Stephen Fodor

Pioneer of “Massively Parallel Genomics”

The biotech revolution, like the computer revolution with which it has become thoroughly entangled, involves an unprecedentedly tight interaction between the worlds of science, engineering and business. This interaction is not just about partnerships between organizations, it’s about individual human beings stretching their minds and personalities to encompass diverse, often divergent perspectives.

There’s the creative and exploratory world-view of the scientist, in which solid experimental results or elegant theories are the proof of success. There’s the pragmatic and functional perspective of the engineer, in which a high-quality working system is worth more than anything. And then there’s the sometimes cut-throat vantage of the businessman, in which the bottom line is always a financial one, and Bill Gates is vastly more valuable than Einstein. Typically, historically, these different orientations toward life have resided in different people’s brains. But more and more people each year, in order to achieve their goals, are being forced to internalize all these perspectives, and weave them together into an integrative approach.

In the domain of biotechnology, this emerging synthesis is wonderfully exemplified by Dr. Stephen Fodor – a scientist whose groundbreaking scientific/engineering achievements led him into the business world, where he’s now managing the development and marketing of technology based on his initial breakthroughs. His firm, Affymetrix, was one of the most promising of the biotech start-ups of the late 90’s, and shows no sign of slowing down.

And in his spare time, among other things, Fodor is thinking about the ethical aspects of genomics, a discipline that is well-known as an ethical minefield, with new issues like stem cell research and human cloning popping up every day. In the ethics of genetic research, commercial, scientific and engineering perspectives intersect with humanistic and even spiritual issues, and Stephen Fodor and others with his diverse background are uniquely positioned to deal with such issues in an integrative way.

From the Lab to the Boardroom

Dr. Fodor’s career began like that of a typical overachieving young bioscientist. He received his B.S. chemistry in 1978 and his M.S. in biochemistry/biophysics in 1982, both from Washington State University – a solid school, though not a world leading institution. He moved on to Princeton University for his PhD, which he received in 1985. Following a post-doctoral fellowship at Berkeley, he wound up at Affymax Research Institute, where his group led the development of new technologies, oriented towards creating very dense arrays of biomolecules by combining photolithographic methods with traditional chemical techniques. The advantage of packing biomolecules together in very dense arrays is that one can then study a large number of molecules all at once, in a single experiment, as opposed to traditional experimental biology approaches in which one studies one or a handful of at a time. This work was an interesting example of interdisciplinary crossfertilization of ideas, Fodor’s chemistry and biophysics background spurring him to think about the problem differently than traditional biologists would.

As the work became more and more promising, the potential commercial possibilities became more and more clear. If one could affix a large number of different segments of DNA or protein to some surface, in a tightly packed array, then one could effectively experiment on all of them at once, gathering millions of times as much data as was possible using traditional approaches, where one worked with many fewer pieces of DNA or protein at a time. There were still a lot of technical issues to be worked out, but, the viability of the idea was clear. With this in mind, in 1993, Fodor and a group of other Affymax scientists decided to form the firm Affymetrix, dedicated to the creation and dissemination of radical new technology for genomic and proteomic data gathering, based on the research of Fodor and his colleagues.

When Affymetrix was founded, Fodor was Scientific Director, but over time, he found himself becoming more and more involved with the business side of the company, and in 1997 became President and Chief Executive Officer. And the company would seem to have benefited significantly from having a leader with a passion for all aspects of its operations, scientific, engineering, marketing and financial. It’s still the technology, and its potential to transform bioscience as a whole, that gets Fodor most excited. But, a consummate realist, he has realized that focusing on the technology alone is not the optimal way of going about the process of transforming bioscience. Getting the technology out there in use in as many places as possible is just as critical as making the technology effective.

Gene Chip Technology

Fodor’s technology, called the “DNA chip,” is a leading example of the next-wave, post-human-genome-project, bioscience revolution. The human genome project focused on enumerating all human genes; DNA chips, on the other hand, allow us to study the “expression” of DNA, biologists’ term for how DNA is used to create other molecules that ultimately build up to form organisms like ourselves.

