Would we be wise to prioritize “shovel-ready” science over curiosity-driven, fundamental research programs? In the long term, would that set the stage for the discovery of more medicines?

To find solid answers to these questions, scientists at Harvard and the Novartis Institute for Biomedical Research (NIBR), publishing in Science Translational Medicine, looked deep into the discovery of drugs and showed that, in fact, fundamental research is “the best route to the generation of powerful new medicines.”

“The discoveries that lead to the creation of a new medicine do not usually originate in an experiment that sets out to make a drug. Rather, they have their origins in a study — or many studies — that seek to understand a biological or chemical process,” said Mark Fishman, one of three authors of the study. “And often many years pass, and much scientific evidence accumulates, before someone realizes that maybe this work holds relevance to a medical therapy. Only in hindsight does it seem obvious.”

Fishman is a professor in the Harvard Department of Stem Cell and Regenerative Biology, a faculty member of the Harvard Stem Cell Institute, and former president of NIBR. He is a consultant for Novartis and MPM Capital, and is on the board of directors of Semma Therapeutics and the scientific advisory board of Tenaya Therapeutics.

CRISPR-cas9 is a good example of discovery biology that opened new opportunities in therapeutics. It started as a study of how bacteria resist infection by viruses. Scientists figured out how the tools that bacteria use to cut the DNA of an invading virus could be used to edit the human genome, and possibly to target genetic diseases directly.

The origins of CRISPR-Cas9 were not utilitarian, but those discoveries have the potential to open a new field of genomic medicine.

Blood pressure medication is another example of how fundamental discoveries can lead to transformative medicines.

People who suffer from high blood pressure often take drugs that act by blocking the angiotensin-converting enzyme. Those medicines would never have been created without the discovery of the role of renin (a renal extract) in regulating blood pressure in 1898, or without the discovery of angiotensin in 1939, or without the solid understanding of how the enzyme works, shown in 1956.

This work was not tied earlier to making pills for hypertension, mainly because hypertension was generally believed to be harmless until the 1950s, when studies showed its relationship to heart disease. Before then, the control of blood pressure was itself a fundamental science, beginning with Stephen Hales’ measurement  of blood pressure in a horse in 1733.

The discovery of ACE inhibitors really reflects the convergence of two fields of fundamental, curiosity-driven discovery.

Yet some observers believe that projects that can demonstrate up front that they could produce something useful should take priority over projects that explore fundamental questions. Would there be many more medicines if academics focused more on programs with practical outcomes? How would that shift affect people in the future?

To find answers, Fishman and his colleagues investigated the many scientific and historical paths that have led to new drugs. The study they produced is a contemporary look at the evidence linking basic research to new medicines.

The authors used a list of the 28 drugs defined by other scientists as the “most transformative” medicines in the United States between 1985 and 2009. The group examined:

  • Whether the drug’s discovery began with an observation about the roots of disease;
  • Whether the biologist believed that it would be relevant to making a new medicine; and
  • How long it took to realize that.

To mitigate bias, the researchers repeatedly corroborated the assignment with outside experts.

They found that eight out of 10 of the medicines on their list led back to a fundamental discovery — or series of discoveries — without a clear path to a new drug.

The average time from discovery to new drug approval was 30 years, the majority of which was usually spent in academia, before pharmaceutical or biotechnology companies started the relevant drug development programs.

Fishman concluded, “We cannot predict which fundamental discovery will lead to a new drug. But I would say, from this work and my experiences both as a drug discoverer and a fundamental scientist, that the foundation for the next wave of great drugs is being set today by scientists driven by curiosity about the workings of nature.”

What industry and academic leaders say

Leaders in biomedicine from industry, business, and academia warmly welcome this new body of evidence, as it supports the case for funding curiosity-driven, non-directed, fundamental research into the workings of life.