NIH

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Going the Distance: Setbacks and a Meaningful Career in Science

Allison Webel, PhD

On July 4th, me and 60,000 of my closest friends ran in the 50th Peachtree Road Race in Atlanta, Georgia. This was my first 10K run and as a relatively new runner, my inclination for training for this race was to go hard and go fast – a manta not just for running but possibly for my entire generation. But as I would eventually learn, distance running is not about just getting it done. It is about being patient, listening to (and adjusting) my body, and having a long-term mindset focused on the process as much as the goal.

nih rejectionsThroughout my training, I was struck by how similar distance running is to a career in science and to grant writing in particular. When I finished my PhD 10 years ago, I was confident in my ability to write manuscripts and proposals, secure funding, and ultimately do and disseminate the science that would leave a lasting impact on the health of vulnerable populations. This confidence continued even when, during the last few years of my K award, I submitted grant after grant to the NIH only to have them be not discussed repeatedly.  I understood that NIH success rates were low, with institutes reporting a range of success rates from ~10% to 35% in 2018. Mentors reminded me that failure was part of the process and that everyone has a string of not discussed grants in the early phase of their career. I just needed to keep listening to the reviewers, getting more preliminary data, refining my ideas, developing great teams, and above all writing, and eventually my ideas would hit. However, when my string of not discussed/not funded grants grew to 15 (Figure 1), each set of pink sheets more soul crushing than the last, I knew that statistically I was failing more than I should. And I questioned if I should even be in science or if these past few years were just wasted time.

These setbacks can be devastating – causing approximately 10-15% of early career scientists to leave the field. But what about those who stick it out? What happens to them and, more importantly, what is their long-term impact on science? These are the questions explored in a recent article by Yang Wang, Benjamin Joes, and Dashun Wang, “Early-Career Setbacks and Future Career Impact”. Through a series of pretty cool analyses they examined if early success in obtaining an R01 award from the National Institutes of Health led to more success and a higher impact (measured as highly-cited manuscripts) compared to those who almost, but just missed the funding threshold. Essentially, they wanted to figure out among early career health scientists which perspective is true: Do the “the rich get richer” or will “what doesn’t kill you makes you stronger”?

Unsurprisingly, the results were somewhat mixed but encouraging for an early career scientist who has had many misses. While those with near misses had approximately a 10% chance of leaving the NIH funding system entirely over the next 10 years; of the scientists remaining, those who had an early career funding failure wrote higher impact manuscripts, compared to those who had early funding success. This is a striking finding which needs to be carefully considered (specifically that junior scientists do not need additional roadblocks in their path in order to become “stronger scientists”). Yet, the authors do suggest that for those scientists who persevere, “early failure should not be taken as a negative signal” rather viewed as a chance for refining and improving their program of research.

Wang and colleagues start their manuscript with a quote by Robert Lefkowitz, winner of the 2012 Nobel Prize in Chemistry, “Science is 99 percent failure, and that’s an optimist view.”  While he many have been referring to failed experiments, what Wang’s  new analysis reveals is that even the process of obtaining the funding to support research is likely to be fraught with heartbreaking setbacks. But if you’re in science because you believe in its power to answer important questions which will help us to better understand and improve the human condition, perseverance is necessary.

I finished my first 10K in under 60 minutes. Not a medal-winning time but I preserved through the heat, sun, fatigue, and even a bit of pain to cross the finish line. Similarly, late last year I received the Notice of Award for my first R01 from the NIH- leading a research study that I believe in with a team that inspires me every day.  So whether you are submitting your first or 15th research grant, know that setbacks are common and despite the outcome on any one application, with a long-term mindset you can have a lasting impact on science.
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The First Funded R01 Ever

Daniel Tyrrell, PhD

The first two extramural grants for a research project (the precursor to today’s R01) were given on March 21, 1938 to Dr. John Bittner at Jackson Laboratory (then, the Roscoe B. Jackson Memorial Laboratory) in Bar Harbor, Maine for his work on breast cancer1,2.

Bittner J. Mammary Tumors In Mice In Relation to Nursing. Cancer Research. 1937;30(3).

Bittner J. Mammary Tumors In Mice In Relation to Nursing. Cancer Research. 1937;30.

