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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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« Synthetic Chemistry: All Mined Out? | Main | Delightful, But It Apparently Works »

September 23, 2010

Chemical Biology - The Future?

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Posted by Derek

I agree with many of the commenters around here that one of the most interesting and productive research frontiers in organic chemistry is where it runs into molecular biology. There are so many extraordinary tools that have been left lying around for us by billions of years of evolution; not picking them up and using them would be crazy.

Naturally enough, the first uses have been direct biological applications - mutating genes and their associated proteins (and then splicing them into living systems), techniques for purification, detection, and amplification of biomolecules. That's what these tools do, anyway, so applying them like this isn't much of a shift (which is one reason why so many of these have been able to work so well). But there's no reason not to push things further and find our own uses for the machinery.

Chemists have been working on that for quite a while. We look at enzymes and realize that these are the catalysts that we really want: fast, efficient, selective, working at room temperature under benign conditions. If you want molecular-level nanotechnology (not quite down to atomic!), then enzymes are it. The ways that they manipulate their substrates are the stuff of synthetic organic daydreams: hold down the damn molecule so it stays in one spot, activate that one functional group because you know right where it is and make it do what you want.

All sorts of synthetic enzyme attempts have been made over the years, with varying degrees of success. None of them have really approached the biological ideals, though. And in the "if you can't beat 'em, join 'em" category, a lot of work has gone into modifying existing enzymes to change their substrate preferences, product distributions, robustness, and turnover. This isn't easy. We know the broad features that make enzymes so powerful - or we think we do - but the real details of how they work, the whole story, often isn't easy to grasp. Right, that oxyanion hole is important: but just exactly how does it change the energy profile of the reaction? How much of the rate enhancement is due to entropic factors, and how much to enthalpic ones? Is lowering the energy of the transition state the key, or is it also a subtle raising of the energy of the starting material? What energetic prices are paid (and earned back) by the conformational changes the protein goes through during the catalytic cycle? There's a lot going on in there, and each enzyme avails itself of these effects differently. If it weren't such a versatile toolbox, the tools themselves wouldn't come out being so darn versatile.

There's a very interesting paper that's recently come on on this sort of thing, to which I'll devote a post by itself. But there are other biological frontiers beside enzymes. The machinery to manipulate DNA is exquisite stuff, for example. For quite a while, it wasn't clear how we organic chemists could hijack it for our own uses - after all, we don't spend a heck of a lot of time making DNA. But over the years, the technique of adding DNA segments onto small molecules and thus getting access to tools like PCR has been refined. There are a number of applications here, and I'd like to highlight some of those as well.

Then you have things like aptamers and other recognition technologies. These are, at heart, ways to try to recapitulate the selective binding that antibodies are capable of. All sorts of synthetic-antibody schemes have been proposed - from manipulating the native immune processes themselves, to making huge random libraries of biomolecules and zeroing in on the potent ones (aptamers) to completely synthetic polymer creations. There's a lot happening in this field, too, and the applications to analytical chemistry and purification technology are clear. This stuff starts to merge with the synthetic enzyme field after a point, too, and as we understand more about enzyme mechanisms that process looks to continue.

So those are three big areas where molecular biology and synthetic chemistry are starting to merge. There are others - I haven't even touched here on in vivo reactions and activity-based proteomics, for example, which is great stuff. I want to highlight these things in some upcoming posts, both because the research itself is fascinating, and because it helps to show that our field is nowhere near played out. There's a lot to know; there's a lot to do.

Comments (33) + TrackBacks (0) | Category: Analytical Chemistry | Biological News | Chemical News | General Scientific News | Life As We (Don't) Know It


COMMENTS

1. cookingwithsolvents on September 23, 2010 8:47 AM writes...

I wanted to add a counter-point for the discussion.

I'm not convinced that biology *always* does it better. Biological systems evolved to...make more of themselves. There are plenty of biological transformations which are extremely convoluted because everything has to be done in homeostatic conditions (STP, water around, etc)...the precise conditions which make many other biological transformations attractive.

