Subverting Sperm & Germs
Biophysicist Richard Cone has toiled for years, and endured several "funding black holes," in his quest for a contraceptive that also prevents disease. With BufferGel, he and his colleagues may be on the brink of something big.
"This is a heroic experiment," he says, smiling as he picks up the paper and hands it to a guest. "What's heroic about this experiment? It's just a measure of pH, on the vertical axis, vs. time, on the horizontal axis. But look at where the pH was being measured and what was happening at the time."
The chart's title reads: "Vaginal environment and seminal-fluid content (in vivo determinations)."
"So a couple starts making love, and [the researchers] interrupt the couple every now and then to probe around her vagina and check the pH," Cone explains, noting that the experiment was conducted in 1960 by William Masters and Virginia Johnson, pioneers in studying human sexuality. Cone, laughing, shakes his head as he considers the unbelievable, unavoidable awkwardness the test involved.
He has a quiet but colorful sense of humor, this tall, thin Hopkins biophysics professor with a Quaker-style beard. It's not the kind of humor that jumps out or seizes the stage at meetings or parties, but the kind that emerges in one-to-one conversations. He seems to use it partially as a way of helping people who aren't accustomed to talking about sex, pregnancy, and sexually transmitted diseases (STDs) feel a little more at ease when discussing these matters, which are at the heart of his research program.
Cone, with his trademark humor, sums up his work as an attempt to block "sperm and germs." He and his research group at Hopkins' Krieger School of Arts and Sciences--known collectively as the Mucosal Protection Laboratory--are at the forefront of a movement to develop microbicides, a new method for STD prevention. Similar to spermicides, the microbicides being developed are compounds that can be applied vaginally or rectally in the form of gels, suppositories, films, foams, or creams. Organizations worldwide, from the World Health Organization to the National Institutes of Health, are hailing microbicides as potent new weapons to curb growing epidemics such as HIV. Last year, a who's who of women in the U.S. House and Senate introduced bills to facilitate the development of microbicides; the bills are currently in committee.
Many of the microbicides under development will introduce new virus-fighting mechanisms into the vagina--proteins or bacteria that could kill or build resistance against HIV or other STDs. Other microbicides being developed create a physical barrier to block infection.
But the Cone group's entry, a gel to be applied vaginally before intercourse, is elegant in its simplicity--and it packs a double punch. BufferGel cleverly uses the natural acidity of a woman's vagina not only to prevent pregnancy but also potentially to kill sexually transmitted diseases such as HIV, human papilloma virus, herpes simplex virus, and chlamydia. BufferGel has already begun clinical trials in the United States for its ability to block conception; this summer, trials will be launched in Malawi, Zimbabwe, South Africa, Zambia, Tanzania, and India to test its ability to prevent the transmission of HIV.
If BufferGel is proven effective and gains approval, it will add a significant new choice to disease control--a method that doesn't require the woman to rely upon her partner's willingness to use protection--combined with a simple-to-use contraceptive.
This is no small feat when last year alone, more than 2 million women worldwide contracted HIV, many through sexual contact. In sub-Saharan Africa, almost a quarter of young women 15 to 19 are infected.
"I firmly believe that this issue, this development of microbicides, could do for women's reproductive health the same thing that the Pill did for women's reproductive health 40 years ago," says Lori Heise, who is director of the Global Campaign for Microbicides. "This could do for infection what the Pill did for fertility control for women in terms of putting power into their hands."
|"[Microbicides] could do for women's reproductive health the same thing the Pill did 40 years ago."||
In developing nations, cultural norms dictate women often
have little or no say in matters of sex, birth control, and
protection against STDs; many husbands do not consider
condom use acceptable with their wives. Public health
campaigns have been more effective in encouraging commercial
sex workers to use condoms, but workers' HIV infection rates
are still high.
"The fact that [BufferGel] isn't terribly obvious if you use it, that women may be able to use this without the knowledge of their partner, or their partner may be more able to accept it, that's great," says Patricia O'Campo, an associate professor in population and family health sciences at Hopkins' Bloomberg School of Public Health, who has dedicated her career to studying the intersection of HIV prevention, domestic violence, and contraception.
It would seem that with BufferGel, Richard Cone stands on the brink of fulfilling a two-decade-old dream of making a difference for others. Yet it was a personal tragedy that became the impetus for his setting aside years of research and setting off in a completely new direction.
