- Dr. Garret FitzGerald studies pharmacology at the University of Pennsylvania
- He was influential in the development of low-dose aspirin
- He also demonstrated possible risks in the controversial drug Vioxx
Dr. Garret FitzGerald's career in medicine almost fell through because of a cockroach.
His big zoology exam at University College, Dublin, involved dissecting the mouth of a cockroach under a microscope. To his horror, one of the major components jumped out of his field of vision. "It's over," he thought.
But it wasn't. The exam proctor, whom he remembers looking like Helen of Troy, got down on her hands and knees to help. After about five minutes of searching, she emerged with the mouth part on her thumb.
"If she hadn't found it, I would not be a physician," he said. "It's these quirks of nature that lead you to what you do."
FitzGerald went on to show that low-dose aspirin could prevent cardiovascular disease. He recently shared the Grand Prix Scientifique from the Lefoulon-Delalande Foundation of the Institute of France, a €500,000 ($668,000) award. Last year he won Canada's top cardiovascular research prize, the Louis and Artur Lucian Award.
"Dr FitzGerald for the past 30 years has been one of the leaders in cardiovascular disease research," said Dr. Jacques Genest, Lucian Award chairman and cardiovascular researcher at McGill University Health Center. "He has (been) just like a surfer, perpetually riding the crest of the wave, and he hasn't come down yet."
Now a professor of medicine and pharmacology at the University of Pennsylvania School of Medicine, FitzGerald's work on the cardiovascular implications of pain medicines has resulted in therapies that save lives and improve the quality of life for millions of patients, said Dr. Sanjay Kaul, cardiologist at Cedars-Sinai Medical Center and professor at the University of California, Los Angeles, School of Medicine.
"He's fearless, he's passionate, he's curious, visionary, very, very, collaborative, and most important, he's very nurturing. In my opinion he's the real deal," Kaul said.
FitzGerald's spacious office has a full view of the Philadelphia skyline, but his accent betrays his Irish origins. He grew up in Dublin during a time of austerity in the 1950s and '60s.
He trained clinically in Dublin, but the institutions there didn't have a lot of money for science. FitzGerald was interested in mechanisms, and wanted to work in laboratories, so he headed to London. He worked at what was then called the Royal Postgraduate Medical School, a pre-eminent spot for physician researchers in Europe. He also completed a master's degree in statistics at the London School of Hygiene.
The late 1970s were a difficult time to be Irish in Britain, because of violent attacks by the Irish Republican Army. FitzGerald commonly heard Irish jokes as well as hostile comments.
"It taught me a little bit about being a despised minority, and gave me a certain empathy with people who have to fill that role in this country," he said.
How aspirin works
FitzGerald fell into cardiovascular disease research without any personal connection to the subject. Much later, he found out his father had some cardiovascular problems, and his mother had hypertension, but most people do as they age, he said.
"If any of us discover one thing that matters, we're lucky, because most of us don't," he said. "I think what people often don't understand is that it takes decades for stories to unfold, particularly to know if something stands the test of time. Persistence, focus and hard work are really important."
FitzGerald and his wife headed to the United States to Vanderbilt University in Tennessee in 1980. This is where FitzGerald began to focus on aspirin.
Specifically, he studied fats called prostaglandins, which are instrumental in blood clotting. They also play a role in metabolism, sleep-wakefulness cycles, fertility and cardiovascular disease.
The first step in forming a clot that can lead to heart attacks is the aggregation of blood cells called platelets. In a test tube, it was shown that aspirin can block the platelets sticking together. Specifically, it blocks thromboxane, a type of prostaglandin (fat) that platelets form.
"So, it seemed like a short leap from those observations to showing that aspirin had clinical usefulness," FitzGerald said. "But it turned out it wasn't a short leap."
The 1982 Nobel Prize in Medicine was awarded to Sune Bergstrom, Bengt I. Samuelsson and John R. Vane for the discovery of how anti-inflammatory drugs including aspirin prevent prostaglandins from forming by blocking an enzyme called COX.
Over a decade, researchers conducted trials looking for evidence that aspirin had cardioprotective effects. The Nobel Prize-winning research showed aspirin could potentially prevent heart attack and stroke, but researchers could not find an association in clinical trials.
What was missing, FitzGerald said, was understanding the mechanism by which the drug actually worked in humans, so that populations in which it would be useful could be identified.
FitzGerald and Dr. Carlo Patrono, chairman of pharmacology at the Catholic University, Rome, with whom he recently shared the big French prize, investigated this. They established that lower doses of aspirin than were used for pain relief in arthritis were just as effective in blocking platelets.
"Low-dose aspirin protected the heart and minimized the risk of harm to the stomach, a common complication of the higher doses in arthritis," FitzGerald said.
