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The Raelian Movement
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Source: http://www.sciencemag.org/content/338/6105/318.full
In the late 1950s near Salem, Oregon, scientists started testing a birth control drug called WIN 18,446 in male prisoners. Men took responsibility for most birth control then, so a male contraceptive seemed a natural fit for American society. WIN 18,446 worked well, too: The prisoners felt fine and seemed quite healthy, except that their sperm was suddenly stunted and feeble. Unfortunately, when clinical trials shifted to the general population, men started getting sick—vomiting, sweating, headaches, blurry vision. They seemed poisoned. After some digging, scientists pinned down the culprit: alcohol. Because prisoners couldn't drink, no one had realized at first that WIN 18,446 did not mix well with liquor. The drug was abandoned, and 60 years later, no one has gotten any closer to the “male pill.”
for those who are not afraid of the future : http://www.rael.org
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Source: http://www.sciencemag.org/content/338/6105/318.full
Reinventing the Pill: Male Birth Control
Researchers tinkering with cancer drugs and related molecules have found reversible ways of altering sperm; now they need to secure money and regulatory support for drug testing.
WIN 18,446 is a perfect example of why creating the male pill is so hard. It did exactly what it was supposed to do—stopped sperm production in everyone who took it—and it was reversible. Sperm levels returned to normal after men stopped taking it. Yet it failed anyway as a drug because of an arguably minor side effect.
Male contraceptives are held to high standards partly because the calculus for male and female birth control is different. For example, taking the female pill increases a woman's chances of developing blood clots. But because pregnancy increases the chances of blood clots by 10 times more, the pill's side effects seem worth the risk. With men, there's no counterbalancing risk of pregnancy, so the tolerance for side effects drops to zero. That's especially true because “you're dealing with healthy people, not people with an illness, and you'd have to use [the pill] for long, long periods,” says Diana Blithe, a program director at the U.S. National Institute of Child Health and Human Development (NICHD) in Bethesda, Maryland, which funds research into male contraception.
Drug companies have all but abandoned the male contraceptive field in the past decade. After acquiring smaller companies, for instance, both Bayer and Merck shut down those programs. (Bayer refused to say why, and a Merck spokesperson said only, “It is not a priority area.”) In addition to the medical challenges like the high safety standard, Blithe points out one other obstacle for companies: The U.S. Food and Drug Administration (FDA) has no guidelines about what levels of safety and efficacy the male pill would need to have to win approval. FDA declined to comment about whether it planned to develop guidelines or whether it has even discussed doing so.
Over the past half-century, contraception has become largely a female issue—and drugs for women work relatively well, making a male pill seem less urgent. But intrauterine devices require a medical provider to insert, can have serious complications, and cost up to $1000. And not all women can tolerate the far more popular female pill, says Lawrence Finer, director of domestic research at the Guttmacher Institute in New York City, which specializes in reproductive issues. Because half of all U.S. pregnancies today are unplanned, he says, there's clearly a need “to increase our contraceptive repertoire.”
With so little private support for a male pill, Blithe's program focuses as much on getting products to market as on basic biology. She will host a closed meeting in November in Houston, Texas, for about 30 top biologists to swap ideas about new genetic and biochemical leads for male contraceptives. The most promising leads involve disrupting the maturation of sperm in the testes, and although funds are tight, clinical trials for a few approaches could begin within the next few years. These researchers hope they can outsmart nature, but they know that producing an effective, safe, cheap, targeted, well-tolerated, bioavailable, easy-to-manufacture, side-effect-free, and (whew) completely reversible male pill won't be easy.
Different targets
Plugs. Hormones. Special underwear. Autoimmune attacks. The “dry orgasm.” There's no shortage of approaches to male contraception (see diagram, p. 319). But all share the same goal: slowing down the relentless proliferation of sperm in men and holding sperm counts to about 1 million per milliliter of ejaculate. Even the reduced concentration “may sound like a lot,” says John Amory, a doctor and reproductive biologist at the University of Washington, Seattle, “but that's a pretty good, effective contraceptive” that will reduce fertility by 99%.
Until recently, scientists modeled most male pills on the female pill and attempted to disrupt male hormones—testosterone above all. The biochemistry is convoluted, but artificially raising testosterone levels suppresses other hormones necessary to make mature sperm. This works wonderfully—sperm levels plummet—but it's a sledgehammer approach that affects tissues throughout the body, causing widespread side effects. There's no good way to administer testosterone, either. Oral testosterone breaks down so quickly in the body that men must take several pills a day to keep levels high, and alternatives like testosterone gels or injections are a hassle. Hormonal contraception doesn't work anyway in 10% to 20% of men, Amory says.
