Chapter 1: The Landscape of Biomedical Research

How do scientists determine the direction of their research endeavors? Ideally, one would hope they adopt a scientific perspective, focusing on pressing issues and assessing which of these can be addressed with the resources at hand. However, the reality of how research initiatives are proposed and funded may reveal different influences at play.

Historically, fields like particle physics and astronomy recognized the need for a collective strategy in their research planning, leading to the development of large-scale scientific projects. This "big science" model, which emphasizes collaborative long-term objectives, has yielded significant breakthroughs, such as the detection of the Higgs boson and gravitational waves. Yet, challenges remain, as illustrated by the abandoned Superconducting Super Collider in Texas, now owned by a chemical firm named Magnablend.

So, what is the situation in other research domains that are often organized in a more decentralized manner?

In late 2014, four distinguished life scientists from the United States published a thought-provoking essay titled “Rescuing U.S. biomedical research from its systemic flaws.” The authors highlighted two significant trends: a continuous rise in the number of biomedical researchers in the U.S. and a corresponding decline in real funding from the National Institutes of Health (NIH). This combination, they argued, has led to a state of “hypercompetition” for grants and job positions, ultimately stifling creativity, collaboration, and the risk-taking necessary for groundbreaking discoveries.

Some suggested solutions from the essay, such as reducing the number of Ph.D. candidates in biomedical fields, were met with resistance. Nonetheless, the authors' assertion that low success rates for NIH grant applications have fostered conservative, short-term thinking among researchers, reviewers, and funding bodies resonated widely. The prevailing system now rewards those who can promise immediate results over those with innovative ideas that carry inherent uncertainties.

Funding agencies are cognizant of this dilemma. Jon Lorsch, director of the National Institute for General Medical Sciences (NIGMS), noted that “most scientists do not wish to adopt a conservative approach in their work.” However, he lamented that tight funding pressures compel both researchers and reviewers to adopt a more cautious stance. The pervasive anxiety over funding loss can significantly inhibit an investigator's willingness to embark on bold or ambitious research.

A troubling implication of this hypercompetitive environment is the demographic trend showing more NIH-funded principal investigators over 65 than those under 35, suggesting a potential stagnation in the field's innovative capacity.

Evidence from research literature supports the notion that biomedical research is increasingly conservative. A study by Andrey Rzhetsky and colleagues from the University of Chicago utilized natural language processing to analyze over two million research papers and nearly 300,000 patents related to more than 30,000 biomedical molecules over the past three decades. Their findings indicated that researchers predominantly focused on well-established molecules and tended to explore closely related compounds. Over time, the choices made by these researchers became even more conservative. Interestingly, those with a history of success, such as award-winning scientists, were more likely to take less conventional approaches, often linking disparate molecules.

The current landscape shows an alarming trend: an increasing number of NIH-funded principal investigators are over the age of 65 compared to those who are under 35.

This prevailing conservatism comes with significant drawbacks. One might assume that governments and funding bodies could steer scientific research by prioritizing specific diseases. However, research by Lixia Yao and her team revealed that resource allocation in U.S. biomedical research is influenced more by past allocations than by current health needs. In 2011, conditions such as various cancers, renal failure, heart diseases, and respiratory issues were among the most heavily studied. Additionally, an analysis of 111 medical conditions globally showed that research attention disproportionately favored diseases prevalent in developed countries over those affecting the developing world.

Chapter 2: The Role of Theory in Biomedical Research

Are there deeper, more fundamental reasons for the conservatism observed in the life sciences beyond funding constraints? The skepticism many life scientists exhibit toward theoretical approaches and mathematical models may contribute to this issue. Unlike physics, where theory and experimentation are seen as equally crucial, theoretical work holds a lower profile in the life sciences. This is particularly surprising given that one of biology's foundational concepts—evolution by natural selection—originated as a theoretical framework.

Bill Bialek, a theoretical physicist, has argued for the importance of theoretical contributions to biology, highlighting numerous instances where theoretical insights have significantly advanced the field.

Despite the complexity and unpredictability of biological systems, Bialek criticized the prevailing mindset that biology has evolved without substantial theoretical influence. He stressed that the biological community is unlikely to cultivate a genuinely receptive audience for theoretical discourse on its own; instead, he suggested that the physics community should take the lead in this area. However, he acknowledged that many physicists may also be hesitant, viewing biological phenomena as too chaotic and lacking fundamental principles.

The term “conservative” does not typically apply to theoretical physics. While life scientists are increasingly preoccupied with securing funding for their experiments—often eschewing theory and mathematical analysis—many theoretical physicists continue to work with minimal resources, relying on just paper, a laptop, and internet access. It is no surprise, then, that their creativity often flourishes in ways that might seem unfamiliar to biologists.

