Medicine: Getting Personal
A host of advances in biomedical science has transformed the way doctors think about drug use, matching prescriptions to the individual and not just to the disease.
Is that cough keeping you awake at night? Try swigging some cough syrup.
Chances are it contains a codeine derivative, and if you are like most people—that is to say, around 80 in every 100—it should help calm your cough within the next quarter of an hour. But you may not be that lucky. You may be one of up to 10 out of every 100 for whom codeine has no effect at all, and you will keep right on coughing. Or you may be among the up to 10 others in whom the merest drop of this synthetically produced morphine extract would be more than enough to help settle your cough.
You need not be a doctor to know that people react differently to the same medicines,” says Dr. Yoseph Caraco, head of clinical pharmacology at the Hadassah– Hebrew University Medical Center in Ein Kerem. “We know that smoking, kidney dysfunction and drug interactions affect the way drugs work. But they do not explain all the differences. Why, for example, does the anticoagulant warfarin help most patients, but can be dangerous for others? Why did sulfa drugs [an early antibiotic] harm red blood cells in many African American soldiers during World War II but rarely cause this kind of damage in Caucasian troops? It has long been suspected that something else is involved.”
That “something else” has been uncovered by two landmark advances in biomedical science.
One of these advances began with the deciphering of the human genome. This led to a map of common genetic variations or haplotypes—a so-called HapMap—on which scientists can identify the genes that make us susceptible to common diseases. The second advance is in technical capability: computer software that enables analysis of hundreds of thousands of biomarkers in a single biological sample.
“Taken together, [these developments] transformed our understanding of health and disease,” says Dr. Yaakov Naparstek, head of internal medicine at Hadassah. “They have led us to discover that what seems to be the same disease in different patients is not the same at the molecular level. This means that the mechanism of the illness, its prognosis and, most important, the way it responds to treatment will differ in each patient.”
“The medicine of the future will treat the patient, not the disease,” explains Dr. Shlomo Mor-Yosef, Hadassah Medical Organization’s director general. “We now know that it’s inappropriate to rely on standard treatment protocols for each disease”—codeine for pain, warfarin as an anticoagulant—“because patients are not standard. Each of us has unique variations in our DNA, which means that the right dose of the right medication is different for every individual.”
All this is so recently learned that the approach hasn’t yet got an official name. Known variously as personalized, customized or individualized medicine or targeted treatment, the lack of a label hasn’t hindered the arrival of what many believe to be medicine’s future.
“The future is already here,” says Dr. Mor-Yosef. By way of example, he cites Herceptin, a drug given to patients with advanced or recurrent breast cancer. “It’s been found that Herceptin is effective only in patients whose tumors have abundant levels of a protein called Her2,” he explains. “In others, it produces no benefit and often unpleasant side effects, so it’s important to know who has the right receptors. At Hadassah, no patient receives Herceptin without the necessary testing.”
The anticoagulant Coumadin (a form of warfarin) is another medication tailored to individual patients at Hadassah. “Coumadin is a very widely used blood-thinning medication prescribed to those at risk for blood clots or heart attacks,” says Dr. Caraco. “In the United States, about a million prescriptions are issued for it each year. But it doesn’t work the same way in every patient.”
In the past five years doctors have learned why. “Coumadin relies on an enzyme in the body known as CYP2C9 to break it down,” explains Dr. Caraco. “One in five people carry genetic alterations that result in low CYP2C9 activity, which means they don’t clear the drug from their bodies as efficiently as the general popuation. Our lab at Hadassah and others worldwide have shown that these patients need lower doses of Coumadin.”
Although the reason for varied responses to Coumadin has only recently emerged, doctors have long been aware they exist. As a result, patients start on low dosages that are adjusted as necessary. “Our lab asked: Is there a better way than this trial-and-error approach?” says Dr. Caraco. “Can Coumadin therapy be tailored to individual patients from the outset?”
Now completing a pioneering four-year study of 200 patients, he is able to answer, yes, it can. “Half our patients were prescribed Coumadin by the traditional trial-and-error method,” he says. “The other half were genetically profiled and medicated according to their genetic background. We saw very clearly that the second group needed fewer blood tests, shorter hospitalization and benefited from the drug far earlier.”
