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Personalized medications

Putting genese to work

by Mary Niehaus

"Medicines matched to an individual's genes? By 2005? That is just too soon. No one will believe it." The journal editor was prodding the University of Cincinnati researcher to push the date to at least 2010. But Stephen Liggett was not budging, insisting his prediction about personalized medications was valid.

When the national publication came out, however, Liggett's article clearly read 2010.

Did the editors of Nature Medicine have an explanation? "They said they forgot," says the chief of pulmonary and critical care medicine and professor of medicine and pharmacology at the College of Medicine.

"I know that 2005 is only four years from now, but it seems to me we've underestimated the pace of the progress of the human genome," he contends. "At one time, we said it wouldn't be finished for several more years, and it's already complete."

Liggett's pioneering attitude is typical of UC's approach to genetic discovery and basic science.

"Genome" is scientific shorthand for the full set of genes an organism carries in each cell. Early in the search, scientists were able to identify individual human genes only after long hours of painstaking laboratory studies of microscopic strands of DNA.

As the race heated up, computerized robotics were used to check thousands of DNA samples per second, 24 hours a day. By June of 2000, scientists from the publicly funded U.S. Human Genome Project and a private company, Celera Genomics, jointly announced that they had successfully mapped and sequenced the 30,000 genes of the human genetic code.

Today, David Millhorn, [above] chairman of molecular and cellular physiology at the College of Medicine and director of the new University of Cincinnati Genome Research Institute (UC opens new genome research institute) says "tons" of genomic data are now available for study in this "post-genome" era. "The challenge," he confirms, "is to take this information and apply it to understanding complex biological problems and disease processes that are regulated by the simultaneous expression (turning on) of numerous genes."

Most of us think of genes as those invisible bearers of qualities we inherited from our parents and grandparents: brown eyes like Grandma's, a freckled nose like Mom's or athletic ability like Dad's. Genes are the things we praise or blame when we identify characteristics that "run in the family," such as twins, longevity or allergies.

genetic revolution

Medical researchers, on the other hand, treat genes very seriously. Consider, for example, a few medical strategies under serious discussion today -- ideas that once seemed like science fiction material:

  • Tiny variations in each person's genes will be recorded in a simple binary "bar code." Physicians will be able to choose the medication most likely to work best and have the fewest side effects by matching it to the patient's personal code.
  • In the near future, individuals will be able to have their genetic profile checked at the doctor's office as easily as blood pressure is done today. The information will help predict disease years in advance, so that prevention or treatment can begin at the earliest stages.
  • "Biologic" therapy -- whether gene- or antibody-based -- will kill diseases like cancer through new strategies that help the body recognize a tumor as something abnormal, something the immune system should attack.

"Knowing the human genome is really going to help us," researcher Liggett says. "We can go find the gene we're interested in, and then look at the diversity there, the ways it varies from one person to another.

"Previously, what we really failed to realize -- or refused to realize," the physician maintains, "is that key proteins (directed by genes) that make your heart, lungs and the rest of your organs work are different from one person to another. This was not well appreciated in science or medicine, perhaps because we just didn't want to believe it, or perhaps because the pharmaceutical firms might then have to consider that one medicine does not fit all."

Liggett's research team, working mainly with asthma and congestive heart failure, began to show in 1992 that variations in a person's response to a medication could be influenced by genetics, rather than their environment or the severity of their disease. The College of Medicine researchers were the first to demonstrate that a drug response could be predicted using genomic markers from an individual's DNA.

"For example, there are five different classes of drugs that we use for treating asthma, and within each class there are three or four brands of drugs, so the doctor has 15 different things to choose from and no way to know which one is going to work," he says. "For the patient, that trial-and-error process means multiple visits and lots of frustration."

If a person were to be tested for a panel of "polymorphisms" or gene variations at the time a health problem is identified, more effective remedies might be prescribed. Liggett, honored by the university as the 2001 Distinguished Research Professor, envisions being able to provide doctors with a three-tiered report on pharmacological options: drugs most likely to work, those least likely to help and those apt to cause side effects.

Could this kind of gene screening actually predict a person's susceptibility to a serious condition like congestive heart failure? Liggett believes it could, but the caution will be phrased in percentages of risk, rather than in absolutes. Knowing that they have a "predisposing gene" for cardiovascular disease probably would make patients take diet and exercise more seriously.


