Barry Bochner, Chairman and CSO, Biolog, Inc.

Can you start off by giving us a bit of background to the company?

I am the scientific co-founder of Biolog, the other co-founder of the company retired several years ago. We started the company physically in 1984, so we have been around for 20 years and we have been a profitable, self-sustaining company for most of those years.

The company was started primarily around one patent that I applied for when I was in graduate school. This patent is on a very simple and general method for testing the metabolism of cells. At that time we worked on bacterial cells and over a period of years we have evolved the chemistry to work for eucaryotic cells; first yeast and filamentous fungi and now in human and mouse cells as well. We are mostly known in the field of microbiology because that’s where our products have been on the market since 1988.

We now have a second business thrust in the area of genomics because we have a cellular technology that is nicely complimentary to the molecular genomic technologies. We started working on the new technology about 5 years ago and have been issued a number of patents.

The new technology is the Phenotype MicroArray™. What is this?

When we initially started Biolog we had this chemistry that allowed detection of the metabolism of cells in a very general way. It theoretically could work for any kind of cell and initially we were looking at carbon metabolism pathways in cells. We developed 96-well test kits that could measure different carbon pathways in a cell, and these are being used to identify about 2000 species of microorganisms: bacteria, yeast and filamentous fungi.

I always had this idea that we could go beyond looking at carbon metabolism, and the need to do that really came to the fore during the genomic era. People had ways of measuring whether genes were turned on and off, but there is always the question remaining: just because a gene is turned on, does it really mean that its corresponding biological pathway gets turned on? The regulation of pathways is much more complicated than just turning genes on and off. We want to be able to use our technology to measure thousands of cellular pathways and whether they are actually turned on and off in living cells.

With a grant from National Institutes of Health we developed our first set of Phenotype MicroArrays which allowed us to measure 2000 phenotypes or pathways in living cells, specifically E. coli bacteria. Within a few years we have generalized the technology to work for most cells that researchers experiment with. A nice thing about our technology is that it is easy to use and low tech. We do the hard part which is to manufacture these array sets with different chemistries dried down into 2000 different wells. When you actually do an experiment with this technology, all you have to do is grow some cells, suspend them in a special liquid and then add them into the 2000 wells. Then you put the arrays inside an instrument called the OmniLog® which is a combination incubator and reader. It incubates the cells at whatever temperature you want and reads the color in the wells every 15 minutes. Typically we would let the cells go for 24 - 48 hours and continually record the response in all 2000 wells. The data is all sent to a computer which produces kinetic graphs at the end of the incubation run.

One of the most powerful uses of the technology is to look at gene function. One of the problems that cropped up in the wake of the massive genome sequencing work was the realization that around a third of the genes in these cells have absolutely no ascribed function. This shows that our knowledge of biology is still very incomplete. It is likely that these genes are providing important and interesting functions, but those functions remain to be discovered.

Fortunately, geneticists have developed some very nice tools for knocking out one gene at a time in a cell. They can take a cell, target a certain gene that they are interested in and knock that gene out. Then using our technology you can compare a completely normal or healthy cell to the same cell with one gene knocked down. We put the cells into our 2000 tests and we try to diagnose what happened to the cell when it lost that gene function. We can see what properties of the cell changed, what pathways appeared or disappeared, got stronger or weaker.

Within a few weeks of having our first arrays, we started working with E. coli bacteria, and in collaboration with Kenn Rudd, a Professor at University of Miami, we discovered our first function of an unknown gene which turned out to be a penicillin drug efflux pump in E. coli bacteria. It had never been discovered; in all the years that E. coli and penicillin had been studied, this drug efflux pump had been missed.

We have gone on to do a lot more work. We published a couple of papers and then we set up the PM Services lab within Biolog that allows even people working on small projects to access PM technology. They send us the cells and we test them and provide the data. But what we would really like is for people to purchase our technology and acquire the full range of uses of the technology. The technology is so versatile; you can use it with a wide range of cell types and for a wide range of applications. Purchasers are trained by our technical staff on how to use all aspects of PM technology. Then they are fully capable of doing it themselves.

What kind of applications does this technology have within the drug discovery area?

That is another major use of the technology that we have demonstrated partially. You can take a chemical or drug for example, and add it to cells and compare that to cells without a drug added, and you will get a fingerprint in the Phenotype MicroArray of the effect of the drug on the cell under these 2000 different growth and stress conditions.

We had a lot of interest in this technology from the anti-microbial or antibiotic development companies in the United States and in Europe, and one of their main interests was in using this as a tool to sort out their chemical libraries. It is a very simple and very descriptive tool for fingerprinting the effects of chemicals on cells. It also allows you to look at drug combinations in a very simple way, to look for drug synergies and drug antagonisms and also allows you to detect the effects of drugs on pathways other than the target pathway. In other words, our technology can be used to look at secondary or side-effects of a drug which leads into the field of toxicology.