The Haber-Bosh process is a great example. It's nifty that nature does it at STP but 1) it wastes one H2 per turnover (i.e. 2 H+ and 2 e-) and 2) only turns over 2 per s per site. The industrial catalyst TON's are orders of magnitude higher and the system has been so well engineered that the main energy sinks are from the need to stop it from time to time to bleed of the Ne, Xe, etc from the feedstock and from H2 production by reforming CH4. (remember, it *is* an exothermic reaction). Sure, we should look for ways to do it at STP or with light or new catalysts or whatever, but we all ready produce it on the same scale as mother nature does (perhaps even more than nature per year by now).

Photosynthesis is only 1% efficient and the active site needs to be replaced two times an hour from oxidative degradation (I think I'm getting the frequency right). We can all ready be more efficient than that; it just costs too much. I'm confident that we'll figure it out for the cases where fuel cells make the most sense. The CO2 side of the equation is another story and we are really in our infancy for CO2 --> fuels/value-added chemicals, etc.

Finally, if I want to make some crazy-complicated molecule sterospecifically...sure gimme the bio-inspired systems.

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2. PTM on September 23, 2010 9:28 AM writes...

"I'm not convinced that biology *always* does it better."

It does if you make a fair comparison, which means including the actual purpose the process is serving and the conditions under which it has to operate.

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3. Daniel Levy on September 23, 2010 9:48 AM writes...

To add my perspective, biology evolves for its own purposes. For example, naturally occurring compounds of medicinal interest were not designed by nature to serve the medical needs of humans. However, they do provide interesting starting points and insight into how certain biological targets can be artificially modulated.

Regarding chemical biology, many people have been working in this area for many years. One professor, Peter Schults at Scripps, produced pioneering work in the areas of catalytic antibodies and the inclusion of unnatural amino acids into proteins through use of a nonsense codon.

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4. rhodium on September 23, 2010 9:59 AM writes...

A distinction between chemical biology and biochemistry that I like to make is that chemical biology includes making things that nature never thought of. Since chemical space is effectively infinite and biochemistry has been around for a only a limited time, there should be lots of other interesting things out there. PNAs and LNAs are my personal favorites. The late John Osborn asked a fascinating question: What would biochemistry be like if transition metals like Pd and Ru were in greater abundance. I think biosynthesis could use olefin metathesis, for example. And perhaps biosynthesis missed a bet by generally ignoring the azide functional group. Whether human society is rich enough these days to explore these curiosity driven questions is a different problem. At least undergrads are cheap.

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5. Mattt on September 23, 2010 10:31 AM writes...

Could you guys name top 5 chemical biology professors ?

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6. Various Positions on September 23, 2010 11:07 AM writes...

@Mattt

Daniel mentioned Pete Schultz. There is also Stuart Schreiber and Carolyn Bertozzi. Maybe someone else can add the last 2.

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7. Aspirin on September 23, 2010 11:10 AM writes...

1. Stuart Schreiber
2. Peter Schultz
3. Kevan Shokat
4. Reza Ghadiri
5. Chris Walsh

(not necessarily in order of importance)

Permalink to Comment

8. Derek Lowe on September 23, 2010 11:40 AM writes...

Don't leave out Ben Cravatt at Scripps!

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9. no no no on September 23, 2010 11:48 AM writes...

oh no sir...

I'll give you walsh/schreiber/schultz

but ghadiri and shokat?

bertozzi definitely should be in that list... plus, i'd even toss in muir/cravatt/degrado/arnold/liu before those two

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10. purp lehaze on September 23, 2010 12:59 PM writes...

There are many fascinating chemical biology labs. Check out the labs of Linda Hsieh-Wilson or Kate Carroll. Yes, it's fascinating to turn zebra fish different colors. However, a strong chemical biologist uses those tools to investigate an unknown...many times for a better understanding of a biological mechanism or process.