The original motivation for the gene chip work was to create a device that would hold thousands of molecules in place so they could be tested simultaneously to determine which ones were viable drug candidates. Fodor saw how, as he put it, the DNA or protein molecules stuck on the chip could act "as thin strips of molecular Velcro." By seeing which molecules stick to which other ones, one can discover all sorts of things about genes -- detecting mutations, revealing information about diseases or treatments, figuring out which genes interact with which other ones during cell development, etc.

Essentially what one has here is massively parallel genomics and proteomics. In computer science, massively parallel processing involves supercomputers that carry out thousands or millions of computational operations at once. Massively parallel bioanalysis, on the other hand, allows biologists to carry out huge numbers of biology experiments all at once.

The process of making the chip itself, perfected by Fodor and his team, is clever and subtle. Effectively, one is making DNA as if one were making a semiconductor chip! First, a process known as “photolithography” is used to create a huge number of molecules, directly on a silicon wafer or a glass surface. A single chip measuring 1.28 cm X 1.28 cm can hold more than 400,000 of these “probe” molecules. Next, a “target” molecule is labeled with fluorescent dye and is simultaneously hybridized to all the probes on the chip. A fluorescent image results, which is scanned by a laser beam, producing data for computer analysis. The intensity of the fluorescent light generated in this process varies depending on how well the target molecule hybridizes with the probe molecule stuck at each position on the chip. All this began as a chancy, complex experimental procedure and is now fully automated; Affymetrix manufactures 5-10,000 DNA chips per month.

In heavy use by pharmaceutical firms, the DNA chips aren’t cheap, and so many academic researchers make use of an alternative, less complex technology called the “DNA microarray,” which involves using a robotic device to precisely spot very small droplets of molecular samples on an ordinary microscope slide. This method is less powerful than Affymetrix technology, providing a lesser degree of parallelization, but is still an important competitor due to its low cost. Increasingly, Affymetrix is providing academic research facilities with inexpensive access to DNA chips for experimentation, but still, one expects that microarrays will continue to flourish and develop

The Genetic-Ethical Frontier

The ethical issues associated with this sort of research are thorny and intricate, and, as a man wearing several different hats, Stephen Fodor has been forced to view them from many different perspectives.

At a 1999 Princeton University symposium on bioethics, he observed that “Having a commercial background brings a different bent to the ethics around the subject….” To illustrate this, he offered an amusing anecdote. “I was talking to a friend of mine,” he said, “whose father used to run a dry cleaning company near New York City. Every day when the clothes came in, he would go through the pockets of the clothes, and see what he found in there. One day he found a hundred dollar bill. He said this raised a serious ethical question -- whether he was going to tell his partner. [i.e., whether he was going to share the $100 with his partner or not] So, ethics is in the eye of the beholder….”

This little story has the empirical directness of the scientist about it. As a pragmatic businessman, Fodor has long since realized that humanistic sentiments don’t make the business world go around. As a rule, the only principle that can be relied upon to mean anything to a corporation is the maximization of shareholder value. As a scientist, he sees this situation quite plainly as an empirical fact.

Why, then, as an ethically concerned individual, is he relatively unworried by the consequence of this cut-throat attitude for the development of biotechnology? It’s simple. He believes that the power of the technology to do good is far greater than its power to do damage.

One ethical worry associated with genetic analysis is that ambitious parents will use it to overengineer their progeny – killing a fetus if, for example, its genes indicate that it won’t be sufficiently musically or athletically talented. Some people find this unproblematic, others find it repellent. As for Fodor, when asked if there should be regulations on using DNA chips for prenatal screening, he hems and haws a bit, observing that “Prenatal screening is a bigger question than just these chips….” His main concern in this connection is “… personal privacy. I’m not an advocate whatsoever of the possibility of health care organizations doing screening and databasing and letting you know what the options are. I think the best case is that people get the information themselves and decide what to do with it, that the information is in their control. The levels of privacy I think have to be worked out.”

