Story by Mona Gable. Photography by Mark Berndt
SEVEN YEARS AGO, Janet Pregler, M.D., invited a small group of successful executives to breakfast. Over coffee and croissants, the affable director of the Iris Cantor-UCLA Women’s Health Center proceeded to tell the highpowered bankers, lawyers and assorted professionals an improbable tale.
Deploying a Power Point presentation, she trotted out a series of blunt facts. Did they know, for instance, that when she was in medical school in the 1980s, that apart from obstetrics and gynecology, there wasn’t a single course devoted to women’s health? Were they aware that, historically, medical-research subjects were often exclusively men, in part because women had this reproductive issue that made it easier and cheaper for scientists to study males? Furthermore, did the audience realize that even the mice used in studies – the mice! – were usually male?
The guests at the breakfast, who happened to be exclusively female, had heard enough. “All those things were new to me,” recalls Julia Gouw, one of the attendees, “Whether it’s research or medical treatment, women are the stepchild of the medical field.”
Soon after, Gouw, president of East West Bank and a member of the board of directors of The UCLA Foundation, placed a few strategic calls. She told her friends about the funding crisis in women’s health, and then she asked them a probing question: Would they be willing to kick in $10,000 a year to advance research solely on women? They, in turn, asked other prominent executives they knew. And with that, a unique philanthropic effort was born called the Iris Cantor-UCLA Women’s Health Center Executive Advisory Board.
“It has always made me angry that research was not done on women,” says Jan R. Cloyde, co-founder and former president of Grandpoint Bank, and one of the three original board members Gouw recruited. “So I was immediately interested in helping support and grow this group. Originally, we thought if we could get 10 or 15 members, that would be great. We now have 27.”
Since then, “the capitalists,” as they jokingly call themselves, have provided UCLA scientists with more than $1 million to advance women’s health, including more than $600,000 in seed money for research related to women’s health. With that funding, investigators across UCLA have tackled studies ranging from heart failure in women and sex differences in migraine to understanding menstrual irregularity and the effects of female hormones on stress.
Each year, Dr. Pregler huddles with a group of handpicked scientists who sift through proposals from campus researchers to winnow the recipients to four. In many cases, the researchers have been able to leverage those initial small studies to obtain much larger grants.
The chemistry between the capitalists and the researchers has also led to another memorable meal. Now, every winter, Dr. Pregler and Gail Greendale, M.D., research director of the Cantor Center, host a “Lunch with the Scientists.” There, over iced tea and grilled salmon, the female rainmakers hear presentations from the researchers who’ve benefited from their feminist vision and largesse. “To sit in the lunch with those scientists,” says Cloyde, “is beyond words.”
Here are stories of some of those researchers whose work has been supported by these forward-thinking women.
WHEN DANA REEVE DIED IN 2006 OF LUNG CANCER, AT AGE 44, the beloved widow of actor Christopher Reeve had never smoked a cigarette. Her shocking diagnosis led many to ask the same question: How could she have gotten such a toxic form of lung cancer and died at such a young age?
It was precisely because of her high profile that Reeve drew attention to a largely invisible medical crisis. Since 1987, lung cancer has surpassed breast cancer as the leading killer of women; more than twice as many women die of lung cancer as succumb to breast cancer. And, like Reeve, an astonishing 80 percent of nonsmokers who get the deadly disease are women.
Richard Pietras, M.D., Ph.D., is all too aware of these grim statistics. For the past seven years, he’s been researching what he calls the “epidemic” of lung cancer in women. He will tell you that female lung cancer deaths have soared 600 percent since 1950. He will also tell you why there’s so little awareness of this fact. “It gets lost in the wave of publicity for all these other cancers, especially breast cancer,” says Dr. Pietras, professor of medicine-hematology/oncology and director of the Stiles Program in Integrative Oncology.
While there are advocacy groups to fight breast cancer and prostate cancer, lung cancer is another story. There’s no real advocacy group for lung cancer because the survival rate of patients is so poor. “In the first five years, most patients with advanced lung cancer will pass away,” he says. “You don’t have these survivor groups for research funding.”
