A very good overview with some detail, into the activities of Elixir Pharmaceuticals as of April 2003.
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Take This Pill and Live Forever
by James Burnett
From the April 2003 issue.
http://www.bostonmag...play.php?id=228
Well, maybe not that long. But a growing number of respected scientists believe it will be possible — in the not-too-distant future — to create drugs that not only extend your life by decades but also stave off diseases.
Sound too good to be true? You haven't seen what's going on at Elixir, a Cambridge startup that may well live up its mystical name.
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Can you feel it? It's happening right now, and the worst part — nature's cruelest twist — is that the fuels your body relies on are in on the conspiracy. The oxygen in the breath you just drew, the grapefruit you ate for breakfast, the diet soda you had at lunch — they all play nasty pranks when you invite them inside. They muck up your cells, the billions of motors that power your organs, by sticking the biological equivalent of discarded chewing gum on the gears. They fling short-fused firecrackers, and the shock waves short your circuits and drain your batteries. Your built-in pit crews scramble to repair the damage, but they can't keep up. The motors gradually break down. As your body cranks out replacements, the thousands of intricate parts don't always come together quite right. You wind up with a go-cart where you had a Mercedes. Or maybe something that doesn't have any wheels at all. And if you don't already, you will: You'll feel it in your aching joints, see it in the wrinkles creeping into your skin. You are growing old.
You drag yourself into the gym. You eat right and remember to take your vitamins, and maybe you also start popping ginkgo biloba or human growth hormone or one of the other unproven products that make up the $6 billion market for antiaging supplements. You keep yourself healthy. You convince yourself that you're still in control. But you're wrong. You're not. Your cells are working against the longings of your soul, and there's nothing you can do to stop them. The switch is out of reach. Your best hope — maybe your only hope — is that Elixir Pharmaceuticals, a biotech startup promising enough to have financial backing from Boston University, MIT, and Oracle CEO Larry Ellison, will figure out how to flip it for you.
At Elixir's Kendall Square headquarters, well-credentialed scientists are racing to develop something other scientists were once certain was impossible: a drug that can grant the universal wish to stay young. Not forever — but for several decades longer than you could without it. Lenny Guarente, a molecular biologist at MIT, launched Elixir with two like-minded scientists three years ago. The company already knows how to double the life span of yeast cells and microscopic worms by goosing their genes. The leap to accomplishing a similar feat in human beings, though daunting, is shorter than appearances suggest. And the gap is closing all the time. In February, Elixir merged with Centagenetix, a Cambridge firm that was fast becoming its crosstown rival. Cofounded by Tom Perls, an associate professor of geriatrics at BU Medical School and head of the acclaimed New England Centenarian Study, Centagenetix wants to understand the secrets of the roughly one in 10,000 people who live to be 100: how they defy the odds; why so many of them are in such surprisingly good health. Last year, Centagenetix researchers found a gene that seems to give some of its owners an advantage in the race against time. They're calling it CGX1, and they have submitted their findings to a prestigious journal. "Batten down the hatches," says Perls, who has grown accustomed to media attention. You will hear a lot about CGX1 later this spring. (haven't seen anything on CGX1 yet.. kp)
The next challenge, the next act leading up to what would be a whiz-bang finale, is to transform the discoveries made by Guarente and Perls into a viable product. Scientists at the combined venture — which has tentatively decided to keep the Elixir name — have begun initial tests on two pharmaceutical compounds and are hunting for other formulas that might do the trick. During a tour of the company's facilities, Elixir CEO Ed Cannon, a veteran biotech entrepreneur, shows off the sleek, brightly lit laboratory where eager postdocs hunch over microscopes and pull vials of vividly colored chemicals from crowded shelves. He points out a refrigerator full of petri dishes crawling with worms and an alcove used to operate on research mice. Then Cannon leaves the lab and walks down a hallway toward an unmarked door. On the other side, he says, is "the bowling alley." Before images of dotcom frivolity can be conjured, he turns the handle and reveals ... a big, empty warehouselike room, 5,000 square feet of cement floor and exposed ductwork.
