Tag Archives: National Institutes of Health

Human Pipettes: Scientific training and education in biomedical research

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David Rubenson and Paul Salvaterra share their thoughts on a damaged and damaging research system

A recent cancer research symposium displayed a familiar asymmetry. 90% of the attendees were PhD students or postdocs sitting obsequiously in the rear and asking 10% of the questions. 10% of the attendees were front-sitting faculty providing 90% of the inquiries.

A simple case of youthful hesitancy and opaque presentations requiring years of experience to comprehend? But did individual Principal Investigators (PIs) meet with conference planners before advising their students to attend? Did conference planners consider the likely audience and ask speakers to modify their talks? And did faculty members attend the related trainee poster session?

 

Are junior scientists little more than human pipettes?

Are junior scientists little more than human pipettes?{credit}Paper Boat Creative/Getty{/credit}

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To improve reproducibility, listen to graduate students and postdocs

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The National Institutes of Health (NIH) should implement a national exit interview portal to collect feedback from mentees on their experiences.

Funding agencies should not penalize poor performers; instead they should reward good mentorship, says Ahmed Alkhateeb

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US research ethics agency upholds decision on informed consent

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United States regulators are standing by their decision that parents were not properly informed of the risks of a clinical trial in which premature babies received different levels of oxygen supplementation.

From 2005 to 2009, the Surfactant, Positive Pressure, and Oxygenation Randomized Trial (SUPPORT) trial randomly assigned 1,316 premature babies to receive one of two levels of oxygen supplementation in an effort to test which level was best. Even though the lower level was associated with increased risk of brain damage and possibly death, and the higher level with blindness, the study leaders said that they did not disclose these risks to parents because all ranges of oxygen used in the trial were considered to be within the medically appropriate range at the time.

The study was supported by the US National Institutes of Health (NIH). On 7 March 2013, the US Office of Human Research Protections (OHRP) issued a letter determining that the trial investigators had not adequately informed parents about the risks to their babies in the SUPPORT trial. The NIH and many researchers disputed the decision, arguing that it would impede “comparative effectiveness research” studies that are designed to test the best use of approved interventions. Parents of children in the trial, however, and others supported the OHRP’s determination that parents hadn’t received adequate information. The two sides clashed at a meeting convened by the NIH and the OHRP in August 2013.

Today, 24 October 2014, the OHRP has issued guidance reiterating and clarifying its position on what types of risks must be disclosed to study subjects in comparative effectiveness research studies such as SUPPORT. The agency has determined that risks of the intervention must be disclosed to study participants even if the risks are considered acceptable according to current medical guidelines, if the study intends to evaluate these risks and if the patients’ risks will change when they enrol in the study.

The OHRP said that even though both the low and high levels of oxygen supplementation were considered within the acceptable range, “the key issue is that the treatment and possible risks infants were exposed to in the research were different from the treatment and possible risks they would have been exposed to if they had not been in the trial”.

“[F]or the great majority of infants in the trial, it is likely that their participation altered the level of oxygen they received compared to what they would have received had they not participated,” the OHRP added.

The agency said further that if a trial is designed to compare the risks of potential side effects of a treatment already in use, then the risks are “reasonably foreseeable” and that prospective study participants should be made aware of it.

“If a specific risk has been identified as significant enough that it is important for the Federal government to spend taxpayer money to better understand the extent or nature of that risk, then that risk is one that prospective subjects should be made aware of so that they can decide if they want to be exposed to it,” OHRP said.

The guidance is open to comments until 24 December.

In Massachusetts, nine NIH-funded research projects in this year’s $10 million club

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So far for 2012, the NIH has approved 3,810 grants in Massachusetts – some for new projects, others for familiar, ongoing research centers. The big money is going to genetics, HIV/AIDS and biodefense. Few topped $10 million –according to NIH, the av

erage award amount nationwide was $44,642 for 2011. Among the group – genomics superstar Eric Lander, whose name cam

Here’s a look at the projects that, so far this year, have broken the $10 million mark – and a few that come close.e up during the recent presidential search at MIT and Daniel Kuritzkes at the Brigham, who got a standing ovation at the recent AIDS conference when he annouced findings on two more AIDS patinets who became virus-free after bone marrow transplants.  Also note that Harvard Med School dean Jeffrey Flier is listed as the PI on the grant to the troubled primate research center. Continue reading →

Who’s getting grants in Boston as NIH cuts back? New research funding for May

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Nearly $8 million in NIH funding for new projects flowed into Massaschusett in May. Here’s a sample, with links to labs and full project descriptions:

  • $936,346 for strategies to treat antibiotic resistant bacteria to Harvards Thomas Bernhard

IDENTIFYING AND VALIDATING NEW ANTIBIOTIC TARGETS IN CELL WALL SYNTHESIS PATHWAYS New strategies to treat antibiotic resistant bacterial infections are sorely needed. This project combines small molecules and genetic methods to identify and validate new antibiotic targets in the pathway for assembly of the bacterial cell wall. The proposed work may lead to new therapies against methicillin-resistant Staphylococcus aureus (MRSA) and Gram-negative ESKAPE pathogens.

