At A Glance
Name: Israel Biran
Position: COO and head of business development, Molecular Cytomics
Background: PhD, biotechnology, Tel-Aviv University; BSc, economics, Hebrew University
SAN DIEGO — At IBC’s Assays and Cellular Targets conference held here last week, a poster presentation from Israel Biran of biotech company Molecular Cytomics was piquing the interest of many passersby. It described the company’s flagship platform for conducting a variety of assays on individual live cells in an array, borne from academic research at Bar-Ilan University in Israel.
Biran sat down with Inside Bioassays during the meeting to discuss the assay technology and the future direction of Molecular Cytomics.
Tell me a little bit about your background, and what you did before Molecular Cytomics.
I got my PhD from Tel-Aviv University in biotechnology, and then I did a postdoc with David Walt in the chemistry department of Tufts University. I was always focused on the integration of cellular biology and instrumentation. So in my PhD I did electrochemical biosensors in live cells, using electrochemical detection to measure cell responses. And we developed a technology for live cell arrays that can be used as this biosensor. And the substrate for detection was an imaging fiber — an optical imaging fiber. After my postdoc I joined Molecular Cytomics.
Can you tell me a little about the history of Molecular Cytomics and how you became involved with the company?
Molecular Cytomics is about a year old, and it’s a spin-off of the [Schottenstein Center for the Research and Technology of the Cellome] at Bar-Ilan University in Israel. Basically the company has all the IP for the technology developed at this Cellome center, which is in the physics department. And the main asset is what we call the live cell array — this is the core technology. So the R&D department of the company is based on the experience and the knowledge of the people at the university. The lead inventor is Professor Motti Deutsch [of Bar-Ilan], and all the biological applications were developed by Naomi Zurgil. The basic technology has been developed in the last ten years. It has different configurations, but the main idea was to be able to assay different cells, and look at the cells over time — not like microscopy or flow cytometry. For example, in flow cytometry, you just look at the cell for one second, and then the cell is gone. There is a need to look at the individual cell, but look at it for a longer period of time and see the processes. So the idea was to develop technology to solve this problem.
In this platform, where are the cells physically located, and what material is that made from?
The basic device is made of glass, and it’s a disposable device. It’s basically a matrix of microwells. In our first product, each well will be 20 microns in diameter, and it’s etched on a glass substrate. The idea is that each well can accommodate individual living cells. We make a matrix of 10,000 — although that number can change — but basically, the first product will have 10,000 microwells in an area of 2 millimeters. This array is based on a microscope slide, at least for the first product. So in the middle part of this microscope slide we place this array, and there are some microfluidics that will allow [the user] to apply the cell suspensions into the array. The cells will fall into the well via gravity so you get an individual cell in each well.
And each well is only large enough to accommodate a single cell? How do you know you’re ending up with one cell in each well?
Basically you try to match the size of the well to the size of the cell the cells you’re dealing with. Of course, one of the applications is for a heterogeneous cell population like bone marrow. There, you have cells of different sizes, and your limiting factor is the bigger cells. So you need to accommodate those cells, and smaller cells will also go into the wells. The idea is to have dilutions in such a way that there will be fewer cells than wells, and that way, you can get one in each well. Typically about 80 percent of the wells are populated, so you’re talking about 8,000 individual cells, which is a very large number. For any other means that are used today, people usually do one, two, ten or twenty cells, but we will go into the thousands.
For single cell analysis, there are other methods commercially available for doing that, correct? How would your platform differ?
Yes, there are technologies — what they call the high-content screening arena is focused on in vivo cells and measuring cell processes over time in individual cells. But what our technology brings to this arena is the ability to work with non-adherent cells. It’s really a field that hasn’t been explored enough because of the lack of technologies. And there are some pretty important cells — all the blood cells, bone marrow, immune system — these are all non-adherent cells that are really hard to investigate currently with high-content analysis because when you do high-content analysis, you need to hold the cell and look at it over time. And if you apply different solutions, if you don’t have something to hold the cells, they will just wash away. So we feel that this is our main advantage. And when I say non-adherent, the significant thing is that we can work with primary cells. The other opportunity that we see is that most of this high-content screening is based on very sophisticated and expensive instruments. So this is not very accessible for most academic researchers. If you want to get into systems biology, which involves such experiments, you really need an affordable tool. Our product would be a disposable device that you could just place on a microscope, and if you have a microscope in the lab, you can do high-content analysis.
You don’t think that there will be a need to optimize instrumentation for this, even if you could keep it low-cost?
We think we can just stay with microscopes, which are becoming incredibly sophisticated. All we do now is use existing equipment. So we really want to target researchers that want to move towards single cells, and high-content analysis, and to the field of systems biology, and make a tool that would really allow them to use the device that they have on hand to do their assays. We have some proprietary assays, but most of the assays that we do use existing reagents. So we take reagents from companies like Molecular Probes or Sigma, and we do, for example, apoptosis or mitochondrial membrane potential. So we use other reagents, but on our device. The same goes for imaging software. So most off-the-shelf software can do most of the [analysis]. Again, we have some proprietary algorithms for more advanced analysis, but that’s for really specific applications.
Obviously the low cost would be attractive to researchers, but I imagine drug companies like to save money too. Do you see this as being attractive to a large pharmaceutical or drug discovery company?
Definitely. In this context, we see the most attractive feature again being the ability to work with non-adherent cells. I know most of them work with adherent cells now, because that is what is possible. But I can definitely envision them moving, if there’s an available tool, to non-adherent cells. It’s clear that any drug, as it goes through the process, has to go through primary cells. One of the good examples that I keep coming back to is bone marrow. So if you want to do bone marrow toxicology, you have to take primary cells from a mouse or rat, and test your drug. But this can be a very tedious and expensive assay. And I believe without a doubt that we can make assays that will save money and provide access to cell lines that are difficult to work with.
Your poster presentation mentioned apoptosis and mitochondrial membrane potential assays. Do you envision supporting a variety of other assays, or do you think one type is more optimal than others?
We tested many assays, if you look at the website. But basically, any fluorescence, or even non-fluorescence assay, or even just looking at cell morphology can be done. And you can measure the function of the cell when it’s alive, but then you can fix the cell and do Geimsa staining, so staining of fixed cells. And you can correlate information on how the cell behaved when it was alive to after it was fixed. Again, in the pipeline, there are a few proprietary assays that can take advantage of this format, but any kind of cell or assay can be used.
Has a patent been issued, and who owns the rights to the intellectual property?
Molecular Cytomics does.
What needs to be done before this is commercially viable?
Our plan is to launch the first product towards the beginning or middle of next year. The product would be a kit that will include the microscope-format live-cell array, and reagents, so it would be a kit for a specific assay — for example, apoptosis, or calcium. More toward the end of ‘05, we’re going to launch a 96-well plate format. So the same microarray will be on the bottom of each well in the plate, and this would be more for use with a high-content instrument. But the product would be an assay kit with three or four specific reagents.
Another goal of the company right now is forming collaborations. If there were a specific application in industry or academia that needs this sort of technology to develop a specific drug, or to screen a specific drug, then we would want to form collaboration.
Do you have early users or beta-testers, or are you actively seeking them right now?
Definitely. We want to build the company on collaborations. We already have one beta site at the New England Medical Center, with the lab [of Orian Shirihai] at the Tufts University pharmacology department, which focuses on hematology, bone marrow, and diabetes research. We’ll have two beta-sites in Europe — one at EMBL, and one in the Pasteur Institute. And we just got funding for an additional five beta sites in Israel, so almost any university in Israel will be able to have this technology. And we plan to have these beta-sites in place by mid-2005.