NYC pilot study pushes Human Genome Project toward cures for disease
With the completion of the Human Genome Project (HGP) in sight, a group of New York City scientists are undertaking a strategic pilot study to turn that knowledge into promising drug targets as quickly as possible.
Dubbed the “structural genomics initiative,” the study focuses on proteins that cause disease in humans, as well as those that are used in treating disease. It advocates using recent advances in computational biology to increase the speed at which these proteins are analyzed and categorized.
“We are embarking on a program, which, if proven effective, will provide a way for researchers to come to grips with the impending flood of genetic data and speed its translation into therapeutic use,” says Andrej Sali, assistant professor, Alfred P. Sloan research fellow and Sinsheimer scholar at The Rockefeller University. “The initiative is aimed at developing a comprehensive mechanistic understanding of human and microbial physiology at the molecular level. This strategy should lead us to medically relevant data more quickly.”
Sali will discuss the initiative at a symposium scheduled for 3 p.m on Sunday, Feb. 20, at the annual meeting of the American Association for the Advancement of Science at the Washington Marriott Wardman Park (Cotillion Ballroom South, Mezzanine Level) in Washington, D.C. He formulated the proposal along with Richard M. and Isabel P. Furlaud Professor Stephen K. Burley, Patrick E. and Beatrice M. Haggerty Professor John Kuriyan and Assistant Professor Terry Gaasterland, all of Rockefeller University, and colleagues at the Mount Sinai School of Medicine, Weill Medical College of Cornell University, Brookhaven National Laboratory and the Albert Einstein College of Medicine.
The HGP is often portrayed as an end in itself, but most scientists recognize that its completion represents only a starting point from which to ask questions about other biological processes. While genes carry the “blueprints” for life, proteins perform the vital functions necessary for life to exist.
Proteins, long chains of building blocks called amino acids that fold into compact but flexible shapes, carry out virtually all of life’s essential functions through chemical reactions. Their structures are determined by the order of the amino acids, which is prescribed by the genes carrying instructions for making the proteins.
“In architecture, it is said that form follows function–you begin with a purpose that dictates the style and shape of a structure,” Sali says. “In structural biology, function follows form, because the shape of a protein is the very definition of what task it performs.”
It would take decades to determine every three-dimensional structure of every protein encoded by the human genome, and this undertaking would yield many of the same shapes over and over. Because of this, the scientists suggest focusing primarily on disease-related proteins.
As the scientists explained in a commentary published in the journal Nature Genetics, focusing on these “likely suspects” will bring a quicker payoff. Such an approach is possible only through dramatic advances in computational biology–most notably, specially designed software that finds all the protein-coding regions in a genome and also allows researchers to use structural and biochemical information to understand protein function.
The scientists say that choosing medically relevant protein targets will provide benefits whether its folds are “new” (i.e., different from those in other proteins already solved) or “old,” and whether its function is already known or is unknown. They also think choosing these targets will have important consequences for disease and patient-oriented research:
- First, any newly determined structure will be of immediate relevance to academic and/or industrial research teams studying that biological system.
- Second, by publicizing target lists on the Internet, the structural genomics pilot studies could generate scientific interest and expertise and attract suggestions for additions to their respective target lists.
- Third, the pilot studies will be able to serve as an important resource for distribution of tools and reagents for research. “One can imagine that some future NIH grant applications would include both a request for funds and a request for a supply of a particular purified protein deposited in a centralized cold-storage facility,” Sali says.
The discovery of the double helical structure of DNA by Watson and Crick in the 1950s ushered in the modern field of molecular biology, and since then molecular and cell biologists have become proponents of the “gene product theory of human disease.” Instead of examining microbial invaders, for example, the biomedical research community studies the consequences of introducing foreign proteins–such as fungal, bacterial and viral virulence factors–into humans, or the results of genetic mutations that disrupt the function of normal genes.
This molecular view of disease has contributed to the importance of studies of the three-dimensional structure of proteins using techniques such as X-ray crystallography and nuclear magnetic resonance spectroscopy, which allow researchers to visualize the various shapes that enable proteins to perform their vital functions.
Although the human genome is estimated to contain about 100,000 genes, with each gene encoding one protein, there are not a corresponding 100,000 shapes into which the proteins can fold. In fact, scientists now estimate that there are only 1,000 to 5,000 distinct spatial arrangements of polypeptide chains found in nature.
While some researchers fear that structural genomics will put X-ray crystallographers and nuclear magnetic resonance (NMR) spectroscopists out of business, Sali and his colleagues contend that technological advances will improve the efficiency of all structural biologists. They also argue that structural genomics may even provide the means to address one of the great unsolved problems in molecular biology–the relationship between one-dimensional sequence information (the order of amino acids in a protein) and three-dimensional structure (the folds of the complete protein).
Rockefeller is renowned for its tradition of fostering breakthrough discoveries in protein and peptide chemistry. This strength was demonstrated once again in October 1999, when RU Professor and HHMI Investigator Günter Blobel received the Nobel Prize for Physiology or Medicine. Blobel, who made the seminal discovery about how proteins are directed to their appropriate places in the cell, was the 20th scientist associated with the university to receive the award.