Lung cancer also has an image problem; it is a grim disease with a grim outcome and often elicits judgment and disdain as something that is self-inflicted. “Most people would right away think you were responsible for getting lung cancer because you smoked,” Dr. Pietras says. “Even patients themselves feel that way. They don’t want people to know.”
As it happens, one of the under-reported findings of the 15-year, National Institutes of Health’s Women’s Health Initiative study was that women who took hormone-replacement therapy were more likely to die of lung cancer than women who had a placebo. Dr. Pietras was already studying the hormone-lung cancer connection, and he suspected that estrogen was fueling the disease. With a grant in 2008 from the Iris Cantor-UCLA Women’s Health Center Executive Advisory Board, he and co-investigator Diana Marquez-Garban, M.D., made a pivotal contribution to the field: Dr. Pietras confirmed the presence of estrogen-receptors in lung-cancer cells. That research has enabled Dr. Pietras to pursue a new study, one that could lead to better treatments for the deadly disease. Along with Edward Garon, M.D., professor of hematology and oncology, he is now running a clinical trial to explore the benefits of using anti-estrogen therapy in more than 100 female lung-cancer patients.
“We always knew the breast was a target,” says the scientist of estrogen’s role in breast cancer. “But most people never thought about the lung as a target organ. So having this seed funding is very critical to try to inspire people to move forward in areas where there’s not a proven track record.”
AS EVERYONE LEARNED IN HIGH SCHOOL BIOLOGY, males carry one X and one Y chromosome while females have two X chromosomes. Yet in females, this XX is toxic. So during embryonic development, a remarkable thing happens. One of the Xs in females is “silenced,” or inactivated.
How does this process happen? Scientists don’t really have a clue, but it is a puzzle that Alissa Minkovsky finds fascinating. “It’s a crazy thought you can silence an entire chromosome,” says the young researcher, a fourth-year student in a joint M.D./Ph.D. program in the David Geffen School of Medicine at UCLA .
And it’s a puzzle the enterprising medical student could eventually help solve. Last year, Kathrin Plath, Ph.D., assistant professor of biological chemistry, invited Minkovsky to join a pilot study she’s leading to unravel the mysteries of the double X. With a $30,000 grant from the Iris Cantor-UCLA Women’s Health Center Executive Advisory Board, Dr. Plath and Minkovsy are trying to understand how X inactivation occurs. They’re hoping to find the proteins involved.
If they succeed, the researchers could provide insights into one of the most important mysteries surrounding female biology. As Minkovsky explains, “The larger part of women’s health focuses on studying the function of reproductive organs and hormonal axes. Yet X-chromosome inactivation is one of the most basic cellular differences between men and women.”
X-inactivation affects the outcome of mutations on the X chromosome. Rett syndrome, for instance, a rare brain disorder caused by a genetic mutation on the X, occurs almost exclusively in girls. After six to 18 months, girls with the disease suddenly develop severe learning, communication and language problems. Male cells only have one X, and if that X has a mutation, embryos die.
“On average, every cell in a girl with Rett syndrome will have 50 percent of cells expressing a mutant form of the protein and 50 percent of the normal one, due to X inactivation,” says Minkovsky. Therefore, females are born but carry the disease. In the lab, the two scientists have been taking normal cells and manipulating them into stem-like cells that express the normal protein. Potentially, these cells could be made into neurons and then reintroduced into patients to treat disease. “The beauty of that is you’ve derived the cells from the patient to begin with,” Minkovsky says.
Although it’s not yet clear, studies suggest that X inactivation could play a role in breast cancer and other diseases affecting women. “You’ve got this whole chromosome that’s been inactivated,” says Minkovsky. “It’s such an important process, and if it goes wrong, female cells don’t behave correctly at all.”
For researchers to prove that intimate connection, she adds, “We must identify more molecular players involved in silencing the X chromosome.”
In 1997, WHEN MAUREEN MCMAHON, M.D., graduated from the University of Chicago’s Pritzker School of Medicine, women’s health was not a priority at the well-regarded institution. “It did strike me as a little odd,” recalls Dr. McMahon, assistant clinical professor of rheumatology at the David Geffen School of Medicine at UCLA .
