A Toronto scientist balances
cutting-edge pharmacogenetic research with family trips
to Disney World. 
To most people, a pharmacist is the person who fills your prescription and warns you not to drink alcohol while taking antibiotics. But even as an undergraduate in pharmacy, Micheline Piquette-Miller knew she wanted to do research. "I didn't want to memorize or dispense drugs," she says. "I wanted to figure out how they worked." That interest led to increasing involvement in basic and clinical research at the University of Alberta in Edmonton, Alberta, where she completed her PhD. Her doctoral thesis in pharmacokinetics focused on how drugs and the body interact. Now, pharmacy researcher Piquette-Miller all but bounces in her black leather armchair as she explains why she likes her job. "Every day is completely different: I can be working in the lab, speaking to graduate students, giving a presentation at an international meeting, lecturing to undergrads – something different all the time." She lets out an exuberant laugh just before she adds with mock seriousness, "Of course, I have zero time for myself." This is a common complaint, of course, even among people with fewer commitments than Piquette-Miller, who at 37 could the poster child for the modern woman scientist. She has a busy lab, important research, a growing international reputation – and two kids and a husband, whose pictures adorn her otherwise stark office at the University of Toronto. "My saving grace," Piquette-Miller says, "is that I'm a high-energy person; I have a hard time sitting still for very long." Until recently, women in science were under pressure to choose, she says: they could do science or they could have a family, but not both. "You were supposed to" – she gives her voice an arch intonation, so that you can hear the capital letters – "Give Up Your Life For Research." When Piquette-Miller began advanced training in pharmacology at the University of Alberta, there were few women in the graduate programs, and she felt very much in a minority. But she was not daunted: "I felt I could do it all – I wanted to have babies, I wanted to be married, I wanted to be a scientist." Luckily, changes were coming, albeit slowly. After getting her PhD, Piquette-Miller received a fellowship to study at the University of California at San Francisco, in the lab of pharmacologist Kathleen Giacomini. She also became pregnant with her first son. The problem was that her scholarship included no provision for maternity leave – a detail that took some "creative negotiation" to overcome. It helped that Giacomini, herself a mother and successful scientist, was on side. Now, though, such awards routinely include maternity leave provisions, and applications for research grants, the lifeblood of science, take motherhood into account. "The times are changing," Piquette-Miller says, "but they had to." Beyond Trial and ErrorDespite giant strides in medicine and biology over the past century, Piquette-Miller says, "We really don't understand very much about drugs. Most medications are – to put it bluntly – discovered, tested, and used essentially by trial and error." Once a drug is in the clinic, it is prescribed for the disease, not the patient. And, since patients differ even when they have the same disease, this can lead to problems, ranging from simple ineffectiveness to unpleasant and dangerous side effects. Science is, of course, always progressing. With advances in molecular techniques and the completion of the human genome project, "We are now just starting to understand why a drug may be effective in one person and not in another, or why one group of patients displays side effects whereas another group doesn't. And even that partial understanding is a long way from what is now the long-term goal," Piquette-Miller says. "Ultimately, we'd like to be able to individualize drug regimes for each person." Stopping the Body's Internal War on DrugsResearchers are exploring many aspects of human biology to bring that goal to reality. For Piquette-Miller, the key question is what happens when you are ill. "My research now has two foci," she says, "I want to understand at the genetic level how and why humans respond differently to drugs. This has led to a niche, if you will, on how diseases affect the genetic regulation of proteins involved in drug trafficking in the body." When it is suggested that the phrase "drug trafficking" might get her into trouble in some circles, Piquette-Miller's exuberant laugh rings out again, as if she had never heard this feeble joke. The phrase, she says, refers, in this case, to a group of proteins in the body that regulate the distribution and removal of drugs a person happens to be taking. These drug transporters or "drug traffickers" called P-glycoproteins have a useful role in a healthy body, sweeping toxic substances of out cells or tissues before they can cause damage. Jake Thiessen, an associate dean of pharmacy at the University of Toronto, describes proteins like P-glycoproteins as "little elevators" that move chemicals or drugs out of cells. "When these elevators shut down, that has implications for well-being as well as drug effectiveness." P-glycoproteins cannot tell the difference between toxic substances and therapeutic drugs. By