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Pettitt on Applying Theory to the Improvement of Biochips

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At A Glance:

B. Montgomery Pettitt

2004 — Professor of Chemistry, University of Houston; Director, Keck Center for Computational Biology

2001-2004 — Dean of Computer and Computational Science, Univ. of Houston

1998-Present — Professor of Physics, Univ. of Houston

1994-Present — Director, Institute for Molecular Design, Houston

Education:1980 — PhD, physical chemistry, Univ. of Houston

1975 — BS, mathematics; BS, chemistry, Univ. of Houston

 

B. Montogomery Pettitt is the Hugh Roy and Lillie Cranz Cullen Distinguished Professor of Chemistry at the University of Houston. He has spent more than a decade applying his background in math, physics, biology, and biochemistry to theorizing about ways to improve the surface chemistry of biochips. He is in Australia this week giving a presentation on work conducted in his lab aimed at providing better design principles for future gener-ations of chips. He started off his interview with BioArray News, by stating, “Because of the math background, I’m a theorist. So, in some respects that means I don’t actually do anything.” Read for yourself and decide.

How did you first get involved in working with biochips?

I was talking with a colleague, Mike Hogan, over at Baylor College of Medicine. We had a long-standing collaboration on the biophysics of DNA, where he was doing experiments and I was doing the theory and calculations, and he started telling me about all of these strange problems when you attach DNA to surfaces. They really didn’t understand what was going on because whatever was happening in solution was apparently very different when they put the DNA on an array. So, I said, ‘Sure, I’ll think about it,’ and here I am 13 years later still thinking about it.

So you work mostly on surface chemistry?

I’m a physical chemist interested in the theory of solutions and interfaces, and part of my shop works on proteins and peptides and part of my shop works on nucleic acids. This is just such a fascinating problem. When I went into it, I realized that physical chemistry had very few tools to work on this particular problem of why hybridization would be different on a chip than it was in solution. A big part of what we had to do was build some new techniques and new tools. It probably took us seven or eight years to build the tools before we could actually address the problem. We did an enormous amount more of what amounted to DNA biophysics just to do the controls for the project, and eventually we did the first simulation of the surface amount of DNA in solution — a biochip basically. We began to look at different theoretical methods and got quantitative theories for how this surface shifts the hybridization efficiency or binding temperatures. Then I got Hogan and other experimentalists to do the experiments to verify not just the qualitative nature of the theories but the quantitative nature. And sure enough we did pretty well.

What did you find?

We could predict things like electric field effects, simple effects that could have to do with people not paying attention to ground, while either doing the hybridization or the actual scanning and measurements. A few folks figured out that there was more than just the biological prep problems, which are significant, and I don’t mean to minimize that. But we can give folks a hand with things like what are the optimal surface preparations … what kinds of temperature ranges are going to work for SNP chips versus simple genotyping. We basically built up a bunch of theory confirmed by simulations and then actually checked by experiments to try and ultimately describe hybridization efficiencies. It turns out that the surface density is a critical parameter in chip design.

Did you develop a chip itself?

No. I developed a lot of algebra and computer codes. I got other folks to do the experiments to make sure this is actually working.

Have people taken notice of your experiments and results?

Yeah. Suddenly people are reading this stuff, and myself and a couple of talented postdocs, Arnold Vainrub and Clem Wong — those are the guys who have been in the trenches doing the hard stuff — we’re getting asked to go talk at different places. Part of it had to do with getting the literature out of the physics and chemical physics literature and getting into more biologically oriented journals where it would be read by the non-surface science audience.

Can you tell us the name of some of those journals?

Biopolymers and the Journal of the American Chemical Society, for example.

Have you been contacted by people in the industry looking to work with your lab?

Not really. Other than asking us to come in for a day trip to their place. Maybe because this is not engineering and the like, I’m not sure that it’s gotten that kind of commercial interest. It is still pretty much fuzzy-headed science-type stuff. But enough folks are paying attention and the number of citations to the papers is going up.

What do you see as the next step for this research?

Two things. One has to do with the quest for using better quality theories, better approximations. I would like to get some of the differential sequence effects that current theories cannot pick up. That’s going to push the chemical physics side of things to put in this next level of atomic correlations into what’s going on. Then, I have a chunk of the lab that is working on other types of chips, like peptide and protein chips, and there the physical processes are not so heavily dominated by electrostatics, as polyelectrolytes like DNA are. Almost all of the early work on proteins and surfaces wound up in the surface-fouling literature, because if you put proteins on a surface they tend to turn into goo. It took people a long time to devise surfaces where you could get any percentage of the protein not to denature. The forces that hold proteins together are a very different balance of forces than what holds nucleic acids together, and so what happens on surfaces is very different, and that’s a new set of problems.

How many people do you have in your lab?

Twenty folks. I get the money and the calls, and I pay the bills.

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