This strategy suffered its latest blow in April 2011, when a high-profile study led by the U.S. nonprofit group CONRAD and co-sponsored by the World Health Organization was called off early. The study had monitored more than 200 couples taking various hormones for more than a year, but side effects such as acne, weight gain, and mood changes convinced scientists that the therapy would fail in the marketplace.
Most current research into a male pill has shifted away from widely circulating hormones toward molecules specific to the testes. One promising approach being explored by Amory and others involves disrupting retinoic acid, one of a group of molecules known collectively as vitamin A. Like hormones, vitamin A plays a role in many different tissues, so scientists can't just shut down the pathway. But sperm are so sensitive to retinoic acid that reducing its levels even a little could prove effective.
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CREDIT: Y. HAMMOND/SCIENCE
Amory's research sprang from WIN 18,446, the failed prisoner drug. Because WIN 18,446 sickened people who drank, Amory suspected that it disrupted the breakdown of alcohols. Wine, beer, liquor, and other booze contain ethanol, which the body metabolizes into acetaldehyde. Because acetaldehyde is poisonous, an enzyme called ALDH converts it to acetic acid (vinegar, essentially). In a paper in the Journal of Andrology first published online in August 2010, Amory's team proved that WIN attaches to ALDH and gums up the process, allowing acetaldehyde to accumulate.
Amory, though, saw the bright side. The testes also convert an alcohol (retinol, another form of vitamin A) into retinoic acid. During spermatogenesis, retinoic acid binds to the RAR protein, creating a complex that turns on genes necessary to convert precursor cells into mature sperm. The testes use a unique ALDH called ALDH1a2 in this conversion. So Amory's team tried to tweak WIN 18,446's molecular structure to make it lock onto ALDH1a2 only, and not onto the ALDH that prevents alcohol poisoning.
It didn't work. “We tweaked the hell out of WIN 18,446,” he laughs. “Our poor organic chemist made 100 versions” in 2009 and 2010, but every one proved a dead end. Still, intrigued by the specificity of ALDH1a2, his team screened 60,000 other molecules and found seven more that gummed up ALDH1a2. They're now tweaking those seven to make them testes-specific. Amory expects four or five of them to fall short in future tests—some might prove toxic or might not cross the blood-testis barrier, a tissue firewall that separates the testes from general blood circulation. But within 5 years, he hopes to approach FDA about clinical trials.
Debra Wolgemuth, a reproductive biologist at Columbia University Medical Center, is also targeting retinoic acid's role in sperm maturation. Through chemical screening, Wolgemuth's team identified a compound that prevents the binding of retinoic acid to RAR, so the downstream genes never get activated. Here, too, the effects are systemic: Retinoic acid binds to similar RAR proteins in other tissues, so Wolgemuth is working with chemists to tweak the drug and make it testes-specific.
Like many in her field, Wolgemuth sees her work as important not just for domestic family planning but also for keeping Earth's overall population at sustainable levels. By some projections, Earth's population could top 10 billion by midcentury. She also says the research could help control animal populations around the world, an important application. She jokes that testing birth control in rodents gave her another idea as well. “We could use it for rats in the New York City subway,” she suggests.
Beyond retinoic acid pathways, there are hundreds of genes expressed only in the testes, and disturbing any one of them might disrupt the machinery of sperm production.
One potential monkey wrench came from James Bradner, a chemical biologist at the Dana-Farber Cancer Institute in Boston. While screening potential cancer drugs a few years ago, Bradner came across JQ1, which inhibits cancer cell division. It does so by interfering with bromodomain (BRD) proteins, which turn on a master regulatory gene that promotes cancer cell proliferation. As part of the screening process, Bradner explores how drugs behave in various tissues, and he found that JQ1 also inhibited a testes-specific BRD called BRDT. Not long before, Wolgemuth's team had showed that knocking out BRDT made mice infertile, and research led by Douglas Carrell of the University of Utah in Salt Lake City showed that natural BRDT variations in men led to infertility. Bradner also knew from experience that many cancer drugs halt the proliferation of sperm, too. All signs suggested that JQ1 had potential as a contraceptive.
