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Johns Hopkins Gary Brooker On Academic, Commercial Biotech Endeavors

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At A Glance

Name: Gary Brooker

Position: Research Professor, biology, Johns Hopkins University; Director, Integrated Imaging Center, Johns Hopkins Montgomery County Campus

Background: Founder and Chief Scientific Officer, Atto Bioscience (acquired by Becton Dickinson) — 1985-2003; Professor, biochemistry and molecular biology, Georgetown University — 1981-1988; Associate Professor and Professor, pharmacology, University of Virginia School of Medicine — 1972-1981; Assistant Professor, medicine and biochemistry, University of Southern California School of Medicine — 1968-1972; PhD, pharmacology, University of Southern California — 1968

A true pioneer in the field of cellular and molecular imaging, Gary Brooker has a great deal of experience in biotechnology from both an academic and commercial perspective. From his earliest days as a pharmacologist, Brooker was designing instrumentation to facilitate his studies, and holds several US patents for imaging and microscopy technology. Some of this technology became the cornerstone for Atto Bioscience, a company Brooker helped guide towards its recent acquisition by industry giant Becton Dickinson (see Inside Bioassays, 7/6/2004). Now a professor at Johns Hopkins University, Brooker continues to investigate ways to further imaging technology as the director of a Hopkins-affiliated integrated imaging center. Last week, he took some time from his schedule to discuss his commercial and academic endeavors with Inside Bioassays.

Your career has spanned medicine, biochemistry, cell biology, pharmacology — a lot of different fields. How did you develop your overarching interest in microscopy and imaging?

My interest in microscopy started out early on, during my graduate years, when I began doing electrophysiology of cardiac muscle. Of course, to insert microelectrodes in and do single-cell recording, you have to use a microscope. So I began to learn about and use microscopes really early. Also, in graduate school, there was a person who was actually building some microscopes — microspectrophotometers, in those days — that were pretty primitive compared to what we do now, so I became experienced in machining and optics and so forth. Before going to graduate school I got my bachelors degree in biochemistry, and then I got my PhD in pharmacology, which is the study of how drugs work, so it’s really cell biology. I did a lot of enzyme kinetics, and the chairman of the department was a Pauling-trained kineticist, so I was very biophysically oriented. Then I became interested in studying agents that affected the heart, and became interested in the mechanism of hormone action. When I moved early in my career to the University of Virginia department of pharmacology, I was interested in the signal transduction mechanism at the very early stages [of hormone action]. I began to try to understand how hormones such as beta-adenergic agents acted. I began to realize you could get a lot more information from a cell by studying its biochemistry, and I began to realize that through microscopy, you could start to localize where reactions were taking place, rather than just seeing the result of a total reaction by the electrophysiological response. In that vein, I began to synthesize compounds to study beta-receptors in both cardiac cells and in a cell culture system, which a friend of mine at UCLA and I developed — the C6-2B glioma cell line, a very widely used cell line. It turns out that this cell line had a lot of properties similar to cardiac cells, in terms of hormonal response. Now we realize that some brain tissue and cardiac muscle have some of the same enzymes, especially type 5 and 6 adenylyl cyclase. Anyway, that’s really how I got interested in imaging — realizing we could potentially localize where things were happening. We had synthesized the first good radioactive probe for the beta-receptor, which was called iodopindolol, and then I began to make fluorescent derivatives of pindolol, and in those days, there wasn’t any way of imaging — it was primitive. So I had to build my own cameras, and my own image processor, et cetera. The whole frame memory was one frame of 256K — that was it.

You founded Atto Bioscience in 1985. Tell me about that transition from academics to commercial biotech?

It kind of happened in parallel — it actually started in my basement. It wasn’t quite so big a company. But it grew and grew. And really, making equipment started early in my career, because equipment wasn’t available. Necessity became the mother of invention. When I look back now at some of the equipment that was state-of-the-art then, it was pretty primitive compared to what we do now, but I guess that’s the way it is with anything you look at. And we did a lot of interesting things with much less complex equipment. We didn’t get the instant gratification because it didn’t calculate everything right away, but we were able to do our work.

