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Molecular Diagnostics Detects Cancer Early
ith prevention always preferable to a cure, Lee Hartwell, 2001 Nobel laureate in physiology or medicine, has been extolling the virtues of molecular diagnostics for the early detection of cancer and promoting better reimbursement for efforts in this field. Unlike blockbuster drugs, research in diagnostics earns little encouragement or reward. Nevertheless, the president and director of Fred Hutchinson Cancer Research Center in Seattle, US, believes that the molecular approach still holds the best hope for making large-scale progress in attacking the cancer problem and turning the fast-rising disease tide. He describes his vision to INNOVATION's Lay Leng TAN.

What positive developments have recently taken place in cancer treatment and diagnostics?

Hartwell: Surgery and radiation have proved themselves effective for decades in treating localised cancer. In terms of new developments in drug therapy, about half of the new therapeutics currently awaiting approval are protein therapeutics rather than small-molecule therapeutics. I feel optimistic about their effectiveness and feel they will eventually completely change the way doctors practise medicine.

Diagnostic approaches available now remain limited, and most are expensive, with the exception of the Pap smear, which has long been effective in detecting early-stage cervical cancer. Other techniques involve imaging — colon or gastric — which have limited effectiveness, as changes do not show up well and the cost is too high for widespread use. Thus, we need biomarkers for accurate detection of cancer risk or early onset of disease that do not involve costly imaging techniques. I believe that the most informative biomarkers will be proteins, and there are now powerful techniques available for identifying protein markers that may be highly informative with respect to detecting risk or early onset disease, or for determining the best course of therapy.

Are you involved in any collaboration in Singapore?

Hartwell: Yes, I am involved in three major collaborations. One is in the biomarker area — a group led by David Lane at the Institute of Molecular and Cell Biology participates in our Biomarker Consortium. John Potter, head of our clinical science group, has been active in organising large-population cohort studies, in which several groups in Singapore participate. Third, we engage in collaborative research involving bone-marrow transplantation, in particular a new technique developed at the Hutchinson Center called the mini-transplant, with John Wong, head of National University of Singapore's Yong Loo Lin School of Medicine.

The mini-transplant is a relatively new procedure that eliminates the need for high doses of radiation and chemotherapy and instead relies on the cancer-fighting properties of donor immune cells. Clinical trials around the world use this method for different diseases, mostly leukaemia and lymphomas, but the technique likely will have many applications in autoimmune disease and potentially solid-tumor cancers as well.

Do any areas of research in Singapore particularly impress you?

Hartwell: At the moment, I am impressed with Singapore's growth and enthusiasm to become a world centre for biomedical research. I find its highly organised efforts impressive. Many US medical-research centres have grown up mainly by happenstance whereas Singapore has looked at the playing field and made a plan. In the last five years, the country has built up the basic sciences and over the next five years, it will build up clinical and translational research science.

On which area of research do you think Singapore should focus?

Hartwell: I am not in a position to say what is best for Singapore. It depends so much on the individuals that come here, the programmes they develop, and the interaction among them. Many opportunities certainly exist in such collaboration.

The main thing involves taking the long-term view and training local people. These kinds of strong programmes have attracted international senior people who provide leadership and security and who invest in training young people.

What new methods can researchers use to catalyse molecular diagnostics research?

Hartwell: One of the main bottlenecks in biomarker discovery work has been the lack of a cost-efficient method to validate promising markers. ELISA, or the Enzyme-Linked ImmunoSorbent Assay, now stands as the only existing method sensitive enough to measure proteins in low concentration; however, it costs a lot (US$1 million per protein). The past year has seen a breakthrough in the use of the mass spectrometer to develop very sensitive and specific assays. I think that will move the field of molecular diagnostics forward very rapidly.

Do you see a multidisciplinary approach as the best way to proceed?

Hartwell: It depends very much on what problems you try to solve. For basic insight into biology and discovering new mechanisms, the individual laboratory should still be left to its own devices because no one can predict where things will go. Trying to direct basic science just does not work.

As soon as you get into any area of applied research like clinical research and biomarker discovery, then the problems become very big. You require lots of expertise that can become multidisciplinary and international. No one institution by itself can solve problems of that magnitude. Take for example the Human Genome Project — it took a lot of people and resources.

Does any geography-based census that looks at cancer exist?

Hartwell: A lot of research and data collection has been done in this area. Cancer incidence clearly varies enormously according to geography. For almost every cancer, you will find countries that have a high incidence and a low incidence separated by a factor of 10. The question becomes whether disease arises from ethnic diversity, lifestyle, or exposure. We have not really answered that question thoroughly. Cases that we know of are often environmentally based, not ethnically based. For example, there is a great deal of geographic variation with respect to the incidence of infection-associated cancers. Viruses cause such cancers as those of the liver and the cervix, but for other cancers, like breast cancer, we just do not know all the risk factors. Tremendous variations exist, and scientists are looking into whether we can identify environmental risk factors that will lead to prevention or whether we can correlate the result with different genes in different populations.

What do you think the field of cancer research will look like in 10 years?

Hartwell: I think scientists will make new discoveries in terms of understanding basic molecular biology and the genetics of cancer. One ongoing project involves DNA sequencing of a variety of cancers to identify mutations of general importance. The question of how much we will reduce cancer-death rates depends on placing greater emphasis on prevention and diagnosis. In the last century, 100 million people died from smoking-related diseases such as cancer and cardiovascular disorders. In this century, experts estimate that a billion will die from such diseases. We can do a lot of good emphasising smoking prevention.