Coumadin and Herceptin are forerunners in a world in which genetic data will be routinely used to calculate drug dosage.
“Within the decade, patients will be analyzed for markers and receive treatment targeted to their genetic profile,” predicts Dr. Naparstek.
Chairman of a committee charged with Hadassah’s strategic planning for the next 15 years, Dr. Naparstek is among those in the forefront of this approach. “We are uniquely positioned to play a leadership role in personalized medicine,” he says. “It combines three areas in which Hadassah already excels: cell therapy, molecular medicine and treatment of immune-mediated disease. What’s needed is an infrastructure, and this is what we’re building.”
The changes to come will be accommodated in the new multistory inpatient tower soon to be built at Ein Kerem. Meanwhile, a preliminary investment of $2 million has purchased sophisticated equipment, which will arrive in 2006, as well as specialized manpower, recruited from Hadassah, Israel and abroad.
A key player in Hadassah’s new Center for Personalized Medicine is the clinical pharmacology unit. Its director, Dr. Caraco, was a member of a team at Vanderbilt University School of Medicine in Tennessee that discovered codeine’s limits. He authored “Genes and the Response to Drugs,” an editorial in the New England Journal of Medicine (December 2004).
He and his team at Hadassah are working to develop gene-based designer drugs—a science known both as pharmacogenetics and pharmacogenomics—to maximize not only the effectiveness of treatment, but also its safety. A recent study in the United States found that 2 million people were hospitalized last year for adverse reactions to properly prescribed medicines; 100,000 of them died.
Why are the all-important enzymes that metabolize medicines sometimes absent, inefficient or overactive? The question is the focus of other key players in this new medical world: the molecular biologists and geneticists.
“Tiny alterations in our genes alter the instructions to the proteins and enzymes that break down drugs in our bodies,” says Dr. Eyal Mishani, head of Hadassah’s cyclotron radiotherapy facility, located in the medical center’s Department of Medical Biophysics and Nuclear Medicine, headed by Dr. Roland Chisin. “Instructions for making each protein are usually contained in a single gene, so even a minuscule genetic change can impact on the form and function of that protein. We’re trying to identify these genes and thus redefine disease on a molecular level.”
This is a major challenge. The human DNA code comprises 3 billion letters, 99.9 percent of them identical in any two people. Molecular biologists and geneticists are targeting the crucial 0.1 percent of differences. Their pivotal tool is the noninvasive nuclear-imaging technique known as positron emission tomography (PET), which measures physiological, biochemical and pharmacological functions at the level of molecules.
“All other imaging techniques—CT, MRI, ultrasound and X-ray—look at anatomy or body form,” adds Dr. Mishani. “PET…shows us metabolic processes [for example, glucose uptake] in real time, as they happen, and allows us to measure chemical and biological factors. Molecular imaging enables us to uncover the biochemical parameters of disease…very early on, which leads directly to therapy and improved therapy outcomes.”
Dr. Mishani and his team are working on image-guided treatment of cancer. “Our aim is to identify the biochemical processes in a malignant tumor and target them by biochemical methods,” he says. “PET allows us to monitor how patients respond to this targeted therapy from the earliest stages. We’re examining several different compounds to identify and monitor different substances and processes, some in their early clinical stages and some still preclinical.”
During the past two years, the treatment of some 30 cancer patients at Hadassah has been monitored through molecular imaging. It has helped oncologists decide when to continue treatment and when to stop. A number of academic papers will soon be published describing this breakthrough work.
Though still in its infancy, the era of personalized medicine has clearly arrived. Eventually it is expected to address all diseases across the board. Pharmacogenetics is expected to add hundreds of gene-based drugs to the pharmacy shelves. Molecular diagnosis, now a slow process, will become a routine, even assembly-line, procedure. And if technology continues at its current pace, the $10 million price tag for sequencing the genome of each individual may shrink to $1,000, making a genetic profile a routine part of a medical record.
“Within five years,” says Dr. Mor-Yosef, “we’re hoping to see personalized medicine move from research…to a regular Hadassah service.”
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