e don’t know what induced an ancestral human in pain to eat the seed head of the opium poppy. We do know, from the Ebers papyrus, that by 1500 B.C. the Egyptians were using complex mixtures of plants as medicine, and that they realized there was a fine line between doses that improved health and doses that caused toxicity. Opium might bring relief from pain, but it also caused sleepiness, addiction, and even death.
Until relatively recently, all drug discovery began with folklore and folk medicine, like the elderly woman in the 1770s telling William Withering that her recipe for dropsy (heart failure) included the purple foxglove plant, which contained digitalis.
Today, thanks to our understanding of cells, molecules, and genes, drug discovery begins with “targets,” molecules in the body’s cellular pathways that are part of a well-balanced functioning organism and that are disrupted in disease. It is a miracle, or at least amazing, that we can understand the body’s workings so well. If the proper study of humans was only humans, progress in that understanding might have been quite slow. But Homo sapiens share with the lowly yeast and the fruitfly, fish, and mouse many of the fundamental molecular pathways that are disrupted in disease.
With knowledge gleaned first from fundamental investigations, or what some call basic science, we can make drugs aimed at specific molecular targets, and do so in a rational way.
But how are such targets discovered? Are they first identified as part of a project to discover a drug? Or do they arise from scientists trying to understand nature? If the latter, when did someone recognize, “Hey, there might be a drug somewhere in there?”
As scientists who, between us, have devoted our careers to fundamental discovery, medicine, and the development of effective new drugs, we tried to find answers to those questions. To do this, we examined the evolution of what eventually became 28 “transformative” drugs approved by the FDA between 1985 and 2009.
With help from nearly 80 scientists and physician experts from around the globe, we defined the discoveries that led to these 28 medicines. As we wrote recently in Science Translational Medicine, on average more than 30 years elapsed between the first relevant insight and FDA approval of a new medicine.
For the vast majority of the medicines we examined, the foundational discoveries were made by scientists trying to understand nature. They had no evident intent to make a drug. In fact, for most of these drugs, decades elapsed and insights accumulated to refine the original observation. Only then did the potential for a new drug become clear and the search was on for a chemical or protein that might become a therapy.
In some cases, disparate fields of research needed to converge before this happened. The now widely used statins, for example, emerged from a clearer understanding of the biochemical steps of cholesterol synthesis and how cells handle cholesterol and other lipids.
Sometimes the applicability of an insight had to wait for a better understanding of disease. An example is reflected in the class of medicines that regulate the formation of angiotensin, a protein involved in the control of blood pressure. The story reasonably begins in 1898 when Robert Tigerstedt and Per Bergman, for reasons that aren’t entirely clear, injected extracts of kidneys into rabbits and showed that these injections caused blood pressure to rise. Thirty-six years later, poor blood flow to the kidneys was linked to high blood pressure and release of the protein renin.
Over the next 15 years, investigations by several groups showed that renin itself did not affect blood vessels, but rather activated a blood protein called angiotensinogen, making angiotensin. Further work showed that even that protein needed to be modified by an angiotensin converting enzyme (ACE) to influence blood pressure. ACE became the actual target for a medicine to lower blood pressure.
The first ACE inhibitor was synthesized in 1975, and was approved by the FDA to reduce high blood pressure in 1981.
We aren’t the first to have observed that drug discovery often begins with basic research that wasn’t aimed at finding a new therapy. More than 40 years ago, in response to President Lyndon Baines Johnson’s warning that basic research not stay “locked up in the laboratory,” Julius Comroe Jr. and Robert Dripps showed that major advances in treating heart and lung diseases began with basic research. More recently, Fred Ledley and his colleagues have modeled the long maturation curve of fundamental understanding needed before a drug can emerge from a novel target.
An often-cited statistic is that it takes a pharmaceutical company 10 years to bring a new medicine to the marketplace. Our research suggests that there’s an even longer “incubation period,” often in academia, before that process ever gets underway.
Given the growing impact of dementia and depression in countries around the world, why don’t we yet have great drugs to prevent or cure them? It isn’t for lack of effort. Rather it is because we simply don’t know enough about them at a fundamental level. Until we do, any drug discoveries for such disorders will be as much due to luck as to talent or focused effort.
Judging from the past, the development of new drugs will continue to be a lengthy journey. The first step, often recognized only in retrospect, likely will be an insight in yeast or fish or mice without any obvious relevance to a new medical breakthrough.
There’s really no shortcut. The only way to lay the foundation for the next generation of new medicines is to invest in learning the fundamental truths about how the body functions and how it falls apart.
Mark C. Fishman, M.D., is a professor in the Department of Stem Cell and Regenerative Biology at Harvard University and the former president of the Novartis Institutes for BioMedical Research. Jonathan M. Spector, M.D., is executive director for global health at the Novartis Institutes for BioMedical Research. Rosemary S. Harrison, Ph.D., is head of portfolio management and strategic planning at the Novartis Institutes for BioMedical Research. Fishman is a consultant to Novartis; is on the scientific advisory board of Tenaya Pharmacueticals; and is on the board of directors for Semma Therapeutics.