DNA profiles may transform health care into prevention

Special In personal medicine, a gene chip can be read and analyzed by a computer.

Evelyn Crist took Coumadin for three, maybe four months. Then one day, standing in her Denver bedroom, she looked down at her feet and saw a pool of blood.

"I thought, 'Egads, what's happening? Then I went to the bathroom and there was another pile of blood."'

Crist's neighbor took the 87-year-old widow to Rose Community Hospital's emergency room, where doctors told her that a vein in her lower leg had burst. They stopped the bleeding.

And Crist's regular doctor stopped the Coumadin.

Millions of people take what should be life-saving medications, like Coumadin, for all sorts of conditions.

But once in a while, the same drug that saves one person lands another in the emergency room. Coumadin is a blood thinner, and bleeding is a potential side effect.

Adverse reactions to medications generally kill an estimated 100,000 Americans every year. In the past couple of years, researchers have figured out why. Like so much else, it's hard-wired in genes.

Now, researchers are working on the who. Already there are tests on the market that can predict with a prick of a finger who might be allergic to a drug or need a larger-than-average dose of medication for everything from asthma or arthritis to high cholesterol and leukemia.

Some day such tests, now rare, will become routine.

It's all part of an emerging field called personalized medicine, which has researchers excited, ethicists wringing their hands, and drug and biotech companies racing to profit.

Personalized medicine - an umbrella term for a number of growing specialized fields - expands on the research that identified genetic causes for diseases to predict how more subtle genetic aberrations can predispose an individual to heart disease or diabetes, obesity or mental illness. And it uses that knowledge to tailor medications and treatments to individual patients. Ultimately, some doctors say, it may fundamentally change the way medicine is practiced.

They envision the day tests are administered at birth so everyone could carry around for life microchips loaded with information about what diseases they might be prone to and which medications would most help treat them.

Some who are less enthusiastic say testing is advancing faster than treatment, leaving patients potentially worried about their genetically charted future but unable to do anything about it. And though many states, including Colorado, have taken legislative steps to prevent it, concerns about protection against genetic-based discrimination linger.

Bits of personalized medicine are already reality:

At St. Jude Children's Children's Research Hospital in Memphis, Tenn., a new genetic test that tells doctors which children with leukemia will benefit from chemotherapy and which could be devastated by a normal dose "is standard practice in our institution," said Dr. William Evans, who helped develop the test.

Now, Evans is involved in research trying to figure out why some children don't respond to chemotherapy at all.

In Edwards, Colo., Joan Zimmerman is fighting non-Hodgkin's lymphoma, a cancer of her lymph system, with a vaccine made from the DNA of her own tumor. Unlike conventional chemotherapy that blasts poison all through the body, killing many good cells with the bad, the experimental vaccine Zimmerman takes uses cancer cells and anti-cancer drugs to stimulate her body's immune system against the disease.

In New Jersey, a company known as Seryx is marketing a test it calls "Signature Genetics" to doctors. "Now, for the first time, you can offer your patients a service that will ... personalize their medical care by providing customized information about inherited differences in drug responses," its website promises.

Reggie Downey, Seryx's vice president of sales, won't say how many doctors have bought the test since it debuted in October. But he did say the company is so encouraged by the response that it plans to roll out a companion test this fall that predicts people's chances of illness based on what they eat.

In Wisconsin, Dr. Michael Caldwell has convinced thousands of stoic German farmers and their families in rural Wisconsin to walk into his clinic and lay bare their life stories - medically speaking: their genetic proclivities, their allergies, their very DNA. Caldwell is head of the Marshfield Medical Research Foundation's personalized medicine research center, which was created in 2001.

In its first year, the center got $3 million in grants for studies of topics including why glaucoma treatments fail in fully 20 percent of patients, but fight back the disease in others.

Marshfield scientists are also studying Coumadin, which helps prevent blood clots. When it comes to the number of patients taking the drug, Coumadin ranks 27th in the country. But it's the No. 1 drug for side-effects and complications, Caldwell said.

"In people who are remarkably sensitive, it doesn't take much to have hemorrhagic consequences," he said.

The center is also studying why the widely used painkiller codeine works in 93 percent of the people who take it, but not in the remaining 7 percent.

Scientists know that most medications are metabolized by a group of enzymes in the liver known as P-450 enzymes. A form of that enzyme, called CYP2D6, metabolizes about 20 percent of all prescribed drugs. But researchers at Marshfield have found that CYP2D6 doesn't work in 7 percent of people.

