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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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« Receptors, Moving and Shaking | Main | The Infinitely Active Impurity »

January 25, 2010

GSK and Sirtris: A Bit More

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Posted by Derek

Nature has a short item on the Pfizer paper that questions the reproducibility of some key sirtuin work (covered here and here). There are some good points to temper the pessimism. Leonard Guarente of MIT, a key pioneer in the field, says:

". . . that the latest findings are neither surprising nor worrisome. The compounds may work only with fluorophore-conjugated peptides in vitro, says Guarente, but the situation is different in cells and in animals. The Nature paper, among others, went beyond the test tube and indicated that SIRT1 was more active in cells and in animals after application of the Sirtris compounds. Furthermore, resveratrol administration made no difference to the lifespan of yeast that did not have Sir23, indicating that the compound's action depends on this gene.

According to a statement from GlaxoSmithKline, Ahn's conclusion "ignores any possibility of direct activation of SIRT1 that may occur in a cellular environment that is not reproduced in vitro".

True, but there's still that problem of the Pfizer group not being able to reproduce the in vivo effects, which to me was perhaps the most worrisome part of the paper. Now, it's worth remembering that animal studies are not the easiest things in the world to do right, since there are so many variables. Small differences in animal strains and the like can sometimes throw things off severely. Even the Pfizer group admits this readily, with Kay Ahn telling Nature that "every in vivo experiment is a little bit different" and that "Under our conditions we didn't see beneficial effects, but we don't want to make a big conclusion out of those results."

That's an honorable way to put things, I have to say. Rather less honorable, though, at least to me, is David Sinclair's response from the Sirtris team. See what you think:

A possible explanation for the discrepancy, says Sinclair, is that Ahn and her colleagues did not provide information on the characterization of the compounds, which they synthesized themselves. So there is no way of knowing how pure they were or whether they're the same as those made by Sirtris. "The fact that mice died indicates that there may be an issue with purity,"

That's. . .not so good. In fact, it comes close to being insulting. Although I say a lot of uncomplimentary things about Pfizer's management, the fact remains that they have a lot of very good scientists there. And I assume that they can reproduce Sirtris's published procedures to make the sirtuin ligands. If they can't, frankly, that's Sirtris's fault. Everyone (well, everyone competent) checks out compounds thoroughly before putting them into an animal study. Asking "Are you sure you made the right stuff?" at this point is really a bit much, and doesn't do anything improve my opinion of Sirtris. (Which opinion actually was pretty good - until recently).

Comments (40) + TrackBacks (0) | Category: Aging and Lifespan | Drug Assays


1. Anonymous on January 25, 2010 9:51 AM writes...

Hey Derek, it looks like you mixed up Sirna and Sirtris in your title.

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2. theotherguy on January 25, 2010 9:59 AM writes...

Questioning the compound purity is pretty random. Then again, Sinclair is a total joke. Between shilling for the reveratrol hawkers and the 60 Minutes performance, he has no credibility. Maybe he's been following the reactome story and figured "When in doubt question the chemical characterization." Yet another example of my old maxim, Don't Let Biologists Talk About Chemistry.

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3. Postdoc for life on January 25, 2010 10:09 AM writes...

Take a look at the procedures Sirtris published. Who in their right mind would design this route? And the characterization is incomplete in several instances. What is the final salt form? I have actually made SRT1720 recently for an academic research group and had to scrap the published route.

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4. Hap on January 25, 2010 10:21 AM writes...

If Sinclair's stuff is wonky, then a better motto would be "Don't let scientists talk about chemistry to VCs or pharma executives", because this wouldn't be as much of an issue if GSK hadn't sunk $720M into it.

If you can't rely on your in vitro tests to determine in vivo activity, where do you even start to develop drugs?

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5. Anonymous on January 25, 2010 10:41 AM writes...

This statement that is attributed to Lenny Guarante in the Nature news article is not true:

"The Nature paper, among others, went beyond the test tube and indicated that SIRT1 was more active in cells and in animals after application of the Sirtris compounds."

One of the amazing things about that Nature paper (Nature. 2007 Nov 29;450(7170):712-6) was that the authors never showed that their compounds activated SIRT1 in animals (e.g., by blotting for acetylation of a SIRT1 substrate). So there is no evidence that the compounds modulated the target in vivo. Even the evidence that the Sirtris compounds activated SIRT1 in tissue culture was incredibly weak (Figure 1c; look at those error bars!)