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11. S. Pelech - Kinexus on September 23, 2010 1:08 PM writes...

As enthusiasm for nanotechnology grows, it will become pretty apparent that the most facile strategy for adding functionality to microscopic structures is to reverse engineer from ourselves. As we learn more about our own molecular biology, as amazing as it is, it is clearly not that efficient.

For one example, we generate at least 30 times more DNA than what we need in our chromosomes. Easter lilies, butterflies and lungfish produce 31- to 48-times more DNA than we do in their chromosomes. In another example, we phosphorylate our proteins at as many as 700,000 phospho-sites, which is probably 100 times more than what is necessary for optimal cellular regulation. These processes have very high energy and material resources requirements, in particular with the consumption of adenosine-triphosphate. ATP is the main source of energy to drive all biological chemical reactions either directly or indirectly.

Nature has to start with what it has and then in a very haphazard way fumble into improved structures for proteins that have to serve structural and catalytic functions. Bacteria are more highly evolved from a molecular perspective than mammals, so their cellular processes are often more efficient. This is because the optimization that works with natural selection operates much faster in life forms that can reproduce in half an hour compared to those that may take decades.

Enzymes may be viewed as "molecular robots" that can be reprogrammed with slight mutations to adopt new functionalities or even tailored to work better. I believe that enzymes such as genetically engineered protein kinases will eventually become basic components in the design of nanoprocessors to drive computers in the not so far future. This might be partly achieved, for example, by creation of eukaryotic-like kinase signalling systems in prokaryotes that terminate in the regulation of chemoluminescent reporter genes.

While there has been some interest in using aptamers with oligonucleotides as biological catalysts, I suspect that this is unlikely to be a fruitful direction. It may have been at onetime that life was based in an RNA world. However, nature obviously found proteins to be much more efficient biological catalysts. With RNA (or DNA), four types of oligonucleotides serve as the building blocks for long polymers that twist and fold to adopt functional structures. With proteins, we have 20 types of common amino acids, which are slight smaller than the oligonucleotide bases, to use as building blocks for much greater versatility. It seems that oligonucleotides work best in an information storage capacity or as scaffolds for binding functional proteins.

The genetic code used by all known life on this planet uses 61 triplets of four base nucleotides to specify 20 common amino acids. However, there are hundreds of possible amino acid structures. Moreover, it is already feasible to re-engineer tRNA's so that 63 different tRNA's can specify 63 different amino acids, i.e. the 20 common amino acids plus 43 new amino acids and a still leave a stop codon. As we exploit this possibility, this will markedly expand the potential for bio-engineering and permit the synthesis of even more durable and robust proteins. Where this will go in terms of synthetic life enters into the realm of science fiction and human imagination.

Permalink to Comment

12. DLIB on September 23, 2010 3:04 PM writes...

You guys are funny...have you ever heard of pharmacology.

Permalink to Comment

13. daen on September 23, 2010 3:54 PM writes...

I would also suggest Nathanael Gray at Harvard and Thue Schwartz in Copenhagen.

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14. SP on September 23, 2010 4:15 PM writes...

You can, of course, use non-natural bases (Eric Kool) just as you can use non-natural amino acids (Liu under Schultz)

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15. Wavefunction on September 23, 2010 4:41 PM writes...

I would probably have Schreiber, Schultz, Carvatt, Walsh and Bertozzi on the list. Also Muir and Arnold. Interesting that all of these are American. I am sure there are great European groups but the US certainly seems to lead in chemical biology.

Permalink to Comment

16. Skeptic on September 23, 2010 7:34 PM writes...

More bullcrap. These "geniuses" shrug their shoulders regarding cardiotoxicity and slap a label on the bottle. Dirty drugs is apparently progress as of late 2010.

I don't care that Schreiber is an expert molecular tinkerer. He co-founded that joke called Ariad Pharmaceuticals, todays stock price $3.47. Are all these new age experts holed up in Institutes?

Permalink to Comment

17. leftscienceawhileago on September 23, 2010 8:01 PM writes...