Elixir has been paying for this vacant wing since the company moved into the building last May. It plans to fill it with the bustle of discovery by no later than the end of this year. The company, which has $17.5 million in the bank and is in the process of raising $8 to $12 million more, figures that it can afford the extra monthly rent. The few days of research it would lose while its equipment sat in moving boxes, by contrast, would be irreplaceable. "You don't want to have to keep relocating," says Bard Geesaman, a vice president who came over from Centagenetix. "And with where we're headed, we're going to need the space."
There is no story more enduring than the story of humankind's quest for perpetual youth. It forms the plot line of the oldest recorded narrative, the Gilgamesh epic, a tale woven more than 4,000 years ago in ancient Sumeria. It has inspired the classic tragedies of Faust and Dorian Gray, provided fodder for the high comedy of Monty Python, and prompted an expedition of Spanish explorers to wander around a place we now know as Florida, hunting for a fountain said to restore youthful vigor to all who drank from it. But it has also been a long time, as the New York Times noted, since a respected scientist has seriously suggested — as Lenny Guarente did in one of the 170 academic articles he has written — that "the spirit of Ponce de Leon lives on!"
Guarente responds with an exaggerated wince when he's reminded of that quote. His performance is not entirely convincing. "When molecular biologists showed, in experimental organisms, that you can actively regulate aging, that was a major sea change," he says. "It makes me want to jump up and down, and maybe provoke a little bit." Guarente is willing to risk professional ridicule in order to ensure he's heard. After all, what he's talking about could change the world.
In developed countries, where fatal infections have largely been corralled by antibiotics, doctors spend the bulk of their time battling killers — Alzheimer's disease, Type 2 diabetes, cardiovascular disease, cancer — whose leading accomplice is aging itself: The longer you live, after all, the higher the chance they'll catch you. What makes centenarians so remarkable is their ability to outrun those illnesses. When today's 100-year-olds were born, average life expectancies held that they wouldn't survive to see color TV. In sticking around to watch their great-grandchildren program their TiVos, they have had more than luck on their side. Perls and his associates have found that 40 percent of centenarians manage to avoid infirmity until their late 80s. Another 20 percent escape major ailments entirely, and the rest endure despite chronic conditions. If it can develop pharmaceuticals that help your cells to mimic that inborn resilience, Elixir could ultimately make it possible to fend off the monsters associated with old age with no more than a handful of pills. And that, predict believers, would be a very big deal indeed. Ron Klatz, president of the American Academy of Anti-Aging Medicine, puts it this way: "It would be," he says, "the most significant development in medical history."
For the moment, supporters like Klatz remain significantly outnumbered by skeptics. The company itself cautions that it could be 10 years before its products are available at the corner pharmacy: As Guarente likes to say, "It's all very much blue sky." And yet the clouds that could produce the thunderbolt are gathering. In addition to the findings of Guarente and Perls, Elixir has a license for a gene identified by one of its original founders, Cynthia Kenyon, a professor at the University of California at San Francisco. The company is also looking at INDY, or "I'm Not Dead Yet" (Monty Python, again), a gene isolated at the University of Connecticut, and has its eyes on a recent finding by David Sinclair, a Guarente protégé now on the Harvard Medical School faculty. "Any new intellectual property, we want to be on top of it. We know this field is moving pretty fast, and we constantly have to be watching our backsides," says Cannon, who, even as he heads a cutting-edge company, is too old-fashioned in his manners to use the more colloquial term for that particular part of the anatomy.
The clock is ticking, and the puzzle is coming together, but there are still so many pieces to connect. On his way out of the Elixir offices, Guarente is stopped by one of the company's scientists, who wants to fill him in on some test results. As they talk, the current starts to pulse through him. They toss around a few hypotheses, and then another scientist joins them, and five minutes later, they're still standing there, Guarente staring at a chalkboard only he can see, no longer aware of the visitor at his side. Across town, Perls works at his desk in the South End. A caller asks for his address. He answers that it's on Harrison Avenue, that he's pretty sure the intersection is East Newton Street, that he's sorry, but he can't quite recall the exact street number. Somehow, it doesn't seem strange that he'd decline to waste disk space on such trivia. In other academics, in more prosaic disciplines, aloofness can be off-putting. In the cases of Guarente and Perls, it only makes you more curious about what's going on in their heads.