The bigger lie in this whole field has been that we all know that Sirtuins and resveratrol are important for aging, but we just don't know the mechanism. Not true! Lenny Guarante's original discovery that Sir2 is required for the effects of dietary restriction in yeast has really been marginalized by later experiments -- it is only true in a specific yeast strain, in a specific assay of yeast life-span, and involves a mechanism (reduction of rRNA circles) that no one believes is relevant to humans. Sinclair claimed in Science that resveratrol extends lifespan in worms and flies via Sir2 (Science. 2004 Jul 16;305(5682):390-2). Linda Partridge carefully showed that these effects are not reproducible (Mech Ageing Dev. 2007 Oct;128(10):546-52) and Andrew Dillin showed that Sir2 is not involved in dietary restriction in worms (PLoS One. 2009;4(2):e4535. Epub 2009 Feb 20). Four different labs have shown that Sinclair's claim in Nature that resveratrol activates Sir2 is false (J Biol Chem. 2005 Apr 29;280(17):17038-45., J Biol Chem. 2005 Apr 29;280(17):17187-95, Chem Biol Drug Des. 2009 Dec;74(6):619-24., Pfizer paper in J Biol Chem. 2010 Jan 8). Sinclair's own data shows that resveratrol does not extend the lifespan of normal mice (Cell Metab. 2008 Aug;8(2):157-68.). Several transgenic mice have been made that overexpress/activate SIRT1; none of them have extended lifespan.

So what are we left with? Lenny Guarante speculating that the Sirtris compounds activate SIRT1 only in cells and do so by a mysterious mechanism (without presenting any data to support this). David Sinclair, a biologist, speculating that Pfizer failed to properly synthesize the simple Sirtris compounds.

What a joke.

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6. anonagain on January 25, 2010 11:30 AM writes...

Adding to Anonymous' list, there's another paper from Anne Brunet's lab that shows that resveratrol lifespan extension in worms is dependent on AMPK (Aging Cell. 2009 April; 8(2): 113–127).

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7. anonymous on January 25, 2010 11:56 AM writes...

Good !

Now we need to setup AMPK assay and will sell some screening artifacts to GSK for $$$.
Hmm, I think we already have that plasmid in a freezer...

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8. CMCguy on January 25, 2010 12:07 PM writes...

Derek you say 'Everyone (well, everyone competent) checks out compounds thoroughly before putting them into an animal study. Asking "Are you sure you made the right stuff?"'.

Not that long ago I would have disagreed that this was the predominate MO of many places as common medchem purity was a "clean" NMR and "one-spot" TLC and maybe an IR for characterization (OK for grad work right?). Since likewise at many shops the medchem group often prepped the initial material for animal testing that same criteria was followed. Although typically would be the correct structure claimed the purity was sometimes not as good as advertised, as process chemists later found to significant consternation. It has changed now that HPLC is wide-spread there is greater probability of decent purity however until the Analytical chemists really tackle the methods there is always suspicion that many impurities are hidden and one of those could be an extra potent species responsible for the activity observed.

As far as #2 theotherguy statement "Questioning the compound purity is pretty random." I do disagree as if Biological or Clinical results do not match expectations/previous results the default position is that the (Syn)chemists must have done something wrong/different. The factor that their testing environments are frequently much more variable seems to be forgotten when they can blame the "new lot of compound".

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9. d on January 25, 2010 12:39 PM writes...

Agree with CMC!!
In my experience, every time there was an irreproducible result in a biological assay, the common response from the person responsible for it was to call back the chemist(s) responsible and question his/her/their ability to reproduce the original compound.

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10. Mark on January 25, 2010 1:16 PM writes...

I have personally met Kay and have talked science as a competitor and I can honestly say, she knows her stuff and is pretty adept at saying the right things.

David Sinclair's response sounds typical. Whats the first thing anyone does when someone can't replicate your work? They suggest you don't know what you are doing and its something YOU did that is wrong with your data cause our is right. Pretty tacky (and arrogant) to suggest it in public like that and really makes me never want to work there.

