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Carnegie Mellon s Alan Waggoner on Academic, Industry Trends in Cellular Analysis

Alan Waggoner
Molecular Biosensor and Imaging Center

At A Glance

Name: Alan Waggoner

Position: Director, Molecular Biosensor and Imaging Center; Professor of Biological Sciences, Carnegie Mellon University, since 1999.

Background: Co-founder, vice-chairman, Biological Detection Systems; principal scientist and head of fluorescence, Amersham Biosciences; co-founder, Cellomics; chairman of scientific advisory board, Cellumen; Postdoc, Yale University; PhD, physical organic chemistry, University of Oregon.

Alan Waggoner has been working in fluorescent probes for cellular imaging and other biological analyses for more than three decades, and has worked extensively in academia and industry. He is the co-founder of three companies, including high-content screening stalwart Cellomics, and holds 15 patents related to imaging and fluorescent dyes, including patents related to the widely used family of cyanine dyes.

As director of Carnegie Mellon's Molecular Biosensor and Imaging Center, Waggoner currently has his hands in everything from deep-tissue live-animal imaging using quantum dots; to cellular biosensors for discovering protein-protein interactions; to a NASA-funded project for detecting sparse microorganisms in extreme environments. Waggoner, who last week delivered a talk aptly titled "Fluorescent Probes: Some Fun Applications" at IBC's Assays and Cellular Targets meeting in Bellevue, Wash., sat down with CBA News for a few moments to discuss his past work, some trends in cellular analysis in academia and industry, and some changes occurring at the Carnegie Mellon MBIC.

Have you always been interested primarily in fluorescent dyes and biosensors, or did this come about through other work?

I came from a chemistry point of view — I was trained as a chemist, and I sort of fell in love with fluorescent molecules when I was doing my postdoc, and got involved in developing the membrane potential sensing indicators. We got a lot of experience there, and got to be known a little bit, which helps. After moving to Carnegie Mellon, we worked on developing the fluorescent labeling reagents, the cy-dyes, and we've done pretty well there. And now we're beginning to work on the development of intracellular biosensors, so we'll see where that goes.

You've worked at all levels of biology — molecular, cellular, whole organism — in terms of labeling technologies…

Yes, everything from the physics of the dyes and the chemistry and engineering of the dye structures, to the biochemistry of labeling things, to the cell biology — and that's particularly the most important area — but we're also interested in tissue and animal physiology. This explains why we're doing the quantum dot and infrared probe development so you can see deeper into tissues and animals.

What do you think about the recent boom again of cellular analysis in industry?

It's a very exciting area, and if you think about all the networks and pathways in the cells — the protein-protein interactions, protein modifications, protein localization, conformational changes, and all the things happening in the cell — what are the tools that you have to sort it all out? You've got thousands of proteins doing all their regulatory interactions, and there have to be new tools. Fluorescence is one of the ways, and it's already been proven that you can use multi-colored probes within living cells and three dimensions to get information out. And there are plenty of imaging microscope systems to do that. So why not continue to push this field? With all the different regulatory proteins in the networks and pathways, there is still a lot of work to be done yet to develop the probes.

You've moved back and forth between industry and academia — your most recent move back to academia in 1999 seems to have coincided with academia taking a more industry-like approach in some areas of drug discovery. Why do you think that is?

That's an interesting observation. I hadn't thought a lot about that, but it does seem to be that way. Part of it is that I think the academics begin to see the success of the probes and their utility in the drug-discovery world, and now there are more people interested in developing the probes and the imaging systems from an academic point of view. Also, I think that the funding agencies have recognized the utility of these tools and are more supportive of funding work this way, so those two parts work together to make academia move in those directions.

Regarding the cyanine dyes that you invented, why have those become such useful biological probes, and so commercially viable?

That took us quite a number of years to develop so they would become useful. When you think about it, organic dyes inherently — even if they are very fluorescent and very strongly light-absorbing — aren't guaranteed to be useful. Organic dyes tend to be very planar and hydrophobic molecules, and they'll stick to everything in the cell, and are not good for DNA probes or as antibody labels. What we did was engineer a way of making the dyes so they are water-soluble and non-sticky by putting sulfonic acid charged groups on the actual rings of the dye structure. We did that and it helped immensely, so the dyes have been useful. Molecular Probes followed this same concept and a little while later came out with the Alexa dyes, which again have the sulfonic acids on the ring structures of the dyes. So that's helped them make useful products as well.

What types of cellular biosensors or dyes are still needed? What are you eyeing down the road?

We want to make dye sensors to detect protein-protein interactions, protein conformational changes, protein modification — those are the first priority; and along with that you can get the location and quantity of the proteins. So those are our immediate goals.

What about instrumentation? Is that suitable or does it need to be furthered?

I think the instrumentation today is very good, and it keeps getting better. There are lots of companies that are trying to continue to make improvements, so that's going to take care of itself. But in our center, we are also going to pursue some new approaches to imaging that we think might be interesting, and maybe will be integrated into the instruments of the future that are commercially available. This involves these correlation techniques for studying small regions of the cell and what's going on with the various fluorescent proteins in the regions. Our new center is mainly centered on the development of the fluorescent reagents, these correlation methods of imaging, and informatics, such that once you have image — how you can extract the information out? But we're flexible, and will go in whatever directions we need to get the important biological information out for basic research and drug discovery.

The center you direct at Carnegie Mellon has been undergoing some changes, correct?

Well actually, the new center from the NIH — the Technology Center for Networks and Pathways — was an add-on. We've been calling ourselves the Molecular Biosensor and Imaging Center now for five or six years, since I came back to academia, and we managed to get pretty good funding for doing that. But this new NIH support adds a new dimension and will really allow us to do some exciting things — and also to transfer the inventions that we develop and get the reagents, instrumentation, and software out to users in the drug industry and research labs — because NIH requires us to be as effective as possible at doing this. Also, we're required to do training, and also maybe have a meeting that we'll sponsor. Basically, our purpose is to advance the scientific community in this area of fluorescent probes, imaging, and informatics.

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