The Chemistry Nobel Prizes

Nearly all the chemist-bloggers I read felt that the chemistry nobel prizes should go to chemists, and that the work of Ramakrishnan, Steitz, and Yonath on the X-ray crystallography of the ribosome is more biology than chemistry.

I suppose that in a sense they have a point. Ribosomes come from cells, and cells are, traditionally at least, the province of biologist, not chemists.  Still, I can’t help but feel the attitude that only “real” chemists deserve the chemistry Nobel is somewhat provincial and narrow-minded.

For example, ribosomes have become a great tool for chemical synthesis (Here’s one example). Ribosomes catalyze the template-directed, sequence-specific polymerization of an increasingly diverse set of monomers. And these polymeric products, the proteins, are themselves amazingly diverse of course. Catalysts, drugs, poisons, you name it.

Maybe you have to squint a little harder than normal to make ribosomes look like chemistry, but it doesn’t seem like too tough a task to me. Then again, I’m not a chemist.

UPDATE: kylefinchsigmate reflects over the fascinating history of the Nobel and biochemistry.

UPDATE 2: I fixed some syntax problems in the first two paragraphs.

A, C, G, and T – For some people, four letters are not enough.

Ever since the time of Phoebus Levene, we’ve known that DNA has contained 4 bases – G, C, A, and T. Erwin Chargraff showed that the number of Gs in DNA were equal to the Cs, and the As were equal to the Ts. Then some guys you have definitely heard of solved the structure of DNA and it all made sense: our genes were written in a four-letter alphabet, with Gs bonded to Cs and As to Ts in a scheme now called “Watson-Crick base pairing”.

Today, we’ve gotten good at reading and writing in this alphabet. We can solve crimes, produce drugs, retrace the steps of human evolution, and even solve complex computational problems by reading and writing As, Gs, Cs, and Ts.

But for some people, four letters are not enough. For many years, several research groups have been working on adding new letters to the language of DNA. For example, Eric Kool and his co-workers have made size-expanded DNA. By this they mean, what happens if you drop in another benzene ring to adenine?

One example of a new letter in the DNA alphabet.

Floyd Romesberg and his co-workers have been coming up with additional DNA letters for as long as just about anyone else. One exemplary finding: Watson-Crick base pairing is not even necessary for the creation of new DNA letters. Instead, purely hydrophobic forces can bind oligonucleotides together, as in the artificial base pair d5SICS and dMMO2.

Two more new letters for the DNA alphabet, d5SICS and dMMO2

Floyd Romesberg, Eric Kool, and many other workers are getting close to engineering new letters for DNA that can be read and written using existing DNA processing tools. That is, some recently reported synthetic nucleotide base pairs can be replicated by DNA polymerases with high fidelity and good catalytic specificity. The As, Gs, Cs, and Ts of DNA will have to make room for new letters.

Soothly we live in mighty years!

Why does infotech have more celebrities than biotech?

Steve Jobs, Bill Gates, Larry Page, Meg Whitman, Marissa Mayer, Guy Kawasaki, Jimmy Wales, Steve Balmer, Sergey Brin, Marc Andreessen, etc. What do these people have in common? If you said “None of them work in biotechnology,” you think like me.

The information technology industry undeniably creates more celebrities than other technological fields, like biotechnology. Biotechnology is a good comparator, because it shares with IT similar global market sizes and an ethos of entrepreneurship and innovation. So why does IT have more celebrities than biotech? Some initial thoughts.

1. More showboaters. Maybe IT types are just more attracted to flattering PR. This explains (in part) the prominence of maybe two or three people on my list, but certainly not everyone.
2. Consumers interact directly with a lot of internet businesses but less so with biotech products. Everyone uses the web, so they can better appreciate the accomplishments of Larry Page than of Herbert Boyer or Walter Gilbert.
3. Relatedly, the internet can turn average joes into hyper-successes much faster than biotechnology, because the internet does not (yet) have an FDA. Web sites and software do not need to go through clinical trials (and rightfully so), and so they can become successful much more quickly, while people are still interested in hearing about them and while the founders are young enough for teens through thirtysomethings to identify with.
4. Internet folks go to more conferences than biotech folks, possibly because working in front of a computer screen all day long is boring, so they need more celebrities to make speeches.
5. What have I missed?

What happened to 3′ tags?

Colleagues of mine have begun making extensive use of 454 sequencing.
This is one of the largest (only?) commercial services for pyrosequencing-based sequence analysis of DNA. Pyrosequencing is one particular type of “sequencing by synthesis”, a cheaper, faster, and more parallelizable method for DNA sequencing than the traditional Sanger technique.

The technique works by exposing a growing DNA strand to deoxyribonucleotide triphosphates one-at-a-time. If the next base of the template is T, the next base of the newly synthesized strand should be an A. When dATP is exposed to the strand, it is incorporated into the new strand, which grows longer by at least one base pair. In the process, pyrophosphate is released, and other enzymes in the reaction mix convert the pyrophosphate into light. This is the signal detected in 454 sequencing. In contrast, when the strand is exposed to dCTP, dGTP, or dTTP, no incorporation is possible, and no light signal is generated.

One problem with sequencing by synthesis is homopolymers. Suppose the template has a stretch of Ts: TTTTTTTTAG, for example. When the reaction mix is exposed to dATP, incorporation and strand synthesis can happen all the way until the next non-T base. This generates a stronger light signal than incorporation of just one base. For short stretches of homopolymer, the strength of the light signal can be used to estimate how many bases were incorporated. But after a point, the noise overwhelms the signal, and it can be very difficult to tell CGTTTTTTTTAG from CGTTTTTTTTTAG, for example.

Last night, I was reading few papers in the history of developing pyrosequencing technology. What puzzled me is that right from the beginning, the early exponents of sequencing-by-synthesis seemed to have anticipated this problem and developed solutions. The most common approach was to put a cleavable tag on the 3′ position of the dNTP. Since polymerases require a 3′ hydroxyl group, and extra non-hydroxyl shizzle hanging off the 3′ end of a dNTP would mean that after incorporation of a single base, no new bases could be incorporated until the extra shizzle was removed. 3′ tags cleavable by light, reducing agents, or palladium, among others, were developed by various teams.

What happened to this technology? I don’t know why it isn’t used in 454 sequencing. Several possibilities:

1. Licensing issues. Are cleavable 3′-tagged dNTPs covered by intellectual property not available to 454 or Roche?

2. Problems with cleavage. As described in various publications, cleavable tags seemed to work well in the laboratory, but I wonder about the accessibility of cleavage reagents to the picotiter plates and emulsion bubbles used for modern 454 techniques. Does the lasers used for photocleavage of some tags effectively reach all parts of the bead surfaces and emulsion bubbles inside each picotiter plate well? Maybe platinum or reducing agent-based tags require reagents that are too expensive or diffusive poorly into the emulsion bubbles?

3. Other reasons?

It seems like better handling of homopolymers would be a great improvement of 454 sequencing technology. What don’t I know about cleavable 3′ dNTP tag technology which makes it unsuitable for fixing the homopolymer problem?