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11. Anonymous on January 25, 2010 3:52 PM writes...

Shoddy science = non-reproducible work. There are several causes. I am listing them in the order I have seen in my short life 1) not carefully looking at your own data 2) never reproducing your own work, but rushing to publish and last but not least, pure fabrication. Biologists are extremely guilty of not being quantitative. This is coming from a biologist.

I have seen examples of this in academia, small biotech and, of course, big pharma.

Thank god there is a lengthy approval process.

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12. Hap on January 25, 2010 5:08 PM writes...

GSK's responses (CancerMan's quote in comment 36 on "Sirtuin Scenarios" and above) to Pfizer's and Amgen's research doesn't really speak well of them. To say that Pfizer was trying and failing to prove a negative, for example, seems like either a dumb misreading of science or an intransigent one - people try to duplicate your results, and if they can't do so they ask why. Even if people can reproduce your results, they may suggest alternative models of reality consistent with your data. Finding another such model isn't "proving a negative" (other than to your stockholders) but proposing (and supporting) an alternative, testable hypothesis.

Suggesting that your compounds can only be tested effectively in vivo is possibly true (sulfas), but is a theory that would require more evidence to support, and would put a deep crimp in generating effective analogs. If Anon #5's references tell the story, the in vivo activity of their compounds might not exist either.

It seems like it would have been better for GSK and Sinclair to have said nothing - if their compounds work, then these problems will have been by necessity defeated, and the eventual research will make that clear. Throwing out nonsensical and insulting statements makes it sound as if you have nothing better to throw out, a counterproductive implication.

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13. theotherguy on January 25, 2010 5:11 PM writes...

I didn't mean to suggest that one can't ask into the details of compound purity in the heat of scientific experimentation, anymore than one shouldn't ask into assay reproducibility. That's totally appropriate and we should all be open and ready to defend the validity of our work product. But to question such an elementary aspect of one's work with no evidence (other than conflicting with your own claims) is, as Mark so rightly describes, tacky.

I think the rush-to-publish bug that Anonymous describes is worse in academia, where 99% of the work will never face the scrutiny of outside verification, and where there's no checks standing above the PI. At least in industry, there's more than reputation at stake ($$$ and jobs). Sinclair, like a true academic, got an exciting result and his first thought was "Tenure is mine!' In industry the first thought would be "What more experiments can I do to convince my boss?"

Say all you want about industry, the bullcrap quotient is alot lower. Money has that effect. Consider Sirtris the exception that makes the rule!? ;)

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14. Skeptic on January 25, 2010 6:17 PM writes...

"Say all you want about industry, the bullcrap quotient is alot lower. Money has that effect."

Thats a strange comment given that a massive decades long credit boom (which drove asset prices up) fueled a monstrously bloated and highly speculative industry in the first place. What possibly could be more bullcrap than handing out debt money to anybody with an unproven idea? If nobody really understands biology very well then why does industry exist?

You guys need to pick up a book on fractional reserve banking rather than pointing to the "MBA's are evil" conspiracy.

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15. Hap on January 25, 2010 7:05 PM writes...

But, even if there's lots of money because it's cheaper to borrow and invest than it should be, shouldn't someone actually be determining whether an idea is good and financially viable before they invest? When money is cheap, people can make riskier investments, but they still should have some idea what the risks are (and ideally some sort of quantitation, to give an estimate of whether the investment makes any sense). Also, if the surplus of credit means there's lots of money around, the cost of investing goes up (because your competitors have money, too), so there still ought to be significant emphasis on making the correct investments.

It doesn't seem as if all the good ideas have been funded, let alone all the bad ones, so someone has a methodology for choosing which ones to fund (at least in part, what one might blame MBAs for) - either the methodogy works, and was ignored in this case, it works, and was employed by incompetent people, or it doesn't work (or doesn't work as well as a supposed). I thought the recent crash seemed to depend on the third case (people assumed far higher risks than they realized, because the underlying models assessing that risk were flawed, or dishonest, and their leverage made that mistake consequential to others). Sirtris may be a risky investment that had just enough of a chance for a high payoff to work (because of cheap credit), but the claims by lots of people that the likelihood of payoff was lower than postulated (or zero) and that that data was ignored may put this investment in the second category.

