Over the past decade, we have witnessed unparalleled advances in our understanding of basic biological processes that contribute to a host of human disorders. The highly celebrated elucidation of the sequence of the human genome and other technological gains have allowed identifi-
cation of a broad range of regulatory proteins and complex signaling systems that play critical roles in a variety of normal physiological processes as well as pathological conditions in virtually all major organ systems.

Today we have an understanding of the mechanisms underlying complex human disorders such as Alzheimer’s disease, dia-
betes, multiple cancers, schizophrenia, and many others. These key new insights may provide paths to fundamental advances in care or even cures for patients suffering from these disorders.

Translation of this new knowledge into practical gains in health care has
moved more slowly, despite the recent doubling of the National Institutes of Health budget, and a 16-fold increase in research-and-development spending by pharmaceutical companies between 1980
and 2002. Many of the drugs currently available were developed before the 1950s, prior to the recent expansion in our understanding of the basic biology underlying human disorders.

Photograph by Dean Dixon

Recent years have seen a steady decline in the number of new drugs approved for clinical use, and many of the recent approvals represent subtle changes to existing medications, providing incremental rather than fundamental advances
in therapeutic strategies. The decrease in introduction of fundamentally new drugs into clinical practice during a time of
increased knowledge and increased research spending stems in part from a fundamental shift in the basic paradigms used for drug discovery.

In the early drug discovery era, novel therapeutic agents were derived from known compounds, often plant extracts,
which had medicinal properties. The major goal was to isolate the therapeutic component of the plant and refine it by making relatively modest chemical modifications. Investment was often made with no understanding of the basic mechanism of the drug’s action, although there was existing knowledge that the compound had properties that allowed it to reach the target organ and have clinical efficacy. Also, there was some level of understanding of the potential toxicity based on clinical experience with the plants from which the compound was derived. Because of this,
the risk that a drug discovery program would fail was relatively low.

Today the properties of known medicinal plants have been largely realized. We rarely have the luxury of embarking on a drug discovery program with this level of confidence in our ultimate success. Instead, we begin with knowledge of a biological system and identification of a potential drug target found among the many potential targets known from our new understanding of the human genome.

Instead of knowing that a drug interacting with this target will have clinical efficacy, we make a hypothesis based on our
still limited and imperfect understanding of complex biological systems. Typically, there are no existing drugs
that interact with that target, forcing a search for a novel compound that has the desired effect and then engineering the
properties required for a useful drug. This process is expensive and inherently high risk – we may reach the end of a project that cost hundreds of millions of dollars only to find that our original hypothesis was incorrect and the drug has no clinical efficacy or has unforeseen toxicity.

Translation of the extraordinary progress of recent years into fundamental advances in human health and patient care
is a major challenge facing today’s biomedical research community. The complexity of this task requires the combined efforts of outstanding scientists, engineers and clinicians with strong expertise in a broad range of disciplines.

Traditionally, the NIH and academic institutions have supported basic biomedical research, while industry has supported
commercial development of medicines and medical products. While scientists in academic and other basic science settings have made significant progress in furthering our understanding in biology, chemistry and related disciplines, they often fail to make the critical link that allows this information to be useful in an industry setting.

Likewise, fiscal pressures that govern research efforts in industry make it increasingly difficult for companies to invest
significant resources in exploratory projects and basic research that capitalize on translating the most exciting discoveries of basic science into marketable products.

The most innovative and high-impact advances in therapeutics will likely come from aggressive efforts to provide a bridge that allows translation of advances in basic science to novel therapeutic agents. While this translation is clearly the mission of pharmaceutical and biotech companies, it is critical that scientists at NIH-funded institutions focus increasing attention on their role in contributing to the therapeutic discovery process.

In addition to the advances in basic biology, we have realized tremendous advances in combinatorial chemistry,
development of large libraries of small molecules, and other approaches to high-throughput synthetic chemistry. These
libraries are now widely available to the research community, and new high-throughput screening technologies have
been developed that allow more wide-spread mining of the libraries.

The combination of high-throughput screening and synthetic chemistry provides an unprecedented opportunity for NIH-
funded investigators to engage in discovery and development of small molecule probes of biological pathways.
These probes could provide the tools needed to directly test whether drug-like molecules can be developed that interact
with a novel target of interest and have the effects that were predicted in studies using molecular and genetic approaches.
Such advances could provide a major step in the discovery of novel therapeutic agents by identifying the most viable
approaches for further investment in an industry setting.

In addition, academic investigators are increasingly engaged in tackling other critical issues inherent in modern drug
discovery paradigms, such as, how do we predict at an earlier stage whether a drug will have clinical efficacy or toxicity? Rather than gaining answers to these questions at the end of a billion-dollar program, basic and clinical scientists can contribute to the design and execution of early proof-of-concept clinical studies that predict ultimate efficacy, and which may lead to the development of biomarkers that predict later toxicity.

Multiple changes in science, business and society are forcing a fundamental shift in traditional approaches to drug
discovery. Realizing the exciting promise of recent advances in the face of fiscal constraints presents a challenging but
exciting opportunity.

Individuals across the spectrum of biomedical research and discovery share a common optimism that we are at the
beginning of the most exciting era yet in changing the face of human disease. It is critical, however, that different players in this arena find new models to leverage our collective resources and talents. This issue of Lenshighlights one
approach for bridging the gap to new therapeutics.

This article appeared in Lens, Summer 2005. Lens magazine is a publication of the Vanderbilt University Medical Center.