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The Future of Genetics--Career Opportunities for Young Scientists

Completed in 2003 after a 13-year international effort, the Human Genome Project placed the 25,000 or so genes that constitute the human genome within easy reach of researchers. But the accomplishments of the project extend beyond genetic data: The Human Genome Project also pushed forward the technology we need to look deep into our genes. Still, although recording all those genetic letters and developing the tools to search and sort them are breakthroughs of historic importance, those genetic blueprints have little value unless we can read them. The challenge scientists now face has shifted from acquiring data to understanding how genetic information governs the structure and function of cells and whole organisms.

Of particular importance is to relate those genetic data to health and disease in humans. Now that genomics tools have become robust enough for routine investigation, "applying the technique to clinical innovation--that is the real challenge," says Klaus Lindpaintner, head of the Roche Center for Medical Genomics in Basel, Switzerland. But for young scientists wishing to work in the field, the real challenge has become to get the broad range of skills they need to get the best opportunities. Still, for those who aren't daunted by the arduous training, the career prospects are very bright.

From basic science to industrial research

Scientists started studying the genetics of rare, single-gene diseases long before the Human Genome Project, and gene therapy was and remains an active research area. "Quite a lot of progress" is being made in this field, says David Weatherall, emeritus regius professor of medicine and founder of the Weatherall Institute of Molecular Medicine in Oxford, U.K. "In the long term, ... it may be possible to correct a few single-gene disorders."

But it is in the field of common diseases that the Human Genome Project is having the most impact on the way research is done. "Before 2000, some people were working on searching for genes that could participate in complex diseases," looking at two to five candidate genes and dealing with 100 to 200 patients and controls at a time, says Javier Benítez, director of the human cancer genetics programme at the Spanish National Cancer Centre in Madrid. "But now we have passed ... to a new type of study where we need thousands of patients for the analysis of thousands of [genetic variations]." This allows scientists to study genetic predisposition in common, complex diseases such as cancer, diabetes, and obesity in a more comprehensive way than before. "A complex disease is the consequence of interactions between genes and environmental factors," says Benítez. Today, he suggests, scientists are positioned to make headway on understanding those interactions and how they lead to the development of disease.

The first task for researchers is to pin down which genes participate. For complex diseases, the genetic variations are more difficult to tease out because most of them are one-letter genetic “typos” that alter the function of the gene or the encoded protein only subtly. On their own, these genetic variations do not cause much harm, but several together can create havoc, each representing a minor dysfunction that adds to the risk for an individual to develop a disease. To make things more difficult, an estimated 10 million single-letter variations occur in the human genome, and most of them are innocuous.

In an effort to determine which genetic variations can contribute to the development of disease, many scientists are comparing the genes of patients and healthy controls in large-scale studies. "In the long term, certainly for some of [the common diseases], knowing the genes involved will help us to understand the mechanisms of disease better and make better treatments," says Weatherall. Progress can already be seen in cancer research, in which the identification of gene alterations has led to better detection tools or treatments for breast and colon cancer. This approach could result in the development of diagnostic kits that would identify "people at risk for developing a specific complex disease, ... and then they would be candidates [for] specific follow-up and management," says Benítez.

Once genes or genetic variations have been linked to complex diseases, the next challenge is to find out "what they are doing in normal conditions, what it means for the gene, and in general for human beings," says Benítez. This kind of work, called functional genomics, is another vibrant area of genetics research. Just this month, the European Commission, the U.S. National Institutes of Health , and Genome Canada launched a joint €56.6m initiative to increase our understanding of the genetic makeup of human diseases by studying the activity of genes in mice.

Increasingly, researchers are studying the interactions between genes and environmental factors. Last August, for example, the UK Biobank initiative got the green light to collect samples and gather medical information from 500,000 volunteers over up to 3 decades. The database, which will cost £61 million and will be the largest to date, should help researchers study the complex interplay of genes, lifestyle, environmental factors, and disease.

Another important area of research that has received a boost from the recent genomics advances is pharmacogenomics, the study of how genes affect how people respond to drugs. Initially, pharmacogenomics focused on the study of side effects, but it was then also found that "a gene variation might lead to the failure of action of a drug, or ... you have to have a certain genetic makeup for the drug to be effective," explains Arno Motulsky, professor emeritus of medicine and genome sciences at the University of Washington, Seattle, and a founding father of medical genetics and pharmacogenomics.Similar to genetic disease research, pharmacogenomics is seeing a shift away from the study of the effects of single genes. "It has become clear that in many cases it's not a single gene that affects response or causes an adverse effect but the interaction of several genes with environmental factors," says Motulsky.

