The Revolutionary New Birth Control Method for Men - Bill Gifford

Accessed 4^th September 2013

http://www.wired.com/magazine/2011/04/ff_vasectomy/all

The Revolutionary New Birth Control Method for Men

By Bill Gifford

April 26, 2011 | 

12:00 pm | 

The promising procedure, developed by scientist Sujoy Guha, is in late Phase III clinical trials in India, which means approval in that country could come in as little as two years.
Photo: Anay Mann

One Saturday in January 2010, Devendra Deshpande left his home in the Delhi suburbs and drove into the city to get a vasectomy. He was 36 years old, married with two young kids, and he thought it was time.

He arrived at the hospital around midday and met Hem Das, then the hospital’s chief vasectomy surgeon. Das had an interesting question for Deshpande. Rather than receive a traditional vasectomy, would Deshpande like to be part of a clinical trial for a new contraceptive procedure?

Das explained that the new method did not have some of the drawbacks associated with a regular vasectomy. First, sperm would still be able to escape Deshpande’s body normally, which meant he would be free of the pressure and granulomas that sometimes accompany a vasectomy. More important, it could be reversed easily, with a simple follow-up injection.

“I am normally not adventurous when it comes to getting myself operated on,” Deshpande deadpans. But the new method sounded good to him, and according to the published studies he read on his smartphone in the waiting room, it seemed safe. He gave his wife, Vinu, a call, and although she sounded nervous on the phone, she said she was fine with it. Deshpande decided to try the experimental method.

When his turn came, he lay down on the table, and an orderly draped his lower body with a green surgical cloth that covered everything but his scrotum. Then Das moved in with a needle containing a local anesthetic. Once the drug had taken effect, Das gathered a fold of skin, made a puncture, and reached into the scrotum with a fine pair of forceps. He extracted a white tube: the vas deferens, which sperm travel through from the testes to the penis. In a normal vasectomy, Das would have severed the vas, cauterized and tied up the ends, and tucked it all back inside. But rather than snipping, Das took another syringe, delicately slid the needle lengthwise into the vas, and slowly depressed the plunger, injecting a clear, viscous liquid. He then repeated the steps on the other side of the scrotum.

The procedure is known by the clunky acronym RISUG (for reversible inhibition of sperm under guidance), but it is in fact quite elegant: The substance that Das injected was a nontoxic polymer that forms a coating on the inside of the vas. As sperm flow past, they are chemically incapacitated, rendering them unable to fertilize an egg.

If the research pans out, RISUG would represent the biggest advance in male birth control since a clever Polish entrepreneur dipped a phallic mold into liquid rubber and invented the modern condom. “It holds tremendous promise,” says Ronald Weiss, a leading Canadian vasectomy surgeon and a member of a World Health Organization team that visited India to look into RISUG. “If we can prove that RISUG is safe and effective and reversible, there is no reason why anybody would have a vasectomy.”

But here’s the thing: RISUG is not the product of some global pharmaceutical company or state-of-the-art government-funded research lab. It’s the brainchild of a maverick Indian scientist named Sujoy Guha, who has spent more than 30 years refining the idea while battling bureaucrats in his own country and skeptics worldwide. He has prevailed because, in study after study, RISUG has been proven to work 100 percent of the time. Among the hundreds of men who have been successfully injected with the compound so far in clinical trials, there has not been a single failure or serious adverse reaction. The procedure is now in late Phase III clinical trials in India, which means approval in that country could come in as little as two years.

But RISUG is garnering interest beyond India. Every week, Guha’s inbox fills with entreaties from Western men. They’ve heard about RISUG on Internet forums or from occasional mentions in newspaper and magazine articles. Some of them even volunteer to travel to India, offering themselves as lab rats. Guha puts them off gently but politely; for now, the trials are open only to Indian men. Everyone else has to wait. “Our options suck,” fumes one frustrated correspondent, a Florida real estate manager who emailed Guha a few years ago. “I’d gladly put my balls on the chopping block for the benefit of mankind.”