One grant for $3,200 was awarded directly to Dr. Bittner, and the other for $9,900 was awarded to the Roscoe B. Jackson Memorial Laboratory by the National Cancer Institute. These first “R01-type” awards were given by the NCI from 1938-1943, and in that time, 65 grants-in-aid were paid2.

Marshino O. Administration of the National Cancer Institute Act, August 5, 1937, to June 30, 1943. JNCI: Journal of the National Cancer Institute. 1944:429-43.

Marshino O. Administration of the National Cancer Institute Act, August 5, 1937, to June 30, 1943. JNCI: Journal of the National Cancer Institute. 1944:429-43.

In the early days of extramural grants in the USA through the 1970’s, most awards were Program Projects, Centers, and Development grants. The NIH preferred to grant awards for multidisciplinary centers to carry out a range of projects in a certain area of interest. It wasn’t until after Watergate and Nixon’s resignation that Investigator-Initiated Research Projects (R01) began to dominate large Program-Project grants (P01)3.

To understand the path from these first grants to today’s R01’s, it is important to understand the history of the NIH. The Hygienic Laboratory became the NIH in 1930 with the passage of the Ransdell Act, and the NCI began with the National Cancer Institute Act in 1937. The NCI could administer extramural grants for research on cancer, but the NIH at large could not3.

The federal government greatly increased research spending in medical research during World War II, and when the war was over, both the government and scientists wanted to continue federally funded research. The NIH couldn’t legally administer extramural grants until the passage of the Public Health Service Act in 1944 which consolidated the NCI and NIH under one roof under the Surgeon General.

In 1946 the Research Grants Office was created to administer extramural research grants and fellowships awards. Congressional funding of the NIH increased steadily, and all the while the NIH was adapting its branding by renaming institutions (i.e. changing “National Microbiological Institute” and “Experimental Biology and Medicine Institute” to flashier names like “National Institute of Arthritis and Metabolic Diseases” and “National Institute of Allergy and Infectious Diseases,” which further enticed congressional funding). From 1946 to 1953, the number of funded projects increased from 80 to 2,000 and the funds increased from $780,000 to over $20,500,0003.

Mandel R. A Half Century of Peer Review, 1946-1996: Division of Research Grants, National Institutes of Health. Division of Research Grants, National Institutes of Health; 1996.

Mandel R. A Half Century of Peer Review, 1946-1996: Division of Research Grants, National Institutes of Health. Division of Research Grants, National Institutes of Health; 1996.

In 1946, the NIH Syphilis Study Section had its inaugural meeting. This was the first study section meeting at the NIH4. From this point, more and more study sections met to discuss the state of science and to review grant applications. In 1950, the standardization of study sections began with the assignment of priority scores from 1 to 5. This made it possible to rank grants based on merit for funding.

Mandel R. A Half Century of Peer Review, 1946-1996: Division of Research Grants, National Institutes of Health. Division of Research Grants, National Institutes of Health; 1996.

Mandel R. A Half Century of Peer Review, 1946-1996: Division of Research Grants, National Institutes of Health. Division of Research Grants, National Institutes of Health; 1996.

These changes lessened the workload of study sections initially, but as research design became more sophisticated, more and more of the meeting time was devoted to project discussions3. Eventually, some within the research community became dissatisfied with the closed-door process of grant review. In 1973, the Office of Management and Budget called for the abolishment of study sections, but the acting NIH Director, Dr. John Sherman, defended peer review as the highest priority.

Political events at the time caused turmoil within the NIH. A combination of budget constraints due to the war in Vietnam along with Watergate and procedural confusion and secrecy regarding the peer review process led to a reorganization at NIH. A familiar name, Ruth Kirschstein, director of the NIGMS in 1974, stated, “How can a system, devised in an era of elitism, of secrecy, and of economic growth…be adopted to an era in which stress in on equal opportunity, openness, and limited availability of funds?”3.

Mandel R. A Half Century of Peer Review, 1946-1996: Division of Research Grants, National Institutes of Health. Division of Research Grants, National Institutes of Health; 1996.

Mandel R. A Half Century of Peer Review, 1946-1996: Division of Research Grants, National Institutes of Health. Division of Research Grants, National Institutes of Health; 1996.