What kind of boy, you wonder, grows up to spend the rest of his life wrestling a foe that has humbled every challenger? Guarente was raised in Revere, the elder son of blue-collar parents. "I was a precocious child by local standards — I stopped smoking in third grade," he writes in his memoir, Ageless Quest. Guarente's mother was the kind of traditional Italian mom who holds the family meal sacrosanct; one summer, when his baseball practice conflicted with her dinner schedule, he was forced to quit the team. He passed a lot of time alone, listening to music. During the school year, he commuted to Boston College High School, a three-hour roundtrip.
Perls, for his part, bounced from Palo Alto to Houston and then back to California again as his father, a German physicist, followed jobs in the U.S. space program. By the time the family finally settled in the comfortable Denver suburb of Littleton, Colorado, Perls was plotting his future medical career. At the age of 16 — while his peers were scooping ice cream or working as lifeguards, scoping girls at the pool — he took a job as an orderly in a nursing home.
Guarente and Perls were both excellent students, of course, but then there are a lot of people who score straight As by studying hard and swallowing the conventional wisdom. What made them ask questions no one else would? What did they see that the rest of us missed? In 1991, Perls was working as a geriatrics fellow at the Hebrew Rehabilitation Center in Roslindale. Medical textbooks told him that his oldest patients would be his sickest, yet he noticed that this wasn't always true: He had trouble performing routine exams on some of them because they were always off playing the piano or cavorting with their 85-year-old paramours. Even though it would have been easy to dismiss those individuals as aberrations — even though he didn't really expect to uncover any long-buried treasures — Perls decided to tug on the thread. Two years later, he launched his centenarian study, focusing initially on eight towns in the Boston area. "When we discovered a couple of families with multiple centenarians, including one in which five out of nine siblings lived into their hundreds, and 21 out of 40 cousins lived into their nineties, that really set off alarm bells," he says. "I said, 'Okay, let's focus on the genetics, because that's where the gold lies.'" Extraordinarily long lives are not a modern phenomenon — Leonardo da Vinci dissected a centenarian to advance his renderings of the human anatomy — but Perls's method of thinking about them is new. He and his staff have so far interviewed nearly 800 centenarians, plus another 600 relatives of centenarians and control subjects. They've also collected samples of their subjects' blood and asked them to consider bequeathing their brains to science for research.
As a molecular biologist, Guarente approached aging from the opposite side of the mountain. MIT had just granted him tenure, and, at 34, he was experiencing what he describes as "a premature midlife crisis." He and his wife had divorced, and he had just ended a "tempestuous" relationship with a colleague. He wanted to tackle a meaningful issue. He was ready to be bold.
Assisted by two eager graduate students, Guarente started trying to create a strain of long-living yeast. It took four years to get it right, then another five to determine exactly how the mutation worked. What compels a man, when the going is so slow, to continue inching toward the summit? For Guarente, the reward was the genie he may now hold in his hands. It's an enzyme called Sir2, and its role was likely more predominant when food was still hunted and gathered, not purchased at Bread & Circus. When an organism confronts famine or environmental extremes, Sir2 sings a chemical lullaby that silences other genes. Its job is probably to delay reproduction until more forgiving conditions return. The effect could be prolonged youth. And a version of the magic already exists in our cells.
Since the 1930s, scientists have demonstrated that laboratory rats survive up to twice as long when denied a third of the calories they'd consume if allowed to feed freely. The rats do not enjoy these experiments — they're known to be more likely to bite — and you wouldn't, either: The likely side effects of sticking to a 1,000-calorie-a-day regimen include lower body temperature and decreased libido. Guarente figures that chemically triggering the Sir2 survival mechanism might let people enjoy the benefits of calorie restriction without swearing off cheeseburgers. Although a link between Sir2 levels and living to 100 has yet to be established, Perls's research does suggest that centenarians possess a heightened ability to overcome one type of stress — namely, the emotional kind. Centenarians are sanguine: They spin their own silver linings. Guarente and Perls clearly exhibit those same attributes, but they're not waiting to find out whether they've inherited the rest of the code. Since Perls, 42, embarked on his centenarian project, he has cut back on his bagel-a-day habit and girded himself against the sweet come-ons of the candy bars in the grocery store checkout line. He has dropped 30 pounds and makes every effort to wedge exercise into his weekly schedule. Guarente, who just turned 50, has always worked out regularly, but he has added more olive oil to his diet and gained a new justification for indulging his taste for red wine.
