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DBL%20Hendrix%20small.png College chemistry, 1983

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: derekb.lowe@gmail.com Twitter: Dereklowe

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In the Pipeline

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November 29, 2005

Ghrelin and Obestatin

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Posted by Derek

There's a peptide hormone called ghrelin that a lot of pharmaceutical companies have worked on in the last few years. It's a good target for obesity (and perhaps diabetes, too), since it's involved in appetite signaling between the stomach and the central nervous system. It's also involved in growth hormone signaling, too, though, so the situation is complicated.

And it just got more so. It turns out, according to a paper in the November 11 issue of Science. A group at Stanford has discovered that the same percursor protein that's carved up to produce ghrelin is also used to produce another peptide hormone that they've called obestatin. That one has its own receptor, and its own signaling network, and it appears to do the exact oppositeof what ghrelin does. Injections of ghrelin stimulate feeding in mice, and injections of obestatin inhibit it, for example. Similarly, ghrelin increases gastric emptying, and obestatin slows it down. (One place where the two peptides don't match up is their effects on growth hormone secretion - obestatin doesn't seem to do anything to the growth hormone axis at all).

So now we know more about the regulation of appetite than we used to, although researchers in that field probably thought it was complicated enough already, thanks very much. What I find particularly interesting about this discovery is how these two opposing hormones are cut from the same larger protein. That means that they both come from the same gene, you know. Which shows you just how far a pure genome-driven approach to drug discovery will get you: not far enough. You'd never know about ghrelin from just reading off human genes, because it's produced after the orginal protein is transcribed. And you'd never know that the same protein is the source for another hormone that negates ghrelin, either. All that complexity is downstream of the DNA. (Update: see the comments for some dissenting voices on this issue).

We already knew that general principle, of course. As soon as the estimates of the total number of human genes starting coming in, it was clear that they were way too low to explain the number of different proteins that we already knew about. But examples like this one just rub it in. . .

Comments (18) + TrackBacks (0) | Category: Diabetes and Obesity


COMMENTS

1. slc on November 30, 2005 7:33 AM writes...

I was visiting a local college chemistry department yesterday and explaining the need for drug researchers to validate targets that come from genomics data. This is a wonderful example of why. My wife suggested that the mouse's personality may play a role, though. I guess that takes 'systems biology' to a new level. We slog on.

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2. otey on November 30, 2005 8:11 AM writes...

Good piece. The kind of piece that begins to clarify (at least for this civilian) why all the hype about the big genome payoff has gotten ahead of itself.

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3. PandaFan on November 30, 2005 10:35 AM writes...

Uh, before you go the 'too much genomics hype' route please reread the paper -- it was a smart computational search of genomic sequencing data that suggested the extra peptide (in particular, note Supplementary Figure S1). It is the depth of mammalian genome coverage that made this work -- sequencing a zoo is a very useful scientific strategy!

The generation of multiple peptide hormones from a single precursor is _extremely_ common. There are almost certainly more of these stories to be told -- but the hard part is finding the biology & the receptors for you candidate hormone peptides

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4. Derek Lowe on November 30, 2005 11:35 AM writes...

Panda, you're right that the generation of multiple active peptides from a single precursor is common. What struck me about this is the "equal and opposite" aspect. If obestatin had effects on growth hormone secretion, the story would have been perfect. . .

And it's true that this group did genomic scanning, but as you point out, it took multiple genomes to make it work. The hype that I'm bashing is of the "Human Genome Sequence Unveils Wonder Drugs" type, which has been laughed at in the industry (and in the relevant academic fields) for several years, but is still current in the popular press.

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5. RKN on November 30, 2005 1:22 PM writes...

What struck me about this is the "equal and opposite" aspect.

Even ghrelin itself evidently has physiologically equal and opposite effects, from the ghrelin link:

  "Ghrelin also appears to suppress fat utilization in adipose tissue, which is somewhat paradoxical considering that growth hormone    has the opposite effect."

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6. bronxite on November 30, 2005 1:46 PM writes...

Were there any details about the agents that do the carving, and how generic they are (proteases?)?

How old (evolutionarily) is this kind of hormone generation (single and multiple hormones cut from the same protein)?