Twenty-three years ago, the scientific, political, and ethical intricacies of research into sexuality and reproduction were far from Cone's mind. A physicist by training, he had come to the Hopkins biophysics department in 1969 and prospered at research into cell membranes and photoreceptors like the rods and cones in the human eye.
Then, in 1979, his "midlife crisis" hit. Cone laughs softly when he uses the phrase, because it's a midlife crisis only by dint of the fact that he was 43 when it happened.
Cone had tentatively begun to consider changing directions in research. A physiology teacher for years, he had become intrigued by how little was known about the physiology of the male and female reproductive tracts. Then his 8-year-old daughter, Tania Harrison Cone, died of cancer.
"She was such a beautiful, beautiful child," recalls Warner Love, a colleague and close friend of Cone's who recently retired from the Hopkins biophysics department. "It was a terrible death, and a tragic situation." Cone and his first wife, Jane Harrison, had been drifting toward an amicable separation before Tania became ill. They reunited for the duration of the illness, then separated legally after her death.
"There's a part when you realize you've survived, and life is worth living, and she had a good life as long as it lasted," Cone says of that time. "It really raises your sense of, 'We're all mortal. We're all going to die. What are you going to do with your life?'"
Cone felt driven to embark on research that could benefit others in his lifetime. He thought about the void that existed in the knowledge of reproductive physiology. And he was very conscious of the fact that the only widely used method for preventing both conception and the spread of STDs was the centuries-old male condom. "I was confident that advances in biology and technology could help create something that would be more desirable to use than condoms," he recalls.
Cone already had tenure at Hopkins, and he praises it as the safety net that let him freely consider what his new goals would be. "I had no idea whether I could get funded or not, but I knew I had a secure job."
Cone inquired about the possibility of spending sabbatical time working in the laboratory of Larry Ewing, a Hopkins School of Public Health researcher who was a world leader in male contraception at the time. Ewing enthusiastically welcomed him. As Cone began to familiarize himself with the field of reproductive health, he was astonished to learn how prevalent abortions were.
"I had no idea that so many women had them, nor did I have any idea how many babies were 'unintended,'" he recalls. "I did know that women live with anxiety every month their period is late--and that alone was a good motivation [for] improving the reliability of contraceptives."
Cone also learned that American men and women, on average, experience two sexually transmitted infections per lifetime, another figure he thought was unacceptably high.
With these two factors in mind, Cone formulated his dream: to help develop technologies that would block pregnancy and provide "broad-spectrum" protection against a variety of diseases--"sperm and germs."
"That's different than the usual approach," Cone says. "Almost everyone in the sciences works on one thing, one disease, one infection, right?"
Barry Zirkin, now head of the division of reproductive biology at the Bloomberg School of Public Health, was working in Ewing's lab at the time and continues to collaborate with Cone today. He praises Cone's ambitious, unconventional approach.
"Richard is both a careful scientist and someone who passionately wants to make a difference for others. He talked about combining prophylaxis [blocking the spread of disease] and contraception long before it was in vogue, and he got slapped around for it a little bit in the funding department, but he was absolutely right," says Zirkin.
|A core group of ReProtect meets to discuss their latest efforts to attract funding from private investors (l to r): Kristen Khanna, Thomas Moench, Cone, and Kevin Whaley.||
In 1981, just a year after Cone started off on his new
direction in research, officials at the Centers for Disease
Control began tracking some of the first cases of AIDS. As
the severity and extent of the AIDS epidemic became clear in
the 1980s, Cone felt his choice of a new direction in
research had been reaffirmed.
The new direction was an uphill climb. Cone had to learn a great deal about a wide variety of scientific disciplines, including immunology, molecular biology, microbiology, and reproductive physiology. That hasn't been a problem for Cone, who says he loves keeping up with the various sciences, and by all accounts does very well at it.
Finding funding for his research, however, was another story. Cone says he knew he had to build his credentials in the new area to improve his ability to get funded, but he didn't really know what a "feast or famine" experience he was getting into. Cone fell into his first "funding black hole" in 1980-81 and another in the early 1990s, with Cone and a research associate foregoing their salaries for a year.
It wasn't until Bernadine Healy became the first woman to head the NIH, in 1991, "that the NIH devoted funds to studying vaginal immunology, physiology, and microbicides," Cone recalls, describing that changeover as the NIH's "discovery of the vagina."
Notes Polly Harrison, director of the Alliance for Microbicide Development, "We are now seeing a sea change in the microbicide field, and greater interest in support on the part of NIH, other international governments, and foundations that are making these significant advancements possible. A lot of people have been slamming their heads against this wall for a long time, including Richard and his colleagues, and now they're finally starting to get the level of resources and financial support that this field deserves."
