Science and Medicine: Cell Technology

Washington Post science writer David Brown were online Tuesday, April 8 at 11 a.m. ET to answer questions about the advancement of cell sorting technology, which is providing unprecedented insight on the molecular basis of disease and the rise of "personalized medicine."

He was joined by J. Paul Robinson, professor of immunopharmacology and biomedical engineering at Purdue University, and the president of the International Society for Analytical Cytology.

A transcript follows.

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David Brown: Welcome chatters. This is a discussion about cell-sorting and cell-counting technology. (It is not about the cost-effectiveness of prevention in medicine; that's a different subject). We are lucky to have on the chat today Prof. J. Paul Robinson, of Purdue University, an immunologist with a biomedical engineering interest who has become in recent years a historian of cell-sorting technology. He joins us today from West Lafayette, Ind.

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Harrisburg, Pa.: Do you have a rough estimate on how long it will take these technologies and advances in research to be applied towards the public health? I realize numerous tests need to be conducted, yet I often am sympathetic to the terminally ill who are often denied potentially life saving procedures because they are not approved and ready for use.

J. Paul Robinson: This is a very interesting question. For many years we have talked about "next gen" technologies that will change public health. I believe in the next 5 years, there will be a revolution in these technologies driven by the basic electronic consumer products that are now very cheap and accessible. These low cost consumer products will become the bases for the true next gen public health tools particularly in diagnostics and basic tests.

David Brown: I should make it clear that cell-counting and cell-sorting technology is in clinical use today, with the best example being the CD4-cell counts (also known as T-cell counts)routinely done for people infected with HIV. It is also used clinically for people with some forms of cancer, especially blood-cell cancers.

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Basel, Switzerland: By when will cell sorting methods be routine in daily medicine and is it already clear which diseases will be first treated successfully

J. Paul Robinson: Sorting is expensive - instruments cost 3 or 4 hundred thousand dollars - so the next step is to make micro fluidic systems actually work - there is good evidence that this works now and I think in a few years it will be possible to have a small instrument that will slowly, but surely sort what you want and put a few cells into a small container - probably a microchip and perform other reactions. Of course you can do this now in the research lab, but to do this routinely in a commercial instrument is another thing.

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Washington, D.C.: Thank you, David, for a very nice article. I'm the Smithsonian curator who did the cell sorter videohistory that you cite. It's heartening to see that the materials that I helped to create are being used to inform and educate a much broader audience. Again, thank you and Prof. Robinson.

Ramunas (Ray) Kondratas, Ph.D.

Curator

Division of Medicine and Science

National Museum of American History

J. Paul Robinson: Ray - without your outstanding work of making the history of cytometry - this would never have happened. I hope to meet you sometime! Paul

David Brown: I think we should acknowledge the extreme importance of collecting the oral histories of important scientists. Their accounts are not the last word on what happened, but they are the first and can obviously never be captured once a person has died. So thanks.

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Tampa, Fla.: Even if you can identify the cause of diseases like fibromyaglia, how would this technology generate a treatment?

J. Paul Robinson: Tools such as flow cytometry is an important research tool. As such we use this technology to understand cell processes and the underlying biochemistry of how cells work. Many diseases are now much better understood because of our ability to first identify specific cells, then sort them, followed by detailed genetic or proteomic analysis. However, it is the combination of many individuals research and many different technologies that ultimately solves problems such as fibromyalgia. This is the reason that funding our national institutes of health is so important.

David Brown: The easiest way to identify and sort cells is through molecules that are on the outer surface of the cell. It is harder to identify cells by molecules that are inside them. This requires getting chemical tags inside the cell, which often is often damaging to the cell's integrity. However, it is sometimes possible to use the cell's normal process of taking up external molecules via endocytosis to do this. All this is to say that it will be hard to use this technology to identify cells on the basis of what genes are being activated and transcribed inside the cell. But it is not impossible, and research will undoubtledly make it easier over time.

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Frederick MD: David,

I remember from reading Shapiro's book about cell sorting that the technology (laminar flow cell and light scatter) were invented in the early 1940s by engineers at Fort Detrick so that aerosol particles could be sized. The technology involved a flow cell that created laminar air flow which kept the particles in the center as they flowed through. The lens-focused light beam was generated by a Ford Headlight which was regarded as the most powerful light source at the time. Obviously, other technologies were combined to create the Cell Sorter that we know now but when I tell this story I like to mention that this useful medical and biological technology was originally developed to serve biological warfare research which illustrates the paradox that one rarely knows at the outset what benefits may acrue research efforts, even those aimed at weapons development.