Patrono and FitzGerald initially worked independently, but then became close friends, jogging buddies and collaborators.
"He's not a superficial reader of reality," Patrono said. "He's very deep in his desire to know and understand what's happening, not just in science but in society."
Who should and shouldn't take it
FitzGerald and colleagues established that aspirin would particularly benefit people with acute coronary syndrome -- patients with episodes of chest pain that ultimately culminate in heart attack. During each of those episodes there was a huge spike in the formation of thromboxane -- the prostaglandin that aspirin blocks.
Three placebo-controlled trials with aspirin for people with acute coronary syndrome showed a huge effect: about a 50% reduction in death rate and a 50% reduction in heart attack rate, FitzGerald said.
FitzGerald and colleagues also did basic research to show that aspirin could work in conjunction with a clot-busting drug called streptokinase in people with heart attack. Paradoxically, they demonstrated that platelets were also activated when the clot was broken up, which opened the way for a benefit from aspirin. The ISIS-2 clinical trial confirmed in a large human population that each of these drugs reduces risk of death, but in combination the effect is doubled.
But other drugs in combination with aspirin can be harmful, FitzGerald showed. At high, chronic doses, other NSAIDs can not only be detrimental to the stomach, but may also undermine the cardioprotective effects of aspirin. This led to an FDA advisory warning against combining these drugs.
Interestingly, while FitzGerald and colleagues have shown the mechanisms behind the protective action of aspirin against heart attacks, he points out that there's a lot less known about another substance that millions of Americans take every day for health benefits: vitamins.
Clinical trials have largely failed to show the positive effect that consumers may believe in; vitamins may even be harmful.
FitzGerald's group developed ways of measuring free radicals -- atoms and molecules that damage cell membranes and DNA -- which antioxidant vitamins are supposed to suppress. The researchers showed that vitamins C and E have no effect on normal levels in healthy people; but there may be particular groups of people who would respond.
"Just like the earlier experience with aspirin, the clinical trials may have been performed in populations that were never likely to be responsive to vitamins," he said.
An inflammatory anti-inflammatory
When FitzGerald came to the University of Pennsylvania in 1994, he and colleagues began work on anti-inflammatory drugs called COX-2 inhibitors that hadn't yet come on the market, now known as Celebrex and Vioxx.
They used similar techniques to the ones they had developed around aspirin to try to understand how they worked in the human body, and found that these drugs could carry a cardiovascular risk. These studies published in 1999 on Celebrex and Vioxx were funded by the drug companies, but led by the researchers, and were the first to raise questions about these drugs' potential to cause a problem.
Vioxx was voluntarily withdrawn from the market in 2004, after a study called APPROVe, sponsored by Merck, found a clear connection between this drug and heart attack and stroke, and after Merck was accused of hiding information about risks. Since then, 10 different randomized trials have found that three COX-2 inhibitors -- Celebrex, Bextra and Vioxx -- carry a cardiovascular risk, FitzGerald said; the first two, however, are still on the market.
Perhaps surprisingly, FitzGerald doesn't think Vioxx, which was reported to be linked to thousands of heart attacks and deaths, should have been pulled. He would prefer a scientific investigation to separate the risks from the benefits. He's working in a consortium of dozens of groups investigating who are the people for whom particular anti-inflammatory drugs are most likely to work, and for whom they are most likely to cause a problem.
This 10-year research effort is chasing the dream of personalized medicine -- the idea that a person's individual genetic makeup can reveal which specific medical treatments are best for him or her.
Because pain isn't a disease, understanding how different pain medications work differently in different people is a big challenge -- but it's what FitzGerald would like to see happen in the next decade.
"I think it would not only provide incredible benefit to how we treat pain and inflammation, but I think it would also potentially be a sort of paradigm that we could then extrapolate to other large classes of drugs that are used to treat these syndromes or disease," he said.
"And if we had done it once, we could do it much faster than over a decade for the next class of drugs."
The cell clock tango
FitzGerald's other major research interest is called molecular clockworks. This is a fairly new science that can be applied to many areas of physiology, based on the idea that the body has within it 24-hour clocks, regulated by genes that operate in these daily cycles.
There's a master clock in the brain, and FitzGerald and colleagues identified a possible signal from the brain to instruct clocks in the vascular system. They have also investigated the role of various genes that are relevant to the clock in determining the oscillation of blood pressure.
The heart clock can send messages to the brain clock, too. It's like an orchestra, says FitzGerald, in which musicians not only follow the conductor, but can also function independently, and -- according to his unpublished research -- even influence each other.
An exciting area of exploration is how these clock networks interact across different tissues, he said. Could the clocks be manipulated so as, for example, to slow down the progress of Alzheimer's while not messing up metabolism?
"I think it's the beginning of an era as far as this field is concerned," he said.