role in discovering the brain’s opiate receptors. In 1980, he founded the School of Medicine’s Department of Neuroscience, which in 2006 was renamed the Solomon H. Snyder Department of Neuroscience.

lab to lcinic
The research team is building a smaller portable version of the laboratory’s cancer detection system. Source: Milind Rajadhyaksha, Ph. D., Memorial Sloan-Kettering Cancer Center, New York, NY.


A common surgery for non-melanoma skin cancer, known as Mohs surgery, typically achieves excellent results but can be a long process, as the surgeon successively removes the area of concern until the surrounding tissue is free of cancer. To determine whether further tissue removal is necessary, the borders of the lesion must be processed in a laboratory to check for residual cancer tissue — a process that takes 20 – 45 minutes and is often repeated numerous times. Now, National Insititute of Biomedical Imaging and Bioengineering (NIBIB)-funded researchers have developed a microscopic technique to analyze removed tissue rapidly right in the clinic — dramatically reducing the length, inefficiency, and expense of this procedure.

With approximately 3.5 million new cases per year in the U.S., Mohs surgery is a fairly common procedure that many people undergo repeatedly as new skin cancers appear. It can take one to three hours, or even longer depending on the size and location of the lesion. The process is lengthy because after a section of tissue is removed, it must be frozen and stained so it can be examined to ensure the borders are clear of residual tumor. Although highly effective, the current practice is labor intensive for surgeons and assisting staff, as well as lengthy and stressful for patients. The time spent by surgical personnel and those analyzing the tissue in the lab increases the expense of the procedure, which has been estimated to cost $ 2-3 billion per year in the U.S.

NIBIB-supported researchers led by Milind Rajadhyaksha, Ph.D. at Memorial Sloan Kettering are using their expertise in optical imaging to improve this common procedure. Optical imaging is a technique that uses visible or near-infrared light to obtain detailed images of organs, tissues, and cells. The investigators developed a new pathological assessment technique called strip mosaicing confocal microscopy — a type of optical imaging — that can provide high resolution images during removal of basal cell and squamous cell carcinomas (non-melanoma skin cancers) and perhaps other tumors of the skin. The new technique uses a focused laser line that performs multiple scans of the tissue to obtain image “strips” that are then combined, like a mosaic, into a complete image of the excised tissue. The process takes only 90 seconds and eliminates the need to freeze and stain the tissue samples for analysis — a process that takes 20 to 45 minutes.

The new imaging technique was tested on 17 patients with 34 tissue samples. The overall image quality was excellent, with high resolution and contrast, providing for good visibility of the epidermis and dermis. Researchers compared the new technique against the Mohs approach with its frozen section processing. The new technique achieved a promising 94% in preliminary measures of sensitivity and specificity for detecting skin cancer margins, which is comparable to the “gold standard” Mohs procedure. These preliminary results demonstrated that the optical technique could potentially detect skin cancer margins with the same accuracy as the conventional frozen section technique.

The results of this study were obtained under laboratory conditions; a clinical trial is now being conducted to demonstrate the feasibility of using this technique in the clinical setting, the ultimate goal of the research group.

Steve Krosnick, M.D., NIBIB director for the Program for Image-Guided Interventions, explains the utility of the optical system: “The technology is particularly well-suited for Mohs-trained surgeons, who are experts at performing excisions and interpreting images of tissue samples removed during the Mohs procedure. Image quality, ability to make accurate interpretations, and time savings will be key parameters for adoption of the system in the clinical setting, and the current results are very encouraging.”

The research was conducted by a team consisting of two laboratories at Memorial Sloan-Kettering Cancer Center, New York, NY, as well as students from Bronx High School of Science, New York and Livingston High School, Livingston New Jersey. The work is published in the October 2013 issue of the British Journal of Dermatology.

Thanks to Dr. Rajadhyaksha for bringing this to the attention of the It’s Interesting community.


STOCKHOLM (AP) — Two Americans and a German-American won the Nobel Prize in medicine on Monday for discovering how key substances are transported within cells, a process involved in such important activities as brain cell communication and the release of insulin.

James Rothman, 62, of Yale University, Randy Schekman, 64, of the University of California, Berkeley, and Dr. Thomas Sudhof, 57, of Stanford University shared the $1.2 million prize for their research on how tiny bubbles called vesicles act as cargo carriers inside cells.

This traffic control system ensures that the cargo is delivered to the right place at the right time and keeps activities inside cells from descending into chaos, the committee said. Defects can be harmful, leading to neurological diseases, diabetes and disorders affecting the immune system.