Now we are working on human cells. We just received a $2.5million grant from the National Institutes of Health to do this. Our grant is specifically in the toxicology area of drug development, but we see the same multiple applications of the technology, not just in toxicology, but more generally in drug fingerprinting.

Today, pharmaceutical companies generally pick some targets they are going to look at that year and they have thousands or millions of chemicals in their libraries that they will pull out one at a time and screen against the target. Hopefully they will get a couple of hits and then they will follow up on those hits by getting their chemistry departments to synthesize other chemicals that have similar structures. It is a lot of work, it is very expensive and every time they start on a new target they have to go through and re-screen their entire chemical library.

What we are proposing with our technology would be a completely different approach and we think it would be much more efficient and save lots of time and money. What we are proposing is for companies to basically go through their chemical library one time using our technology to generate a library of the fingerprints of all of the chemicals in their library, so using our technology as sort of a reference standard. Then if they have a target that they are interested in, they can knock out the gene for that target in the cell and generate a cellular fingerprint of what the desired chemical fingerprint should look like. Once you have this target fingerprint then the company could just search their computer library without actually pulling out all the chemicals again. You have fingerprints of all the chemicals already stored in your computer and you just go through the computer to find the best match of all the million chemicals in your library. Hopefully you will find a small number of chemicals that come close to matching your target fingerprint and you will immediately be able to focus on the best chemicals in your library.

A second aspect of this is that it is highly unlikely or virtually impossible that a chemical in your library is going to give you an exact match to the desired target fingerprint. The fact that it is not matching is showing you that the drug is having some other effects on the cell, which drugs almost always do. Basically that is telling you the toxicology. So the distance between the fingerprint pattern of your drug and the pattern of the desired result (i.e. the target pattern) is a measure of the toxicology of your drug. As you then develop other variants of that chemical, you can again use our technology as a preliminary toxicology screening tool to figure out which chemicals are most precisely hitting the target and not hitting other targets in the cell secondarily.

By adopting Phenotype MicroArray™ technology as a general reference standard for drug screening, we think that drug companies can realize a huge advance in the efficiency of screening drug targets and also in preliminary screening of toxicology. They can really streamline the process of finding a specific drug that hopefully won't have side-effects. An issue with toxicology is that a chemical may not be toxic to the liver but might be toxic to say cardiac cells; it is just what happened with Vioxx, the COX-2 inhibitor which now has turned out to be a disaster for Merck.

With PM Technology, one would try to avoid this pitfall by testing the library of chemicals with different cell lines representing the different important organ tissues of the body. This would provide a much more comprehensive experimental model of whole animal toxicology. So far we have worked successfully with liver, colon, lung, and various blood cell lines and we haven't found any cell lines that have not worked. We have also worked with some mouse cell lines.

So potentially our technology could unify the whole process of drug candidate screening as it can be used in both basic research where you are screening new targets as well as in toxicology.

What is your current business model?

It is a razor and blade type of business model. We are focusing on the technology platform. We want to be able to sell our instrument which is the OmniLog® and the arrays that go with it.

What would you say are strong points of your technology?

One of the real values of our technology is its simplicity. People have, I think, always had trouble with cell assays because of cell variability from day to day, week to week; biochemical assays are viewed as more reproducible than cellular assays. However our technology is so simple in terms of the way you run the tests. There are very few steps to the process and so there is not much that can change from day to day. We get outstanding reproducibility with microbial cells. We get detailed kinetics that is virtually super-imposable from run to run in almost all of our assays. With the human cells we are getting CVs or coefficients of variation less than 10%. I think we are closing in on 5% now as we get better at it.

What would you say the future of the company is? Where do you see the company in say 5 years time?

We are aggressively evaluating additional market opportunities where we have a well-entrenched strong brand and a significant IP position. Our entry into the $5 billion drug discovery arena with our PM array product line serves as an excellent example of the types of markets we are interested in pursuing. Our technology and products, whether used for microbial identification or drug discovery, have many attractive features - far too many for us to commercialize ourselves. Accordingly, we are also seeking to partner with companies that may have an interest in commercializing certain products in markets parallel to those of Biolog.

The future of the company will lie in our ability to continue to grow aggressively into our chosen markets. We believe we have a strong offering and to date the product cycles have been robust enough to give us confidence that we can continue to expand rapidly. In five years, assuming that the cellular assay market continues to grow; our PM array business should position us well as a dominant figure in the sector.

Further Information: http://www.biolog.com