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50 years in genetics

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NIA Blog Team

I am grateful that the NIA blog team has offered me an opportunity to reflect briefly on 50+ years of work in molecular biology and genetics research.  Here are a few personal reflections—shared in hopes of stimulating scientific conversations and exploring opportunities in these pioneering research arenas.

Birth of molecular biology

When I first entered my mentor Jim Watson’s office as a graduate student in ancient times (i.e., 1957), I saw a slip of paper fastened by scotch tape to the fluorescent light fixture over his desk. On it he had clearly printed in ink:

            DNA --> RNA --> protein

So, there it was—a clear guiding principle; a new science was starting. Although its name, “molecular biology,” had yet to be coined, we knew its birthday: April 25, 1953. That’s the date the DNA structure model was published in Nature.

The molecular biology paradigm

At that point scientists had very little idea of how genes were structured, organized, or regulated; but we had Francis Crick’s notion that “if you want to understand function, study structure.” And, we knew that meant having the right technology.

Over the intervening decades, I have heard people express amazement that critical techniques in molecular biology seem to appear “just in time.” For me, the truth is rather expressed in Fred Sanger’s rule: the development of a new technique that increases the resolution, speed, or accuracy of a method more than about 3-fold itself opens up a whole range of new experiments.

Thus, the techniques for analyzing populations of ribosomes and doing protein synthesis in cell extracts developed during my thesis work helped to make possible later approaches to analyze the genetic code and understand the ribosome cycle in protein synthesis. And, following that, my colleagues and I were able to extend the study of the ribosome cycle to analyze the action of antibiotics on ribosomes, including the mechanism of streptomycin action.

A lifetime of technical progress

Though I’ve seen many great technical advances over my career, one of the most important was the development of new approaches to study structure. In particular, the progressive ability to determine sequences of protein, RNA, and DNA on an increasing scale. This capacity has facilitated the analysis of gene regulation.

Another major achievement was the development of cloning techniques to recover large portions of DNA—this sustained the mapping phase in the first Genome Center that I headed at Washington University in St. Louis (1986-97). Together, early sequencing and cloning techniques subsequently led to whole genome sequences.

An equally important advance is the high throughput sequencing that now provides information about populations and genetic variation involved with disease risk and even aging.

As technology improves, the cost of sequencing a genome is becoming more and more affordable, making this research more accessible. It’s been lowered from millions to $1,000 and will certainly drop to around $100 in the coming years.

Preparing for a prolific future (even for aging)

The technological advances of genetics and its alter ego genomics are so powerful that they drive research in all fields of biology and medicine. This is as significant and motivating a time as was the watershed of 1953. The research community is now committed to attaining an integrated understanding of the development, maintenance, and aging of biological function. Population studies, including NIA’s pioneering SardiNIA project, coordinated by the Laboratory of Genetics, and the Baltimore Longitudinal Study of Aging, can investigate genetic as well as epidemiological factors affecting aging-related traits, aging-related diseases, and even longevity. We have embarked on studies at levels that range from molecules through cells and organs to physiology and pathophysiology.

The prospects for students entering the field now are just as exciting as the ones I encountered at the beginning of my career. And, in fact, I feel that the careers of my cohort of scientists have all been part of a preparation for NOW. But maybe science is always at such a turning point...

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