Are new cancer therapeutics coming online in the next decade?

Hartwell: Estimates put pharmaceutical companies’ investment at about US$20 billion a year to make cancer drugs. Fewer than five come out every year; many of them extend life a few months and cost US$20,000–$40,000 per year of treatment. Nevertheless, I believe some of these will prove useful and have significant impact, such as Gleevec for chronic myelogenous leukaemia and Tamoxifen for breast cancer. An interesting trend is that some of these drugs, like Tamoxifen, actually are useful in preventing tumours.

Do any of these drugs target certain groups of people?

Hartwell: Not necessarily in the sense of groups of people you can predefine before they have cancer, but they do target the types of cancer that arise within a person. Gleevec works on the product of a specific new gene created by mutation in chronic myelogenous leukaemia. It does not work if the patient does not have that mutation. That then is the trend — to develop new drugs aimed at mutations known to occur in cancer.

What incentives do companies need to encourage them to look at cancer detection and prevention?

Hartwell: The main thing we need is better reimbursement or value for diagnostics. Imaging technology is diagnostic: radiologists get paid a lot. The instruments cost a lot as well, so the companies making them are well reimbursed.

On the other hand, molecular diagnostics is undervalued so there is less incentive to invest in this area. The perception that the old model, such as cholesterol monitoring, remains relatively inexpensive means that doctors perform these tests on many people to get reimbursement via volume, but that does not allow investment in discovery and validation. As a result, very few new diagnostic markers have come onto the market, perhaps only one a year is approved by the US Food and Drug Administration.

Moreover, unlike the cholesterol test, cancer will require a whole panel of markers. I imagine in 20 years’ time, you will go into a drug store with a drop of blood to test for something and you will get a read-out on a computer of 10,000 tests looking for all kinds of diseases and health problems. That means you need all those tests on the same plate.

We really get into the problem of intellectual property here. In the current model, if someone finds a marker they think is informative, they patent and license it to some company. It is highly unlikely that they will combine that marker with 100 other markers people want.

This problem has been solved in information technology where making any chip or device for a computer requires thousands of patents. A patent pool exists so that everybody can create. Medicine probably needs a similar strategy.

What do you consider the most significant discoveries in medicine today?

Hartwell: I think two things in particular in the last few years. One comprises stem cells, their development, and their role in disease. It appears that cancer stem cells drive all cancers.

The other would be the RNA interference (RNAi). A lot of regulatory biology has been happening in this enormously powerful technology, essentially in deactivating genes in cells. We shall see the results within a decade. It allows people to treat mammalian cells as organisms on which you can do genetics. Thus, many pharmaceutical companies try to identify drug targets by inactivating a gene with RNAi, seeing the outcome, and then making a drug out of that protein — or even RNA. It allows one to take human and mammalian cells and perform very rapid multiple genetic tests simultaneously.

What role does serendipity play in research?

Hartwell: Absolutely a major part. Big breakthroughs usually come by accident. I was very interested in cell division, and my team was using mutants of yeast to study this process in a whole variety of ways. It took three years, however, before we made the breakthrough to the best method to study the genes that control cell division.

It happened that I gave an undergraduate in my lab a crazy project; he was taking photographs of cells during microscopy. As soon we looked at the photos, we realised that this was the way to look at cell division. Human cells get bigger and bigger and they divide, but a yeast cell forms a little bud on the surface and the size of the bud tells where the cell falls in the cell-division cycle. By looking at individual cells using photomicroscopy, we obtained a lot of information. We had actually to see it before we realised the significance.

What challenges does biomedical research offer a scientist?

Hartwell: Two fundamental things: one, recognising the enormous complexity of biology. Three billion years of natural selection by trial-and-error created great complexity. Cells make tens of thousands of proteins that interact in myriads of ways.

The second arises from applied medicine: the biggest challenge lies in individual human diversity, which makes it hard to find things generally true. We do our discoveries with organisms genetically the same, even mice, which are inbred. What you see in one mouse will apply to another. This is not true in humans, however, so it is hard to arrive at a conclusion.

For example, the healthfulness of the things we commonly believe in such as diet, exercise, and the like are not well established because we do not have the data. The Women's Health Initiative in the US did a study to try to answer the question of whether changes in the amount of dietary fat consumed affects the incidence of breast cancer. The million-dollar study ended up with inconclusive results despite the involvement of hundreds of thousands of people because the differences remained statistically small. Trying to answer rigorous questions about human biology provided a difficult challenge.

What qualities should a researcher possess to do good work?

Hartwell: Obsession. To create new things, people have to trust their own ideas even when everyone else thinks them crazy. Then they have to obsess over the ideas and work at them until they bring them to reality. I see this quality most in creative scientists.

In my case, we learned some fundamental things about cancer by using genetics. We wanted to understand some aspects of cell division, and we used yeast since we could not do the work with mammalian cells, a so-called crazy idea. People today understand that all biology is fundamentally the same. Whatever organism you want to study is going to teach you about humans — this is a given. Only now that we have the human genome and sequences can we understand the amount of change taking place in genes even over a billion years, and the divergence among different animals actually remains relatively small.

What advice would you offer young people entering research?

Hartwell: Biology provides the most exciting intellectual endeavour to learn about life, and there is much to be gained from not focusing our efforts simply on the potential applied outcomes of the research. The intellectual reward of learning more about life should drive the study. If that information eventually becomes useful and applies to other things, then that is wonderful.

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