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Strosberg Hopes to Bring Yeast Two-Hybrid to Bear on Drug Discovery



NAME: Donny Strosberg

POSITION: President and CEO, Hybrigenics

PRIOR EXPERIENCE: Co-founded Ideon in 1989, which was sold to Incyte in 1992.

How did you first get involved with proteins?

I was actually trained as a chemist [at the Free University of Brussels], and then I was trained as protein chemist [as a graduate student at the Free University]. I started to work on lysozyme. This is a small enzyme you can find in egg whites — you can find up to 80 mg in one egg. That was the first protein to be crystallized. I was one of the first to do the immunochemistry of lysozyme, to find what the epitopes were. That was my PhD thesis.


Any medical reason for studying lysozyme?

The lysozyme is really utilized as an antibiotic in the eye, because it cleaves the membrane of some bacteria. It was used as an antibiotic in the eye, but it wasn’t really of tremendous [medical] interest; it was really basic research.

It was a small protein. It was crystallized, so there was a lot of knowledge about the protein, and there was nothing known about the immunochemistry, so we were really the first there. We were looking at the crystals, and trying to figure out which residues were important for antibody reaction and so on. We were pretty much pioneers in that field. It was a very small protein, so you could very easily do a lot of interesting work.


Where did you do your post-doc?

I moved to the Mass General Hospital in Boston [to do a post-doc], and I worked on the first of what we used to call antibodies of restricted heterogeneity. These were antibodies that you used against Pneumococcus in rabbits, and rabbits would make tremendous amounts of antibodies, and we would then sequence those antibodies. We had the first protein sequencer that was available, which [inspired] the spinning cup sequencer built by Beckman. That was Edman degradation, and it was done in solution. You had to babysit the sequencer because it was the first [prototype] instrument. We stayed up all night to make sure the reactions would continue. Then every time an amino acid [was released] we had to do gas chromatography because that was the only technique available to identify the released amino acid. It was a pioneering time.

What brought you back to Belgium?

I [became] a professor of biochemistry at the Free University of Brussels Medical School. I went from Mass General where I stayed three years and was an instructor at Harvard Medical School to become a professor in Belgium, and that’s where I started to do all the work on receptors. We were the first to purify by affinity chromatography a GPCR, which was the ß-1 adrenergic adrenaline receptor from turkey rerythrocytes. That was between ‘73 and ‘77, and then I got a faculty position in Paris, and started to work a lot on receptors. We discovered a new GPCR called ß-3 adrenergic receptor, and I was also the first to isolate muscarinic receptors. We basically worked on at least 10 different types of GPCRs.

I’ve also done a lot of sequencing of lectins, because that was just an easy protein to work on. We utilized lectins to standardize our sequencers. I had the first gas phase sequencer on the European continent, from Applied Biosystems.

Meanwhile I had become very close to the people who had started Incyte. They got me very interested in genomics, but I kept saying, ‘you have to look at the proteins behind there.’ That didn’t really happen. They stayed with genomics and of course they did a superb job. That’s when we started Hybrigenics.


How were you involved with Incyte?

I had started another company called Ideon, which became Incyte. I was the one who hired most of the initial founders of Incyte. I hired Roy Whitfield, Jeff Seilhamer, and Lisa Peterson — most of the crew who founded Incyte was hired by me for another company that became Incyte. I stayed to become an advisor to Incyte and I worked with them a lot. Then we decided that it was time to move to proteins again, since I had a long experience in proteins. I started Hybrigenics [in 1997].


Why leave to start Hybrigenics?

It naturally evolved. They had lots of information on genes, but they felt they could not themselves work on the corresponding proteins because that was really the work of their customers, you see. Because they were selling the information to their customers, they could not at the same time work on it; otherwise there would be sort of a conflict of interest. So that was the main reason why they didn’t work more on the proteins.


Why choose to do yeast two-hybrid?

We felt we needed a high-throughput technology to rapidly identify the function of many proteins. Looking around, the best technology for that purpose was really the yeast two-hybrid that had been developed at the Pasteur Institute. It not only gives you protein interactions, it also gives you a tool to do dominant negative mutants in human cells.

So you could immediately check on the phenotypic changes, utilizing the tool that we generate with the technology. These are those famous SIDs, the selected interacting domains. We have a technology for the protein interactions, but more importantly we have a technology for validating the function of proteins in human cells.


How exactly do you validate the function of proteins?

We identify the domains involved in the protein-protein interaction, [and then utilize] those domains, which are sometimes small peptides. We inject those in the cells in which we would like to test the role of a pair of interacting proteins. If that injection in a cell modifies the phenotype, since we know where the peptide comes from, we can then derive immediately a functional role for the protein.

We have a very high-throughput technology to transfect cells, express at high levels, and we have a very high throughput of dominant negative domains, which are really unique tools to define the function of proteins. That’s what we call validation. If you can connect a protein with a phenotypic change, you’re in business, because that’s exactly what you want to do with a drug: You want to modify the phenotype.


What would you like Hybrigenics to do in the long run?

We are now moving to chemistry. I’m going full circle. I started as a chemist, I did a lot of protein chemistry, then I went to genomics, then molecular pharmacology. After that, I went back to genomics, proteomics, and now I would like to do more chemistry. It makes a lot of sense because now that we have the function of many proteins, we’d like to develop ligands, and we’d like to develop compounds that will bind and that will modify this function. We are in a very good position because we have all these validated targets, so we can basically have our pick.

Do you have to build a chemistry group?

We’ve started some interviews. We started to talk to people. We don’t know yet whether we’re going to buy a company that already exists or whether we’ll start from scratch. That’s a decision we still have to make, but basically we’ve decided we are now going to add medicinal chemistry to what we already have.


Are there other goals that you have professionally that you’d like to achieve?

Well, I think this is pretty good. Clearly, we’d like to be a little bit better implanted in the US, because we are still very much a European company. But in terms of what we’d like to achieve, if I could take a gene to a protein, to a function, to a compound, I would be delighted. Since I discovered this new ß-3 adrenergic receptor [as an academic], I’ve been helping pharmaceutical companies develop compounds to treat obesity. For instance, GlaxoSmithKline has a compound in phase I which was really derived from the research I did on the ß-3 receptor. I think that’s pretty neat, but I wish I could do that in my own company. Obviously, it’s more interesting.


At this point there’s no desire to go back to academia?

The work we’re doing is really of academic quality, and we’re helping so many academics. Hybrigenics collaborates with roughly 200 academic scientists, so I feel like I’m doing good work here. I’m not eager to go back to the grant writing, [and other] traditions of academia. Especially in France where we don’t have grants for postdocs, it’s very painful to get postdocs in France. No, I’m in no rush to go back there.


Do you plan to have the company move beyond collaborating with others into doing your own drug discovery?

Exactly. Not necessarily up to phase IV, but certainly up to phase II, and as much as possible in collaboration, [although] we will go all the way with a number of topics, that’s for sure. But we want to have partnerships [because] we want to limit the burn rate as much as possible. We have plenty of cash, and we want to keep it as much as possible, because we know today cash is king. For instance, we have developed fantastic bioinformatics tools, and everybody asks us, ‘Why don’t you commercialize those?’ I know it’s not going to earn us a lot of money. [Instead], we offer [the tools] to partners to complement the biochemical data in a browser. We’re certainly not going to go into the business of selling bioinformatics tools.

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