Decoding Phenotype: The Holy Grail for Today's Medical Scientists

We've figured out DNA, but we need to start watching and measuring with greater precision how it interacts with the environment.


Starting with the elucidation of its structure by Watson and Crick (PDF) in 1953, medicine has been captivated by the power of DNA, by the ability to understand our health and treat disease based on subtle differences in the four-letter code that comprises our genetic information -- our genome.

The technology of DNA sequencing has progressed to the point that the readout of an entire human sequence -- a feat that just a decade or so ago was considered medical science's holy grail, worthy of a massive, Manhattan-Project style mission, and ultimately celebrated by a Presidential press conference -- has evolved into an almost routine activity for a number of technology companies, at a cost now closing in on $1,000 per genome, and dropping fast.

Perhaps not surprisingly, the spate of data emerging from sequencing efforts has not only revolutionized our understanding of disease, but has also highlighted fundamental limitations in our scientific understanding. As we try to wring meaning from the petabytes (that's over a billion million bytes) of data, it's become increasingly clear that sophisticated -- and actionable -- understanding of biology and disease requires not only a parts list, but also a nuanced readout of how the parts operate together in the context of a cell, an organ, a person. In a word: phenotype.

While it's essential for researchers to view patients as partners, we must recognize that they want to spend their time living their lives, not thinking about health.

Phenotype is how something looks, acts, or behaves; in contrast to DNA sequence, which is fundamentally discrete and universal, phenotype tends to be much "messier," more challenging to reliably assess. Two investigators across the world can easily agree on the exact DNA sequence within a specific cell, say, but might come to very different conclusions about how the cell behaves in culture.

The greatest challenge may also be the most important: measuring complex human phenotypes, such as how a patient is experiencing a particular disease, or responding to a given treatment. Too often, and quite understandably, the approaches used by physicians and medical researchers have been relatively simple, episodic assessments -- measuring a patient's blood sodium, or blood pressure, for example, at the time of an annual physical. Such evaluations can provide important and useful information, but rarely capture the complexity of a patient's health and experience over time.

We envision improved measurement of phenotype as the underlying basis for the next generation of medical progress. Improved measurements of patients can guide -- immediately -- the treatment approach used by physicians, who often have very little visibility into what happens after a patient leaves the office. Better measurement can also guide medical product development, focusing attention on a patient's true unmet needs.

The FDA, to its credit, has recognized the need for improved measurement, and has been an early champion of the need for better "assessment science." Speaking at a conference on the subject last year, the director the FDA's Center for Drug Evaluation and Research, Dr. Janet Woodcock, noted (PDF, p.13) that "the identification, development, and qualification of new clinical trial outcome assessments has not been aggressively pursued by the scientific community," adding that "the consequent lack of assessment tools has been impeding, I think, the development of new drugs because we really, in many cases, don't know how to measure the impacts, both for good and ill, of the drugs we test in people."

Presented by

David A. Shaywitz & Dennis A. Ausiello

David A. Shaywitz is an adjunct scholar at the American Enterprise Institute and a strategist at a biopharmaceutical company in San Francisco. Dennis A. Ausiello is physician-in-chief of Massachusetts General Hospital.

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