"You ain't seen nothing yet," says father of flow cytometry

 
"Flow cytometry and single cell biology are only just beginning to show their potential," said Dr. Leonard Herzenberg, on receiving the 2006 Kyoto Prize in Advanced Technology.

"I truly envy my younger colleagues for the amazing discoveries they are now pursuing. I only wish I were young enough to start over again."

Founder of ScienceXperts and Professor Emeritus at Stanford University Medical School, Herzenberg spoke optimistically of the exciting future of the field he helped to create.

"But, I am pessimistic as well," he said. "The very name Kyoto echoes with concern about the warming of our globe, a problem that too many governments — especially my own — still refuse to take seriously. How many glaciers have to melt before our political leaders wake up too late?

Herzenberg explicitly criticized political, business, and religious leaders who irrationally ignore the findings of scientific research, whether about the dangers of nuclear radiation and global warming or the life-enhancing promises that stem from a Darwinian understanding of evolution.

The Inamori Foundation presented Herzenberg with the award and a purse of 50 million yen (about $427,000) at ceremonies in Kyoto during the second week of November. Created by Kazuo Inamori, founder of the Kyocera Corporation, the Kyoto Prize is considered Japan’s equivalent of the Nobel Prize.

Read Dr. Herzenberg's Kyoto Prize acceptance speech

Read Dr. Herzenberg's Kyoto Prize commemorative address: "The more we learn"

Herzenbergs win Torino Medical Award

Italy's La Stampa interviews founders of ScienceXperts  

[This is the original English version of La Stampa's interview with Drs. Leonore and Leonard Herzernberg, which appears on the Internet in Italian.  Photo courtesy of Stanford Office of Communication & Public Affairs.]

In 1968, Dr. Leonard A. Herzenberg came to the University of Torino as a young scientist eager to work in the laboratory of Dr. Ruggiero Ceppellini, who was at the time one of the world’s leading immunologists.  Now white-bearded at 75, Dr. Herzenberg leaves his own laboratory at the Stanford University Medical School in Palo Alto, California, to return to Turin. There, on June 19 in the Great Hall of Molinette Hospital, he and his wife Dr. Leonore A. Herzenberg will receive the first Ceppellini Award from the International Foundation for Research in Experimental Medicine “for their internationally recognized contributions to medicine.”

Professor Herzenberg, in November you won the Kyoto Prize, Japan’s equivalent of the Nobel Prize, and now you and your wife are about to receive the Ceppellini Award in Turin.  Among your most important discoveries is “flow cytometry.”  Can you explain to someone who is not an expert, What is flow cytometry?

Leonard:  It’s an tool for looking at a large numbers cells, counting them, describing them, and sorting them so they can be studied.  It started with the Fluorescence Activated Cell Sorter, or FACS, an instrument I first developed in 1967, right before I came to Dr. Ceppellini’s lab on a short sabbatical from Stanford.  Today, cell sorters and analyzers use multiple lasers and can look at millions of cells in only a few seconds.  If you have poor eyesight, as I do, it sure beats staring through a microscope at a few cells on each slide.

Who uses these high-speed sorters and analyzers?

Leonard:   Medical and biological research centers, pharmaceutical companies and hospitalso.  The instruments are best known for identifying cancer cells and monitoring T-cell counts in patients infected with HIV or AIDS, but researchers now use flow cytometry for everything from finding bacteria in drinking water to figuring out the best way to do a bone marrow transplant.  Astronauts and cosmonauts even had a flow cytometer aboard the International Space Station.

Leonore:   Without flow cytometry, our colleagues at Stanford and elsewhere could never have discovered the promise of human stem cell therapy, which could possibly help cure Parkinson’s disease, paralyzing spinal injuries, heart and brain defects, and who knows what more.  Nor would we have any hope of isolating different kinds of stem cells and unraveling the mystery of how they develop into basic skin, nerves, or muscles, and why the process sometimes goes wrong.

What stem cell research are you now doing in your laboratory at Stanford?

We don’t do any research on human stem cells, which have to come from aborted fetuses.  The regulations that President George W. Bush put in place make it impossible for scientists like us to do this kind of work.

But you two are among the top scientists in the world.

Leonard:  Tell that to President Bush. 

Leonore:  We are also trying to overcome external limits on another promising area of flow cytometry.  Howard Shapiro, one of the leading experts in the field, has been suggesting that someone should build a low-cost, highly portable, and easily serviced cell counter that could do T-cell counts for HIV and AIDS patients in Africa and other impoverished parts of the world.  We’ve decided in our lab to build the machine, and have put the project into the hands of our colleague David Parks, who runs the Stanford Shared FACS Facility and has contributed to many of the most important technological advances in the field. 

David figures that he can build a new cell counter that could sell for between $5,000 and $10,000.  Compare that to what we now have to pay for a full-blown flow cytometer, anything from $40,000 to several hundred thousand dollars.  A little, inexpensive machine like this, with no moving parts, could be used in all kinds of small hospitals, or even nursing stations, in small towns and villages all over Africa and Asia.