He may yet have that opportunity. Thanks to a novel collaboration between Guha and a San Francisco reproductive health activist, RISUG could soon be on the road to FDA approval in the US.

In both the East and the West, the need for better contraceptives couldn’t be clearer. India will soon surpass China as the world’s most populous nation; in the poorest Indian state, women bear an average of nearly four children. Cheap to produce and relatively easy to administer, RISUG could help poor couples limit their families—increasing their chances of escaping poverty. In the developed countries, it would help relieve women of the risks of long-term birth-control-pill use and give men a more reliable, less annoying option than condoms. About half of all pregnancies in the US are unplanned. Come up with a better contraceptive and the likely results are all good: fewer unwanted kids, fewer single parents, and fewer abortions.

Marooned in the marshes of West Bengal, 20 hours by rail from New Delhi, the small city of Kharagpur is a likelier spot for a prison than for one of the world’s most elite technological institutions. In fact, under the British, it was the site of the notorious Hijli detention camp, where rebel intellectuals were imprisoned. After India’s independence in 1947, Prime Minister Nehru pointedly established the first Indian Institute of Technology on the site; today, a steady stream of recruiters from Microsoft, Sun, and Facebook make pilgrimages to the campus in search of the brightest Indian talent.

Guha was a member of IIT’s fifth entering class, in 1957—attending school where his uncle, a radical writer, had been imprisoned years earlier. After Guha reached retirement age in 2002, he returned to Kharagpur from Delhi. Driving around campus today in his 1967 Fiat sedan, Guha points out buildings that he has reclaimed from the jungle and retrofit with labs and workshops—a kind of rogue operation within the university walls. A former mining department building now serves as a RISUG production facility, where his staff mixes up batches of the polymer used in the procedure.

Besides RISUG, Guha is also developing an artificial heart based not on a human heart but on that of a cockroach, which has 13 chambers. His artificial version has five chambers in its left ventricle, which allows it to step up pressure more gradually, inflicting less stress on the mechanism and materials than a conventional design. In another building on campus, he is raising goats that will eventually receive the experimental hearts.

A birdlike man with clear, olive-toned skin and an elegant manner, Guha seems to have been transported from another century. In a sense, he was: Born in 1940, before independence, he still uses Britishisms like see here and good man. He doesn’t waste oxygen on small talk, so when he does speak you know to listen. Nevertheless, he has a lively sense of humor, and when something amuses him he’ll burst into a delighted, high-pitched laugh. At age 70, he still does not need glasses, which he attributes to his daily eye exercises. Every night, he jogs 2 miles around the IIT campus carrying a rolled-up belt to ward off stray dogs. “Every part of the body must be exercised,” he says.

Guha has a penchant for simple yet profound inventions. As a young graduate student at St. Louis University during the mid-1960s, he devised an electromagnetic pump that had no moving parts; instead, it used the ionic charge of seawater to create force. As he explained to a visiting reporter from Popular Science, his pump could also serve as a silent engine for ships—or nuclear submarines. A version of that electromagnetic “caterpillar drive” is, of course, at the center of the film The Hunt for Red October. As has happened with medical discoveries from penicillin to Viagra, Guha was searching for something entirely different when he stumbled across the idea that became RISUG. In the early 1970s, at the behest of the government, Guha was looking for a way to purify water in rural pumps. Treating the water chemically could be too expensive and infrastructure-dependent; he needed a method that was permanent, safe, and cheap. Then a hotshot young professor at the IIT campus in Delhi, Guha figured out a way to line the pumps with a substance that would kill bacteria without depleting itself.

But the project was never completed. In the mid-1970s, India awoke to its urgent population crisis, and the government’s priorities changed. Guha refocused his work on the field of contraception. He soon realized that the same basic concept could work inside the pumping mechanism of the male anatomy—the vas deferens.