While information privacy is an important concern, it’s perhaps idealistic to think that genetic information, among all medical data, is going to be kept from the vast health care establishment. All in all, where this sort of issue is concerned, one gets the impression that Fodor is slightly bored and not 100% engaged. Rather than worrying about what-ifs, his focus is on building the technology and doing the best things he can with it, and what society as a whole makes of it, is indeed beyond his control. The key point, in his view, is the vastness and diversity of “wonderful commercial and scientific possibilities. We’re in the early days of this…. There’s a tremendous number of medical and scientific applications…. What are the good things you can do? What are the values you can create for people going forwards?” This is what gets Stephen Fodor excited, not worrying about negative possibilities.

With a salary and bonus package pushing a half million dollars a year, and many tens of millions in stock options (much of it fully vested), Fodor is certainly profiting personally from his turn towards the commercial world. And he is clearly experiencing many money and business oriented distractions, such as a recent lawsuit against Incyte (a particularly perplexing lawsuit given Affymetrix’s ongoing partnership with this firm) But in practical terms, in spite of the inevitable over-busyness of his multifaceted role, he is doing his best to work toward realizing beneficial applications of his technology as well as toward personal and corporate profit.

And indeed, he would appear to be correct about the potential for good in this technology. It is tremendous. The medical applications of DNA chips may well be revolutionary. As Fodor says, "Affymetrix was founded on the belief that understanding the correlation between genetic variability and its role in health and disease would be the next step in the genomics revolution." And the results to back up this vision have started coming in.

For instance, 2 years ago researchers at the Whitehead Institute used DNA chips to distinguish different forms of leukemia based on patterns of gene activity found in cancerous blood cells. This approach has led to real practical benefits, for example in some cases reversing the incorrect diagnoses made by other, cruder methods. And this is only the barest beginning. As Dr. Lander of the Whitehead Insitute says, "the research program aims to lay a foundation for the `post-genome' world, when scientists know the complete sequence of DNA building blocks that make up the human genome." Mapping not only what is in the genome, but what the things in the genome do, is the real secret to comprehending and ultimately curing cancer and other diseases.

One of the more interesting developments in the medical application of DNA chips is the creation of the Affymetrix spin-off company, Perlegen Sciences Inc. Perlegen’s goal is to use DNA chips to help understand the dynamics underlying various diseases – startin out with the rare disease “ataxia telangiectasia” (A-T), with which the two sons of Perlegen co-founder Brad Margus are afflicted.

Ataxia is a word for loss of muscular coordination; telangiectasia refers to the small blood vessels that pop up on the skin and eyes A-T victims. A-T typically affects youths; 40% of A-T children develop cancer, and few live past their 20s. Margus was the boss of a $100 million-a-year shrimp processing company when he discovered his sons were afflicted with A-T -- and, in a remarkably systematic and dedicated fashion, began to devote more and more of his life to researching the biological foundations of the disease. He helped raise millions of dollars for research on A-T and its genetic basis, a quest that ultimately led him to Stephen Fodor.

Affymetrix array chips, it seemed to Margus and his bioscientist collaborators, could be used to study the way different individuals with A-T would react to different medications. It could vastly accelerate the drug discovery process, by allowing so many experiments to be run in parallel. Of course, this is exactly the kind of humanistically valuable application of DNA chip technology that makes Stephan Fodor happiest. It didn’t take much effort to convince Fodor that Affymetrix should help Margus in his quest, by helping to form Perlegen.

With cases like this all around him, it’s not hard to see why Fodor is relatively unruffled by the ethical dilemmas that some find in genetic research. Are there potential dangers in this technology? To be sure. But there is also tremendous potential to help people. And so far there is no doubt that the positive far outweighs the negative. DNA chips have helped find cures for diseases, and they haven’t harmed anybody.

Of course, as Fodor says, this is just the beginning. We’ve mapped the genome, and now, baby step by baby step, we’re starting to understand the process by which strands of genetic material interact with other molecules to form organisms like us. As we move along this path of understanding, we’ll be able to cure more and more diseases, and more dramatic possibilities for genetic screening and genetic modification will open up. One can only hope that the optimism and focus on positive applications that Dr. Stephen Fodor embodies will continue to carry the day.