Leonore:  Yes, it could.  But the machine won’t make any difference at all unless we can find the resources to manufacture and distribute it.  So far, none of the big instrument makers has shown any enthusiasm to move in this direction.  Not enough profit, I guess.

Leonard:  He who pays the piper ...

Leonard:  It’s not that simple.  When we first developed the Fluorescent Activated Cell Sorter, I decided that the only way to make it widely available to other scientists was to get a large corporation to manufacture, sell, and support it.  So, I took the project to a company that is now called BD Biosciences, which became the world’s largest maker of flow cytometry equipment.  They are a multi-billion dollar corporation, one of several that now make and sell the most highly sophisticated flow cytometers.  There’s no way I could have made all this happen if we had kept everything here at Stanford.  Like them or not, big corporations have the financial resources, marketing expertise, distribution networks, and service and support staffs that universities will never have.

Leonore:  And it’s not just with machines.  For flow cytometers to identify and analyze different cells and parts of cells, we need to have pure, high-quality monoclonal antibodies and other biological and chemical reagents to mark the cells in ways that the instruments can detect.  We started by making these reagents in our lab and giving them away free to our colleagues around the world.  But, we soon realized that we could never make enough of them for everyone who needed them.  So, we worked with BD Biosciences and other corporations, and today flow cytometry reagents are a bigger business than making the machines.  Len and I now serve on an advisory board for a company called Invitrogen, which makes and sells a whole series of markers that let us do cutting edge work in flow cytometry.

So why didn’t you start your own corporation?

Len:  We’ve thought about it at various times, but we decided that we’d personally rather do basic research.  The closest we’ve come to running our own business is in recent years is with Lee’s work in computer software.

Computer software? 

Leonore:  Absolutely.  In the late 1970s, we began to understand that our research in immunology would require increasingly complex flow cytometry instruments.  And these, we realized, would need increasingly sophisticated software, not only to run the machines but also to plan experiments and save the huge data files in an easily accessible way.  At the time, we had a young hippie named Wayne Moore working in the lab feeding our mice and cleaning their cages.  He was really good at it, the best animal caretaker we’ve ever had.  But somehow we discovered that Wayne was a reformed computer hacker, one of the first and most proficient in the computer world.  So, we gave him a more constructive outlet for his brilliance, and put him in charge of designing and running a computer system to collect and process flow cytometry data for all the users at Stanford.  We were probably the only immunology lab in the world to make such an early commitment to computers.

In the early 1980s, Wayne created a truly revolutionary software program called FACS/Desk that provided many of the basic functions we needed to run and archive our flow cytometry experiments.  I worked with Wayne on the software design, and could not have had a better teacher and colleague.  By 1996, this work won the Computer World Smithsonian Award for Heroic Achievement in Information Technology.

What reactions did you get?

Leonard:  Lee and I tried to convince our friends in industry that this advanced computer approach was the future direction of flow cytometry.  No one seemed very interested.  They were making good money selling their machines and reagents, but the software they created was always rather limited.  They would not invest the time, money, and intellect to harness the computer to make the scientists’ work either easier or better.  So, we brought in a second high-level software engineer named Stephen Meehan to work with Wayne , and they created a new system that greatly improved and expanded FACS/Desk.  One of their breakthroughs was to incorporate Protégé, a knowledge-based software system that Dr. Mark Musen, a computer scientist at the Stanford Medical School had created. 

Then, a couple of years ago,  Stephen, Mark, Lee, and I joined with Ken Tominaga of Tomy Digital Biology in Japan to form a small company called ScienceXperts, which now makes, sells, and services innovative scientific software.  The commericial version of the old FACS/Desk has become two linked products:  CytoGenie helps researchers design protocols and pick the right combination of reagents for their flow cytometry experiments, while ScienceDataStore provides highly-secure, easy-to-use archiving for the huge data files that flow cytometry, microarrays, and other new technologies now create.

Leonore:  Our goal was to make available to colleagues all over the world the Computer Aided Design and storage system that we’ve used for years in our lab at Stanford.  Happily, our friends at Invitrogen recognized the advantages of this approach and threw their financial and marketing muscle behind what we were doing.  This spring, they began promoting our basic version of CytoGenie, which ScienceXperts offers free to anyone who wants it.  As a result of Invitrogen’s efforts, nearly 1,000 people have signed up for it just in the last several weeks.  We could never have done that by ourselves.

Are we seeing here the beginning of a new way to do scientific research?

Leonard:  I think we are.  Most of our younger colleagues are extremely comfortable with computers and are using them in highly innovative ways.  But computers are not simply a generational thing.  Take Lee.  She’s still working night and day on new software projects to enable immunologists and other researchers do more and better work.  I get exhausted just watching her.