Best regards.

Art

J. Paul Robinson: This is a very accurate statement. Gucker was in fact a mining engineer and studied mechanisms for measuring mine dust. He also tried to use this technology over 60 years ago to identify potential biological warfare agents - remember that a similar situation existed with Fulwyler who built the first cell sorter - he was an engineer who had seen Richard Sweet's development of the ink jet printer and Fulwyler was able to transform that idea into one that could manipulate cells.

David Brown: It is true that one cannot anticipate where a novel scientific insight will lead. This fact is one that the people in charge of funding research acknowledge and they want to be able to keep an open mind (and an open wallet) when it comes to seemingly "pointless" but interesting ideas that researchers have and want to pursue.

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Munich, Germany: Isn't the cost comparison between sickness prevention and cure blurred by the fact that healthy people incur the most health care costs because they live the longest? Cancer differs from heart attacks, I think, because cancer is a slow death that requires costly hospitalization, whereas many heart attack victims perish quickly. Perhaps if the cost of prevention is perceived as increasing the quality of life, then the money may be well spent.

J. Paul Robinson: While it is true that discovery often requires expensive, hard to get technology, our ultimate goal from a public health perspective, is to ensure that diagnostic tools, some of which result from tools such as flow cytometry, become low cost, widely available tools for public health monitoring. As an example, these expensive tools are now being transformed into very low cost devices that will become important in developing countries for HIV/AIDS - so while a large amount of money might have once been spent on developing the technology, it will ultimately be used for the greater good. This is exactly what is happening in Africa where CD4 measurement is so vital for therapeutic monitoring of HIV/AIDS patients. It has to be low cost, easy to use and readily available - we have not quite got to that point, but we will.

David Brown: Many people realize there is a tremendous need for technology like cell-sorting in the developing world and that helping countries there get the machinery is a high priority. The Clinton Foundation in 2004 brokered a deal with five medical technology companies in which they agreed to lower the price of equipment, including cell sorters, in resource-limited countries with high HIV burdens so that people under treatment there can receive optimal treatment.

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J. Paul Robinson: The story of how the original Fulwyler cell sorter was discovered is interesting. It was almost accidental. One evening during the Christmas break in 2004, I was reviewing some video material that had been made by the Smithsonian Institute and I saw an instrument in the background of the video. Mack Fulwyler then started to demonstrate exactly how this instrument worked and then Boris Rotman discussed how he used this instrument in his work. I literally opened google and search Boris Rotman - I found a paper he had written in 2003 and his email was attached to the paper. I emailed him asking if the instrument was still in his lab. It turned out that he had retired and his lab was going to be renovated and the old instruments discarded. The original Fulwyler instrument had been in the back of his lab since delivery in 1967. He got permission to donate the instrument to us for safe keeping and it was packed up by a technician from Beckman Coulter who also paid for its delivery to Purdue. We have reconstructed the instrument exactly as it was in in 1967 with virtually every original part.

David Brown: That's a great story.

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Vienna, Va.: I have breast cancer. Is there any blood cell count that can distinguish these cells? Also, can you assay cells in the lymphatic system?

J. Paul Robinson: Flow cytometry is definitely capable of identifying abnormal cells from many clinical syndromes. Determination of cancer cells has been a goal since the 1940s when Papanicoleau developed his initial screening tests. In fact, it was because of the difficulty of using imaging modalities that flow cytometry was enhanced (there were no computers to do advanced image analysis at the time).

In regard to ability to identify cells in the lymphatics, this is also a future possibility. With the development of next generation, micro devices, I have no doubt that it may be possible to monitor cells in draining lymphatics - but it s not possible now. There are a number of issues to be resolved apart from the engineering problems associated with manufacturing such small devices and implanting them - these include how do you determine the abnormal cells without a tag of some sort? If you added a tag, what would you use? There are many new developments in nanomedicine that may answer these questions in the future. There may be image guided devices developed that could monitor these vessels but that is also in the future. I have no doubt that as we enhance our technology capabilities, we will see a transformation in diseases where we must find those very small populations of aberrant cells that reflect cancer.

David Brown: And I think on that futuristic note we'll close it down. Thanks very much for your attention, and thanks to Professor Robinson for joining me.

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