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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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« Engaging the Public? | Main | Where Drugs Come From: By Country »

November 8, 2010

Epigenetics: The Code Isn't The Object

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Posted by Derek

Here's an excellent background article on epigenetics, especially good for getting up to speed if you haven't had the opportunity to think about what gene transcription must really be like down on a molecular level.

This also fits in well with some of the obituaries that I and others have written for the turn-of-the-millennium genomics frenzy. There is, in short, an awful lot more to things than just the raw genetic code. And as time goes on, the whole the-code-is-destiny attitude that was so pervasive ten years ago (the air hasn't completely cleared yet) is looking more and more mistaken.

Comments (17) + TrackBacks (0) | Category: Biological News


COMMENTS

1. TwoYaks on November 8, 2010 1:11 PM writes...

The whole Code-is-Destiny thing is a bit of a straw man. People have known about maternal effects, environmental induction, and the rest of it for decades. Epigenetics as a field right now is one part new mechanisms and interesting observations, and 99 parts hype. And I'm a little confused how environmental determinism is any more 'liberating' than genetic determinism. Either is equally wrong headed.

For a good critique of epigenetics, check out Lysenko Rising in the latest issue of Current Biology.

Permalink to Comment

2. Poul-Henning Kamp on November 8, 2010 2:13 PM writes...

There is an angle on the whole "code-is-destiny" spin that is totally missed out in most public contexts: Even if it were true, we may not be able to hack the code.

Over in an obscure corner of the IT world where I live (I'm only come here for the "Things I won't work with" entries :-) we have a concept called "spaghetti-code".

Spaghetti-code is characterized by being tangled and unsystematic in every possible way one can imagine.

Progress in programming languages have all but erradicated spaghetti-code from sober contexts (but see also: http://www.ioccc.org/)

It does crop up still, 100% consistently, in one place: When we try to develop programs using biology-like evolutionary methods.

In IT we have known for 50 years, and geneticists have recently started to realize, that tinkering with any small bit of the spaghetti-code, can and usually will have "interesting" effects far away.

And no, they are "effects" and not "sideeffects", because the code was "written" to do both things with the same snippet of DNA.

I attribute much of the genomics failure, not to lack of knowledge about how genes work, but to ignorance of the knowledge we already had about such coding practices: Old assembler programmers could have told them how futile that would turn out to be.

Poul-Henning

Permalink to Comment

3. turing on November 8, 2010 2:23 PM writes...

The author is correct enough factually, but argh the overblown rhetoric! And look at the size of the straw men!

Take this:
"To think of a methylated cytosine (the nucleotide base most commonly affected) as still the same letter “C” that it was before its methylation, but merely tagged with a methyl group, is to miss the full reality of the situation. What we are really looking at is a metamorphosis of millions of letters of the genetic code under the influence of pervasive and poorly understood cellular processes. And the altered balance of forces represented by all those transformed letters plays with countless possible nuances into the surrounding chromatin, reshaping its sculptural qualities and therefore its expressive potentials."

Thanks, I'll think of it as a methylated cytosine, which affects expression. Not some misty Shroud of Turin playing the pan flute and dancing with the fauns on the meadow.

I share the author's wonder at the beauty and complexity of life, and am at least as skeptical about premature declarations of determinism. But you have to walk before you r...uh, dance. We had to start with the 1D code before we could consider the full 3D nature of the molecule. And somebody had to push that as a worthy destination to get funding. So there's more to it than that--is that really such earth-shattering news?

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4. hn on November 8, 2010 4:14 PM writes...

This kind of mysticism is what we get from biologists who think of molecular biology as letters and cartoons rather than dynamic molecules. To a chemist, methylated cytosine is obviously a different molecule than cytosine.

When in doubt, always blame the biologists.

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5. HK on November 8, 2010 9:43 PM writes...

I think it's refreshing to have a piece written to inspire scientists to A) engage in more interdisciplinary thinking (the holistic approach) and B) suggest certain concepts are less straightforward and more abstract than we thought 15-20 years ago. Yes, a lot of it is obvious, but he's not necessarily writing to chemists, or to biologists, or even just to scientists and it's hard to write a piece directed at both the layman and the erudite without oversimplifying or overstating some concepts.

It's really well-written and fairly comprehensive, not as detail-oriented as I'd like but nothing's perfect.

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6. alig on November 9, 2010 8:08 AM writes...

Since the Code has the code for epigenetic enzymes which are the tools used to modify the Code, isn't the Code still destiny?

Permalink to Comment

7. RickW on November 9, 2010 10:02 AM writes...

I think epigenetics inspires this sort of prose because it isn't well understood yet. There may be more entropy in the system than some would like, but epigenetics is not A Clockwork Orange nor any of the beard-scratching nonsense in the last section of the linked article.

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8. MIMD on November 9, 2010 11:22 PM writes...

Perhaps the "turn-of-the-millennium genomics frenzy" was in part due to the Syndrome of Inappropriate Overconfidence in Computers. Yeah, the genetic code is simple, just a few symbols, we'll crack it real soon.

That syndrome hasn't gone away.