 Dr, Bernhard will be giving a talk on his work on June 21 at The Forsyth Institute, Seminar Room A, 245 First Street, 17th Floor, Cambridge, at Noon, on “The ABCs of Bacterial Cell Division,” as in ABC tranporters.

  •   $356, 356 for a prospective study looking at fat consuption and and breast cancer to Heather Eliassen  at the Brigham and Women’s hospital

CIRCULATING FATTY ACIDS AND BREAST CANCER RISK: A PROSPECTIVE STUDY  Fat intake has long been hypothesized to increase breast cancer risk, but cohort studies have not shown strong associations with total fat. This proposal seeks to expand our knowledge of the role of fat in breast cancer etiology by measuring specific fatty acids in the blood, representing fats from meat and dairy, processed foods, and vegetable sources, areas where dietary evidence suggests an association, as well as a marker of the internal transformation of fats with breast cancer risk. Characterizing these associations and further exploring potential mechanisms, will provide important knowledge about breast cancer prevention.

  •  $677, 984 for a exome chip data on 1,800 ADHD probands and their parents to Benjamin Neale at the Broad Institute

QUANTIFYING THE IMPACT OF RARE MUTATIONS ON ADHD We will generate exome chip data on 1,800 ADHD probands and their parents. The exome chip provides the first look at rare variation in the coding regions of genes that is heavily enriched for potential biological function. We will comprehensively analyze this data at a single locus, gene, and biological pathway level. This experiment promises to quantify the impact of rare mutations on ADHD.

  • $304,950 for research using in vitro studies to reveal biochemical and physiological functions of ribosome specialization to Wendy Gilbert at MIT.

FUNCTIONAL CONSEQUENCES OF RIBOSOME HETEROGENEITY:Translational regulation is essential for human health and development, but only a handful of translational regulatory mechanisms are understood. The proposed work will provide the first detailed understanding of the biochemical and physiological functions of ribosome specialization, an under-studied topic in the translational control field. We anticipate that our results will have broad implications for the study of eukaryotic gene expression, and will also illuminate the etiology of disease states, including cancer, that are associated with dysregulation of ribosome function.

  •  $278,213 for research into virulence factors secreted by many different pathogenic bacteria Alejandro P. Heuck at UMass medical school in Worcester

MOLECULAR MECHANISM OF TRANSLOCON ASSEMBLY INTO CELL PLASMA MEMBRANES I have developed a set of fluorescence techniques that have been successfully used to characterize the structure and pore-formation mechanism of various homo- oligomeric cytolytic toxins. I now propose to extent the use of these techniques to multi- protein transmembrane complexes, like the T3S translocon. The fluorescence approach will be combined with other biochemical and biophysical techniques (e.g., electrophysi- ology measurements, single molecule techniques, and cryo-electron microscopy) to un- ambiguously address fundamental structural aspects of the T3S translocon structure and assembly. By selective incorporation of various probes (e.g., environment-sensitive fluorophores, crosslinkers, gold-nanoparticles, charged groups, etc.) in the P. aerugi- nosa translocators, we will experimentally identify, among other things: which segments of these proteins are essential to determine the characteristics of the translocon channel, what segments form the contact interface between the needle and the translocon, and how the translocators are arranged in the translocon complex formed in the mammalian cell membrane..

Who’s getting grants in Boston as NIH cuts research funding?

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When Barbara Alving, the former head of National Center for Research Resources (NCRR), spoke at Harvard last spring, an audience member complained that even Harvard’s superstar scientists couldn’t get NIH grants. Alving, whose NIH agency was about to be shuttered suggested scientists get used to it – NIH funding would be tight for a while.

A search on the NIH data base proves her right. While the agency funded 403 new projects in Massachusetts in 2010, that number dropped to 335 in 2011.

Does that make the grant winners super superstars? Or was the research in the labs at the right place at the right time? So many variables go into NIH funding, it can be hard to tell. Still it’s worth looking at where the money is going.

The 11 new winners so far for 2012 are looking into influenza, herpes, DNA replication timing, structural vaccinology for malaria and the search for biologically active antitumor and anti-infective agents in natural products. Our data is current as of this morning, but the numbers change constantly as NIH adds new grants to the database.  Grants went to Boston University, UMass med school and Brandeis University. But, Harvard-linked researchers – and infectious disease — dominate the list.

At $530,282, the biggest new grant so far this year went to Harvard chemist Suzanne L. Walker for research into the “structure, function and inhibition of human o-glcnac transferase.”