At the time, Dr. McMahon was beginning to focus on lupus, a littleunderstood disorder that afflicts some 1-million Americans with conditions that range from arthritis to severe fatigue. The disease can damage the brain, the kidneys and other organs. “Lupus was interesting to me largely because it’s a disease that can affect women, and often young women,” she says. “It has a wide range of what it does.”
When she had the opportunity to launch her own study, Dr. McMahon thought she’d approach it a little differently. The scientist knew that women with lupus are at much greater risk of heart attacks and strokes, even when you consider normal cardiac-risk factors like high blood pressure. Yet, despite the high prevalence of heart disease in females in both the general and the lupus populations, Dr. McMahon was struck by one prevailing fact: “When you start to look through the cardiovascular literature, a lot of the studies had been done on primarily male populations. The number of studies done in populations of women with additional risk factors like lupus was even smaller.”
She also knew that some men with heart disease had an elevated level of dysfunctional, pro-inflammatory HDL – the so-called “good” cholesterol. Was this dysfunctional “good” cholesterol playing a similar role in women with lupus and their enhanced threat of heart disease?
In 2007, with $20,000 in seed money from the Iris Cantor-UCLA Women’s Health Center Executive Advisory Board program, Dr. McMahon set out to test her theory – this time using women as her research subjects. In the study, she examined more than 300 women with lupus and more than 165 healthy women for atherosclerosis and the HDL abnormality.
The results were staggering. “We found, lo and behold, that HDL does seem to strongly associate with the risk of heart disease in lupus patients,” says Dr. McMahon. Nearly 87 percent of the women with lupus and thickening of the arteries characterized by cardiac disease had dysfunctional HDL . Even after accounting for traditional cardiacrisk factors, women with lupus and dysfunctional HDL were 10 times as likely as women with normal-functioning HDL to develop atherosclerosis. Similar increases in risk were seen in non-lupus women with dysfunctional HDL .
Although it wasn’t her primary goal, Dr. McMahon also set straight a widespread misconception about women and heart disease. “Our mean age was about 45,” she says of the participants, “so it’s a younger age than you’d think of as being the age for onset of heart disease. Yet in women with lupus, we do see this increased risk.”
She also proved the importance of doing gender-based studies on women. Unlike men, women typically have “silent” heart attacks, where their symptoms aren’t obvious. “Looking at men doesn’t give you the full picture of risk in women,” says Dr. McMahon. “There’s a lot we don’t understand about the most significant risk factors in women. By studying a population of women who have inflammation, it might give us some insights into what’s going on with women in the general population.”
IN 2009, CAROLYN CRANDALL, M.D., published a landmark study on breast cancer. The findings, which appeared in the Archives of Internal Medicine, showed that women who experienced breast tenderness after taking menopausal hormone therapy had nearly twice the risk of developing breast cancer after a year than women who did not have achy breasts.
It was the first time such a link had been made. For women going through menopause and conflicted about menopausal hormone therapy, the implications were profound. “We never really understood if there was any way to predict who gets breast cancer while they’re taking hormones,” says Dr. Crandall, professor of medicine, who examined data from more than 16,000 women involved in the 15-year, National Institutes of Health’s Women’s Health Initiative study.
“Maybe breast tenderness is such a hint? It’s important because fear of breast cancer is one of the most marked fears women have,” Dr. Crandall says. “Women are afraid to take hormones.”
For physicians, the findings were a long-needed wake-up call. “When women complained of breast tenderness, doctors always patted them on the shoulder: ‘Oh, we’ll change brands, or maybe we’ll change the dose,’” says Dr. Crandall. She pauses. “Maybe that was the wrong answer.”
The Women’s Health Initiative study was the most ambitious effort ever taken to understand the link between menopausal women on menopausal hormone therapy and breast cancer, among other issues. But in 2002, the study was halted, when researchers found that women who were taking the estrogen-plus-progestin treatment had a marked risk of breast cancer. Although Dr. Crandall’s discovery generated a frenzy of international media attention, the initial response from some in the medical establishment was more like a yawn. When she sought to publish her research in a prestigious medical journal, Dr. Crandall was politely told it wasn’t of interest.
