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Stephen Naylor on Mass Spectrometry In the Early Days of Proteomics

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At A Glance

Name: Stephen Naylor

Age: 50

Position: Adjunct professor of genetics and genomics, Boston University School of Medicine; visiting faculty member, division of biological engineering, Massachusetts Institute of Technology.

Background: Chief Technology Officer, Beyond Genomics, 2001-2003.

Director of biomedical mass spectrometry and functional proteomics center at Mayo Clinic, 1991-2001.

Posdoc, Massachusetts Institute of Technology, 1987-1989.

PhD, Cambridge University, 1984-1986.

 

What were you working on during your early years of research using mass spectrometry?

I did my PhD with Debbie Williams at Cambridge in the department of chemistry. That was 1983 to 1985. Back then, the role of mass spectrometry in the analysis of biological molecules was incredibly limited. The only work of any significance that had been done was by Klaus Biemann at MIT, who’d been breaking down peptides into individual amino acids, derivitizing those amino acids and looking at them by conventional gas chromatography/mass spectrometry.

In the late 1970’s, early 1980’s, there was almost nothing in the literature about the role of mass spectrometry in biological sciences. And then a man called Michael Barber who was at the University of Manchester Institute of Science and Technology invented a technique called fast atom bombardment mass spectrometry, so FAB-MS. That technique allowed you to take either peptides or even small proteins and deposit them into a liquid matrix, something like glycerol, put that matrix in to the source of the mass spectrometer and then splatter the mixture off into the mass spectrometer.

And so Barber had invented that technique back in 1981, and I arrived at Cambridge in ‘83. I spent all of my PhD doing two things, and it became kind of a theme throughout my life — of looking at the fundamental aspects of the process. I was very interested in the ion physics of what was occurring when you took this mixture of peptides, put it into a glycerol matrix and then bombarded that matrix in the mass spectrometer with, in this case, fast atoms. We learned an amazing amount of stuff about what was going on. But the other thing that was also very important to me was: How do you use this new technique? If we can look at peptides, then how can we apply this?

Were you doing the same type of work at MIT?

At MIT, I joined the lab of Steve Tannenbaum. Tannenbaum had a program back then that was incredibly innovative. He was looking at proteins in blood that were basically mopping up toxins that you’re exposed to in the environment. So the idea was that I was interested in looking at hemoglobin adducts of toxins known as benzopyrenes. They produce highly carcinogenic metabolites. So I was looking at hemoglobin carcinogenic metabolite adducts. And the tools that we used were predominantly mass spec-based, but also a variety of fluorescent tools as well. Around that time — this was ‘86 through ‘88, Fenn had just reported in his landmark Science paper about electrospray mass spectrometry.

So when I got to MIT, while I was working in Tanenbaum’s lab, I also had access to Klaus Beimann, who was down in the basement of the building I was in. They had a state-of-the-art mass spectrometer with one of these newfangled electrospray sources. And so I was able to really focus more in those couple of years at MIT on trying to understand what goes on in a simple protein molecule in your blood, like hemoglobin — how that interacts with environmental contaminants.

That really began a long thought process of beginning to appreciate just exactly what incredibly complex and important role blood plays in human biology. Because here I was looking at something very specific in terms of asking the question: Can you monitor exposure of contaminants in the environment by looking at chemical adducts of hemoglobin? Well the answer is, “Yes, you can.” Then you follow that on with — well, hemoglobin is actually able to react with toxic and anoxic chemicals, so what else is the blood doing? And then you start this really interesting journey of beginning to try to understand truly at the molecular level the complexity of what goes on.

When did people start looking into proteomic biomarkers? Were you doing that at the Mayo Clinic?

I joined Mayo in ‘91 and had a tremendous budget to build what became known as the biomedical mass spectrometry facility. And I hired a group of people, both technical staff as well as post doctoral fellows, and brought in some graduate students from the Mayo graduate school. Also I formed the first alliances between a mass spec company and a medical center. The mass spec company is what is now Thermo Finnegan. They put in several of their state-of-the-art instruments and supported the facility in a significant way financially as well as with hardware. We acted as their North American demo site for five years. What that enabled us to do was grow a facility almost overnight. Within six months, I had a fully staffed and fully operational mass spec facility.