There was rampant favoritism and bias in the review process, and over the next decade, the NIH worked to standardize peer review practices. This included extending project length beyond 3 years in 1984, scoring grants by percentiles in 1987. In the late 1980’s and through the 1990’s, grant applications could be submitted on discs rather than paper and a centralized database of applications was developed.

While the first grant application wasn’t submitted electronically using the PHS-398 form, it was the first time an NIH institute, the NCI, funded an extramural grant for an individual research project, which we now refer to as an R01.

 

References:

  1. Bittner J. Mammary Tumors In Mice In Relation to Nursing. Cancer Research. 1937;30(3).
  2. Marshino O. Administration of the National Cancer Institute Act, August 5, 1937, to June 30, 1943. JNCI: Journal of the National Cancer Institute. 1944:429-43.
  3. Mandel R. A Half Century of Peer Review, 1946-1996: Division of Research Grants, National Institutes of Health. Division of Research Grants, National Institutes of Health; 1996.
  4. Pederson T. The “study” role of past National Institutes of Health study sections. Mol Biol Cell. 2012;23(17):3281-4.

 
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Representation Matters: How Can We Improve Equity and Diversity in Our Professional Lives?

Jeffrey Hsu, MD, PHD

This past August, the phrase “Representation Matters” commonly graced entertainment and popular culture headlines. Why? In what was ultimately called “Asian August,” several major movies starring Asian-American actors were appearing in theaters, led by the first American film to feature an all-Asian cast in 25 years – “Crazy Rich Asians.” This fervor was inspired by over two decades of under-representation of Asian-American culture in the entertainment industry.

As I am an Asian-American, this particular movement did indeed resonate with me in my personal life. However, I regrettably was not mindful about it in my professional life. Throughout my training, I felt that I had worked with, learned from, and/or befriended men and women of a wide variety of colors, beliefs, and socio-economic backgrounds. Perhaps it was because I was fortunate to train in programs that were diverse, but I don’t necessarily recall reflecting on the diversity nor the benefits of diversity.

In early December 2018, Dr. Hannah Valantine visited our campus at UCLA to deliver our Medicine Grand Rounds lecture, and she was kind enough to meet with many of our faculty and trainees. A renowned physician-scientist and advanced heart failure/transplant specialist, Dr. Valantine is the NIH’s first Chief Officer for Scientific Workforce Diversity. She led an outstanding, eloquent, and (of course) evidence-based discussion on the importance of improving the diversity in academic medicine. She highlighted the emphasis that the NIH is placing on this mission, and the resources her office has developed to not only educate professionals on the issues at hand, but also a toolkit they have created to help promote diversity at our institutions, including how to create a diverse talent pool and perform unbiased talent searches.

Dr. Valantine presented data showing that while there has been improvement in diversity of trainees early in their training, there remains a significant “transition barrier” for diversity upon entering the junior faculty stage of an academic career (between “Postdoc” and “Independence” in the slide below).

 

Further, she also mentioned data supporting the improved performance of more diverse groups. In an article from Nature this past year, the subjective and objective benefits of diversity were featured. Interestingly, in an analysis of over 9 million scientific articles, one group found that research “papers written by ethnically diverse groups were cited 11.2% more than were papers written by non-diverse groups.”

With clear reasons for why we should work to focus on a culture of equity and diversity in our scientific workforce, I realized that I will soon be at a stage where I will be choosing the members of my research team. In the spirit of the New Year and with the help of tools provided Dr. Valantine, I have made the following “resolutions” to myself to help prepare myself as I embark on organizing a research team in the future:

  • Discover and explore my implicit biases: There are online resources/tutorials on implicit bias, including an excellent one from my home institution, UCLA, as well as tests you can take to discover your own implicit biases. Regrettably, after my first test, I already learned that my results suggested, stereotypically, “a moderate association for ‘Male’ with ‘Career’ and ‘Female’ with ‘Family.’”
  • Be mindful of the benefits of diversity when present: Whether in a research group or the team I am rounding with in the hospital, I plan to acknowledge these benefits when present, whether aloud or to myself.
  • Follow the NIH Scientific Workforce Diversity blog: It is an excellent reminder of reasons and ways to create an effective & diverse scientific team.

 

In one of her excellent blog posts from last year, Dr. Valantine wrote:

“Our nation is presented with the unique opportunity of connecting an increasingly diverse talent pool of scientists with the full range of biomedicine careers encompassing basic discovery to health applications, a critical part of the NIH mission to advance human health.”

