Truth to be told I am not really interested in the Resveratrol story neither as a researcher nor as a life extension supporter. First, it is about classical pharmacology, seeking the molecular targets of a relatively simple molecule back and forth, testing its effect on different animals with standard setups, no hint at a new type of research seeking for new methods, like stem cell biology, or tissue engineering. Secondly, it’s potential effect on healthy lifespan (more years to live, more tens of years?) is minuscule compared to a technological possibility, like systemic regenerative medicine which aims indefinite life extension via a continuous regenerative treatment, that fixes the physiological age. At least I was not interested in the story till David Stipp’s article in Fortune (19th of January), had not been published. Now I am interested in its science, its effect on life extension, its commercial consequences (Sirtris) and in the people behind that, like David Sinclair and Christoph Westphal. Stipp’s piece is a perfect coverage of the whole story through the details with an easily comprehensible and ingenious language. After reading the report I knew the author is not just a simply professional journalist.
Here are some exciting parts out of it (emphasis added): “You have to go back to the advent of antibiotics in the first half of the 20th century to find such broad therapeutic potential. …Most biotechs pioneering new science take years before testing drugs on people; Sirtris’s drug reached the clinic less than 18 months after the company’s launch….Westphal’s colleagues are accustomed to his daily barrage of e-mails, which begins around 5:30 a.m. “I must get 50 e-mails a day from him,” says Boston hedge fund manager Richard Aldrich, one of Sirtris’s founding investors. “He probably over communicates.” (Westphal says that over communication is a nonissue because “nobody reads my e-mails.”)…
Rather, he’s determined to avoid any whiff of “fountain of youth” hype – specifically, of giving the impression that Sirtris is a bunch of flakes chasing miraculous elixirs, which is the kiss of death for a startup trying to raise millions of dollars from hard-nosed money managers. He spends a lot of time explaining that his company is working to cure diseases of aging, not to cure aging itself. There’s a difference, especially in the minds of regulators, who view aging as part of the human condition, not an illness warranting treatment.
Further, proving that a drug extends life span would require an impossibly long clinical trial. And then there’s what Westphal calls the “vortex of inflated expectations,” which invariably spins up around scientifically credible anti-aging research. “I don’t want to get sucked in,” he says….
Like most entrepreneurs, Westphal is fixated on the new. Ironically, however, the line of research that led to Sirtris dates from the 1930s, which is when scientists at Cornell University discovered the life-extending effects of calorie restriction, or CR.
As for how resveratrol does its thing, therein lies a raging academic debate, Sinclair being one of the combatants. The dispute stems from the fact that resveratrol is a “dirty” drug, i.e., a blunt instrument that interacts with a complex array of molecules in the body. …Sinclair is in the latter camp: he believes that an enzyme called siRT1 is resveratrol’s key target, and that the compound works its magic mainly by activating that enzyme. (siRT1 is a member of the sirtuin class of enzymes, hence the company name.)
The mouse studies also gave hints that resveratrol induces basic metabolic changes akin to those that CR does. One of the most intriguing was the production of fresh mitochondria, the key components of cells that serve as power generators; they essentially burn sugar in slow motion to release energy…. Resveratrol’s ability to engender new mitochondria is especially exciting because it seems the fresh ones are more efficient than the worn mitochondria they replace, hence are less prone to churn out damaging radicals. CR appears to do the same thing – it’s like replacing a smoky old coal burner with a cleaner burning gas-fired plant. Resveratrol’s effect on mitochondria may be enough by itself to account for much of the compound’s riveting effects in animal studies. In particular, the effect would seem to account for the abrupt Olympic-caliber running abilities observed in mice.
The large, unfathomable risks most biotech startups face make investors’ due-diligence process seem like shining a penlight into Carlsbad Caverns. Thus, venture capitalists often look to the stature and track record of the people involved as the best indicator of potential. Says Sirtris board member and co-founder Richard pops, CEO of Alkermes, a biotech concern in Cambridge: “pedigree is everything” in early-stage biotech.
Since combining forces with Sinclair, Westphal has organized what is arguably the most pedigree-rich scientific advisory board in biotech.
The Sirtris team wasted very little time reaching its first milestone, which was to develop “high throughput” screening tests that enabled it to quickly analyze nearly 500,000 compounds for resveratrol- like activity. The rapid-fire winnowing led to several potent molecules that promise to replicate resveratrol’s health benefits at doses hundreds of times smaller than are required with the natural substance. These two standard steps in drug development often take several years; Sirtris completed them in a little over a year.
Of all the decisions Westphal has made the biggest may prove to be simply speed. Sirtris’s rapid push into clinical trials, the costliest stage of drug development, is likely to force it to raise more money soon. One option: license drug rights to big pharma concerns. But those who reach into pharma’s deep pockets tend to get entangled in its bureaucratic strings. Major decisions on developing a drug, for instance, must go through layers of managers.
Further, if Sirtris licenses rights to its drugs, it might hand over compounds to a pharma partner before their full value has been assessed and factored into the deal – the possibility that the drugs could treat many diseases of aging is still too tentative to put a pricetag on. Despite the controversy over how resveratrol works, there’s no telling how many diseases it can treat. And resveratrol’s ability to boost mitochondria, those cellular power plants, indicates Sirtris’s medicines will be highly versatile. In fact, the list of disorders thought to involve malfunctioning mitochondria includes adult-onset diabetes, heart disease, stroke, cancer, and Alzheimer’s and Parkinson’s diseases-all diseases of aging.
“If I had $500 million today,” says Westphal, “I’d be tempted to take our drugs into the clinic against two or three devastating neurological conditions and other metabolic diseases besides diabetes. That would be incredibly risky.
At some point Sirtris will probably go public, raising the money Westphal would need to pursue this vision. In fact, the excitement about resveratrol may well allow Sirtris to make an initial public offering at an earlier stage of development than is feasible for most biotechs. Westphal declines to comment on that. When asked about it, though, he suddenly reverts to vortex-avoidance mode: “part of my job is to calm people down,” he says. “You have to remember, most things in biotech don’t work.”
Sobering words – especially for us hopeful resveratrol watchers of a certain age. But here’s an antidote: pour a glass of pinot noir, and while imbibing, step back and regard the big picture. Humanity has dreamed for millennia of medicines that extend life span. Sirtris may not fulfill the dream. But the company’s very existence shows that the quest for compounds that slow aging has been transformed from sorcery into the fairly routine process of pharmaceutical development. Thus, the dream is likely to be realized within, at most, a few decades. The question now is when, not if.”