Your Genetic Future

During the earliest days of this millennium, the Rockville, Maryland-based company Celera posed a surprise challenge to the scientists involved in the public human genome sequencing effort and raced them to a tie with a simultaneous publication of a draft sequence in February 2001. Celera's idea was to make money by selling access to its high-quality sequence database. At its peak, Celera had more than 200 institutional subscribers. Wilmington, Delaware-based Incyte had a similar business model: The company owned a collection of single-nucleotide polymorphisms (SNPs)--one-letter genetic “typos”--that had drug-discovery professionals drooling.

In the 5-plus years that have passed since those first draft sequences were published, the business models embraced by both companies have changed. Celera’s database subscribers dwindled as the quality of publicly available genetics data improved, until last year when the company announced that it would end its subscription program altogether and release its data into the public domain. Celera flirted with drug discovery until late last year when it turned its focus to diagnostics. Incyte, meanwhile, has also abandoned its subscription model, transforming itself into a full-fledged drug-discovery company.

"In some ways [these transformations] are completely expected. Any company that has significant diagnostic information and genomic capabilities, if they want to go for the gold ring, they try to figure out how to make it useful to the health industry rather than just producing research tools," says David Galas, a professor at the Institute for Systems Biology in Seattle, Washington, and the vice president and chief science officer for biological and life sciences at the Battelle Memorial Institute in Columbus, Ohio.

The state of the industry

For aspiring geneticists, the lesson of the two companies' transformations is that genetics is moving into the realm of the practical, with the promise of personalized medicine and pharmacogenomics. Genetics will almost certainly transform medical practice as diagnostics are developed to predict disease susceptibilities and identify which drugs a patient is most likely to respond to. The age of the billion-dollar blockbuster drug is most likely passing, to be replaced by drugs with genetically targeted markets. That means fewer sales per drug--but genetic tests should make clinical trials cheaper and faster, and a higher percentage of trials should lead to U.S. Food and Drug Administration approval--assuming FDA can keep pace. Celera has developed genetic markers to predict disease prognosis in coronary heart disease, deep vein thrombosis, stroke, and hepatitis C-induced cirrhosis. These markers could be used to preselect clinical trial participants--and, eventually, patients--to those most likely to benefit from a new drug.

But all of this presents some serious uncertainty. One big question is how FDA will handle the changing paradigm. The agency is used to weighing a drug's side-effect profiles against the severity of the condition and the drug’s overall effectiveness. Highly targeted drugs, perhaps linked to a genetic test, call for a completely different regulatory mindset. Side effects may suddenly be verboten--and volumes of genetic data will be a stiff challenge to FDA’s reviewers.

How will the agency react? Probably slowly as it has so far, Galas says. The agency is underfunded, and that makes it difficult to keep up with current research trends. That uncertainty in turn makes investors nervous, potentially slowing the growth of the industry--and employment opportunities.

In anticipation of targeted medicines, pharmaceutical and biotechnology companies are increasingly performing genetic studies of clinical trial participants in hopes of identifying genetic profiles that predict therapeutic outcomes. A drug that only benefits 15% of participants might seem like a clinical failure--but if those respondents share a genetic profile, the drug might be admitted to the market with an accompanying genetic test.

But such data can be difficult to interpret, so it could even slow down an approval process. This could be a disincentive to doing such tests in the first place. Until FDA’s stance is clarified, pharmacogenomics will be a volatile and unpredictable business and career path. "Young companies trying to get into pharmacogenomics and personalized medicine are facing daunting challenges because of uncertainties with FDA and just the inherent difficulties of trying to change the paradigm to something where side effects are unacceptable," says Galas.

Getting back to careers ...

So expect a career in human genetics to be volatile--but promising. The field is rife with opportunities to improve human health and to take part in the inevitable health-care revolution. So what's the best way to prepare yourself? Given the importance of interdisciplinary research, it's not surprising that--according to John Sninsky, vice president of discovery research at Celera--it's important to be well-rounded. Multidisciplinary training is increasingly emphasized. "Not that it hadn’t been done before, but it has become an even sharper focus," says Sninsky, who also serves on the advisory board for Purdue University’s department of biology.

Combining population statistics or epidemiology with an understanding of Mendelian and multifactorial genetics "serves you really well," says Sninsky. "It’s also really beneficial to be able to step back and look at the forest and the trees, to have the breadth to look at the study design, and the interest and skills to drill down and examine the tree in the context of the forest."

Computational and programming skills are also important, including the use of Java and other languages to write programs to do routine analysis. Quantitative and computational expertise "is not unusual among geneticists because they deal with quantitative data and tend to be good at statistical analysis. So in some ways it’s natural for geneticists to move into integrated [drug] discovery programs," says Galas.

The future probably holds even more integration of genetics with other fields. Galas suspects it will be incorporated with protein-expression data in individuals, for example: "You’ll be looking at individuals not just for SNPs but [for] expression profiles, proteomics studies, medical history. You’ll take all this data and begin to infer things about medical mechanisms and implications for therapies and diagnosis. I think this is where the whole field is going." It follows that training in one or more of those other fields can only help aspiring genetic scientists.

The new landscape

There are and will continue to be jobs at companies that develop instruments and kits, such as microarrays, reagents, expression kits, and other supplies to fuel research programs. But Galas expects them to be a smaller fraction of the job market in the future. "Those jobs are inherently more applied, and there aren’t as many of them. There will be demand for really good people in developing new instrumentation, particularly as they move toward nanotechnology and microfluidics platforms. Still, the abundance is probably going to be much higher in the pharmaceutical and diagnostics companies. If you look at the research budget of [an average] pharmaceutical company, it dwarfs the research budgets of all of the service and research tool providers put together."

As a class, drug discovery and diagnostics companies will represent the greatest share of opportunities. However, Galas sees a shift in the size of companies that will provide the most employment. "There’s a huge shift that’s occurred over the past 5 years. Jobs in the large pharmaceutical companies have not grown at anywhere near the pace as jobs at small companies. That has occurred in many different ways, with pharmas spinning off small companies, new companies forming, and small companies growing rapidly. They still have the flexibility and the commitment to risk-taking that some of the larger companies believe they can’t afford anymore. I think the huge pharmaceutical research monoliths are probably going to be a thing of the past, although there will probably be a few like Merck and GlaxoSmithKline," says Galas.

Not all opportunities will be directly related to drug development. The security and global pandemic concerns of the 21st century have also encouraged the rapid growth of monitoring for infectious disease and bioterror agents. Genetic assays can pinpoint particularly dangerous strains of otherwise mild microbes. Genetic tests to detect these microbes could be used by public health researchers trying to find and quarantine outbreaks of bird flu, for example, or by military personnel looking for evidence of a bioterror agent. "That wasn’t much of a field in 2001, but it has grown enormously. That field had been neglected for many years but has now come back to be modernized," says Galas.

Despite these new opportunities, genetics remains a field defined by uncertainty, as both FDA and industry wrestle with questions of data analysis, side effects, and other issues. The uncertainty is likely to be a drag on job growth in medical genetics. "If you’re coming into the field now, the market for your type of jobs may not grow as fast as you had hoped," says Galas. "We always underestimate the impact of these types of technologies, but we also overestimate the speed at which they’ll be adopted. There’s going to be a huge need for people to do this work. The better the people and the more of them there are, the faster it will happen."

Jim Kling writes from Bellingham, Washington.

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