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The Howard Hughes Medical Institute (HHMI) has spent 60 years experimenting and learning how to support biomedical research effectively. From the time Mr Hughes first began funding research in the 1950s, institute leaders and scientists have found that the most important advances and influential discoveries often come unexpectedly鈥攁nd that often, the profound 鈥渂reakthroughs鈥� derive from deep fundamental insights of surprising, sometimes obscure biological systems.

HHMI鈥檚 experience suggests that scientific research is far from understanding the fundamentals of human biology or physiology and that there are several paths to gaining the necessary knowledge of molecular mechanisms governing disease pathologies. Studying model organisms such as yeast, worms, and flies remains a powerful and productive way to learn new biology. Directly studying human diseases caused by single or small numbers of mutations that allow for in-depth analysis (ie, hemoglobinopathies, familial hypercholesterolemia, and cystic fibrosis) offers another effective path to discovering the molecular basis of disease. In both approaches, success requires a sustained, diverse pipeline of scientists inspired to 鈥渇ollow their nose鈥� and equipped with the best research tools available.

At the same time that HHMI has increased its commitment to its mission to support basic research in innovative ways, it is disheartening to see that less and less of the total research funding in the United States goes to discovery research. For example, it has become increasingly difficult for scientists to obtain funding from federal or state agencies to explore model organisms such as Caenorhabditis elegans, Arabadopsis, and Drosophila, which all have led to fundamental discoveries such as programmed cell death, novel RNA metabolism, and critical cancer pathways. Funding targeted to translational and clinical work continues to increase disproportionately, despite clear historical evidence that most 鈥済ame-changing鈥� discoveries and technologies come predominantly from single investigator鈥搃nitiated research motivated by basic biological questions. No group has more forcefully made the case for robust funding of basic research than the heads of biotech and pharmaceutical companies, who have firsthand experience in the perils of drug development when there are deficits in understanding the complex biology so critical to developing successful new therapeutics and diagnostics.

To illustrate the disruptive potential of basic research tools, consider 3 recent examples: The CRISPR/CAS9-mediated genome editing system has revolutionized rapid and efficient targeted homologous recombination to generate knockout or knock-in mice and has enabled a plethora of ancillary technical capabilities in genome manipulation, molecular imaging, and transgenic organisms.^1,2 The development of Cryo-EM Direct Detectors and accompanying single-particle reconstruction algorithms has enabled the high-resolution^3,4 determination of megadalton multiprotein assemblies and molecular machines including the ribosome, the human transcription preinitiation complex, and details of cytoskeletal structures.^3-6 Super resolution light microscopy modalities such as PALM and the more recent Lattice Light Sheet Illumination systems have overcome the light diffraction limit and now allow single-cell real-time tracking of individual molecules in action, informed by detailed quantitative kinetic/dynamic analysis of molecular transactions in the nucleus and cytoplasm of living cells.^7,8

Although these diverse advances originated from individuals or small groups of independent thinkers often working in relative obscurity, these and other 鈥渂asic discoveries and enabling technologies鈥� will have, and in some cases already do have, an immense influence on biomedical research, accelerating a deeper understanding of cellular and molecular biology. For example, the original discovery of sequence-specific DNA binding transcription factors was inspired by an esoteric journey to probe the mechanisms governing the central dogma of molecular biology in animal and human cells. As it turns out, transcription factors played a key role in the 鈥渞eprogramming鈥� of adult patient cells to become induced pluripotent cells in the critical path toward development of modern regenerative medicine. In another example, using the new imaging modalities, it is now possible to 鈥渨atch鈥� master regulators such as Sox2/Oct4 explore the nucleus and bind to cognate DNA sites in living embryonic stem cells.⁹ Fundamental insights and technological platforms have often proven to be essential for guiding studies of human disease pathologies that directly or indirectly improve and accelerate the development of more efficacious and safer drugs. It is imperative to make more of this work possible.

The increasing imbalance between resources devoted to clinical disease-specific research and fundamental discovery science has an even more damaging consequence for the biomedical enterprise: discouraging the best and brightest students and early career stage scientists from entering the biomedical field or persevering in the increasingly challenging research funding environment. Exciting advances in the biomedical and health sciences have the potential to attract and engage gifted young minds, not only in biology but also in physics, chemistry, computer science, engineering, and other disciplines.