The choice to invest externally (outsourcing, purchasing other companies) seems to be based not only on the cheapness of credit but on presumed models of risk and productivity that don't seem to be working (or, worse, whose functioning may not be determinable at all) and an ignorance of long-term goals - these seem to be the hallmarks of quantitative business, and of MBAs, hence the blame. Alternatively, this could just be old-fashioned robbery by scientific executives who don't care, or old-fashioned ignorance (people who don't know business, but think they do) by people who should know better (opportunities made more lucrative by the presence of cheap credit). It's getting hard to tell.

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16. Anonymous on January 25, 2010 7:05 PM writes...

it seems odd that guarante's statement about what data was presented in the Sirtris Nature article was repeated by the Nature news reporter as if it was a fact, even though the data he cites is clearly not anywhere in that article. I mean, did the reporter even bother to read the Nature paper? it seems particularly bad to get something like that wrong when the paper in question was published in the journal that you write for!!! it gives one the impression that the people at Nature have no idea what is going on.

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17. CMCguy on January 25, 2010 11:53 PM writes...

theotherguy I probably should have given more credence to your context then the actual phrase you used because this was a tacky/arrogance tone so not disagreement there. However more times than I can count I have had to defend the compound/purity/process when an oddity was observed in bioassay or even clinical result so it does not appear "pretty random" and it was the inherent presupposition of certain groups/individuals.

I am not sure I understand what you mean about industry's bullcrap quotient being alot lower. Perhaps if talking about focus on publications I can see a point but although it may come from different sources the industry generated manure can be just as deep. Industry could not as noticeable since Marketing can wrap it in a nice box with a ribbon (since they get so much practice on the stuff they produce).

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18. anon the II on January 26, 2010 9:04 AM writes...

While we're on the topic, this just showed up on Forbes.

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19. theotherguy on January 26, 2010 10:34 AM writes...

All I will say is this: Anyone who's ever been in the room when the VCs and their BS sniffers come to determine whether or not your research deserves that second round of cash, knows that they cannot be snowed. In my experience, an investor and his cash are not parted by rosy hand waving, but by hard data. There are exceptions of course, and Sirtris may be one, but if it were so easy to wheedle money out of the hapless, wouldn't we all be working for start-ups rolling in cash?

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20. Anonymous on January 27, 2010 3:12 AM writes...

@ 19. But Sirtris had that kind of data - both in vitro and in vivo. VCs and their cash might not be easily parted, but they're unlikely to question in detail how the experiments were run, what controls were used, whether there could be assay artifacts explaining the results etc. The problem is that the Sirtris data doesn't appear to stand up to *scientific* scrutiny

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21. Will on January 27, 2010 11:49 AM writes...

I love this kind of explanation by the Sirtus scientists.

It is the "inverse-Occam's razor" principal.

The least parsimonius explanation must be the correct one.

I have seen this so many times following up on Nature, Science, Cell, Patent, and Inlisensing deals.

>> Maybe we are missing something important from our in vitro assay. Maybe it doesn't work in TRIS- only in HEPES? Are we sure we have made the correct isomer? Well maybe it is cell type specific.. Maybe our batch of HEK cells are different to theirs... Well maybe it doesn't work with DMSO as the solvent... Well maybe it only works in this rat strain...

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22. Hearditallbefore on January 27, 2010 12:07 PM writes...

The head of chemistry at Sirtris is from a place in Cambridge that's known to be full of incompetent stuffed shirts., nothing more needs to be said

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23. chemist on January 27, 2010 12:21 PM writes...

Quote from above,

"It seems like it would have been better for GSK and Sinclair to have said nothing"

EXACTLY, and if they were so certain of their results that's EXACTLY what they would have done, "said nothing". Hell, it would even be in their interests to guide other researchers as to how to reproduce their results.

Come on, we all know what this is really about, the same tired old smoke and mirror show put on for the unsuspecting investor.

The real danger with these shenanigans is that the people with the money, who potentially fund our research and cut our paychecks, are going to become more and more jaded regarding the whole drug discovery enterprise. This is the last thing we need right now given the current environment.

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24. Anonymous on January 27, 2010 1:58 PM writes...

So I'd like to throw out a couple questions.