To my knowledge, none of these guys have had much to do with a drug that has gotten to the market.

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18. Aspirin on September 23, 2010 8:11 PM writes...

@Skeptic and leftscience: Absolutely right! As we all know, the main function of academia is to discover new drugs and found pharmaceutical companies. Advancing basic scientific understanding is sooo 17th century. What were these guys thinking?! They really need to hire you as consultants...

Permalink to Comment

19. Skeptic on September 23, 2010 9:59 PM writes...

Oh yeah, PCR is a real academic chemistry Tour de Force:

DNA double strands break up when heated
pairs up A-T , G-C when cooled
extension process using enzyme polymerase

Thats all you need to know for PCR and its been known for over 50 years.

There is no basic science going on in academia. Just authority figures raking it in and slaves.

Permalink to Comment

20. Aspirin on September 23, 2010 10:48 PM writes...

-Thats all you need to know for PCR and its been known for over 50 years.

Oh, right. That's why you invented it and got the Nobel Prize for it in the 50s. Sorry, I tend to forget how you, the great Skeptic, has single-handedly revolutionized biomedical research and then published variously under the nom de plumes Mullis, Berg, Woodward, Corey and Kornberg. It's time you let the world knew your real identity, o genius in the shadows!

Permalink to Comment

21. skeptic's skeptic on September 23, 2010 11:32 PM writes...

@ Skeptic:

and all that was needed for calculus was a handful of greek letters and some thought about where things go in the limit. Liebniz and Newton were just authority figures raking it in.

All these developments are "obvious" in hindsight. OF COURSE you use polymerase derived from a heat-resistant single-celled organism found in hot springs, tag your molecules of interest so only they are amplified by this special polymerase at its higher-than-normal temp, and cycle back and forth to duplicate and split.

If you are going to stand on the shoulders of giants--and you unavoidably are, you can't wipe your arse on the loo without being beholden to many many others--you should learn a little respect.

I'm sure you build up your copies of DNA by hand to avoid glorifying such worthless research...oh wait, there was no way to do that without spending years of time. You must be using the product of someone else's sweat and inspiration, AND demeaning their contribution at the same time. Classy.

Permalink to Comment

22. Morten G on September 23, 2010 11:40 PM writes...

@leftscienceawhileago: I think the post was on using biomolecules for organic synthesis - not necessarily drugs.

I think I heard of a company that mixed biosynthesis genes from various plants good at small molecule chemistry and put like 4 or 5 of them in yeast and looked at the products they got. Aiming at a whole pathway rather than a single step. I think it was called Evolva or something. Started in Denmark but headquartered in Switzerland or India... This is pretty vague, huh?

Permalink to Comment

23. PTM on September 24, 2010 6:29 AM writes...

"In another example, we phosphorylate our proteins at as many as 700,000 phospho-sites, which is probably 100 times more than what is necessary for optimal cellular regulation."

Nonsense. Considering how little we know about those networks your claim that you could optimize them by cutting 99% of phosphorylations is simply absurd.

Permalink to Comment

24. Anonymous on September 24, 2010 6:44 AM writes...

Chemical Biology is one of the results of reshuffling the names. Its kind of academic restructuring. Think:

Chemistry
Biolgy
Physics
Biological Chemistry
Chemical Biology
Chemical Physics
Biological Physics = Biophysics

May be in a few years, I will write funding application to start a new department of ChemBioPhysics or may Physical Biology...

Permalink to Comment

25. p on September 24, 2010 7:13 AM writes...

You may well be able to make it more efficient by cutting 99% of all phosphorylations.

The interesting question: which 1% would you keep?


When you figure that out, get back to us.

Permalink to Comment

26. Anonymous on September 24, 2010 7:35 AM writes...

Shokat is the best person in chemical biology. He's developed tools that actually go somewhere, i.e. are used by biologists to address real biological problems.

Bertozzi, Muir, Cravatt have all done the same thing to some degree.