In 1979, when Guha was 39, he published a simple four-page paper that outlined the basic concept of RISUG. He had begun experimenting with a common polymer, called styrene maleic anhydride. The SMA was mixed with a solvent called dimethyl sulfoxide, or DMSO, and injected into the vas deferens of 25 male rats. Each male was placed in a cage with three breeding females. After six months, none of the female rats had become pregnant. (In the control groups, all of the females became pregnant.) Guha and his team also showed that the substance could be flushed out with a simple injection of DMSO. Normal fertility soon returned.

They refined the method and tried it successfully in monkeys, whose reproductive physiology is close to that of humans. As a high-molecular-weight polymer, the mixture was not absorbed by the body, nor was it flushed out by the flow of seminal fluid. It anchored to the inner wall of the vas, and in laboratory tests it appeared to be nontoxic. Plus, it seemed to retain its effectiveness indefinitely, like a magnet. In 1989, it was injected into a human subject for the first time. It worked.

HOW IT WORKS 

1.
A reversible vasectomy begins like a regular vasectomy: The surgeon makes a small puncture in the scrotum and extracts the vas deferens, a slender white tube. But rather than severing the vas, the doctor injects the vessel lengthwise with a nontoxic, stable polymer mixture. The process is repeated on the other side.

2.
The polymer, a compound of styrene maleic anhydride (or SMA, an ingredient in floor polish) and dimethyl sulfoxide (or DMSO, a common solvent) anchors itself to the tiny folds in the vas, clinging to the tissue. Sperm and other fluids can still get through, avoiding the backup pressure sometimes associated with a vasectomy.

3.
As sperm pass through the vas, the positively charged polymer interacts with the negatively charged sperm, rupturing cell membranes and damaging sperm tails. The sperm are thus incapable of fertilizing an egg. Sperm production and male hormone levels are not affected. 
—Bill Gifford

Illustrations: Teagan White

Ever since the birth control pill was approved by the FDA in 1960, scientists in the West have been looking for a male equivalent. It’s been a rocky road, in part for biological reasons: Hormonally, it’s much easier to control a single monthly event like ovulation than to try to stop the endless onslaught of sperm.

An equivalent “pill” for men would somehow have to stop sperm production without neutralizing their libido or erectile function. Pharmaceutical companies and government agencies have sunk millions into hormone-based contraceptive research that has yielded few viable products.

And then there’s RISUG. Rather than shutting down sperm production, with the potential side effects that entails, it acts more like a tollbooth on the sperm superhighway. As the negatively charged sperm pass by, they are essentially zapped by the positive charge of the SMA polymer. So a RISUG-injected man will still ejaculate millions of sperm, but most will be dead: tails snapped off, cell membranes ruptured.

As a contraceptive, RISUG faces a far more difficult road to approval and commercial acceptance than, say, a new antidepressant medication. While an antidepressant would be considered a success if it worked in 75 percent of patients, a contraceptive like RISUG will be compared to a conventional vasectomy, which works more than 99 percent of the time. Furthermore, it has to be free from the serious side effects that were common with early experimental hormone-based male contraceptives. And it cannot cause birth defects down the line—ever. “Nobody wants another thalidomide,” says Ron Weiss, the Canadian vasectomy doctor.

In human tests, RISUG performed extremely well. In the first clinical trial of 17 men, published in 1993, all the subjects who received above a certain dosage became azoospermic—that is, they produced no viable sperm. By 2000, it was in Phase III clinical trials in India, the final stage before approval. The compound was injected into 139 men, and the early results looked promising. In May 2002, it was announced that RISUG was on track for approval in India and would be rolled out on a limited basis within six months.

At around the same time, a World Health Organization team came to visit Guha’s lab in Delhi and examine his data. This itself was a triumph: It meant RISUG was finally on the international radar. Weiss, a long-time advocate of the process, was with the group and performed the operation. But the five-person team came away skeptical.

In its report, the WHO team agreed that the concept of RISUG was intriguing. But they found fault with the homegrown production methods: Guha and his staff made the concoction themselves in his lab, and the WHO delegation found his facilities wanting by modern pharmaceutical manufacturing standards. Furthermore, they found that Guha’s studies did not meet “international regulatory requirements” for new drug approval—certain data was missing. The final recommendation: WHO should pass on RISUG.