Permalink to Comment

9. Jose on November 10, 2010 12:33 AM writes...

From the NY Times, experts guessing what the next big thing in their field will be: ("Voices: What's Next"). Fits with the mass media, education post, and:

David Haussler
Director, Center for Biomolecular Science and Engineering

“You’ll have a number of reports where people will have their genome sequenced, but there will be new types of genomes being read. We can read genomes from your immune cells. They adapt throughout your lifetime so they can protect you from diseases. Reading those genomes will be important, and you’re going to hear a lot about them next year.”

Permalink to Comment

10. Cartesian on November 10, 2010 5:21 AM writes...

Epigenetic is really important about the transmission of some skills to the babies, and it seems that the moment when one is breeding is important, because it should be better to do it when the skills are in action to do a performance.

Permalink to Comment

11. Anonymous on November 10, 2010 10:23 AM writes...

Always consider the source of information. The author of the article, Steve Talbott, works for the Nature Institute, which appears to promote an anti-reductionist, “holistic” approach to understanding nature. His academic background is in philosophy, not science, which explains the overblown rhetoric. He does seem to have a good grasp of the science, but his interpretation of what it all means in the bigger picture is probably much different than most scientists. It has hard to take seriously someone who believes that modern science “is not at all adequate to the active becoming, the contextual relatedness, and the living wholeness we discover in the world's phenomena” (www.natureinstitute.org/qual/index.htm).

Permalink to Comment

12. Dr Jimbo on November 10, 2010 12:55 PM writes...

I read most of the article. The author talks a lot about the subtle nuances of nucleosome spacing and other such structural factors affecting things like gene transcription in ways that we can describe in general but not really understand or predict in detail. The details of a lot of this were new to me, and well-described in a non-sciencey way. However, what my non-expert brain was pointing out to me while reading, getting quite persistent and annoying about it (hence not finishing the article) and what the author doesn't seem to get, is that such structural nuances are encoded in the linear sequence of bases. Sure, in ways that we can't model or predict very well, but they are almost certainly mostly contained therein. Similarly to protein tertiary structure being determined by the amino acid sequence (assuming expression in the right environment), it is pretty believable (to me) that chromosomal structures and regulation of expression are determined by the primary sequence, much of which is involved in regulating that structure, and which may be modified during cellular development.
There may be effects of sequence on nucleosome binding, methylation, assembly into higher order structures (perhaps at more levels of organisation than for proteins. It's surely complicated, but pretty easy to imagine for someone familiar with the basics of cell biology.
No mystical effects are required, and no-one need be concerned about how different chimpanzees are, or how few genes we have. There's enough information in the sequence to make something as complicated as we are, and we are not fundamentally more complicated than a chimp, or elephant, electric eel, or fruit fly.

Permalink to Comment

13. halvorz on November 10, 2010 7:12 PM writes...

"...such structural nuances are encoded in the linear sequence of bases. "

Not really. The linear sequence of bases contains a large portion of the information required to make the organism, but there is significant information conveyed by context, i.e., the cellular environment.

That is to say, I do not think you could deduce the entire structure of any organism from its genetic code. Even if you knew what every sequence of transcribed DNA coded for, what every transcribed RNA and every translated protein did, what reactions they catalyzed and what interactions they have, that would not be enough.

All the molecules are coded for by the DNA, directly or indirectly, but those molecules are arranged in a specific structure, a cell. That arrangement is necessary for interpretation of the information in the DNA. I don't think you could deduce that arrangement de novo from the DNA sequence- that indicates to me that it contains information different from the information contained in the DNA sequence, and that information is necessary for life.

Permalink to Comment

14. jekbradbury on November 10, 2010 8:48 PM writes...

Great article, until it veers off into Goethean-phenomenological land (in the words of the Nature Institute itself, that's what their guiding philosophy is). Also, the Nature Institute is essentially anti-GMO, ostensibly because we "can't predict" what the non-targeted effects of a given gene insertion will be.

Permalink to Comment

15. Dr Jimbo on November 11, 2010 5:26 AM writes...

@ 13. halvorz
Perhaps encoded was the wrong word. But many of the phenomena discussed in the paper (exact location of nucleosome binding, effects of local helix structure on transcription) will be dependent on the local sequence. The right cellular environment will also be critical to allow genetic sequence to establish functional chromatin structure. Similarly, a protein won't fold into the 'correct' tertiary structure in the wrong environment, and requires cellular machinery as well the appropriate cellular milieu. And we can't yet predict tertiary protein structure based on primary sequence (afaik). But I don't hear many arguments that protein structure is not dependent on, and even determined by, amino acid sequence. I agree with the article that lots of the junk has important functions, much of it independent of whether it ever gets transcribed. It's structural, much like the bulk of a protein is involved in ensuring that crucial residues at the active site are arranged in a functional way (to make a very simplistic analogy).

Permalink to Comment

16. sgcox on November 11, 2010 10:26 AM writes...

Dr Jumbo has a very valid point.
For example, it was recently shown that exons are favorable histone positioning sites and have sequnce length very close to nucleosome wrapping size. Some even proposed pmodels how it helps to find intron-exon junctions and facilitate splicing.

Permalink to Comment

17. halvorz on November 11, 2010 2:37 PM writes...

@ Dr. Jimbo

All true, and very good points.

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