The (As Yet) Unfulfilled Promise of Personalized Genomics

    By Kevin E. Noonan --

One of the many benefits touted by proponents of the Human Genome Project has been the prospect of personalized medicine, based on a determination of an individual's entire genomic DNA sequence.  The advantages of this information are expected to include an understanding about the status of disease propensity-associated genes, as well as the existence of isoforms of enzymes, such as the P450 system in liver, that can affect how efficacious a particular drug may be in the individual, or alternatively, how ineffective or even toxic the individual's reaction to the drug may be.  Since both types of information represent a huge increase in specific knowledge about an individual (as opposed to the statistical data that underlie such determinations at present), the prospect of being able to ascertain this sequence information is widely considered to be the harbinger of a brave new world of 21st century medicine.

Two more steps towards this brighter tomorrow were taken today.  First, and entirely fittingly, Dr. James Watson (at left) was presented with a pair of CD-ROMs containing approximately 3 billion basepairs encoding his genomic DNA.  The presentation was made by Dr. Richard Gibbs, director of Baylor College of Medicine's Human Genome Sequencing Center, and Dr. Jonathan Rothberg, founder of the company 454 Life Sciences.  Dr. Rothberg's company makes the automated DNA sequencing machines that enabled Dr. Gibbs' team to determine Dr. Watson's genomic DNA sequence in months rather than years, and at a cost of less than one million dollars.  It is thought that expected advances in the technology will reduce the cost even further, to perhaps as little as ten thousand dollars; at that point widespread genomic DNA sequencing may become economically feasible.

The Watson DNA sequence will be made publicly available, with one exception:  Dr. Watson will not disclose the sequence of the gene that encodes apolipoprotein E in his genome, since certain alleles of this gene are associated with the development of Alzheimer's disease.

Ironically, another total genomic DNA sequence will also soon become available, that of Dr. J. Craig Venter (at right), the man whose for-profit company, Celera Corporation, is credited with motivating completion of the human genomic DNA sequence (obtained from a mixture of different individual's DNA) by the Human Genome Project, headed by Dr. Watson.

The other announcement came from the National Human Genome Research Institute (NHGRI), involving a study of 1,000 individuals with symptoms of coronary artery disease.  This study is limited to determining the genomic sequence of between 200 and 400 genes known to be associated with this disease, although there will also be an analysis of other genetic variations.  These genomic determinations will take about two years, and will be correlated with changes in disease states of the participants.  The goal is better understanding of the association between disease and genetic variability.

As promising as these efforts may be, there are reasons to be skeptical about them, at least in the short term.  The determination of individual genomes, while informative for the individuals, may not provide any broader information about the "canonical" human sequence, because there is good evidence from classical population genetics that such a sequence does not exist.  In studies done 40 years ago, Richard Lewontin (at right) and others showed that natural populations contain a great deal of genetic variation in the amino acid sequence of common cellular enzymes.  This variation did not appear to confer any evolutionary advantage on the organisms expressing them (typically, Drosophila), leading to what has been called the "neutralist" school of population biologists.  The explanation is that organisms have this vast genetic variability that is neutral under normal circumstances, but provides a reservoir of adaptability during times associated with speciation - natural disasters, isolated sub-populations, and geographic allopatry.  Thus, a determination of any individual's genomic DNA can be expected to say little about "the" sequence for any particular gene; "the" sequence will, at best, be the most common sequence in a population, requiring information from thousands or perhaps millions of individuals to be accurately portrayed.

Another reason for skepticism about projects like the NHGRI's is that it will be limited to the 200-400 genes now known to be associated with coronary artery disease.  By limiting the scope of the study to these genes, the data produced will increase our understanding of the genes, but not perhaps the underlying disease, for example, if there are genes not yet identified that play an unappreciated (and perhaps important) role in the disease etiology.

Finally, the problem with applying genomics in this way is reminiscent of Abraham Maslow's aphorism, that "if you only have a hammer, you tend to see every problem as a nail."  The determination of the human genomic sequence has been a landmark achievement, but caution suggests that the problems of biology are unlikely to be solved in any meaningful way merely by detecting variabilities in DNA sequence.  Certainly these do exist - sickle cell anemia is the result of a transversion (A to T) mutation that changes a valine residue to a glutamic acid residue.  However, clinicians know that there is variability in how different sickle cell anemia patients react to environmental stimuli, reflecting the interactions of the millions of other genes they express.  Systems biologists are just now beginning to explore the relationships between the biological products of genes, proteins and the cellular structures they create.  It is well to be reminded that we are merely at the beginning of this journey, and that the projects announced today are only the smallest of steps to unraveling (to the extent we are able) the fascinating riddle of life.

Comments

[anonymous]

This summary is a good or better than similar works appearing in the News and Views section of Science and Nature or in the "science" section of many newspapers. Perhaps Mr. Noonan should consider a second job as free-lance writer.

[Whipper Snapper]

Great post, Kevin.

"The Watson DNA sequence will be made publicly available, with one exception: Dr. Watson will not disclose the sequence of the gene that encodes apolipoprotein E in his genome, since certain alleles of this gene are associated with the development of Alzheimer's disease."

That's just weird. Is he hiding this info for his sake or his kids' sake?

[Kevin E, Noonan]

Whipper:

Watson's mother died of Alzheimer's disease. Maybe he just didn't want to know, or have his kids know (or worse, have some tabloid do a "DNA guy's countdown to dementia" contest).

It does point out the issue of genetic privacy, though.

Thanks for the comment.