But within India, at least, RISUG still seemed to be headed for approval. Then, in mid-2002, after Guha and his team had spent years cultivating allies in India’s infamous bureaucracy, a new health minister took over, and the Indian Council for Medical Research (equivalent to the US National Institutes of Health) put the brakes on the trials. Before new patients could be injected, the NIH asked that some of the subjects be analyzed further and that basic toxicology studies be redone.

Of particular concern was the possibility that SMA—a resin found in floor polishes and automobile body panels—is toxic. Styrene and maleic anhydride are indeed toxic separately. But Guha points out that while sodium and chlorine are also toxic individually, “we take sodium chloride all the time.”

The analogy holds for RISUG: Lab tests show that SMA is nontoxic. Guha had convinced the Indian government of the compound’s safety back in the ’80s; now he had to do it all over again, and he was exasperated. Mysterious press reports appeared, stating that some patients had experienced “complications”—which turned out to be nothing more than transient scrotal swelling. In the press, Guha suggested that his doubters had deliberately slowed RISUG to make way for competing hormonal injections developed by foreign companies. True or not, it didn’t make him any friends.

“It was not a problem of science,” says A. R. Nanda, an early supporter of RISUG and former secretary of the department of family welfare. “It was a problem of politics and ego.”

In the middle of it all, Guha reached mandatory retirement age, leading him to leave his post at IIT Delhi, close to the levers of power. He retreated to Kharagpur, in the jungle. But instead of giving up, he dug in, remembering what an old mentor had told him early in his career: that any new scientific idea had to experience four stages of reaction, which correspond to the name of the Hindu god Rama.

“In the first instance, there will be rejection—R,” Guha says, sitting in a folding chair in his fluorescent-lit lab. “If you pursue it, there will be anger. You have to persist. Then, a phase of mellowing will come: ‘Ah, yes,’ people will say. ‘Maybe there’s something to it!’ Then, if you still have patience and courage, will come a stage of acceptance.”

From his home base in Ottawa, Ronald Weiss marvels at the possibilities of RISUG. “If you’re looking for the better mousetrap, this is it,” he says. “I have received emails from men all over the world kind of champing at the bit to get RISUG.”

Weiss had been trying to bring the process to Canada starting in the late ’90s. But when he presented his notes and Guha’s published studies to the regulators at Health Canada, they shot him down. Guha’s studies did not meet their standards, they said. All of them would need to be redone. “Essentially, we were in a situation where we would have to start from zero,” Weiss says. “We would have to redo every single study to get approval. And I didn’t have millions of dollars at my disposal.”

He looked around for a corporate partner but found no takers. Unlike birth control pills, which must be used daily, sometimes for years, RISUG is a long-lasting, low-cost treatment (the syringe could end up costing more than the material it injects). “Pharmaceutical companies are not interested in one-offs,” Weiss says. “They’re interested in things they can sell repeatedly, like the birth control pill or Viagra.”

Reluctantly, Weiss gave up on his plans to commercialize the procedure in North America. But a woman named Elaine Lissner picked up where he left off. Lissner’s interest in male contraception started in the late 1980s, when she was an undergraduate at Stanford. She took a seminar there from Carl Djerassi, one of the inventors of the female birth control pill, who once famously declared that no woman then alive would see a male contraceptive in use during her reproductive lifetime.

Lissner found herself asking the same question that millions of men and women have asked: Why not? Why should there be plenty of options for women and none for men? In college, she’d seen the reproductive havoc wreaked on her friends by a world that places most of the contraceptive burden on women. She wrote a paper outlining what was being done about nonhormonal methods of male contraception, which could be summed up in two words: not much. There were actually, she discovered, men who soaked their testicles in scalding hot water, thinking (correctly but painfully) that it would reduce their fertility. There had to be a better answer.