However, the flow of cross-disciplinary and diverse students and postdoctoral fellows is becoming constricted by limited funding sources that encourage and foster productive cross-cutting research collaborations. Indeed, the highly influential discoveries highlighted above resulted from just such a convergence of technologies and cross-disciplinary experts working collaboratively. For example, the development of PALM by optical physicists Eric Betzig and Harald Hess occurred while they worked closely with cell biologist Jennifer Lippincott-Schwartz and others to bring super resolution to practice. Likewise, development of the CRISPR/CAS9 genome editing system by Jennifer Doudna came about initially through genome sequencing studies of obscure classes of bacteria found in acid mines by her geologist colleague Jill Banfield.

Examples such as these have strongly influenced the way HHMI views its role in biomedical research. In a sense, HHMI can be seen as an experienced talent scout searching nationwide and worldwide for scientific talent. Over the years, HHMI has honed its philosophy of supporting people, not projects. Once HHMI identifies a qualified candidate, he or she is employed as an investigator and supported generously for an extended period, with rigorous reviews every 5 years鈥攚ith many HHMI investigators being supported for 10 to 15 years or more. Importantly, HHMI investigators are expected to make significant discoveries without regard to specific fields of study. They are not penalized if they deviate substantially from their initial stated aims. HHMI鈥檚 primary concern is to encourage bold, original thinking guided by rigorous, high-quality science.

To partly counter the dire situation of early-career scientists struggling to gain a foothold on funding, HHMI is looking at new ways of supporting scientists in the early stages of their independent research careers and directing more resources toward this critical need. This includes support for postdoctoral fellows, international PhD students, and scientists during the first 4 to 10 years after securing their first independent research faculty position.

As HHMI strives to support scientists at the frontiers of innovation who are making the most important foundational discoveries, the institute also realizes that another critically important need is to train high-performing, patient-oriented physician-scientists who forge links between basic biology and medicine. HHMI works to identify extraordinary individuals with deep insight into human disease and a driving desire to develop novel, more effective, safer, and more affordable therapeutics or diagnostics. During the past 2 decades, HHMI has found it increasingly difficult to identify patient-oriented researchers who are both directly connected to and actively treating patients while also deeply steeped in the rapidly emerging fields of molecular biology, genetics, genomics, and other transformative technologies. In particular, there have been some challenges identifying those rare individuals who have strong expertise in basic discovery research and are thus able and keen to study the molecular mechanisms of disease while maintaining an active clinical practice. It is such individuals who will reveal new insights that directly influence pathogenesis and therapy of disease.

One potential bottleneck in the development of such expertly trained physician-scientists is the arduous length of time required to specialize in a branch of medicine and become board-certified while also working toward a PhD, followed by extensive postdoctoral research experience. In most cases, such patient-oriented physician-researchers will be well into their 40s before they can become independent scientists with their own funding sources. Another significant problem is that most physician-scientists will not have basic research experience in an environment that can easily foster close working relationships with physicists, chemists, computer scientists, and engineers. Yet these quantitative physical scientists and engineers are the very people most likely to help physician-scientists launch cutting-edge interdisciplinary research programs that define modern biomedical research.

Given the rapid and spectacular advances in many areas of biomedical research, such as super resolution light microscopy, site-directed genome editing, and structural determination of large megadalton protein machines, there is an opportunity to train a new generation of discovery-driven, patient-oriented researchers. HHMI hopes to help mitigate this pipeline problem in the future.

In summary, after more than 60 years of experimenting with multiple mechanisms to support biomedical research, HHMI is focused on 4 key strategies for driving science forward. First, selecting and supporting people, not projects, which is the most effective mechanism to encourage model-shifting discoveries that invariably lead to better understanding of human disease and ultimately more effective treatments. Second, continuing to emphasize and support fundamental discovery research, which has proven to be the foundation of modern medicine. Too much about complex biological processes and human biology remains to be discovered, and more completely understood, to let up on this effort. Third, placing greater emphasis on supporting and encouraging the best students from many disparate fields of study and diverse backgrounds to seek a career in biomedical research鈥攅specially in this 21st century of biology. Fourth, crafting new ways to streamline the training of patient-oriented physician-scientists to increase the pipeline of next-generation biomedical researchers capable of forging strong links between fundamental biology discoveries and medicine.

Corresponding Author: Robert Tjian, PhD, Howard Hughes Medical Institute, 4000 Jones Bridge Rd, Chevy Chase, MD 20815-6789 (tjianr@hhmi.org).

Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Correction: This Viewpoint was corrected online on January 15, 2015, to correct an author email address.