Were there some outstanding results that you discovered in terms of disease research?

The first great impact that we had was in the immunology community. Part of the problems with MHC Class I and MHC Class II peptides is there are thousands of them, they differ by just one or two amino acids — you’ve got very complex mixtures, small differences in structure, and many of the more interesting ones are present at incredibly small amounts. So you have to have very sophisticated chromatography, exquisite sensitivity in terms of your mass spectrometer, and also excellent tandem mass spectrometry capabilities to sequence these things. So we spent an enormous amount of time developing protocols based upon a new technique that had just come into play, which is capillary electrophoresis. A guy called Andy Tomlinson, my lab manager, grabbed hold of that and developed a whole capillary- electrophoresis mass-spec approach.

How did you get into working for Beyond Genomics?

Well, in the mid-1990’s, I became very interested in using affinity capture methods to look at proteins in body fluids as a way of either diagnosing disease or determining the prognosis of a disease. So my group spent a lot of time from ‘94 to 2001 developing affinity capture methods for proteins online with mass spectrometry. That was really the forerunner to what has become known as the biomarker space. And biomarkers began to attract attention from the mass spec community probably about ‘97, ‘98.

I joined Beyond Genomics as chief technology officer. The company had been in existence for about five or six months, with just a few employees there. I was charged with coming in as CTO to build the systems biology platform that comprised the genomic, proteomic, metabolomic and bioinformatics and knowledge assembly tools that you need to do a systems biology analysis.

What made you decide to leave the company?

Along with the group of people who worked for me, we basically built version 1.0 of this systems biology platform, and I’d helped the company grow to about 60 people, and I’d learned everything I wanted to know about the basic principles of business. BG was beginning to think about what to do with this platform. In particular, they were interested in moving towards discovery — an area which back then I didn’t have any significant amount of experience in. So I thought it was time to go explore other things. I’d tired of the 24-7 kind of work day/week where everything blurred together.

What have you done since then?

So I resigned from Beyond Genomics and for a year, I really couldn’t do anything of any significance because of this thing called the “non-compete” which I had signed with Beyond Genomics. So what I decided to do was take the last year as a sabbatical, and I got two adjunct faculty positions — one at MIT and one at BU School of Medicine. The other things that I’ve done is I did some consulting for the pharmaceutical industry in terms of helping them to unravel the mysteries of systems biology. And I began to think about putting together next-generation companies in either the systems biology space or the biomarker space. The one I spent the most time on and have just recently rolled out is a small company called Predictive Physiology and Medicine, based in Indiana. I founded that company with two old friends, Fred Regnier from Purdue and David Clemmer from Indiana University.

The company’s technology is known as ion mobility mass spectrometry. It really gets to the heart of what’s problematic, coming back to proteomics. You have such complex mixtures today that the resolving power of HPLC coupled with mass spectrometry is not enough to look at these incredibly complex mixtures. So what this company PPM has is an additional dimension of resolution. It’s a gas-phase chromatographic technique. So basically, the peptides ionized in the mass spectrometer — there’s little thousands of them coming in in each droplet — they’re separated by passing them through a long tube called the drift tube which has a gas in it, with a very high voltage across the gas. And that separates these peptides exquisitely based on their physical properties. The idea behind the company is that this next-generation approach will allow us to delve deeper into those proteins that are present at much lower concentrations than what’s presently able to be detected.

Are you looking to develop your company more in the future?

The model that I’ve got in my head for the future is three-pronged. The first prong is I’m going to take up a more permanent academic position that will have more resources and an active research group again. Prong number two will be to help develop PPN, but also think about rolling about a series of other companies, mainly in the proteomics and systems biology space where market needs are not being met. Thirdly, I’ve spent a lot of time over the last years organizing meetings and writing editorials and really trying to stimulate debate and discussion around a variety of topics ranging from how science and technology is reported to what’s wrong with the proteomics space at the moment. My sense has been that in the proteomics space there’s not been much critical evaluation of what’s wrong. I believe that only by asking those questions and stimulating that debate can you really begin to understand where to move forward and break through these bottlenecks.

 

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