It would appear that the GSK management team has made numerous poor but expensive investments(e.g. Sirtris, Praecis, Genelabs, Anacor, ect.) Further, it also appears as if this management team (who have minimal or no small molecule drug discovery experience) have ignored the council of their internal experts based on comments posted on this blog regarding the purchase of Sirtris as well as Witty admitting in the Forbes article that GSK researchers felt their investment in Anacor was "completely mad".

At what juncture is there sufficient grounds for their shareholders to sue and have this team removed? And do former research staff working in the identical therapeutic areas to those companies listed above who were layed off to offset the cost of these investements deserve compensation? Is there precedent for either?

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25. cancer_man on January 27, 2010 10:20 PM writes...

I still don't understand why most posting are so _positive_ that the Sirtris research will ultimately prove to be a bust.

I'm still waiting for studies that are expected to be published in coming weeks.

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26. sgcox on January 28, 2010 4:47 AM writes...

#25 Because, as I understand, several posters have very good first hand experience with this garbage.

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27. Hap on January 28, 2010 10:26 AM writes...

#25 - Besides the comments from people who might be in a position to know about Sirtris (and whose comments you can take with salt as needed), the likely difficulties with testing (they'd have to test in whole cells or in vivo, and there may be potential metabolic liabilities with things that look like resveratrol), there's also the idea that GSK and Sinclair aren't behaving as if they ought to if they think they have a fundamentally sound idea. If the studies published were expected to be positive, for example, why not just say that they think that future results will validate this expenditure and the line of research? (The production of a drug would also validate their research, but that might not happen for lots of reasons not necessarily related to the research even if it's sound.)

You don't need to defend quality research with bad logic (the "trying to prove a negative" bit) and smokescreens - it shouldn't need any defense at all. The comments would indicate that either GSK and Sinclair don't know how to defend their research (fairly stupid, since you would figure that multibillion dollar companies could afford some good PR people) or they have little of quality to defend. I don't think additional research papers would improve their image, because of the refs in comment #5 (lots of the positive research has been refuted or diminished in scope), but probably only positive clinical results would help (although even that wouldn't justify the expense of buying Sirtris, unless the mechanism of action fits with their sirtuin research).

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28. Anon on January 28, 2010 7:11 PM writes...

I just want to put out there that I have seen the wrong thing go into an animal study before, and can take a lot of analytical doglegging to figure out what happened.

However, its a lot less common / more disturbing to have it happen in multiple situations or studies, and its certainly not an accusation I'd make publicly within a company nevermind to another!

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29. cancer_man on January 28, 2010 10:40 PM writes...

There are aspects to this that don't make sense to me. Expanding on what I wrote in a previous post:

1. A guy who says he worked in Harvard's lab commented on Dereck's post " I can assure you threre is a lot more to this story than you are letting on." Now that is an accusation, maybe unintentional, that Derek is actually holding back something. I don't assume this, but that is a strong statement.

He continues, "For one, SIRT-1 is just one of many sirtuin proteins that GSK has access to as a result of the Sirtris deal. SIRT-6 knockout mice have a profound premature aging phenotype, and SIRT-6 has also been shown to modify several of the pathways involved in insulin signaling. While I agree that the Pfizer data is troubling, I think we are a long way from justifiably writing off the sirtuin family of proteins."

2. I don't think Sinclair's statement is so great, although I thought he said last fall that they may be wrong about the mechanism, implying that something still works.

3. Based on a couple of interviews I've seen, Guarente doesn't come across at all like a hypster. If someone like him says "the latest findings are neither surprising nor worrisome" it seems that there may very well be a new turn to the story within a few weeks although maybe not, and he may be wrong.

4. I can't judge, but one comment on the previous post heaped a lot of criticism on the Pfizer study.

5. There were already three studies that showed resveratrol didn't affect SRT 1 "directly." Why does the Pfizer study, assuming correct, add anything sifnificant?

6. Why did Pfizer release the study right after the SRT 501 cancer trial finished and right before Sirtris will supposedly have publications that according to Sinclair are "promising"?
I just don't see what motivated Pfizer to conduct that study. Either GSK has something, or they don't.

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30. Anonymous on January 29, 2010 6:06 AM writes...

were PFE bidding for Sirtris? If so, maybe they are just getting round to publishing some of their own due diligence work

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31. anonymous_too on January 29, 2010 9:49 AM writes...