Throughout the long years of ups and downs, Cone says he's relied on his second wife, Emily Martin, to keep him "saner."
"She has helped me see how many cultural barriers there are to working in this area," Cone says. "Barriers at all levels--peoples, institutions, thought patterns, taboos, figures of speech, proper culture, proper behavior." Martin is an anthropologist formerly on the faculty at Hopkins and now at New York University. Her discussions with Cone about his research eventually infused her own work.
"We'd be talking about the research, and she'd listen to me with an ear for what language I was using and how I was describing this stuff, and quickly realize how much we project our own cultural perspective on that which we study," Cone remembers.
Martin wrote a widely reprinted essay, "The Egg and the Sperm," that described how gender influences biased descriptions of the sexual processes. Citing quotes in scientific literature, she showed how the male components of the reproductive system were often described in active terms while female components were relegated to a passive role. She then turned to her husband's lab work to show how unfair the practice was. Scientists had long assumed that the sperm united with the egg solely through the efforts of the sperm, but researchers in Cone's group had proved that assumption wrong, demonstrating the active involvement of the egg in the final unification.
The couple's daughter, Ariel Martin Cone, a sophomore at Colby College, offers a slightly different perspective on dinner conversation in the Cone household.
"While most families discuss their days at work, or lessons learned in school, we would often discuss the acidic properties of vaginal fluids, or the path taken by sperm, and diseases in a woman's reproductive tract," she recalls. "It's clear that this type of thing is rarely talked about in a family setting, let alone as openly and informally as it was in our house, but then again, most families don't have unmarked bottles of mysterious gel sitting around the house and experiments being conducted with packets of Sure-Gel fruit pectin."
BufferGel was partially inspired by a 1985 press conference called by William Masters. Noting that HIV is acid-sensitive (something that had already been reported by other scientists), Masters suggested acidity as a way of preventing both pregnancy and HIV transmission.
"It went over like a lead balloon," Cone recalls. "And what everybody said is, all we need is an HIV vaccine." Cone believes many in the research community simply found it easier and more comfortable to consider the notion of preventing HIV infection with an injection than to think about methods that would create a physical or chemical barrier for genitalia. "It's just much more appealing to talk about vaccines," he says. "In a busy cafeteria, start talking about the vagina, and note what happens."
|"Until our work with these things, it just wasn't known how many pathogens or major diseases were acid-sensitive, even among sexual disease specialists," says Cone.||
But Cone pondered Masters' remarks, and thought back to the
classic Masters and Johnson experiment on vaginal acidity--
the one he keeps on his blackboard. The key point of that
study: The acidity typically found in a healthy vagina is pH
4. Sexual arousal reduces vaginal acidity mildly, but the
big change comes when the male ejaculates. Semen (with its
pH of 7.2 to 7.8) pushes the vaginal environment all the way
up to the neutral level of pH 7, effectively abolishing
acidity. Biologically, this is a necessary step toward
reproduction because acidity kills sperm. Hours after sex,
as vaginal acidity levels return to normal, any sperm still
in the vagina start to die.
Could vaginal acidity be the key to a "sperm and germ" one-two punch? Together with Thomas Moench, then an assistant professor of infectious diseases at Hopkins Medicine, Cone started checking to see which other sexually transmitted pathogens swoon or perish at pH 4, the level of acidity naturally found in the vagina. The list, it turned out, was a lengthy one; it now includes HIV, gonorrhea, chlamydia, herpes, syphilis, HPV, trichomaniasis (the most frequently occurring STD in the United States), and Haemophilus ducreyi, the bacteria that causes genital ulcers.
"Until our work with these things, it just wasn't known how many pathogens or major diseases were acid-sensitive, even among sexual disease specialists," Cone says. "Never was the question asked. It was like, 'Well, why would you want to know?'"
While on sabbatical in 1993-94, Cone and Moench resolved to find a means of reinforcing vaginal acidity. They settled on a relatively common pharmaceutical compound that had a pH of 4, and they developed it into BufferGel. BufferGel helps maintain the natural levels of vaginal acidity, dramatically reducing the chances that sperm will survive long enough to fertilize an egg.
"We're not acidifying the vagina," Cone says. "We're just keeping the vagina the way it likes to be, and acidifying the ejaculate. Women often start to smile when they realize that what this thing does is act against his stuff, not against hers."