She founded a small nonprofit advocacy group called the Male Contraception Information Project to push for better male options. By 2001, she had concluded that RISUG was the most promising new development out there and began tracking its ups and downs closely.

By 2009, though, she had grown frustrated with the lack of progress on RISUG in India. Luckily, she was in a position to do something about it. At the beginning of the real estate boom, she’d invested a small amount of money in her father’s construction company, which had become wildly successful building houses around Reno, Nevada. She parked the profits in a small private foundation called Parsemus and set about putting money behind RISUG.

In February 2010, Parsemus bought the international rights to the RISUG technology from Guha and IIT Kharagpur for $100,000. They had worked closely together for years, and she had earned his trust. She also hired Gary Gamerman, a consultant who specializes in shepherding products through the complex FDA approval process. The plan was to get RISUG OK’d in the US, perhaps even before it hit the market in India. “What’s the alternative?” Lissner asks. “Just keep complaining?”

Gamerman told her what she already knew: She would have to begin at the beginning—by making a batch of SMA/DMSO compound in a certified pharmaceutical plant in the US. Later this year, Lissner and her team will begin basic toxicology testing, and if the material passes muster—as it always has in the past—then they will test it in rabbits, hoping to repeat Guha’s results on rats from 1979. Oh, and it won’t be called RISUG anymore. One of Lissner’s first acts was to name the compound Vasalgel. But to get human clinical trials going will take more funding than the $500,000 that Lissner has budgeted; Gamerman estimates that the whole approval process could cost $4 million to $5 million. “There should be tons of interested potential partners,” she says, reeling off a list that includes Planned Parenthood, USAID, organizations like the Bill & Melinda Gates Foundation and the Susan Thompson Buffett Foundation (which have invested in population control and women’s health), and a group called WomanCare Global, run by a former pharmaceutical exec.

“If it’s no longer a crazy Indian idea and it’s something that’s working in India and in rabbits in Ohio and in the first 20 men in the US,” Lissner says, “then there’s got to be a point where there’s just no excuse for a Gates or a Buffett not to get on board.”

Just this past year, in fact, Guha received a $100,000 Gates Foundation grant to pursue a variation of RISUG in the fallopian tubes as a female contraceptive. More important, the Gates grant marked an important milestone for Guha, an international validation of his work. It’s been a long time coming—and an important step toward the final stage of Rama: acceptance.

Meanwhile, after a repeat of some of the basic toxicology tests (and another shift in the political wind), Phase III trials have resumed in India with full government support. Five hundred subjects are expected to be enrolled at 10 study centers around the country. One of those patients was Devendra Deshpande, the man who read about the safety of RISUG on his cell phone before undergoing the procedure.

A software engineer for an American company, Deshpande is slim and sharp-featured, dressed in the global nerd uniform of neat burgundy sweater and faded jeans. He and his wife, Vinu, a broad, cheerful woman, are part of the burgeoning new Indian middle class. They live in Noida, a Delhi suburb, in a complex of new two-story town houses. They have a car and a tidy, comfortable home that resounds with the cries of two energetic young children, a boy and a girl.

An hour after the procedure started, Deshpande was on his way home. He had two band-aids on his shaved scrotum, plus a handful of painkillers and a course of ciprofloxacin—Indian doctors do not mess around when it comes to prescribing strong antibiotics. He used the pain pills for a couple of days and felt some tenderness and swelling for a week but no other side effects. There was no recurring scrotal pain, as sometimes happens with a vasectomy; on most days, he forgot that the stuff was in there.

Which, if you think about it, is the goal of any contraceptive (not to mention the theme of endless Trojan condom advertisements): You forget about it. No one had to take a pill every day. Nobody had to have bloating or other side effects. No “accidents.”

And regarding what Indians euphemistically term “the family life,” he says, there was one big plus: He didn’t have to continue using condoms for three months, as is recommended after standard vasectomies.

“It was business as usual,” Deshpande says. Vinu giggles. “Probably better!”

Bill Gifford (bill.gifford@gmail.com) writes frequently for Men’s Journal and Ou