 

I am grateful that the NIH has placed high priority on this mission, because indeed, Representation Matters, and in the field of academic medicine, representation can lead to better science and better treatments for our patients.

 
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AHA18 Reminded Me We Need to Do More for Women

Christa Trexler, PhD

On the surface, it doesn’t really seem that surprising men and women develop heart disease differently or experience different symptoms for the same types of cardiac episodes. However, even though heart disease is the number one killer of both men and women, women have traditionally been omitted from clinical trials and female animals have either not been included in preclinical research studies or the two sexes have been combined1. We just simply weren’t taking half of the population into account at every level of cardiovascular disease (CVD) research for quite some time. I spent my graduate career focused on understanding the baseline differences in the heart between the sexes, and was extremely passionate about this work. Since I spent most of my scientific career working in this field, I wanted to switch it up as a postdoctoral fellow and am currently not researching sex differences. However, when I went to AHA sessions this year, I made it a point to go to any events focused on sex differences and women to get updated on what I’ve been missing this past year. Luckily the “State of the Heart For Women: Top Ten Advances in Gender-Specific Medicine” session provided the perfect summary. After ten great talks focused on a variety of gender specific concerns ranging from heart failure to pregnancy, the take home message was clear: women are still very much at risk, more likely to be misdiagnosed, and are still under-represented in clinical trials. These issues are also worse for women of color.

 

While this is a widespread issue across disciplines, the cardiovascular field has been particularly biased with regard to including women in clinical trials for drug development, leading to drugs being either not as effective in women or causing different side effects2. The good news is, things are changing. In the early 1990’s, reports from the Food and Drug Agency (FDA) demonstrated that less than 20% of participants in clinical trials were women and recent studies reveal that this number is steadily increasing – even in the cardiovascular field3. Fixing this imbalance is the result of the tireless work from many dedicated researchers over the past several decades. One of the main advocates this field has is Dr. Nanette Wenger, who was the first speaker of this session and actually let me ask her a some questions later during the conference while we were both in the Women in Science and Medicine Lounge. When I asked Dr. Wenger about her strategy for making this issue a priority in our field she explained the key steps to creating change:

  1. Investigate — people can’t ignore what the data is clearly telling them
  2. Educate — teach your peers & patients
  3. Advocate for the change
  4. Legislate — it took a long time, but we’re slowly transforming the strategic plan of the NIH

Dr. Wenger also stressed that since the emphasis in our field now is personalized care, many researchers and physicians are more supportive of including sex in their experiments and/or trials, but we need to move forward by not assuming that women are a homogeneous group. Other factors such as race are also important and must also be considered.

While progress has been made we still have a long way to go on many accounts. While there are more women in clinical trials than in the past, women still only make-up about 34% of the total participants in cardiac clinical trials3. Hopefully, with the passing of the 21st Centuries Cures act and the NIH policy mandating sex be included as an biological variable in basic research studies in 2016, these numbers will progressively increase. At the session before the talks even began, I immediately noticed that all but one of the ten panelists were women (which is awesome, but strange for the cardiac field) and the majority of people in the audience were also women. We will need to continue to advocate for this issue and we need men to join us and take it seriously for real change to be made. Additionally, while I really enjoyed this unique session, the speakers were only given ~10 minutes each to summarize their extraordinarily complex topics, which just wasn’t enough time. It would be great if gender-specific cardiovascular issues were given more time at AHA Scientific Sessions as well as other conferences in the future. This session reminded me just how pressing making CVD treatment equitable for all truly is and thankful for the researchers making it happen.

 

References

  1. Blenck CL, Harvey PA, Reckelhoff JF, Leinwand LA. The Importance of Biological Sex and Estrogen in Rodent Models of Cardiovascular Health and Disease. Circ Res. 2016;118(8):1294-312.
  2. Regitz-Zagrosek V. Therapeutic implications of the gender-specific aspects of cardiovascular disease. Nat Rev Drug Discov. 2006;5(5):425-38.
  3. Pilote L, Raparelli V. Participation of Women in Clinical Trials: Not Yet Time to Rest on Our Laurels. J Am Coll Cardiol. 2018;71(18):1970-2.