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The flow cytometer that we have all grown to know and love may have only come into its own in the 1990’s, but who would have known that the first cell sorter was invented as early as the 1950’s?
With the recent death of one of the key developers of fluorescence activated cell sorting (FACS), Leonard Herzenberg, it seems like a good time for an article revisiting his contributions to the invention of the FACS* machine. But first, we’ll start with a quick overview of the process before we delve into the history lesson.
A quick overview of FACS
FACS is a specialized type of flow cytometry that provides fast, objective and quantitative recording of fluorescent signals from individual cells as well as physical separation of specific cells of interest. It basically allows us to sort a heterogeneous mixture of cells into two or more containers, one cell at a time, based on the specific light scattering and fluorescent characteristics of each cell (1).
The technique uses a beam of light, usually a laser, of a single wavelength, which is passed through a stream of fluid containing your cells (2). A number of detectors are aimed at the point that the stream passes through the light beam: one in line with the light beam (Forward Scatter or FSC) and several perpendicular to it (Side Scatter (SSC) and one or more fluorescent detectors).
Each cell that passes through the beam scatters the light in some way, and fluorescent tags either inside or on the surface of the cell may be excited into emitting light at a longer wavelength than the light source. This combination of scattered and fluorescent light is picked up by the detectors, and by analyzing fluctuations in brightness at each detector (one for each fluorescent emission peak), it’s then possible to derive various types of information about the nature of each cell.
Leonard Herzenberg and the development of FACS
The history of flow cytometry can be traced as far back as the 1930’s to the experiments of Andrew Moldavan, who designed a photoelectric cell apparatus to count individual cells flowing through a capillary tube that was mounted on a microscope stage. Then, in the 1950s, Wallace Coulter began the development of the first instrument that could electronically calculate cell volume. The inventor of the forerunner to today’s type of flow cytometers, particularly the cell sorter, was Mack Fulwyler, who in 1965 published his findings in Science.
On hearing about this, Leonard Herzenberg, a professor at the Stanford University School of Medicine, realized he might have found the solution to the eye strain that he was having from manually counting fluorescent cells under the microscope. He began to consider the possibility of combining flow cytometry with fluorescence detection. Together with his wife, he did just that. And by 1969 he had published “Cell sorting: automated separation of mammalian cells as a function of intracellular fluorescence” in Science. But it was not until 1972 that he coined the term FACS. His article in Scientific American spread the technology even more widely in 1976 (3).
Although academic scientists were often leery of engaging biotechnology companies, Herzenberg had the foresight to partner with Becton-Dickinson to commercialize the FACS machine.
For his role in the development of the first FACS machine, Herzenberg was honored with a Kyoto Prize in 2006. He also was awarded a Special Novartis Prize in Immunology in 2004 for his role in developing fluorescent-labeled antibodies to tag cells prior to sorting. At the time of his death on October 27, 2013, he left behind an impressive legacy of science and technology, including more than 550 research papers and numerous patents. And the fact that he has revolutionized science today.
*Although FACS is often used as a generic term to talk about fluorsescent flow cytometry and scientists almost always refer to flow cytometers as “FACS machines”, the acronym “FACS” is trade-marked and owned by Becton-Dickinson.
(2)http://www.millipore.com/publications.nsf/a73664f9f981af8c852569b9005b4eee/f2854208fb10a9e7852575e700577a9c/$FILE/PB3167EN00.pdf (3)Herzenberg, L. A. and Sweet, R. G. (1976). “Fluorescence-activated cell sorting.” Scientific American 234(3): 108-17.