"We think the impact of this type of personalized medicine based on genetics could improve care and decrease costs," the researcher emphasizes. "Ultimately the patient and the doctor will drive this to fruition because they want better care. Or maybe the managed care providers will drive it because it may turn out to be cheaper to get the patient on the right drugs from the beginning, or to encourage people at risk to participate in some modified life style.

"We have the technology and the mind-set," he contends. "That's why I think personalized medications can happen by 2005."

Some of the patients hoping to benefit from the genetic information age are children and young adults with cystic fibrosis, a serious disorder affecting the lungs, pancreas and other organs. The problem stems from a mutation in the CFTR gene, which can cause a child's airways to be clogged with thick, sticky secretions. One answer may be in UC professor and researcher John Cuppoletti's discovery of a way to bypass the defective gene.

"Dr. Cuppoletti's idea is to try to activate another channel in the lungs that's not affected by the CF," explains Robert Wilmott, recently departed director of pulmonary medicine, allergy and clinical immunology at Children's Hospital. Wilmott had been testing Cuppoletti's drug, Omeprazole, with healthy volunteers, to evaluate the effect of various doses on the respiratory tract. The next step is medical trials with CF patients.

"Could this be the cure? I don't think we're going to see a complete cure in one hit," Wilmott says, looking back over 20 years of caring for cystic fibrosis patients. "But if we had one thing that would work really well, we probably wouldn't need to be giving children the large numbers of drugs that we're using right now."

In 1993, Wilmott and two other UC College of Medicine physicians, Bruce Trapnell and Jeffrey Whitsett, initiated a clinical study that attempted to solve CF through gene therapy. The therapy had succeeded in tissue cultures and mouse models, and the doctors were very optimistic.

"We were trying to put a normal copy of the gene that's affected by cystic fibrosis into the airway lining cells of the lungs," Wilmott says. "We were at a very low dose, but it produced a lot of inflammation. We stopped after treating only four patients."

Wilmott believes UC's participation was valuable, even if it was cut short. "At that early stage, not everybody was ready to recognize the toxicity, so I think our contribution was in warning that the treatment wasn't safe and that we had to stop."

Meanwhile, UC surgeon and professor Lyon Gleich is enthusiastic about the use of "biologic therapy" as a viable way to get the human body to fight head and neck cancer. The Archives of Otolaryngology has published two papers about his work with patients at the Barrett Cancer Center.

"Our department has been a national leader in head and neck patient care and research for decades," Gleich points out. "We did lots of the early work on the genes related to head and neck cancer, even before the whole field of genomics took off."

Six years ago, his team began treating patients with a drug that uses a human gene that is part of the immune system. Trademarked under the name Allovectin-7, the drug helps the immune system recognize abnormal markers on tumor cell surfaces, and then attack and possibly kill the cancer.


The first patients chosen to test Allovectin-7 had extreme end-stage cancer, which radiation and surgery had been unable to stop. "Those people had been through everything," Gleich recalls. "They went ahead and signed up for this study, never expecting to help themselves. We thought their immune systems would be too damaged to be able to respond, but some of them actually did get extra time.

"In the multi-institutional study that followed, end-stage patients not only responded, they had no side effects. So we have a cancer therapy that doesn't have significant side effects and can get responses. The key question still to be answered is whether this therapy is strong enough."

Traditional drug treatment for cancer has used chemotherapy, which poisons the body and has intense side effects. Biologic therapies work differently, specifically targeting the cancer or some element within the body that the cancer requires, but that the body doesn't need so much. Gene therapy is one route. Antibody therapy is another.

Gleich currently is using Allovectin-7 to treat patients with very early tongue cancer. Each tumor has been injected with the drug, and will be checked for shrinkage before the cancer is surgically removed. This method may also reduce the rates of recurring tumors and second cancers.

"These new treatments are using the biology of the cancer as a way to kill it," the surgeon reflects. "I think Thomas would like that.

"He was one of our end-stage volunteers. He came to see me and said: 'I was supposed to be dead six months ago!' So he decided to go out and buy himself a Cadillac. I thought, 'Oh my god,' because I knew his chances in the long run were not very good. He lived another whole year and enjoyed that Cadillac every day."

Related articles:

UC opens new Genome Research Institute

UC medical centers at a glance


UC Genome Research Institute (now Metabolic Diseases Institute)