Brent Stockwell: The National Institutes of Health and the Drug Discovery Crisis

Brent R. Stockwell is the author of The Quest for the Cure: The Science and Stories Behind the Next Generation of Medicines, and Associate Professor of Chemistry and Biological Sciences at Columbia University, and an Early Career Scientist of the Howard Hughes Medical Institute.

It is becoming increasingly difficult to discover new drugs. Over the last 15 years, the number of new drug approvals has declined substantially, even in the face of a huge increase in funding for drug discovery research. Put simply, it is becoming increasingly expensive and challenging to create new medicines. It is not overstating the point to say that we are facing a drug discovery crisis, which has stimulated recent mega-mergers and acquisitions within the pharmaceutical industry. Drug pipelines are drying up, and many are asking, what can be done?

The Obama administration has proposed a new initiative to help address this drug shortage. Concerned with the paucity of new medicines, the administration has proposed to create a controversial new center within the National Institutes of Health (NIH) that is focused on aiding the discovery and development of new medicines. This new center, called the National Center for Advancing Translational Sciences, is meant to catalyze the transfer of discoveries from basic science laboratories to clinical studies that involve patients, and eventually into commercial products. The NIH website indicates that the new center will be synthesized from existing programs within NIH, so that the center is an administrative reorganization rather than a dramatic shift in policy. The stated hope of NIH officials is that this new center will make it easier to bring discoveries from basic science into the clinical arena.

What can this new NIH center do that will help address the drug discovery crisis? On a practical level, the center can help to move discoveries down the drug discovery path to the point that they become attractive for commercial entities to adopt and invest in. Pharmaceutical and biotechnology companies and venture capitalists have become increasingly conservative in their investment strategies, especially since the economic disruptions in 2008. This conservatism has resulted in a lack of investment in early-stage technologies and drug candidates, making it difficult to translate these discoveries into a commercial and clinical setting. In short, the well-known “valley of death” that separates basic sciences from commercial and clinical translation has grown larger and more ominous. Therefore, by assisting the development of selected technologies and compounds through the early stages of drug discovery and development, the new NIH center could help to bridge this valley and bring the most promising technologies to market.

However, if the new center were to focus on this simple catalyst role, it would represent a lost opportunity. There is a more significant challenge to discovering new medicines than simply bringing basic discoveries to market. This more fundamental challenge involves the basic science issue of protein druggability, which could have a far more significant impact on the number and type of future medicines.

All known drugs act by interacting with just 2% of the proteins found in human cells. The vast majority of the remaining proteins are considered “undruggable,” meaning that many researchers believe it is not possible to create drug molecules that interact with these proteins. If this is true, it implies that we are reaching a fundamental limit in our ability to create new drugs, and that we may be reaching the end of pharmaceutical medicine. This is a grim conclusion indeed.

However, it is possible that new technologies and approaches could solve this challenging problem of protein druggability. A number of researchers are trying to create drug molecules with superior shapes and properties. For example, drug molecules that are larger and have more complicated architectures may be able to interact with protein surfaces that are not suitable for binding traditional simple drug molecules. Alternatively, it may be necessary to engineer gigantic drug molecules that are almost protein-like in their size, but this would require a new means of delivering drugs to cells—large molecules such as proteins are not generally able to penetrate into cells. Recent advances have in fact enabled the delivery of protein-like molecules into cells, suggesting that a new generation of medicines may soon be upon us.

These efforts to tackle undruggable proteins are in their nascent stages, and are easily squelched by conservative perspectives suggesting that such proteins are inherently intractable and not suitable for study. However, if we abandon the undruggable proteins, we abandon the hope for truly transformative medicines.

The proposed NIH center could have a powerful role in translating the vastly detailed molecular networks emerging from basic science studies into therapeutics. If the center focuses on solving this basic science problem of protein druggability, it would allow the accumulating molecular network diagrams to be converted into therapeutic molecules. Currently, many of the root causes of diseases are considered undruggable and cannot be addressed directly with medicines. If we could solve the mystery of protein druggability, we could open up a vast number of possibilities for new medicines, and ultimately end the drug discovery crisis.