Two years ago, Guarente's father died. He was 82. He had pulmonary fibrosis, and the scar tissue that took over the air sacs in his lungs moved like a lava flow, steadily snuffing his breath. "It was gradual. He got a little bit worse every day," says Guarente.
At the end, his dad carried an oxygen tank with him, and while Guarente is certain his dad derived a measure of happiness and dignity from the extra weeks it gave him, he also believes there must be a better way. He thinks about the wisdom his father accumulated, and what a shame it is that he didn't have longer to share it.
And so, if you're wondering, the answer is yes: Guarente and Perls do have a personal stake in their research. And they do worry about running out of time.
Guarente's lab at MIT is about a half mile from Elixir, so it's easy for him to stroll over and check on the company's progress. Except "stroll" isn't the right word. It's a bitter afternoon — Guarente is wearing dark jeans and a puffy, bright-blue down jacket, an outfit that makes him look a little like an extremely erudite rapper — but his is not the walk of someone trying to get out of the cold, head down, hunched over against the wind. Guarente walks with his chest forward, arms swinging, legs pumping, just one notch below a flat-out jog. He walks like someone who is used to being in a hurry.
Elixir received $8.5 million in seed funding in 2000 from three investors, including Oxford Bioscience Partners, a venture capital firm based in the Back Bay. "This is far out, and this is risky, but we don't get involved unless we think we're going to get 10 times our money back," says Oxford's managing partner, Jonathan Fleming. Oxford also understands that breakthroughs take time, so, as a rule of thumb, it waits seven years before asking for its check. That gives Elixir until 2007 to come up with an effective drug — or at least provide tangible proof that it will be able to come up with a drug if granted more time and money. "In academia, you bring the pressure to bear on yourself," says Guarente. "With Elixir, the pressure is of the same magnitude, but it's much more graphic. The venture capitalists will just beat you over the head." The nature of Elixir's goals adds several degrees of difficulty to the hurdles it faces. The company can't just invent a pill and then — having first proven its safety, of course — give it to volunteers to see if it forestalls aging. The trial would take decades to generate conclusive results. To get around that obstacle (and stay within the FDA's established system), Elixir's plan is to screen its potential products in terms of their ability to prevent one of the major age-related diseases. Once a treatment is on the market, the company would push to expand its list of approved uses.
There is another, less obvious advantage to this strategy. It's one thing for a company to announce a potential cure for, say, Type 2 diabetes, and quite another to hold up the first clinically proven, guaranteed-effective, now-available-for-prescription, gel-coated longevity tablets. Already, Guarente can hear the hissing. Leon Kass, chairman of the Bush administration's official bioethics council, places efforts to control the aging process on the same slippery slope as cloning and designer babies. He is against using any federal money to support such research. Daniel Callahan, cofounder of the Hastings Center, the nation's leading bioethics think tank, is also a vocal opponent of Elixir's stated mission. "I'm at a loss. I just can't comprehend that point of view at all," says Guarente. "All the great advances have had the effect of extending life. What we're doing is no different from biomedicine in general, and to put it into a separate category is really to not understand it."
For the moment, the threat posed by a potential anti-antiaging-research movement remains remote; it doesn't seem likely that Elixir staffers will have to push past angry picket lines to enter their offices anytime soon. The most pressing concerns Elixir has to deal with are much like those that dog every fledgling company and include everything from finding enough desks to accommodate the growing staff (Cannon has had to give up his corner office) to a debate on whether or not it should hang on to its current name. Perls, for one, thinks a change is in order. "I really don't like the name," he says. "I think it's something of a misnomer, and if I had my druthers, we'd come up with a new one." In his view, "Elixir" conjures images of mythical magic fountains and the empty, pernicious sales pitches of slick-talking hucksters. He'd prefer something that more accurately conveys that the company's theories are sound, that what it seeks to do is possible. In our lifetime.