From the application: “O-GlcNAc transferase (OGT) is an essential mammalian enzyme that catalyzes a unique post-translational modification, O-GlcNAcylation. This modification mediates critical cellular processes involved in nutrient signaling, stress responses, and cell division. Aberrant O-GlcNAcylation has been linked to many diseases, and the work proposed here will lead to the development of small molecule inhibitors to probe OGT’s biological roles and potential as a therapeutic target.”

More on Walker’s work here and at her lab’s web page.

Harvard is also offering dibs on her finding to drug developers through the school’s tech transfer program.

Walker’s group is currently investigating the target specificity of one class of inhibitor.These compounds will be useful as cellular probes of OGT biology. In parallel with these efforts, the group is optimizing another class of OGT inhibitors. Through a combination of analog synthesis and structure-based design, this class of OGT inhibitor has sub-micromolar IC50, is non-toxic to mammalian cells, and inhibits OGT activity in HEK cells. More on that here.

Coming in second for January 2012 is another Harvard project,  Samuel Behar’s work on TB immunity, which won a $528,749 grant.

From the application : Apoptosis and efferocytosis: Regulators of immunity to tuberculosis.  Pulmonary tuberculosis, a disease caused by Mycobacterium tuberculosis, is a threat to global health. The disease tuberculosis occurs when the immune system is no longer able to contain the infection. This research proposal seeks to understand how the immune system controls the infection. In addition we seek to determine whether the mechanisms that generate T cell immunity can be enhanced to improve the response to vaccines. Since T cell immunity is important for the control of tuberculosis, it is hoped that by understanding features of host resistance, new strategies can be developed for the treatment and prevention of tuberculosis.

And at third, David Knipe’s microbiology lab at Harvard med school almost made the half-million mark with a $492,229 grant for research into “chromatin and herpes simplex virus latency.”

Herpes simplex viruses cause considerable genital, ocular and nervous system disease, and genital herpes increases the risk of HIV infection. There are drugs that target the active growth of herpes simplex virus but none that target the latent infection. This research will define basic mechanisms of herpes simplex virus latent infection and new targets for potential drugs to treat the latent infection of these viruses.

 

US scientists have their say on plans for biomedical workforce

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Posted on behalf of Gene Russo, Nature Careers editor

US biomedical scientists recently had a chance to set their field’s priorities. And what was the most pressing problem they reported? The very real possibility that there are too damn many biomedical scientists.

The balance between the supply of biomedical researchers and the demand in terms of available career opportunities should be the biggest priority for reforming the US biomedical workforce, according to a survey response issued by the National Institutes of Health (NIH). Other big priorities that scientists highlighted were PhD characteristics (i.e. PhD curriculum, length of the PhD training period, and lack of preparation for diverse career paths) and postdoctoral-fellow training characteristics (i.e. a bottleneck of jobseekers causing long stints as postdocs and poor mentoring).

Many of the respondents did not mince their words. On the supply and demand issue, some called the current structure of the research workforce a ‘pyramid scheme’ that takes advantage of cheap student and postdoc labour rather than hiring mid-career researchers. Solutions included tenure-model reform, decreasing the number of funded trainees per principal investigator (PI) and using more staff scientists. On the oversupply issue, respondents suggested class-size reductions, raising programme entry requirements and better training for ‘alternative’ careers. Regarding the contraction of research funding, respondents suggested increasing paylines and limiting the number of large grants a single PI is permitted to have.

The survey, part of an NIH working group effort, asked respondents to prioritize future issues for the biomedical workforce. It had 219 respondents — ranging from graduate students to senior scientists — who made a total of 498 ‘quotations’ about various priorities; multiple comments were ranked and the working group then calculated the overall priority of a given issue.

In addition to PhD characteristics and postdoctoral-fellow training characteristics, the working group asked for comment on six other categories: postdoc training, biomedical research career appeal, clinician characteristics, the staff-scientist career track, effects of NIH policies and the training-to-research grant ratio. Based on respondents’ comments, it then added four more categories to its analysis: diversity, mentoring, early educational interventions and industry partnerships.

It’s not a big sample size. But the message is clear: improving satisfaction among early-career biomedical scientists and boosting the efficiency of a system that churns out far more scientists than academia alone can accommodate will require big changes. And these changes will have side effects. Want labs with more full-time staff scientists, and fewer students willing to work 60-hour weeks? Lab productivity and publication rates could suffer (see ‘Mid-career crunch’ for more discussions around changes to NIH grants). Want to curtail tenure? Some argue this would threaten academic freedom and deflate the enthusiasm of academia’s rising biomedical research stars (see ‘The changing face of tenure’ for more).The NIH working group — whose ongoing charge includes developing a “model for a sustainable and diverse US biomedical research workforce” — certainly has its work cut out for it.