Because Bradner lacked experience in the field, he called Martin Matzuk, a reproductive biologist at Baylor College of Medicine in Houston. Within 3 weeks of trying JQ1 in mice, Matzuk knew he had something special: With BRDT shut down, spermatogenesis all but stopped about halfway through the maturation process, and the sperm that did squeak through couldn't swim. Bradner and Matzuk reported these results in Cell in mid-August. Importantly, they also provided evidence that JQ1 didn't affect hormone levels and that it was reversible, because 4 weeks after mice went off it, they could father as many offspring as controls.
Tissue targeting remains a challenge: To satisfy the demand for zero side effects, Bradner suspects the team will need to tweak JQ1 and make it perhaps 100-fold more specific for BRDT than other BRDs. As a hedge, they're also screening for other BRDT inhibitors. JQ1 may go into clinical trials next year as a cancer therapy, though, so Bradner and Matzuk may get early feedback on its contraceptive potential.
Another compound inching toward human trials is H2-gamendazole, which is also a derivative of an old cancer drug. A team led by biologist Joseph Tash at the University of Kansas Medical Center in Kansas City determined that it disrupts Sertoli cells. In addition to providing support for sperm precursors, Sertoli cells bind the precursors in place with a sort of harness, keeping them in the testes until they mature. H2-gamendazole unravels the harness, and sperm drift off into the semen stream before they're capable of fertilizing eggs.
Like other compounds, H2-gamendazole acts within weeks and is reversible. Its big advantage is that its target, the Sertoli cells, lie on the blood side of the blood-testis barrier. So unlike with other potential drugs, “one doesn't have to worry about that tight firewall for compounds getting across,” Tash says.
Having completed many safety tests in rodents, Tash had hoped to start talking to FDA last year about clinical trials. But various bureaucratic delays hampered him. He had to focus on renewing his NICHD grant and also needed help from his university to hire consultants before approaching FDA. But for Tash, such delays are nothing new. He has pursued a male contraceptive since his student days in the late 1960s, when a stint in a Chicago hospital showed him how heavily the contraceptive burden fell on women. He laughs now, saying he never imagined back then that creating a male pill would take so long: “The naiveté of youth had not met the reality of funding and of collaborative research.”
Valley of death
Tash laments that his team has now entered the drug developer's “valley of death,” the gulf between cheap early testing and exponentially more costly human trials.
The difficulty of bringing new drugs, especially contraceptives, to market influences how Blithe's program awards money, she says: “Applications are peer-reviewed with product development in mind. You might hear ‘It's too applied,’ or ‘That's something a pharmaceutical company should do’ in normal grant reviews, but not here.” Grants also include money to hire contractors for tasks like toxicology work.
As for partnering with drug companies, most scientists say that companies urge them to keep them updated on any leads. But that's different from a company committing money. Blithe suspects that some companies view contraceptives as a zero-sum game—that every dollar spent on male contraceptives would mean one less dollar spent on female contraceptives. But she believes many couples will actually double up on pills. Amory does, too. “When I mention what I do at parties, people say men aren't interested in contraception,” he says. “But men were the ones responsible for most contraception before the 1960s” and still take responsibility for 30% of contraception today, he says, despite limited options. “Men are interested,” he insists.
The NICHD meeting in November is closed to the public in part because discussing results openly could interfere with the ability to patent compounds. At the same time, both Blithe and Amory suspect that drug companies may hang back because of fears about litigation. Birth defects and infertility are common in the general population, and, statistically speaking, some couples who use the male pill will experience one or the other for reasons having nothing to do with the drug. But bad luck wouldn't necessarily stop people from suing, Amory points out.
Still, the prize could be worth the risk. “Female oral contraception is one of the most important medicines ever developed,” Bradner says. The male counterpart could be in the same league worldwide, and the identification of testes-specific genes and enzymes makes scientists guardedly optimistic that the time for a safe, effective, targeted, and so on, male pill might be nigh. Blithe says: “To say it's a year off or 5 years off isn't accurate. [But] I suspect that if one gets out there, a lot more will follow.”
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"Ethics" is simply a last-gasp attempt by deist conservatives and
orthodox dogmatics to keep humanity in ignorance and obscurantism,
through the well tried fermentation of fear, the fear of science and
new technologies.
There is nothing glorious about what our ancestors call history,
it is simply a succession of mistakes, intolerances and violations.
On the contrary, let us embrace Science and the new technologies
unfettered, for it is these which will liberate mankind from the
myth of god, and free us from our age old fears, from disease,
death and the sweat of labour.
Rael
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