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Richard N. Zare

Eric Hall, Peng Guo, Bor-han Chueh

In the study of a biological population, how important is individuality? Are the members of the population so similar that the average behavior can describe them all, or are deviations significant enough to make this kind of description misleading? The conventional techniques in biology use a large number of cells and generate the ensemble averaged values to describe cellular characteristics. These methods are fast and efficient ways of observation as long as the individual cells exhibit little deviation from this average behavior. If the deviations are significant, however, the large-scale ensemble averaging methods fail to give a proper picture of biological phenomena. A simple example will be the case of a bimodal distribution, where the cells with an average behavior actually represent a smaller fraction of the population.

Recent advances in microfluidics opened a new possibility in single-cell biology by providing the necessary toolkits for handling and analyzing individual cells. We believe that it is an opportune time to apply microfluidic technologies to investigate individuality of cells because important information relevant to the most pressing biological questions is very likely obfuscated by ensemble averaging techniques. Our section develops techniques for performing single-cell analysis on a microfluidic device, more commonly referred to as “lab-on-a-chip”. We have made pioneering contributions to the field, including the development of a device capable of capturing a single cell and delivering precise amounts of reagents,1 and an on-chip chemical cytometer integrated with a picoliter micropipette for cell lysis and derivatization.2 More recently, we have extended this technology to study the phycobilisome degradation process in individual cyanobacteria cells.3

There are currently two main goals in our section. The first is to develop a microfluidic device capable of capturing a large number of single cells and sustaining them in an on-chip culture for a prolonged period of time, using two layers of channels separated by a membrane of conical nanopores (Fig. 1). This will allow for time-resolved observation of a statistically significant number of single cells, an ability currently lacking in flow cytometry and traditional microscopy-based approach. The second goal is to integrate this design with an on-chip device capable of extracting and amplifying sufficient DNA from a single cell for sequencing (Fig. 2).

For more information on how we make microfluidic devices in the Zarelab, please see our guide (PPT or PDF).

Cell Capture picture Cell Analysis picture
Fig. 1. Microfluidic channels and control valves (black) facilitate the capture of single cells on a nanoporous membrane (red). Fig. 2. Cells are manipulated with microfluidic channels (black) and control valves (red) into chambers (blue) designed to deliver specific nanoliter volumes of reagents.
  1. A.R. Wheeler, W.R. Throndset, R.J. Whelan, A.M. Leach, R.N. Zare, Y.H. Liao, K. Farrell, I.D. Manger, A. Daridon, Anal. Chem. 75, 3581 (2003).
  2. H. Wu, A.R. Wheeler, R.N. Zare, Proc. Natl. Acad. Sci. U.S.A. 1010, 12809 (2004).
  3. B. Huang, H. Wu, D. Bhaya, A.R. Grossman, S. Granier, B.K. Kobilka, R.N. Zare, Science 315, 81 (2007).