“Imagine hundreds of thousands of people who are traveling around hundreds of miles of streets; how are they going to find the right way? Where will the bus stop and open its doors so that people can get out?” Nobel committee secretary Goran Hansson said. “There are similar problems in the cell.”

The winners’ discoveries in the 1970s, ’80s and ’90s have helped doctors diagnose a severe form of epilepsy and immune deficiency diseases in children, Hansson said. In the future, scientists hope the research could lead to medicines against more common types of epilepsy, diabetes and other metabolism deficiencies, he added.

Schekman said he was awakened at 1 a.m. at his home in California by the chairman of the prize committee, just as he was suffering from jetlag after returning from a trip to Germany the night before.

“I wasn’t thinking too straight. I didn’t have anything elegant to say,” he told The Associated Press. “All I could say was ‘Oh my God,’ and that was that.”

He called the prize a wonderful acknowledgment of the work he and his students had done and said he knew it would change his life.

“I called my lab manager and I told him to go buy a couple bottles of Champagne and expect to have a celebration with my lab,” he said.

In the 1970s, Schekman discovered a set of genes that were required for vesicle transport, while Rothman revealed in the 1980s and 1990s how vesicles delivered their cargo to the right places. Also in the ’90s, Sudhof identified the machinery that controls when vesicles release chemical messengers from one brain cell that let it communicate with another.

“This is not an overnight thing. Most of it has been accomplished and developed over many years, if not decades,” Rothman told the AP.

Rothman said he lost grant money for the work recognized by the Nobel committee, but he will now reapply, hoping the Nobel prize will make a difference in receiving funding.

Sudhof, who was born in Germany but moved to the U.S. in 1983 and also has U.S. citizenship, told the AP he received the call from the committee while driving toward the city of Baeza, in southern Spain, where he was due to give a talk.

“I got the call while I was driving and like a good citizen I pulled over and picked up the phone,” he said. “To be honest, I thought at first it was a joke. I have a lot of friends who might play these kinds of tricks.”

The medicine prize kicked off this year’s Nobel announcements. The awards in physics, chemistry, literature, peace and economics will be announced by other prize juries this week and next. Each prize is worth 8 million Swedish kronor ($1.2 million).

Rothman and Schekman won the Albert Lasker Basic Medical Research Award for their research in 2002 — an award often seen as a precursor of a Nobel Prize. Sudhof won the Lasker award this year.

“I might have been just as happy to have been a practicing primary-care doctor,” Sudhof said after winning that prize. “But as a medical student I had interacted with patients suffering from neurodegeneration or acute clinical schizophrenia. It left an indelible mark on my memory.”

Jeremy Berg, former director of the National Institute of General Medical Sciences in Bethesda, Maryland, said Monday’s announcement was “long overdue” and widely expected because the research was “so fundamental, and has driven so much other research.”

Berg, who now directs the Institute for Personalized Medicine at the University of Pittsburgh, said the work provided the intellectual framework that scientists use to study how brain cells communicate and how other cells release hormones. In both cases, vesicles play a key role by delivering their cargo to the cell surface and releasing it to the outside, he told the AP.

So the work has indirectly affected research into virtually all neurological disease as well as other diseases, he said.

Established by Swedish industrialist Alfred Nobel, the Nobel Prizes have been handed out by award committees in Stockholm and Oslo since 1901. The winners always receive their awards on Dec. 10, the anniversary of Nobel’s death in 1896.

Last year’s Nobel medicine award went to Britain’s John Gurdon and Japan’s Shinya Yamanaka for their contributions to stem cell science.


Daniel Yuan, pictured at his home in Laurel, raised doubts for years about the work of his colleagues in a Johns Hopkins medical research lab. “The denial that I am hearing from almost everyone in the group as a consensus is troubling to me,” he wrote in one e-mail. In December 2011, after 10 years at the lab, he was fired.

By Peter Whoriskey
The Washington Post Published: March 11
The numbers didn’t add up.

Over and over, Daniel Yuan, a medical doctor and statistician, couldn’t understand the results coming out of the lab, a prestigious facility at Johns Hopkins Medical School funded by millions from the National Institutes of Health.

He raised questions with the lab’s director. He reran the calculations on his own. He looked askance at the articles arising from the research, which were published in distinguished journals. He told his colleagues: This doesn’t make sense.

“At first, it was like, ‘Okay — but I don’t really see it,’ ” Yuan recalled. “Then it started to smell bad.”

His suspicions arose as reports of scientific misconduct have become more frequent and critics have questioned the willingness of universities, academic journals and the federal government, which pays for much of the work, to confront the problem.

