At A Glance
Name: Luke Lee
Position: Director, Biomolecular Nanotechnology Center; associate professor of bioengineering, University of California, Berkeley
Background: Research assistant, TRW Space & Technology — 1986-1990; Member of technical staff, Conductus — 1990-1996; BA in biophysics (1996), and PhD (2000) in applied science & technology, University of California, Berkeley
Luke Lee spent several years in industry before pursuing an education in biophysics from the University of California, Berkeley, where he remains as a member of the faculty. He maintains his interest in industry, however, as a consultant to companies such as Nanophotonics Biosciences, Advanced Bio Technologies, and Intel. In addition, along with two of his graduate students, Lee is hoping to commercialize a microfluidic cell culture array as an inexpensive, flexible system for providing a controlled cell growth and analysis microenvironment. Having recently published several research papers on the technology in recent peer-reviewed journals (see Inside Bioassays, 1/11/05), Lee took a few moments last week to discuss with Inside Bioassays the technology and its commercial potential.
Your group has recently published several papers related to this technology, which is referred to as a microfluidic cell culture array. What does this mean?
Typically, for most cell-based assays, biologists start with a Petri dish. But how can you look at thousands of Petri dishes simultaneously? To do this, we’ve created a miniaturized cell culture chip — a miniaturized version of a Petri dish. However, we also want to provide nutrients continuously, as opposed to just dropping the cells and then watching. That is a very primitive way, and is not very dynamic — you can not watch how a cell behaves in a dynamic manner. So we created this chip, which is a 10-by-10 [chamber] array, and with it we can control the concentration gradient so we can perform multiple experiments, and we can also provide nutrients across the whole 10-by-10 array simultaneously. The most important thing is uniform mass transport into these individual miniaturized chambers.
What type of readout technology would this chip be combined with?
It can be used with existing fluorescence microscopes. You don’t have to change each picture because everything is there, so you can observe the whole thing simultaneously, which allows you to do many experiments at once. Normally, you’re not controlling the whole experiment — in each case, a different individual drops the cells, and there can be many variations. Here, we can load the cells very uniformly, and everything is the same except you’re simultaneously changing temperature, or [drug and nutrient] concentration, or cell lines.
What led your group to develop this technology? Was there a specific problem in your research that needed to be solved?
In my case, I’m interested in developing a quantitative biology tool. By training, I’m a biophysicist, but I used to work in industry, and I decided to create a new high-throughput system for biotechnology. You can do it in industry, but I came here because I wanted to have some freedom to choose the topic. Right now, this particular one is ready to go out, and the students who participated in this project want to start a company. I know that this cell culture chip is really needed in the industry, for any biological assay, or even clinical assay. So the whole motivation for this research was to make a true quantitative biotechnology tool.
How is this different from some of the other microfluidics technology for cellular assays that are on the market. For instance, Caliper does both biomolecules and cells …
Caliper’s main drawback is that it is a static bioassay. They essentially replicate a 96-well plate using microfluidics.
And then there’s a company from Sweden called Cellectricon, and an Irish start-up called Cellix, both of which are doing microfluidics-based cellular assays …
Cellectricon and Cellix have the potential to provide continuous nutrition, but their products are not designed for cell culture or continuous bioassays. Cellectricon only does patch clamp and did not demonstrate that they design their chip for culture based assay market. Cellix has limited ability to perform culture and bioassay, but does not, in my opinion, buy any advantages over current techniques.
Some of the other advantages [our] technology has over existing ones is that there is better control of cell microenvironment, potentially giving more accurate data; a much higher array density — a single culture unit is 100 to 500 microns in diameter, allowing thousands of individual assays per slide; fluidic addressability; disposable PDMS nanoliter-scale microfluidics; and modular designs for possible integration with cell-cell communication, cell lysing, or concentration gradient modules, et cetera.
How do you think this technology might be integrated into the drug-discovery process?
Because we can integrate with a concentration gradient generator, we can screen different concentrations of the drugs, as well as modify proteins on the cell membranes, and see how they respond. To me, this is the best example of making a standardized system. My goal is not one type of assay, but to really show that we can standardize this drug-screening process — just like electronic IC (integrated circuit) chips. Once you establish a microprocessor, everybody follows the same [template]. I want a generic design that everyone can adapt.
Is this mature enough now to be commercialized?
The students that are involved — one student is ready to graduate that wants to form the company. Of course, the details of the system design in terms of interfacing and control, you need to have professional help, but the most important thing is solving the bottleneck of providing continuous nutrients, completing that circuit, which is done. So that is well-established now, so it’s just a matter of packaging, but that depends on manpower — if we can get the manpower behind this, perhaps we can get it done soon, but if we don’t have enough funding, maybe it will take some time. It also depends on the number of people we will have — if we have, let’s say, five to 10 people in the first year, maybe we can finish in a year or two. The strength is that this is really practical and can provide a tool for both research-oriented and clinical biology.
Who are the students involved with this?
One of the students is Paul Hung, and the other is Phillip Lee. Both of them are listed as first authors on the papers, and they contributed equally. Philip, who is a PhD student in Bioengineering at UC Berkeley/UCSF, has BS degree in biology and chemical engineering from MIT, and Paul, who is a PhD student in electrical engineering at UC Berkeley, has a BS degree in electrical engineering from National Taiwan University and took a lot of biology and bioengineering classes at Berkeley during his PhD program. So they really complement each other and make an excellent team.
Are you going to be involved with this startup company?
Yes, I think I am … I have been very careful about this. After I saw that this was really practical, I wanted to show the community that we can really make a new and useful tool. We name this entire initiative BioASIC or BASIC — Biofluidic Application-Specific Integrated Circuit. If you’re familiar with ASIC, it’s a very standardized electronic jargon, meaning Application-Specific Integrated Circuit. The electronics community has already established many different libraries of typical circuits, so you can just grab this individual module and plug into the real circuit. So my idea with the BioASIC is that we create a very specific application using the same design model, and you modify for specific bioassays, but the technology is the same. So a user can pick up module one and module three and make a new integrated module. We can integrate the cell culture with a concentration gradient, or temperature gradient, and so on.
Are you currently seeking funding for this company?
We are trying to do that, and maybe we’ll focus on it a month from new, because the students haven’t finished yet. I don’t want to mix this up with the academics; I want to have it be clean-cut from the school.
So this would be independent from Berkeley?
Yes, even though we will have to license [the technology] back from Berkeley.
Have the patents been issued?
Not yet; they are pending. They’ve been submitted.
Have you had discussions with anyone in industry about partnerships?
Some people are interested, but we haven’t really discussed it in detail, because the students need to finish first — the qualifying exam is next week …
We do have some academic collaborations so far. For instance, there is a researcher at the University of San Francisco who is using our chip to study cell trafficking because they want to obtain all their data simultaneously, instead of one-by-one.
Can you provide any more detail?
Not too much, but you can get a hint from [Erin O’Shea’s] recent Science paper. She’s moving to Harvard, but we’ve been collaborating. And we’ve had many people interested in using this for stem cell research. Even though I personally don’t support embryonic stem cell research, I support adult stem cells, and researchers can use this chip to study the growth factors involved in these cells in a matrix, for a very systematic study. There’s nothing I can do if someone wants to use this with embryonic stem cells. Regardless, many important systematic studies need to be done in this area.