January 2013

(Not so) sudden impact

When I started as a postdoctoral fellow in biophysics at Johns Hopkins School of Medicine in 1984, I had the good fortune to attend some lab meetings involving groups from the adjacent department of molecular biology and genetics. Among the scientists whom I had a chance to know were Professors Hamilton Smith and Dan Nathans, who had shared (with Werner Arber) the Nobel Prize in physiology or medicine in 1978 for “the discovery of restriction enzymes and their application to problems of molecular genetics.”

While exploring genetic recombination in bacteria, Ham (as he is nearly universally known) and his graduate student discovered the restriction enzyme now known as HindII. Ham and his coworkers showed that this enzyme could cleave DNA at specific sites, and Nathans realized how such enzymes could be harnessed as tools to map and later to modify DNA molecules. Nathans and his co-workers applied these tools to study the tumor virus SV40. These studies were powerful in their own right and were full of possibilities; Nathans concluded his Nobel lecture (1) with the statement, “It should be possible to make out the basic regulatory mechanisms used by plant and animal cells, and eventually to understand some of the complex genetic programs that govern the growth, development and specialized functions of higher organisms, including man.”

This prediction of the impact of this basic discovery was, of course, right on the mark. Restriction enzymes became one of the key tools fueling major revolutions in molecular, cellular and developmental biology and other areas. One of Nathans’ major interests was cancer biology, and this revolution facilitated the identification of genes that regulate cell growth and the cell cycle. Biochemical insights gleaned from analysis of this collection of genes included the central role that enzymes known as protein kinases play in controlling these processes.

This insight, in turn, extended the trail of impact. Brian Druker, an oncologist working on leukemia, chose to pursue the observation that the great majority of cases of chronic myelogenous leukemia are characterized by a chromosomal abnormality, the Philadelphia chromosome identified by Peter Nowell and David Hungerford and characterized by Janet Rowley involving a reciprocal translocation between chromosomes 9 and 22. Using the tools of molecular biology, this translocation had been shown to generate a novel gene fusion between the beginning of the Bcr gene from chromosome 22 and the Abl protein kinase gene from chromosome 9. The import of this fusion was that the Abl protein kinase is expressed in an inappropriately regulated manner, stimulating white blood cells to grow out of control.

Druker saw this as a potential opportunity to develop a drug to treat leukemia based on the logic that inhibitors of this protein kinase should block this inappropriate growth signal. Druker and his collaborators, including Nicholas Lydon from the pharmaceutical company then known as Ciba-Geigy, identified a compound that would block the enzyme activity by competing with ATP for the enzyme active site and demonstrated that this compound largely would prevent colony formation by leukemia cells in culture (2). However, Druker encountered considerable challenges when trying to push this project further into the clinical arena due to concerns that it would be difficult to generate an ATP analog that would be sufficiently specific for the Bcr-Abl kinase to avoid side effects. Nonetheless, when a clinical trial was performed to test the safety of the compound in patients with CML, the compound was found to be quite well tolerated and, most importantly, remarkably efficacious, with 53 of 54 patients who took doses over 300 miligrams per day showing complete hematological responses, typically within four weeks (3). This compound, imatinib (marketed as Gleevec in the United States) is now the first-line treatment for CML and has transformed the prognosis for CML patients. Furthermore, this development represents a key landmark in the development of personalized, or precision, medicine (4) and has fueled considerable research and development efforts in both the academic and private sectors.

Examples such as the development of imatinib are crucial in discussing the impact of biomedical research in our society, as they illustrate the ultimate effects of such research on people’s lives. They also illustrate the cumulative nature of such advances, as they involve concepts and tools developed by many scientists over many years or decades (often with different goals in mind) and the interactions between basic scientists, clinicians and the private sector in converting a set of discoveries into a tangible benefit for patients worldwide.

