Analytical Chemistry News & Features
May 1, 1998; pp. 292 A-292 A.
Copyright © 1998 American Chemical Society

The Human Genome Project--and Beyond

I would like to call your attention to a recent U.S. Department of Energy (DOE) solicitation entitled genome instrumentation research, which can be read under Notice 98-16 at the Web address http://www.science.doe.gov/grants/. I do not usually advertise for federal agencies. However, this particular solicitation is consistent with my standing desire to exhort the analytical community (you) to think creatively about long-range research in analytical chemistry, especially on problems that will impact in a major way the future content and role of our discipline. And so I do just that in this editorial. Read this solicitation, and follow up on it if you think you can contribute.

What's it about? The Human Genome Project, which began about 1990, is a massive ($$$) effort to determine the 3,000 Mbases in the human genome, with a 2005 target date for completion. Analytical chemistry is at the core of this daunting objective, and a lot of innovative work on DNA measurements has been fertilized--and been reported--on ways to detect trace quantities of nucleotides in the context of discovering their original arrangement. Progress, in numerical terms, of bases sequenced has, on the other hand, been modest, and meeting the 2005 target date will be challenging (see Science 1998, 279, 36). Nevertheless, once the complete sequence is determined, an enormous appetite will have been kindled for research on related genome-sequencing objectives in the biomedical and biotechnology fields. The analytical chemistry of DNA sequencing thus faces the dual challenges of improving current approaches (to meet the 2005 target, which is politically important) and of creating generically new ones (which could have far greater scientific importance). The DOE solicitation addresses both challenges.

What are the scientific issues? Limitations on existing approaches revolve around the sheer magnitude of required measurements, such that "factory" considerations of speed and cost tend to dominate. The number of bases in a given DNA fragment that can be determined in a single gel electrophoretic sequencing run (the "read length") is a major factor; it is related to the electropherogram's peak capacity. Other significant problems include the measurement error rate.

The more scientifically important analytical issues are those aimed beyond the immediate factory-fix, and current thinking has proceeded in several directions. On one level, the electrophoretic approach is dramatically improved with such innovations as parallel approaches using capillary arrays or microchip arrays. On another level, different methodologies such as mass spectrometry are being brought to bear. And on yet another level, the DNA fragment can be sequenced by enzymatically clipping off bases serially and determining their identities as single molecules. These single-molecule measurements are universally done by fluorescence, and there are substantial lifetime and stability requirements.

I can't begin to explain all aspects and nuances of this topic in these brief words. I merely want to stir some intellectual juices. The Human Genome Project is one of the largest, single scientific projects; and it has had analytical chemistry at its core. In that light, this step of inviting further research ideas that look beyond its completion is a potentially significant event.