removing drugs from cells, they can act as agents of multi-drug resistance. This resistance can be present from the start, or develop after a drug has been used for a period of time. This is particularly a concern with cancer treatments. As W.D. Stein writes in his 1997 study Kinetics of the Multidrug Transporter (P-glycoprotein) and its Reversal, "Most cancer deaths result from the cancer's either being intrinsically resistant to chemotherapeutic drugs, or becoming resistant after being initially sensitive." Researchers are studying how P-glycoprotein affects transport of drugs, but Piquette-Miller is taking another tack – how alterations in genetic expression of transporters such as P-glycoprotein occur within individuals as a result of inflammation or the administration of certain substances. Piquette-Miller's research has opened a new area, Thiessen says, "Can we intentionally change the way these transporters function?" For instance, Piquette-Miller has found that a simple bacterial infection or inflammation can slow down drug removal from cells by turning off the genes responsible for producing these drug-trafficking proteins. These changes can also dramatically raise the levels of a medication in the body. For example, she studied the anti-hypertension drug propranolol, which is sold under dozens of brand names. "We found that blood levels of this drug increased tenfold in those affected by inflammatory diseases such as arthritis," she says. The bottom line? Someone with both hypertension and arthritis is unlikely to get the best results from standard doses of propranolol. Physicians and pharmacists on the front lines of public health are still unaware of much of this research, she says, although knowledge is growing. As a board member of the American Society for Clinical Pharmacology and Therapeutics, Piquette-Miller is helping to bring genetic research and advances in pharmacogenetics out of the lab and into the clinic. "We're trying to train the educators," she says, "but there's still a lot of work to be done before this is part of the average physician visit." And Piquette-Miller's work on drug resistance is attracting attention in other circles – the ones with money to spend on research. In July 2000, she received the prestigious Rx&D Health Research Foundation / Canadian Institute of Health Research Career Award, a C$350,000 national grant for young investigators who show excellence and outstanding potential in research. And that award led to another honor: her nomination as a Mentor of the Millennium by the Alberta Women's Science Network. Mentoring, both formal and informal, plays a central role in science. In the past, this mentoring was known as "the old boys' club," and for decades women were shut out. As a result, women have formed their own networks, Piquette-Miller says. When she worked in California, for instance, she was a member of a group called Women in Life Science. And, of course, it is now part of her job as professor – offering support and counsel to students, especially women, who are trying to follow in her footsteps. "I find it's really fulfilling to play a mentoring role," she says. Running in the FamilyLa famille Piquette is a good French-Canadian clan (lots of kids, lots of relatives) from the small Francophone community of Plamondon, Alberta, northeast of Edmonton. The family farm is still there, but the Piquettes' have spread out – three of the children are in Toronto, Ontario, three in Alberta, and one in New Zealand. If Piquette-Miller refuses to give up science for family, it may be because she had a good example. "My father is one of those genius types," she says. "He started reading encyclopedias when he was three or four." And when he decided to become a chemical engineer, he was not daunted by the fact that he was raising seven children. One of Piquette-Miller's earliest memories is of her father, head down over a pile of books, studying at the University of Alberta, where she would later follow in his footsteps. Still, there was always time for fun. Even in the middle of the school term, if there was snow on the mountains, he would say to the young Micheline, "Hey, let's go skiing." (She is following in her father's footsteps in this way as well. Our interview was squeezed in before she and husband Dean Miller took off with their two boys, Nathan, 10, and Dean, 6, on a family trip to Disney World.) Piquette-Miller says that her eldest sister, Diana, now a senior manager at Microsoft Canada, was her first mentor. "She's a very dynamic person and she would always give me these pep talks," Piquette-Miller says. "It was quite funny – I would be maybe 10 years old and Diana would be saying, 'You're good at math and science, you've got to go for it, you can do anything you want.'" Diana Piquette laughs when asked about her role in molding Piquette-Miller's young mind – a laugh startlingly like her sister's. "It's true," she says. "I was like that." But Piquette-Miller did not really need the lecture, she says, "Mich was always a really determined person. You couldn't make her do anything she didn't want to do." By the same token, it was hard to deflect her from doing what she really wanted. Fortunately, it seems, for both her family and the future of pharmacology, it still is.
|