Shortly after, the frustrated researcher burst into her boss’s office. “I can’t believe the editors of this journal didn’t think it was important!” she fumed to Dr. Pregler. The women’s-health expert promptly gave her a reality check. “Pick up the phone,” she told Dr. Crandall, “call any woman age 50 and over in this country and ask, ‘Do you think it’s important that breast tenderness might indicate breast-cancer risk?’ They’ll say, ‘Duh, of course I want to know this!’“
For the record, Dr. Crandall got a similarly tepid response when she approached government agencies. A pilot study on breast tenderness linked to breast cancer risk? It was so hypothetical and out of the box. There weren’t any data. Besides, agency funders contended, menopausal women weren’t even taking estrogen and progestin anymore.
Wouldn’t you know it, it took a woman – or rather, three women – to see the brilliance in the scientist’s idea. Banding together, interior designer Rose Tarlow, children’s-health philanthropist Jane Eisner and artist and philanthropist Ann Moss, owner of the racehorse Zenyatta, created the Tarlow-Eisner-Moss Research Endowment of the Iris Cantor- UCLA Women’s Health Center. It gave Dr. Crandall the funding she needed to take off.
“Thank god there is an alternative source that exists for this type of work,” she says. With backing from the Iris Cantor-UCLA Women’s Health Center Executive Advisory Board, Dr. Crandall recently completed a follow-up study. While her original investigation examined breast discomfort in women taking estrogen plus progestin, this one looked solely at a group of 8,000 women using estrogen. Will there be a difference?
Whatever she discovers, the need for such gender-focused research is clear. “Women want to know,” she says.
NOT LONG AGO, women were regarded in medicine as merely little men. Obviously, their reproductive equipment was different, but as far as the rest of biology went, their bodies were assumed to behave the same. After all, didn’t they share the same genetic code?
Then, in 2006, a group of UCLA researchers were looking at mice – specifically at the liver, brain, muscle and adipose tissues of mice – when they noticed something extraordinary. There were striking differences in the way genes were expressed in males and females. If this finding was true in mice, it almost certainly was the case in humans. Gender, in fact, did matter. Maybe this discovery could help explain something that baffled physicians: why women and men sometimes respond differently to the same diseases and drugs.
This was heady stuff. So when the study was published in the August 2006 issue of Genome Research, the attention it attracted was immense. “The sex-aspect differences between men and women are perennially of interest to people,” says Thomas Drake, M.D., professor of pathology. “That’s the one paper I’ve been involved with when we’ve had news people call; even TV people come over and videotape us.”
Dr. Drake, working with colleagues Jake Lusis, Ph.D., professor of human genetics, and Xia Yang, Ph.D., then a postdoctoral fellow in cardiology, discovered that even in the same organ, thousands of genes varied according to sex. While the smallest gender gap turned up in the brain, the largest appeared in the liver. This finding wasn’t just academic. With those differences, researchers might be able to understand a variety of common disorders, from obesity to diabetes.
“There are biological differences that almost certainly affect diagnosis and treatment,” says Dr. Drake. “If you find a genetic mutation in a man and the same genetic mutation in a woman, in one of them you could have a very significant risk and in the other no risk. In general, it’s probably not going to be all or nothing, but a modifier.”
The study was also significant in another way because it identified areas for developing gender-specific drugs. In heart disease, for instance, it has long been known that aspirin is more effective in preventing heart attack in men than in women. Yet the drug has been routinely prescribed for women as well.
Dr. Drake and other scientists have been fascinated by gender differences for some time, and they are seeing the mouse-research community increasingly recognize their importance. “You need preliminary data to publish something to show that it’s real,” Dr. Drake says. The $20,000 he received from the Cantor Center “helped us at an early stage.” Mona Gable is a freelance writer in Los Angeles.
Mona Gable is a freelance writer in Los Angeles.