See the video of Francis Collins’ talk at the May 2012 TEDMED conference in Washington:
In many arenas, there have been attempts to distinguish between basic and translational research. In reality, basic and translational research lie along a continuum with no sharp distinctions. Furthermore, even research endeavors at the extreme ends of this continuum are critically dependent on one another. National Institutes of Health Director Francis Collins gave a presentation at the recent TEDMED conference that made this point abundantly clear. Collins devoted a considerable amount of this talk to speaking about the premature aging disorder Hutchinson–Gilford progeria. He chose this example to illustrate how drugs developed for potential use in one disease can sometimes be used to treat other diseases and that this repurposing might speed the development of new therapies.
The mutations that cause Hutchinson–Gilford progeria were first identified in 2003. These frequently occur at one particular position within the LMNA gene. This gene and its protein products, forms of lamin A varying in terms of post-translational processing, have been studied for more than two decades in the context of fundamental studies of cell biology. These studies had shown that lamin A is a key component of the nuclear lamina, the fibrillar network that lies just inside the nuclear membrane. Prelamin A is processed by farnesylation on a cysteine residue near its carboxyl terminus, proteolytic removal of three amino acids from the carboxyl terminus, methylation of the new carboxyl terminus, and a final proteolytic cleavage to produce mature lamin A, incorporated into the nuclear lamina. Mature lamin A lacks the farnesyl group since the peptide fragment that includes this group is removed by the final proteolytic cleavage. Through the use of lovastatin, a small-molecule drug that blocks the pathway leading to farnesylation, it was demonstrated that farnesylation is required for proper processing of prelamin A.
The mutation that causes Hutchinson-Gilford progeria introduces a cryptic RNA splice site that results in the production of prelamin A that is missing an internal stretch of 50 amino acids near its carboxyl terminus. The prior knowledge regarding prelamin A and its maturation pathway allowed researchers immediately to propose and then test hypotheses regarding the biochemical basis for the pathobiological mechanism of the observed mutation. The mutated protein is farnesylated but does not have this farnesyl group removed by proteolysis, and the farnesylated protein does not function properly. This observation is the basis for ongoing clinical trials that aim to block the farnesylation process through the use of drugs and drug candidates that were developed for other indications in which these biochemical pathways are important, including cancer and heart disease. In particular, farnesyltransferase inhibitors, developed as potential anticancer agents based on the fact that the frequently mutated oncogene Ras protein is also farnesylated, are being studied as components of therapy for Hutchinson–Gilford progeria. Such compounds have been shown to reverse the cellular phenotype associated with the expression of the mutated form of prelamin A, but detailed clinical trials are necessary to determine if these compounds have desirable effects in individuals with Hutchinson–Gilford progeria.
This account illustrates how important fundamental knowledge of genes, proteins, and their associated networks and pathways are to the translational process. Because the gene and its products associated with this disease happened to have been well studied in the context of basic research, it was possible to make rapid progress in understanding the molecular basis of Hutchinson–Gilford progeria and developing potential strategies for its treatment. This is not always the case. Even with all that we have learned, in many cases molecules that are found to be associated with specific diseases are relatively uncharacterized and incompletely understood. Furthermore, almost all biomolecules are components of multiple pathways and networks, and our models of these systems undergo expansion and revision constantly as more fundamental knowledge is uncovered. These observations provide a strong impetus for continued studies of fundamental biological mechanisms. Deep exploration of the fundamental processes of life – often most effectively and efficiently obtained in the context of basic studies without any known disease connection in model organisms where the tools of biochemistry, molecular biology, genetics and cell biology can be brought forcefully to bear — pays powerful dividends and leads to unanticipated discoveries that can affect all aspects of research dramatically.
Of course, the interplay between basic and translational research is bidirectional. The characterization of molecules known to be associated with particular diseases and attempts to develop new therapeutic approaches also can reveal new fundamental information. For example, subsequent studies of the mutant form of lamin A associated with Hutchinson–Gilford progeria have revealed additional aspects of the fundamental role of this protein in affecting nuclear architecture. Tools and insights derived in this way can drive both fundamental and translational research.
Fundamental knowledge is the underpinning of all attempts to develop new and improved therapies. Developing such therapies is tremendously challenging in large part because of holes in our fundamental knowledge of biology, particularly the biology of human populations with all of their associated genetic and environmental heterogeneity. We need the concepts and tools of biochemistry and molecular biology now more than ever to drive improvements in human health as well as other critical fields, such as energy and food production, as depicted in the recent National Research Council report on “The New Biology.” Researchers who might regard themselves as sitting on one side or the other of the basic-translational spectrum will benefit from increasing their understanding of the challenges of developing a new drug or therapy from discovery through successful implementation. Successful translation is very challenging and requires considerable strategic and technical sophistication. Success also depends on having a very strong fabric of fundamental knowledge underlying the translational approach. We still have much to discover and learn!
Jeremy Berg (email@example.com) is the associate senior vice-chancellor for science strategy and planning in the health sciences and a faculty member in the computational and systems biology department at the University of Pittsburgh.