Schultz and Schreiber are way past their prime. Schreiber in particular just seems unhinged, and his papers from the last ~15 years are unreadable.

Permalink to Comment

27. daen on September 24, 2010 11:56 AM writes...

@Morten: I used to work with Evolva's CFO, Jakob Dynes Hansen, when we were both at Nuevolution. Not sure Evolva has ever been a Danish company, though (although Jakob himself is, and some of the companies acquired along the way have Danish connections - Arpida acquired Combio A/S, before being bought by Evolva, for example).

Permalink to Comment

28. fgH on September 24, 2010 9:38 PM writes...

Looks like a bunch of chemists are pooling here. Let me ask an undergrad question as to why does it a bond cleavage requires energy in chemistry and bond cleavage in biology releases energy i.e. from ATP to ADP.

Thanks in advance.

Permalink to Comment

29. leftscienceawhileago on September 24, 2010 10:35 PM writes...

@Morten, fair enough, although I hope I can be forgiven in the context of this blog.

But I think it is an important point that "chemical biology" is funded by grants that certainly employ that old workhorse phrase, "may lead to new drugs" (perhaps we should just make a road-sign style graphic and just stamp it on to grant applications to save time); and it is a fair question to ask if they have contributed anything towards that end. I (humbly) don't think they have.

The names being mentioned made me recall a time at a GNF meeting where a senior figure was lamenting the fact that (not exact wording here, but close) "corporate was expecting 3 drugs, currently we have 0...but don't worry I have never failed in my life and I am not about to start".

To my my knowledge, there hasn't been anything that has gotten to the market attributable to GNF.

Permalink to Comment

30. Wavefunction on September 25, 2010 9:49 AM writes...

@fgH: Bond cleavage always requires energy, even in biology. The question is whether the net reaction is energetically favorable, which it is in case of ATP. There are cases in chemistry too; for instance the cleavage of a bond that expels nitrogen as a leaving group is usually very favorable (nitrogen is sometimes called "the world's best leaving group").

Permalink to Comment

31. S. Pelech - Kinexus on September 25, 2010 1:25 PM writes...

With respect to comments 23 and 25.

At Kinexus Bioinformatics Corporation, we have collated data from published papers and other databases for the identification of about 93,000 experimentally confirmed protein phosphorylation sites (phospho-sites) in humans. These data are freely accessible at www.phosphonet.ca. Using this data set in the training for an algorithm that we have developed, we identified about 700,000 phospho-sites that meet a series of test filters that we applied to 21,000 proteins encoded by the human genome to home in on the best candidates. These additional predicted phospho-sites will be post on PhosphoNET later this year.

The existence of around 700,000 human phospho-sites is at first daunting and rather surprising. However, we have accumulated expression and phosphorylation data with several thousand different tissue and cell samples that indicate that hyperphosphorylation appears to trigger protein degradation in a non-specific manner. Consequently, the precise location of most phospho-sites does not appear to be particularly critical.

To identify the most important functional phospho-sites, we have applied evolutionary analyses to determine the conservation of human phospho-sites in over 20 other species. It turns out that only a couple of thousand phospho-sites are highly conserved, and most of these appear in protein kinases. Our PhosphoNET website also provides the results of these evolutionary analyses of human phospho-sites. We are applying a few more tricks to narrow down the most critical phospho-sites. Even 1% of 700,000 phospho-sites provides a lot of latitude for fine regulatory control of the molecular intelligence systems operating in living cells.

Permalink to Comment

32. roxanne on September 26, 2010 8:47 PM writes...

I think it’s very possible! What do you think about this video that proposes that the traditional bench scientist will end up spending more time on computational analysis than on the bench itself. Take a look.
http://www.americanbiotechnologist.com/blog/changing-role-bench-scientist/

Permalink to Comment

33. christian cafe.com on August 18, 2012 7:28 AM writes...

It’s difficult to find knowledgeable people in this particular topic, however, you seem like you know what you’re talking about! Thanks

Permalink to Comment

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