March 2009--Picture every one of the 6 billion people on this planet shimmying all their 46 tightly packed bundles of DNA – containing 20,500 genes – into “average-sized” jeans, one-size-fits all.
Imagine vanilla ice cream only. No pistachio, butter pecan or Cherry Garcia.
It’s neither a pretty thought nor a tasty proposition. That’s because, despite being remarkably similar on a genetic level – in fact, the genomes of any two people are more than 99 percent the same – each recalcitrant one of us remains unique. Even a tiny fraction of variation between the three billion DNA letters that make up one’s genome and that of another can account for the difference between being an XS or an XL; between a penchant for peanuts and a life-threatening allergic reaction to them.
These slight genetic variations – most of which have little or no impact, but some of which have huge implications – imply that every one of us – each a collection of 100 trillion cells – has his or her own “flavor of health or disease,” observes David Valle, M.D., director of the Johns Hopkins McKusick-Nathans Institute of Genetic Medicine.
And yet, physicians practice what Valle calls “average” medicine; average not in sense of “mediocre” but standard. One-flavor-fits-all.
“When a patient comes in, we come to some diagnostic conclusion based on the amalgamation of patients with these kinds of complaints and history,” he explains. “And we prescribe a medication that, on average, is effective and safe for a group of patients with that disorder.”
That paradigm is on the verge of a radical shift here at Johns Hopkins, Valle says, based on physicians’ increasing ability to identify and interpret genetic variations at single bases called single nucleotide polymorphisms – also known as “snips.” In each of us there lurks somewhere on the order of 3- to 5 million of these differences.
“We only recently became aware of changes in the numbers of copies of genes, and little deletions and insertions that are pretty extensive, and certainly able to influence who gets sick and who stays well, and if you are sick, what kinds of complications you’ll get and how you’ll respond to medicine’s attempts to fix you up.”
Fueled by the completion of the international Human Genome Project which in 2003 determined the sequence of the 3 billion building blocks, or letters, in our DNA instruction manual, and building on the foundation of the collaborative HapMap project which identified up to 90 percent of the common genetic variation in our species, Johns Hopkins is launching its own genome research project. The main mission of this effort, called The Johns Hopkins Individualized Medicine Program (JHIMP), is to collect DNA samples from Hopkins patients. Its aim, implied by its name, is to re-tool the practice of “average” medicine and make it “individualized.”
“Anyone who’s had a pap smear or prostate palpated knows that medicine has always been personal,” Valle says. “However, it’s rarely individualized.”
Only a handful of institutions have begun to collect DNA samples for this purpose, according to Valle. Among the forerunners are Children’s Hospital of Philadelphia and Vanderbilt.
Above and beyond what other institutions are doing or propose to do, the JHIMP intends to couple a DNA-collection initiative to the development of research resources for functional testing, and do it all in the context of a new medical school curriculum, Valle says, adding that there’s “excellent support and high enthusiasm” for the project from the directors of Medicine, Surgery, Pediatrics, Psychiatry, Neurology, Otolaryngology, Wilmer, Molecular Biology & Genetics, Cell Biology, Neuroscience and Pharmacology, Homewood Biology and School of Public Health Epidemiology and Biostatistics.
The fact that the forward-looking project builds on strengths across the university helped JHIMP to win support from the Provost’s office: $200,000 annually for the next three years.
This new funding will facilitate a pilot project so Hopkins clinicians can begin collecting DNA samples from patients, enabling researchers to interrogate individuals’ genomes and identify variants that meet particular validation criteria. These validated variants ultimately will appear on the computerized medical charts of those participating in the study.
“Say I write a prescription for a standard dose of 6-mercaptopurine for a young patient who comes in with acute lymphocytic leukemia, and as soon as I push the button it comes back flagged on his chart, indicating that he harbors a single nucleotide variant that makes him exquisitely sensitive to this drug,” Valle says. “So either I do not use it, or I use it at one-tenth the normal dose, avoiding the standard dose that would land that patient in isolation with bone marrow suppression, getting platelets for three weeks.”
In addition to putting patients’ DNA information on their medical charts, another aim of this project is to foster the basic research that leads to even greater understanding of the functional significance of genetic variation.
“At the time of conception, each of us gets our own unique slice of the apple pie that is our species’ genetic endowment,” Valle says. “We’re just now beginning to see the potential for rapidly assessing each individual’s genetic endowment.”