In 1993, together with another longtime Cone research partner, Kevin Whaley, Cone and Moench founded a private company, ReProtect LLC, to help develop BufferGel and other contraceptive microbicides that are based on research coming from the Mucosal Protection Laboratory.
A good track record for safety and minimal side effects are priorities for BufferGel and the other contraceptive technologies ReProtect is working to develop, according to Cone.
"When you're sick with something, you take a drug even though it has side effects because you want to get better," Cone says. "Women aren't sick when they use these things. So almost any side effect is not tolerable."
Aesthetic considerations also have to be weighed. "It mustn't stain the sheets or underclothes," explains Cone. "It mustn't taste bad or smell bad."
Fortunately, the first phase of clinical trials (both in the U.S. and internationally) showed that BufferGel does well both in acceptability and in safety. Seven of 10 women said they would use BufferGel if it were available on the market, a favorable rating for an acceptability trial. The only side effects noted were a slight increase in asymptomatic yeast infections, and a few symptomatic yeast infections. A positive side effect was also noted: a reduction in bacterial vaginosis (BV), a condition that afflicts about 1 in every 4 women at any given time and causes the vaginal discharge to become foul and fishy-smelling.
BufferGel now stands poised for its "acid test": clinical efficacy. For the Phase III clinical trials testing BufferGel's ability to prevent pregnancy, clinicians in the NIH's trial network are currently enrolling 1,000 women at 10 U.S. sites. Study participants will use a diaphragm with either BufferGel or a conventional spermicide.
"We had to fight [NIH] for the diaphragm," Cone says. "That was a real hurdle. It's a difficult issue for scientists, who would rather just test BufferGel alone, but it's not difficult if you put yourself in the position of the user. Do you want to have the best possible protection? Then you need BufferGel and the diaphragm."
Cone notes that BufferGel has already been tested for its ability to kill sperm in women whose fallopian tubes have been surgically blocked, and that it did well. The current trial will be considered a success if BufferGel and a diaphragm can achieve the same level of birth control effectiveness as conventional spermicides and a diaphragm.
The second trial, set to begin enrolling participants at international sites this summer, will test BufferGel's ability to reduce the spread of HIV in 8,000 women. "You need to do those trials in areas where rates of heterosexual HIV transmission are highest, and that meant international trial sites," Moench says. Cone and Moench urged use of a diaphragm in the trial protocol because they believe diaphragms will make microbicides more protective. Scientific advisers from NIH overruled them; clinicians in the BufferGel HIV trials will recommend, however, that all participants have their male partners use condoms, the only proven method for reducing HIV transmission at this time.
Moench says that if all goes well in clinical trials, BufferGel could be on the market by the end of 2004.
|At 65, Cone is still bubbling with projects he's eager to move forward on.||
At 65, Cone is still bubbling with projects he wants to move
forward on. He's eager to further test BufferGel's ability
to reduce BV, originally discovered in the clinical safety
"BV has been thought of as a mild problem that some women just have to live with. It can be treated with antibiotics, and it goes away but then it comes back," Cone explains. In the past five years, though, a body of evidence has begun to emerge that suggests BV significantly increases the risk of HIV infection and the risk of premature birth and perinatal infections.
Other laboratories have shown that BV causes a reduction in bacteria normally found in a healthy vagina and a growth of a variety of other microorganisms. Cone's group has shown that these other microorganisms are all killed in vitro by pH 4.
Many complications have yet to be explored. A tentative link has been established between the microorganisms involved in BV and the prevention of yeast infections. There are also data suggesting that the bacteria in a healthy, non-BV vagina can lower the risk of HIV transmission through production of peroxides. And scientists don't have any idea how douching could be affecting these phenomena.
Describing all the unknowns, Cone gives a pain-filled groan: "In short, there is too much ignorance!"
Meanwhile, Cone wants to get back to an old dream of developing a liquid condom that could be spread on the penis before sex. He and Moench are also working to develop a disposable vaginal cup that they hope might one day be pre-dosed with BufferGel or another contraceptive microbicide, providing the extra protection of a barrier without the fuss of being fitted for a diaphragm by a doctor. And he's working with Whaley to continue developing the possibility of a vaginal ring that regularly releases mass-produced antibodies custom-selected for their ability to block sperm and germs.
"Cone has passion. He really cares," says Zirkin of his colleague's seemingly endless drive to develop new technologies. "He really does want population to be regulable, and he really does want people to derive full enjoyment from sex without fear of unwanted pregnancy and disease."
Michael Purdy is a Baltimore science writer.
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