#24 Anonymous-

I'm not sure you should lump the Praecis acquisition in with the rest. First, it wasn't expensive, ca. $30M once you account for Praecis cash on hand. Second, they are still operating the old Praecis site with something like 50 people, 3 years after the purchase. The fact that they've survived the layoffs in the interim would indicate to me there's something of value there.

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32. Anonymous on January 29, 2010 11:06 AM writes...

cancer_man #29

the difference between the pfizer study and the previous three studies is that pfizer paper showed that the three new "1000-fold more potent" sirtris compounds are also assay artifacts; we already knew that resveratrol was nonsense, but this paper showed that the new compounds are false positives for *exactly the same reason*.

more remarkable, the pfizer paper showed that the new sirtris compounds are incredibly promiscuous, inhibiting dozens of ion channels, GPCRs, enzyzmes in a counter-screen at 10 uM. So basically, the compounds do not activate SIRT1, but they do inhibit dozens of random targets. the in vivo data is meaningless.

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33. cancer_man on January 29, 2010 9:00 PM writes...

But resveratrol also failed to activate SIRT1 yet many studies have shown good results in mice and a few studies have shown positive results in humans.

If the studies showed resveratrol activated SIRT1 but the compounds didn't then I'd say the new compounds are in trouble and GSK wasted a lot of money. But I think interesting possibilities remain and will wait a few more months before calling it over.

Apparently Derek also thinks there is a chance the compounds may prove effective. He is in the field and I'm observing from a different field in science.

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34. Anonymous on January 29, 2010 10:24 PM writes...

Derek is just trying to be polite.

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35. cancer_man on January 30, 2010 12:40 AM writes...

I guessed Derek might just trying to be polite. The one poster who worked in the Harvard lab said he was not adding important informationn. No idea.

I still don't get Pfizers incentive since we'll no soon enough what Sirtis' results are. To me, it seems like a publicity game, but again the incentives aren't clear.

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36. Anonymous on January 30, 2010 9:19 AM writes...

re: the pfizer scientists' incentive, how about "desire to correct an enormous lie that's been propagated throughout the scientific and public press."

that sounds like plenty of incentive to me. i mean, if we don't care about such things, why bother doing science?

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37. Anotheranonymous on January 30, 2010 10:08 AM writes...

#31 Anonymous_too
Former Praecis survived the layoffs because not to do so would require senior management who bought them, again against the advice of their own research staff, to acknowledged their mistake. Internally Praecis is widely thought to have been a bit of a flop, to the great surprise of nobody who was around at the time of Affymax. As with the other acquisitions, internal scientists ended up having to teach them how to do drug discovery when the hype was shown to be just that...

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38. cancer_man on January 30, 2010 8:24 PM writes...

With so many poor publications, why are we to assume that Pfizer has a solid study? I'm in no position to judge, but one commenter laughed at it.

I'll assume it is a sound study, but it is hard to see how we know at this point that Sirtris "perpetuated an enormous lie." Maybe so, but that won't be known for a while longer. And why weren't the previous three studies that showed resveratrol didn't activate SIRT1 sufficient evidence. Suddenly it is Pfizer, GSK's main competitor, that is the decider?

Speaking prior to the Pfizer release, Guarente gave an interview where he said how little is still known about sirtuins and that his lab was at the "very tip of the iceburg."

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39. Skeptical scientist on February 10, 2010 8:42 PM writes...

Wow. Hey guys. Do the world a favor and go edit the wikipedia page of Sinclair, Sitiris and resveratrol. I am glad to see that there are still critical thinkers left in the joke that academic research has become..

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40. CG on August 19, 2010 3:06 PM writes...

Derek, just wondering if you intend to follow up on this saga some months later, what with Sirtris' recent publication by Han Dai et al. in J. Biol. Chem.? The evidence gathered by the Sirtris team provides a satisfying explanation of the peptide substrate-structural dependence of SIRT1 activation and in fact the evidence is at odds with that of Pacholec et al. from Pfizer. As a (former) card-carrying enzymologist, I find the Sirtris data pretty convincing, but then I'm not surprised at its robustness, given that the leader of the effort is Ross Stein, who is a first-rate enzymologist.

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