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7. JSinger on November 30, 2005 2:04 PM writes...

In fairness, I'd like to point out that the new peptide was identified through analysis of cross-species sequence conservation. So one could (quite reasonably, I think) make a case for it as an example of in-silico genomics turning up something that biochemists and cell biologists have missed in a decade of pretty intensive work.

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8. JSinger on November 30, 2005 2:07 PM writes...

Errr, sorry -- there were only two visible comments when I posted that. That'll teach me to refresh...

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9. PandaFan on November 30, 2005 2:48 PM writes...

At least some of the proteases are known, though I forget who they are (kexins?).

There are definitely such peptide hormones in insects, worms, and molluscs & I'm pretty sure they are processed the same way. I don't know whether anyone has looked in the early branchers such as Cnidarians or Porifera.

I know Derek wasn't completely dismissing genomics, but there is the danger that appropriate refutation of the hype (which, I must admit, financed my current lifestyle) will go to complete obliteration of the contribution. Genomics didn't revolutionize medicine or drug development, but it probably will touch the vast majority of such projects going forward, and many in very substantial ways.

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10. Derek Lowe on November 30, 2005 4:21 PM writes...

You know, I actually acree with that, for the most part. This is another one of those wands that will eventually start to emit sparks as we wave it around. (I even put molecular modeling in that category, although it's going to be much longer in that case).

But in the meantime, we have statements like this, from Thomas Friedman of the New York Times:

"The next great breakthrough in medicine, as Marc Andreesen says in a book, could come from a 17-year-old in Romania who downloads the human genome on their cellphone iPod."

You betcha.

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11. The Novice Chemist on November 30, 2005 10:43 PM writes...

Classic Friedman crazy analogizing/exaggeration. Almost up there with the "Beautiful Mahogany Table With Only Three Legs" of the Bush war plan.

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12. Jim Hu on November 30, 2005 11:11 PM writes...

Well, a Romanian 17-year old who is geeky enough to actually download the genome onto their cell phone could make a great breakthrough in medicine...but I sure hope there are great breakthroughs while we wait for this kid to finish college, med/grad school etc.
;^)

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13. Sylvia on December 1, 2005 12:06 AM writes...

A facinating piece of equal & opposite. Think its time genomics was put to better use to unravel such fascinations that are invisible. Science requires more sophisticated interfaces to strip its mysteries!

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14. anonymous on December 1, 2005 11:05 AM writes...

In fact, the whole field of Bioinformatics may be a fraud. See this paper:

Why Most Published Research Findings Are False
John P. A. Ioannidis
PLoS Medicine

http://medicine.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pmed.0020124

Summary

There is increasing concern that most current published research findings are false. The probability that a research claim is true may depend on study power and bias, the number of other studies on the same question, and, importantly, the ratio of true to no relationships among the relationships probed in each scientific field. In this framework, a research finding is less likely to be true when the studies conducted in a field are smaller; when effect sizes are smaller; when there is a greater number and lesser preselection of tested relationships; where there is greater flexibility in designs, definitions, outcomes, and analytical modes; when there is greater financial and other interest and prejudice; and when more teams are involved in a scientific field in chase of statistical significance. Simulations show that for most study designs and settings, it is more likely for a research claim to be false than true. Moreover, for many current scientific fields, claimed research findings may often be simply accurate measures of the prevailing bias. In this essay, I discuss the implications of these problems for the conduct and interpretation of research.

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15. RKN on December 1, 2005 11:28 AM writes...

anon,

I merely scanned the article, but the central criticism isn't aimed at bioinformatics. In fact a search for "bioinformatics" found nothing.

Still it was interesting, though not terribly surprising. I've been cautioned by a number of investigators here at .edu that a large amount of published biomedical research is probably wrong to one degree or another.

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16. sylvia on December 8, 2005 4:44 AM writes...

should all research done with the aid of bioinformatics be viewed with skepticism? Thought big pharma were moving onto in silico for drug discovery and gaining good results!

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18. Dave on February 11, 2007 10:06 AM writes...

Hi, im currently doing a project on RNA interference, where it is possible to switch off genes, and as part of this project come up with a novel use for the technique, just for thoughts, but what about switching off the gene that produces ghrelin, and so swtich off your appetite?

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