In the long run, the hopes for pharmacogenomics are high. Pharmacogenomics is the foundation for personalised medicine: the tailoring of drug therapies to individuals based on their genetic makeup. But experts agree that true personalised medicine is a long way off. "There are a lot of good indications about future applications, but what hasn't been done are careful relevant investigations of large groups of patients," says Motulsky. "There are lots of unknown in that field," says Weatherall. In particular, "I think we need to know how practical it is going to be"--how valuable it will be for the individual.

Meanwhile, much research is being done in that field within academia, and research jobs in the industrial sector are expanding. According to Motulsky, pharmaceutical companies were reluctant at first to leave behind their traditional blockbuster-drug approach. But they believe increasingly that they can't afford not to get involved with pharmacogenomics. "Most of the big [pharmaceutical] companies have started research activities or clinical-oriented activities along these lines," says Motulsky. Most of the interest is in using genetic information for designing drugs and predicting side effects, says Weatherall.

Genetics scientists in pharmaceutical companies increasingly take part in the clinical development of drugs by working together with clinicians to identify heritable variations that may be associated with differential drug responses."The desire is to keep the side effects as low as possible," says Lindpaintner of the Roche Center for Medical Genomics. "If you can get an indication early on of how to use a drug more effectively and safely, it will be a valuable knowledge."

Another value the pharmaceutical industry sees in pharmacogenomics is the prospect of improving treatments by understanding better what disease mechanisms are at play. "It's new because we are applying all these genetics/genomics tools, but the concept is the same [one] that we have been trying to do all along: to differentiate patients that at first seem similar," says Lindpaintner. "I think it will quickly become a form of new medicine, of tests and approaches to patients, because it is the logical continuation of what medicine has been all about. That may not work for everybody, but will for some subsets [of patients]."

Getting a foot in the door

As research opportunities expand, so do career opportunities. Scientists interested in working in basic research "will want to do a usual training in molecular genetics or cell biology," says Weatherall. But additional mathematical training might be the key to finding a good job for those so inclined; Weatherall says there is a shortage of geneticists capable of understanding the complex programmes and computer models used for gene searching and genetics analyses. "I think there will be huge opportunities ... in integrating mathematics and genetics. This is an area of genetics that is less popular and really ... important." Benítez would put statisticians, mathematicians, and bioinformaticians together on the list of skilled people in short supply. "There are only a few of them, but since the Human Genome Project we ... need 10 times more."

Scientists who work both as doctors and researchers should also have no problem finding a place in genetics research. The opportunities for clinical scientists "are going to be in the collaboration with people doing more basic research and defining the phenotypes," says Weatherall. Knowing which genes are involved and how they cause disease should allow the refinement of diagnosis and treatment. We need "a very careful definition of clinical disorders of common diseases like diabetes, of how many clinical families" there are, says Weatherall. Clinical scientists will also be needed to help bring epidemiology and genetics together--to identify how environmental factors contribute to health. Because clinical scientists will have to apply genetics to clinical problems, "they will have to take some time off from their training to get familiar with basic science, molecular and cellular biology, and biomathematics," says Weatherall. He also recommends that both basic and clinical scientists choose training environments in which they work under the same roof, to maximise the opportunities for translational research.

Scientists interested in pharmacogenomics should realise, Motulsky says, that "the field ... is a mixture. It is important getting some training in genetics, but there are other fields you need to know about," including biochemistry, pharmacology, ecogenetics--the study of how genetic factors make individuals more susceptible to damage caused by foreign agents--and statistical genetics. "If someone can get this training, they will be more likely to be desirable candidates to get a job in the pharmaceutical industry or academia," says Motulsky, who adds that in practical terms an MD/PhD is the best starting point. Still, scientists with just a PhD in molecular biology or pharmacology can succeed, provided they are able to put themselves into the right learning environments and pick up new skills. But whatever degrees they have, scientists prepared to deal with a wide range of topics and to help translate findings from the laboratory to the clinic hold the future of research on human genetics and disease in their hands.

"The new demand," says Lindpaintner, is for people who utilise tools from genomics and clinical science "to design and execute the proper clinical diagnostic tests in the context of clinical studies," says Lindpaintner. "We don't have enough [of them]. ... They are very desirable, very sought after." Lindpaintner recommends that aspiring pharmacogenomicists study genetics, epidemiology, population genetics, or pharmacogenetics at university, then try "to make the jump from bench to bedside and back." He shares Motulsky's opinion that an MD/PhD is a good starting point, and he also likes to see a couple of postdocs added to this in job applications--which makes the training phase for this sort of work very long indeed. It is, Lindpaintner says, a "very smart idea if you can do part of your postdoc training in industry. We are always open to the idea of having students or postdocs work with us."

Entering the field of human genetics and health research may be daunting for young scientists, but "opportunities are expanding ... and will continue to expand," says Motulsky. "Genetics has become quite popular, and there are many areas in biology and medicine such as translational works that requires genetics. The field still has a lot of possibilities."

Images courtesy of National Science Foundation.

Elisabeth Pain is contributing editor for South and West Europe.

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