One notable consequence of this freedom in theoretical physics is the existence of theories lacking experimental validation, such as supersymmetry and string theory. Nevertheless, recent confirmations of predictions like the Higgs boson and gravitational waves underscore the critical role theorists play in physics.

Yet, nothing excites a theoretical physicist quite like the announcement of an unexpected experimental finding. For instance, on December 15 of the previous year, the ATLAS and CMS collaborations at CERN reported possible evidence of a new particle with a mass of 750 GeV. In the ensuing weeks, numerous preprints referencing this finding flooded the preprint server arXiv.

This phenomenon is sometimes disparaged as "ambulance chasing," as most experimental results that generate excitement ultimately fail to withstand scrutiny. However, theoretical physicist Mihailo Backovic asserts that the motivation behind such rapid publications is primarily driven by a genuine passion for science. He contends that theorists’ excitement about speculative experimental results is fundamentally similar to their enthusiasm for more established theories.

The first video titled "The Dangers of Andrew Huberman" explores the implications of Huberman's insights on biomedical research.

Another factor contributing to the conservative nature of life sciences, as suggested by Rzhetsky and his colleagues, is that individual researchers often feel compelled to publish continuously to advance their careers. This approach, however, can hinder overall scientific progress. To foster more adventurous research, they propose funding individuals rather than specific projects, assessing research teams collectively instead of individually, and encouraging the publication of results from failed experiments.

“The incentives have to change,” Evans emphasized in an interview, noting that researchers cannot simply be urged to take more risks. Their primary motivation lies in publishing papers, achieving citations, and securing tenure to support their families. Hence, the responsibility for change lies with the major funding organizations.

Julia Lane from New York University echoed this sentiment, advocating for a shift away from evaluating individual grant outcomes to assessing broader portfolios. “Many projects should fail,” she argued, adding that if too many are successful, the private sector should be the one funding the research, not government entities.

At NIGMS, Lorsch and his team are aware of these challenges and employ various strategies, including expert reviews and analysis of publication and citation metrics, to ensure that they support the most promising research. “We are particularly interested in helping researchers explore a broader spectrum of biology,” he stated, “to uncover pathways and processes we have yet to imagine.”

The prevalent use of model organisms such as mice and fruit flies could also be a source of conservatism in life sciences. “Are we missing a wealth of biological insights by focusing solely on a limited selection of traditional model organisms?” Lorsch questioned. “Sometimes I fear we resemble the proverbial drunk searching for his keys under the streetlight—not because he lost them there, but because it is the only area he can see.”

The second video titled "Zack Chase Lipton — The Medical Machine Learning Landscape" delves into how machine learning is reshaping the biomedical research landscape.

References

1. Alberts, B., Kirschner, M.W., Tilghman, S., & Varmus, H. Rescuing U.S. biomedical research from its systemic flaws. Proceedings of the National Academy of Sciences 111, 5773–5777 (2014).
2. Rzhetsky, A., Foster, J.G., Foster, I.T., & Evans, J.A. Choosing experiments to accelerate collective discovery. Proceedings of the National Academy of Sciences 112, 14569–14574 (2015).
3. Yao, L., Li, Y., Ghosh, S., Evans, J.A., & Rzhetsky, A. Health ROI as a measure of misalignment of biomedical needs and resources. Nature Biotechnology 33, 807–811 (2015).
4. Evans, J.A., Shim, J., & Ioannidis, J.P.A. Attention to local health burden and the global disparity of health research. PLoS One 9, e90147 (2014).
5. Bialek, W. Perspectives on theory at the interface of physics and biology. arXiv:1512.08954 (2015).
6. ATLAS. Search for resonances decaying to photon pairs in 3.2 fb-1 of p p collisions at √s = 13 TeV with the ATLAS detector. ATLAS-CONF-2015–081 (2015).
7. The CMS Collaboration. Search for new physics in high mass diphoton events in proton-proton collisions at √s = 13 TeV. CMS Physics Analysis Summary (2015).
8. Backovic, M., Mariotti, A., & Redigolo, D. Di-photon excess illuminates dark matter. arXiv:1512.04917 (2015).
9. Backovic, M. A theory of ambulance chasing. arXiv:1603.01204 (2016).
10. Bohannon, J. Q&A: How to encourage more scientific risk-taking — and efficiency. Science (2015). Retrieved from DOI 10.1126/science.aad7409.
11. Model Organisms for Biomedical Research, National Institutes of Health, http://modelorganisms.nih.gov.

Peter Rodgers is the features editor of eLife. Previously, he served as the chief editor of Nature Nanotechnology (2006–2012) and the editor of Physics World magazine (1996–2005).