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Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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December 13, 2011

The Sirtuin Saga

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Posted by Derek

Science has a long article detailing the problems that have developed over the last few years in the whole siturin story. That's a process that I've been following here as well (scrolling through this category archive will give you the tale), but this is a different, more personality-driven take. The mess is big enough to warrant a long look, that 's for sure:

". . .The result is mass confusion over who's right and who's wrong, and a high-stakes effort to protect reputations, research money, and one of the premier theories in the biology of aging. It's also a story of science gone sour: Several principals have dug in their heels, declined to communicate, and bitterly derided one another. . ."

As the article shows, one of the problems is that many of the players in this drama came out of the same lab (Leonard Guarente's at MIT), so there are issues even beyond the usual ones. Mentioned near the end of the article is the part of the story that I've spent more time on here, the founding of Sirtris and its acquisition by GlaxoSmithKline. It's safe to say that the jury is still out on that one - from all that anyone can tell from outside, it could still work out as a big diabetes/metabolism/oncology success story, or it could turn out to have been a costly (and arguably preventable) mistake. There are a lot of very strongly held opinions on both sides.

Overall, since I've been following this field from the beginning, I find the whole thing a good example of how tough it is to make real progress in fundamental biology. Here you have something that is (or at the very least has appeared to be) very interesting and important, studied by some very hard-working and intelligent people all over the world for years now, with expenditure of huge amounts of time, effort, and money. And just look at it. The questions of what sirtuins do, how they do it, and whether they can be the basis of therapies for human disease - and which diseases - are all still the subject of heated argument. Layers upon layers of difficulty and complexity get peeled back, but the onion looks to be as big as it ever was.

I'm going to relate this to my post the other day about the engineer's approach to biology. This sort of tangle, which differs only in degree and not in kind from many others in the field, illustrates better than anything else how far away we are from formalism. Find some people who are eager to apply modern engineering techniques to medical research, and ask them to take a crack at the sirtuins. Or the nuclear receptors. Or autoimmune disease, or schizophrenia therapies. Turn 'em loose on one of those problems, come back in a year, and see what color their remaining hair is.

Comments (9) + TrackBacks (0) | Category: Aging and Lifespan | Drug Development | Drug Industry History


1. Curious Wavefunction on December 13, 2011 9:56 AM writes...

Speaking of engineers trying to formalize biology, take a look at the most recent issue of Science which has several responses to that editorial by Andy Grove.

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2. Anonymous on December 13, 2011 10:23 AM writes...

"it could still work out as a big diabetes/metabolism/oncology success story", perhaps, but we could also see pigs flying and hear the great duo Moncef and Patrick inform the world that their strategy has been less successful than they hoped for!

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3. JT on December 13, 2011 12:35 PM writes...

Good post Derek. As you say, time will tell.

The recurring theme of how high everyone's (particularly executives') expectations are on the rate at which drug discovery organizations and scientists can turn a fundamental biology insight into a drug is remarkable. (NB: engineers are not the answer). Certainly there are examples where this process has happened quickly but these are the outliers. We too often loose sight of the real scientific back story behind the discovery of medicines - the reality is that they often take 2 decades before we understand enough to make it into a therapeutic concept.

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4. Virgil on December 13, 2011 1:54 PM writes...

Personally, we've had success with the sirtuins by completely ignoring the entire field of aging, and in particular staying away from Sirtris.

If you just look at them from a purely biochemical standpoint, as stress-responsive enzymes that regulate lysine acetylation, the biology is pretty simple, and they are not that bad to work with. Consider...

(i) Knockouts and overexpressing mice for various isoforms are readily available.
(ii) Inhibitors are readily available.
(iii) There are (ignoring Fleur-de-Lys) some decent activity assay that a monkey could perform.

It's only when you get sucked into using molecules like SRT1720, and arguing about the role of sirtuins in caloric restriction and lifespan, that the trouble starts. If you're careful to just treat them like any other enzyme (what happens to phenomenon X when I inhibit this pathway) they're quite attractive targets, academically speaking.

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5. pete on December 13, 2011 6:44 PM writes...

Someday when we better understand these suckers, the sirtuin story could provide a great example in which assumption of conserved gene function in different animal systems can be empowering -- but also can take you into a vision of nature that doesn't exist.

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6. Anonymous on December 13, 2011 6:59 PM writes...

#3: "Certainly there are examples where this process has happened quickly but these are the outliers". And of course every proper scientist (or engineer) knows that the thing to do with outliers is to ignore them as generally irrelevant.

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7. Anne on December 14, 2011 2:51 PM writes...

I just finished reading that article and was pleased to see you had addressed it here. Last summer, I did an internship for the company that developed the Fluor-de-Lys assay (and spent a lot of my summer troubleshooting a new version of the assay for a different sirtuin isoform...). I brought your posts about the situation to my boss's attention (she wasn't around when the assay was developed) and she found it all very interesting. I was waiting for the Science piece to bring up that assay but was disappointed - the overall impression the article seems to leave is that all of the scientists have done the best they can on their experiments, but the failure to follow up on the Fluor-de-Lys results with other, more rigorous tests before the massive purchase of Sirtris does not strike me as science with integrity. In any case, an odd story and an important cautionary tale.

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8. Anonymous on December 16, 2011 3:37 PM writes...

I'm so sick of this story! Who cares?? The only people who seem to care about Sirtuins and aging anymore are you and the business media. Sirtuins have many possible roles in biological systems and many are for more attractive from a drug discovery perspective than lifespan. Did you all do more rigorous tests before you started to target kinases selectively, or before you tried to run GPCR projects without even clearly understanding the role of GPCRs in vivo? So you guys can all tell me that every single project that you ever worked on had very solid understanding of the biology before you started making compounds? Gimmie a break!

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9. Big Mic on January 1, 2012 10:54 PM writes...

Take it easy Anonymous @ 8.

I agree with you but take it easy. This whole thing was fueled by some carnival barkers at Sirtris (I will not name them).
But the fact is, Resveratrol works on humans; It increases healthy lifespan through SIRT1 AMPK and MTOR.

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