Eventually, the Hopkins research, which focused on detecting interactions between genes, would win wide acclaim and, in a coup for the researchers, space in the pages of Nature, arguably the field’s most prestigious journal. The medical school even issued a news release when the article appeared last year: “Studies Linked To Better Understanding of Cancer Drugs.”

What very few readers of the Nature paper could know, however, was that behind the scenes, Yuan’s doubts seemed to be having profound effects.

In August, Yu-yi Lin, the lead author of the paper, was found dead in his new lab in Taiwan, a puncture mark in his left arm and empty vials of sedatives and muscle relaxants around him, according to local news accounts — an apparent suicide.

And within hours of this discovery, a note was sent from Lin’s e-mail account to Yuan. The e-mail, which Yuan saved, essentially blamed him for driving Lin to suicide. Yuan had written to Nature’s editors, saying that the paper’s results were overstated and that he found no evidence that the analyses described had actually been conducted. On the day of his death, Lin, 38, the father of three young daughters, was supposed to have finished writing a response to Yuan’s criticisms.

The subject line of the e-mail to Yuan, sent by an unknown person, said “your happy ending.”

“Yu-yi passed away this morning. Now you must be very satisfied with your success,” the e-mail said.

Yuan said he was shocked by the note, so much so that he began to shake.

But in the seven months since, he has wondered why no one — not the other investigators on the project, not the esteemed journal, not the federal government — has responded publicly to the problems he raised about the research.

The passions of scientific debate are probably not much different from those that drive achievement in other fields, so a tragic, even deadly dispute might not be surprising.

But science, creeping ahead experiment by experiment, paper by paper, depends also on institutions investigating errors and correcting them if need be, especially if they are made in its most respected journals.

If the apparent suicide and Yuan’s detailed complaints provoked second thoughts about the Nature paper, though, there were scant signs of it.

The journal initially showed interest in publishing Yuan’s criticism and told him that a correction was “probably” going to be written, according to e-mail rec­ords. That was almost six months ago. The paper has not been corrected.

The university had already fired Yuan in December 2011, after 10 years at the lab. He had been raising questions about the research for years. He was escorted from his desk by two security guards.

More recently, a few weeks after a Washington Post reporter began asking questions, a university spokeswoman said that a correction had been submitted to Nature and that it was under review.

“Your questions will be addressed with that publication,” a spokeswoman for the Hopkins medical school, Kim Hoppe, wrote in an e-mail.

Neither the journal nor the university would disclose the nature of the correction.

Hoppe declined an opportunity to have university personnel sit for interviews.

In the meantime, the paper has been cited 11 times by other published papers building on the findings.

It may be impossible for anyone from outside to know the extent of the problems in the Nature paper. But the incident comes amid a phenomenon that some call a “retraction epidemic.”

Last year, research published in the Proceedings of the National Academy of Sciences found that the percentage of scientific articles retracted because of fraud had increased tenfold since 1975.

The same analysis reviewed more than 2,000 retracted biomedical papers and found that 67 percent of the retractions were attributable to misconduct, mainly fraud or suspected fraud.

“You have a lot of people who want to do the right thing, but they get in a position where their job is on the line or their funding will get cut, and they need to get a paper published,” said Ferric C. Fang, one of the authors of the analysis and a medical professor at the University of Washington. “Then they have this tempting thought: If only the data points would line up . . . ”

Fang said retractions may be rising because it is simply easier to cheat in an era of digital images, which can be easily manipulated. But he said the increase is caused at least in part by the growing competition for publication and for NIH grant money.

He noted that in the 1960s, about two out of three NIH grant requests were funded; today, the success rate for applicants for research funding is about one in five. At the same time, getting work published in the most esteemed journals, such as Nature, has become a “fetish” for some scientists, Fang said.

In one sense, the rise in retractions may mean that the scientific enterprise is working — bad work is being discovered and tossed out. But many observers note that universities and journals, while sometimes agreeable to admitting small mistakes, are at times loath to reveal that the essence of published work was simply wrong.

“The reader of scientific information is at the mercy of the scientific institution to investigate or not,” said Adam Marcus, who with Ivan Oransky founded the blog Retraction Watch in 2010. In this case, Marcus said, “if Hopkins doesn’t want to move, we may not find out what is happening for two or three years.”

The trouble is that a delayed response — or none at all — leaves other scientists to build upon shaky work. Fang said he has talked to researchers who have lost months by relying on results that proved impossible to reproduce.

Moreover, as Marcus and Oransky have noted, much of the research is funded by taxpayers. Yet when retractions are done, they are done quietly and “live in obscurity,” meaning taxpayers are unlikely to find out that their money may have been wasted.

Johns Hopkins University typically receives more than $600 million a year from NIH, according to NIH figures.