What was the change in your mindset during that transition?

When I was at the University of Virginia I developed the world’s first automated radioimmunoassay instrument, and that was licensed to a commercial firm. They did their best, but it was very frustrating, so I thought that if I ever invented any equipment again, I’d probably not do it in that environment — I wouldn’t want to just invent it and turn it over to a company, because you lose the ability to guide its development. The people that invent are usually the most perceptive about what to do. That’s one of the reasons I decided to come back to the university — so I could continue to have influence over inventions and development, because I think you lose a lot when people who aren’t as current in the technology take over the development. So Atto was founded because of that reason. We began to develop the fluorescence applications, and in the beginning, we made all the hardware and wrote all the software in my basement. We had quite a significant machine shop in the basement. The other thing that’s interesting is that it started without any outside capitalization. And it continued that way until three years ago. The company was quite successful and quite renowned — it was considered to have made the most advanced live-cell imaging equipment and software. It was also a very user-friendly design so the user didn’t have to be a PhD engineer.

So after Atto, you went back to academics, and now you’re director of the Johns Hopkins University Montgomery County Integrated Imaging Center. How is that endeavor going so far?

It’s a little over a year old now, and it’s beyond expectations. Things are really going well. We are beginning to provide services to a variety of users in Washington [D.C.], such as government and university users, including some of the government agencies that you wouldn’t even suspect would need this kind of help. Furthermore, the instrument development and advancement of microscopy technology is going along very well, and we hope that we will spawn new technology from the center, in addition to providing an educational service to the community and beyond. There’s quite a hunger for learning about microscopy because it’s not so widely taught or available. Of course, there are a variety of courses, such as [those at] Woods Hole and Cold Spring Harbor, but that doesn’t seem to fill the appetite of people. There are more people interested in learning microscopy than those courses can accommodate.

Beyond the imaging center, are you engaging in research of your own right now, as well?

Absolutely. Basically it’s a continuation of the past. Actually, all of these activities, in terms of microscope development, have stemmed from our interest in some very basic mechanisms. Unfortunately, I have to say we haven’t solved the problems yet, but we’re interested in the mechanism by which hormone desensitization occurs. A lot of people feel that it’s due to effects at the receptor level, and in fact, that’s why I made probes for the receptor. It turns out that there’s an important component of desensitization that occurs post-receptor. It occurs, for example, in the adenyl cyclase system. We identified this a number of years ago, and a collaborator, Dermott Cooper at Cambridge, isolated and sequenced type 5 and type 6 catalytic adenylate cyclase. It turns out that calcium is an important regulator, which is why live-cell calcium imaging is one of the things we’ve been doing for a long time. The motivation for developing the high-speed imaging has been that these events are occurring very rapidly. We’ve been trying, over the years, to develop higher and higher speed imaging techniques to be able to track and follow these events. They’re calcium-mediated events, but our guess is that they’re very localized. These will be very important mechanism to understand.

So you’re trying to develop new instrumentation for these types of studies right now?

Yes, that’s one of the components of our work here. We definitely have an active instrument development program going on, and we hope that in the future we’ll be able to unveil more innovative methods in this direction.

Do you think you’ll attempt to go commercial again with any of these instruments?

I think it’s likely. Any kind of development like that that’s significant needs to be disseminated to the masses. So for other scientists to use those technologies, it’s really not practical for them to make them their selves, because these are usually very complex systems that involve a variety of disciplines. It’s better if you have a turn-key system. It was that way in the beginning with ratio imaging, which got Atto Bioscience started. In the beginning, people tried to make their own systems, and we developed probably one of the first, if not the first, turn-key ratio imaging systems. Initially we had a little bit of resistance because people were still making their own, but then people began to realize it was a lot easier, cheaper, and better to buy a commercial device. In this regard, as we move forward with new technologies, we think that securing the appropriate intellectual property and making the technology user-friendly will make it feasible to become commercial.

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