The same isn't true of minorities, a fact that isn't unique to codeine, Caldwell said.

"For a number of different drugs, the frequency (of the inability to metabolize) varies from ethnic population to population," he said.

Studies at National Jewish Medical & Research Center in Denver have found significant differences in how blacks and whites respond to some asthma drugs.

Caldwell says as this kind of knowledge builds and expands, approval of new drugs will speed up.

Figuring out the genetic look of a patient who will respond well to a drug - and the makeup of one who would be harmed by that drug - can eliminate the guesswork and the danger, he said.

"You can set up clinical trials (for new drugs) only on those people you know should respond well," he said. "We will, I believe, start having genotype-based tests for a number of medications."

And Caldwell said some of those tests, including those for drugs like Coumadin, codeine and cholesterol-treating statins, will be common within three to five years.

"That's the wave of the future. Instead of the trial and error approach we have to use now," he said.

Three to five years may be optimistic, said Dr. Lanny Rosenwasser, an allergy and asthma specialist at National Jewish, and part of a nationwide group of researchers called the Pharmacogenetic Research Network. Pharmacogenetics, or pharmagenomics, is the term for the area of personalized medicine that deals specifically with individual, genetic-based reactions to drugs.

Rosenwasser is as enthusiastic as anyone about the potential for personalized medicine.

Where he parts company with other proponents is in predicting when it will happen.

"I hate to be negative about it, but when I talk to clinicians who say that in five or 10 years, people will get a card like a King Soopers card and it can be swiped and it will say, you need to be on X medication for asthma and Y for allergies. ... This is probably going to be medicine in the second half of the 21st century."

Not in the next 10 or even 20 years, he said.

Whenever it comes, Dr. Matt Taylor, at the University of Colorado, predicts that personalized medicine will radically change the practice of medicine.

"Much of the care we do is of symptoms or diseases already occurring, and we react to that," Taylor said.

But if people know from childhood what diseases they are most likely to develop, medicine will have to shift into a preventive, rather than reactive mode.

Dr. Robert Roberts, a cardiologist at Baylor University College of Medicine, agrees.

"Doctors, until recently, what they've learned to do is treat the crisis. What this century probably is going to be remembered for will in fact be prevention," Roberts said.

There are changes ahead, too, for patients. Not every woman who may carry the genes associated with breast cancer wants to know that, for instance.

And Roberts' and others' work identifying genes that cause heart disease has progressed further than medicine's ability to treat the disease.

He predicts that in a few years, all high school and college football players, basketball players and other athletes will be screened for the kind of congenital heart defects that killed basketball players Hank Gathers and Reggie Lewis.

So does he believe that people should be screened for diseases even if no treatment is available?

"Absolutely, yes," he said. The best example of why he feels that way, he said, is Tay Sachs disease.

"It's a horrible disease that affects primarily Askenazi Jews. Most of those kids die by the time they're 5 years old and they die a horrible death."

There's no treatment. But genetic testing and counseling, including pre-marital counseling, have helped incidence of the disease drop by more than 90 percent, he said.

Of course the $64,000 question is what effect environment has on all these genetic twists and foibles. Could getting a clean genetic bill of health as a child translate for some to a lifetime pass to the all-you-can-eat buffet?

"I think that's the other difficulty," Roberts said. "It's going to be a very long time before science can predict a person's true risk for many diseases, because genetic portraits don't include your weakness for bacon cheeseburgers or your decision to take up smoking."

"My thinking is we're going to have to change the way we do insurance in this country," Evans said.

Talking about insurance in the context of personalized medicine is to open a Pandora's box of ethical, legal and financial questions.

"People are going to say, this is going to be terrible - insurance companies will get hold of this information and say, 'Don't insure this guy,' or 'Don't insure her,"' he said.

Such are the issues that the Ethical, Legal, and Social Issues in Science group, part of the Human Genome Project, are wrestling with, and have been since the early 1990s.

So far, most insurance companies don't pay for genetic tests, such as the one for the so-called breast-cancer genes.

Downey said insurance doesn't cover the costs of his company's Signature Genetics screening, which average around $2,000 to $3,000, depending on the physician's charges.

Nor should they, he said. "Some of them would love to because they'd love to get their hands on the results."

Still, legislatures have to catch up to science if genetics-based and personalized medicine is to become practice. And there must be legal guarantees against genetics discrimination, scientists say.

"Before we get wide-scale genetic testing ... the question we have to deal with is: Is society ready?" Roberts said.