For someone who has taken on a battle with Johns Hopkins and Nature, Yuan is strikingly soft-spoken.

He grew up in Gainesville, Fla., and attended MIT and then medical school at Johns Hopkins. He worked briefly as a pediatrician and an assistant professor of pediatrics before deciding that he preferred pure research. He has a wife and two kids and is an accomplished violinist.

In 2001, he joined the lab of Jef Boeke, a Hopkins professor of molecular biology and genetics. Boeke’s work on the yeast genome is, as academics put it, “highly cited” — that is, other papers have used some of his articles numerous times for support. Last year, he was named a member of the prestigious American Academy of Arts and Sci­ences.

The lab’s research focused on developing a methodology for finding evidence of genes interacting, primarily in the yeast genome and then in the human genome. Genetic interactions are prized because they yield insights into the traits of the genes involved.

During Yuan’s time there, the lab received millions in NIH funding, and according to internal e-mails, the people in the lab were under pressure to show results. Yuan felt the pressure, too, he says, but as the point person for analyzing the statistical data emerging from the experiments, he felt compelled to raise his concerns.

As far back as 2007, as the group was developing the methodology that would eventually form the basis of the Nature paper, Yuan wrote an anguished e-mail to another senior member of the lab, Pamela Meluh.

“I continue to be in a state of chronic alarm,” he wrote in August 2007. “The denial that I am hearing from almost everyone in the group as a consensus is troubling to me.”

Meluh quickly wrote back: “I have the same level of concern as you in terms of data quality, but I have less basis to think it can be better. . . . I’m always torn between addressing your and my own concerns and being ‘productive.’ ”

Then Boeke weighed in, telling Yuan that if he could improve the data analysis, he should, but that “the clock is ticking.”

“NIH has already given us way more time than we thought we needed and at some point we’ve got to suck it up and run with what we have,” Boeke wrote to Meluh and Yuan.

A few years later, another deadline was looming, and Elise Feingold, an NIH administrator, wanted to know what the lab had accomplished.

“I do need some kind of progress report on what you have been doing the past two years . . . and what you think you can accomplish with these funds,” she wrote to Boeke.

Citing Feingold’s message, ­Meluh wrote to Yuan, asking for help in explaining what the lab had produced. Its members had worked diligently, Yuan says, but hadn’t arrived at the kind of significant findings that generally produce scientific papers.

“I want to make it look like we’ve been busy despite lack of publications,” Meluh wrote.

Meluh did not respond to a request for an interview. Boeke referred questions to the university’s public relations team, which declined to comment further. An NIH official declined to comment.

While Yuan was growing increasingly skeptical of the lab’s methodology, Yu-yi Lin, who was also working at the lab, was trying to extend it. In the past, it had been applied to the yeast genome; Lin would extend it to the human genome — and this would become the basis of the Nature paper.

Lin, who was from Taiwan, was an up-and-comer. As a graduate student at Johns Hopkins just a few years before, he’d won an award for his work in cell metabolism and aging. He was also arranging for a prestigious spot at National Taiwan University.

At one point, when he was still at the Boeke lab at Hopkins, Lin asked Yuan to help analyze the data that would become the basis for the Nature paper, Yuan says. Yuan said he declined to get involved because he thought the methodology still had deep flaws.

Interactions between Lin and Yuan at the lab were few, Yuan said, and at any rate, Yuan had other things to worry about. He was slowly being forced out. He was demoted in 2011 from research associate to an entry-level position. A disagreement over whether Yuan should have asked Boeke if he wanted a byline on a paper erupted into further trouble, e-mail and other records show.

The Johns Hopkins spokeswoman, Hoppe, declined to discuss Yuan’s job termination.

On Dec. 15, 2011, Yuan was forced to leave the lab. He wasn’t allowed to make copies of his cell collection. He spent the next month trying to keep his mind busy. He read books about JavaScript and Photoshop, which he thought would enrich his research abilities. As he looked for other research jobs, he sensed that he had been blackballed.

Then, in February 2012, the Nature paper was published.

The research was a “profound achievement” that would “definitely be a great help to solve and to treat many severe diseases,” according to a news release from National Taiwan University, where Lin was now working.

Upon reading it, Yuan said, he was astonished that Lin had used what he considered a flawed method for finding genetic interactions. It had proved troublesome in the yeast genome, he thought. Could it have possibly been more reliable as it was extended to the human genome?

Lin, Boeke and their co-authors reported discovering 878 genetic interactions, or “hits.”

But Yuan, who was familiar with the data and the statistics, reanalyzed the data in the paper and concluded that there was essentially no evidence for any more than a handful of the 878 genetic interactions.