The National Institutes of Health recently launched a useful webpage (5) that aggregates papers, reports and other items that illustrate the impact of NIH-supported research. The collection covers four major areas: our health, our economy, our communities and our knowledge. This is a valuable resource for American Society for Biochemistry and Molecular Biology members when they discuss the impact of their research and the research of their colleagues with their families, friends and government representatives.

Two examples of the reports available are “Economic impact of the human genome project” (6) and “Leadership in decline: assessing U.S. international competitiveness in biomedical research" (7). The first report concludes that a $3.8 billion investment in the human genome project has resulted in $796 billion in economic activity. While I would quibble that including only the human genome project itself and excluding the underlying investigator-initiated basic research that made the genome project possible and enhanced it along the way underestimates the investment, even if you triple the investment to $11.4 billion, this represents a 70-fold return on investment over a 22-year period (from 1988 to 2010) for an annualized return of more than 300 percent. The second report surveys the aspirations, strategies and investments that other countries have been involved in over the past decade while the American investment in biomedical research has been falling due to nearly flat NIH appropriations (with any increases well below the rate of inflation) and discusses some of the implications of these trends.

After I completed my postdoctoral fellowship, I continued my career at Johns Hopkins and had further opportunities to interact with Nathans on both scientific and administrative projects. After winning the Nobel Prize, he continued his research at full throttle, focused primarily on the examination of genes induced in response to growth factors. When several of these genes turned out to encode zinc-binding proteins, our laboratories collaborated, contributing to the discoveries that members of one class of these proteins are sequence-specific, single-stranded, RNA-binding roteins that regulate RNA turnover.

Nathans was a remarkable man, one of the most clear-headed individuals I have ever met. When the president of Johns Hopkins left relatively suddenly to pursue a different opportunity, Nathans was asked to step in as acting president, and he did a remarkable job, guiding the university through some turbulent times, including a major reorganization involving the School of Medicine and Johns Hopkins Hospital. He was successful because his judgment was universally trusted, despite (or maybe, in part, because of) his relative lack of administrative experience.

A year after turning over the reins to a new president, Nathans was diagnosed with leukemia. His diagnosis coincided with the period when clinical trials of imatinib were getting under way, although he had a different form of leukemia that is not treatable with the drug. Regardless, I am certain that he would have been thrilled by this development as one of the eventual outcomes from the field of molecular medicine that he helped envision. Furthermore, he would have followed with interest the development of other protein kinase inhibitors that have proved to be effective for the treatment of other cancers, although in many cases the results have been less striking than those with imatinib, because most other cancers are much more genetically heterogeneous and complex than CML. Nonetheless, the development of these drugs highlights the essential nature of the patient determination that has been personified by scientists such as Dan Nathans and Brian Druker. Even more, they reveal the long-term impact of basic research that uncovers fundamental cellular mechanisms when coupled with creative efforts to translate this basic knowledge into clinical interventions.
 

REFERENCES
  1. 1. http://www.nobelprize.org/nobel_prizes/medicine/laureates/1978/nathans-lecture.pdf
     
  2. 2. Druker, B. J. et al. Nat. Med. 2, 561 – 566 (1996).
     
  3. 3. Druker, B. J. et al. N. Engl. J. Med. 344, 1031 – 1037 (2001).
     
  4. 4. www.nap.edu/catalog/13284.html
     
  5. 5. http://www.nih.gov/about/impact/index.htm
     
  6. 6. http://battelle.org/docs/default-document-library/economic_impact_of_the_human_genome_project.pdf?sfvrsn=2
     
  7. 7. http://www.unitedformedicalresearch.com/wp-content/uploads/2012/07/Leadership-in-Decline-Assessing-US-International-Competitiveness-in-Biomedical-Research.pdf
     
     

Photo of Jeremy BergJeremy Berg (jberg@pitt.edu) is the associate senior vice-chancellor for science strategy and planning in the health sciences and a professor in the computational and systems biology department at the University of Pittsburgh.
 
 
 
 


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