One of the key problems, Yuan wrote to the Nature editors, was that the numerical threshold the investigators used for determining when a hit had arisen was too low. This meant they would report far more hits than there actually were.

Yuan also calculated that, given the wide variability in the data and the relative precision required to find a true hit, it would have been impossible to arrive at any conclusions at all. By analogy, it would be like a pollster declaring a winner in an election when the margin of error was larger than the difference in the polling results.

“The overwhelming noise in the . . . data and the overstated strength of the genetic interactions together make it difficult to reconstruct any scientific process by which the authors could have inferred valid results from these data,” Yuan wrote to the editors of Nature in July.

His analysis attacks only the first portion of the paper; even if he is correct, the second part of the paper could be true.

Nevertheless, Yuan wanted Nature to publish his criticism, and following instructions from the journal, he forwarded his letter to Boeke and Lin, giving them two weeks to respond.

Just as the two weeks were to elapse, Boeke wrote to Nature asking for an extension of time — “a couple weeks or more” — to address Yuan’s criticism. Boeke explained that end-of-summer schedules and the multiple co-authors made it difficult to respond on time.

A day later, Lin was discovered dead in his office at National Taiwan University.

“Renowned scientist found dead, next to drug bottles,” the headline in the Taipei Times said.

Even in his death, the Nature paper was a kind of shorthand for Lin’s scientific success.

“A research team [Lin] led was featured in the scientific journal Nature in February for their discovery of the key mechanism for maintaining cell energy balance — believed to be linked to cellular aging and cancer,” the newspaper said.

If there was a suicide note, it has not been made public, and it is difficult to know what went through Lin’s mind at the end of his life. The apparent suicide and the e-mail to Yuan suggest only that Lin may have been distraught over the dispute; they do not prove that he acted improperly.

Shortly after the Nature paper appeared, Yuan hired lawyer Lynne Bernabei to challenge the way he was terminated at Hopkins.

In late August, Yuan asked the Nature editors again whether they would publish his criticism. Lin was dead, but Boeke and the others had had a month to respond, and Yuan hadn’t heard a thing.

On Sept. 28, a Nature editor informed Yuan by e-mail that the journal was still waiting on a fuller response from Boeke and that “experiments are being done and probably a Correction written.”

Such a correction has not appeared.

So as a last attempt, he figured he’d try the federal government, which paid for much of the research. But the government suggested that the threat to the federal research, if there was any, ended with Lin’s death.

“It is our understanding that these allegations are being investigated by Johns Hopkins University,” said the letter from the Office of Research Integrity.

Besides, it noted, the person responsible for the paper was Lin.

“Deceased respondents no longer pose a risk,” the letter said.

Thanks to Kebmodee for bringing this to the attention of the It’s Interesting community.

conform and be funded


John Ioannidis, a researcher at Stanford University has, along with graduate student Joshua Nicholson, published a commentary piece in the journal Nature, taking the National Institutes of Health (NIH) to task for maintaining a system that they say rewards conformity while ignoring innovation.

NIH is an agency within the US Department of Health and Human Services, and is the primary federal vehicle involved in offering money in the form of grants to researchers working to make in the biosciences. The agency reportedly has a budget of approximately $30 billion a year.

In their commentary piece, Ioannidis and Nicholson suggest that the process used by those in charge at NIH favors those who wish to work on incremental increases in current fields rather than rewarding those seeking funds for innovative, but more risky ventures. To back up their claims, they ran a search on research papers published in major journals over the past decade and found 700 papers that had been cited by authors in other papers at least 1,000 times. Of those papers, they say, just 40 percent of those listed as primary authors were working under an NIH grant.

To determine who to give grants to, NIH uses what are known as Study Sections. Their job is to read proposals sent to them by prospective researchers and then to decide whether to offer a grant to carry out the things discussed in the proposal. The Study Sections are in reality a group of people – a panel made up of scientists in the . And that’s part of a big problem at NIH, Ioannidis and Nicholson write, because people that serve on the panels tend to get more of the grant money. They note that just 0.8 percent of the 700 oft cited papers listed NIH panel members as a primary author. They contend that being highly cited is a credible measure of the degree of innovation of work.

The result the two say, is a system that systemically encourages incremental studies while discouraging those that are looking for big breakthroughs. And that they say, has led to both conformity and mediocrity. This they add goes against NIH’s mandate, which is to “fund the best science.” They recommend that NIH change its grant review process to encourage more innovation even if it means taking more risks.

More information: Research grants: Conform and be funded, Nature, 492, 34–36 (06 December 2012) doi:10.1038/492034a