How DNA microarrays and expression profiling will affect clinical practice

In Plato's cave the participants are surrounded by shadows that allow them to see reality by careful examination. Similarly, we doctors at the end of the 20th century have found many indirect tests that allow us to follow what is happening in our patients' bodies and cells. We have learnt to cope with the fact that we cannot find drugs unless we pull proteins from those cells and develop inhibitors against them in the artificial context of a test tube. Imagine now a different world in which it would be possible simultaneously to follow many changes that were happening in cells. Imagine a doctor's office where you could take a blood sample from a patient and get an indication of where that patient's heart disease, kidney disease, and depression were plotted in a matrix, allowing us, as doctors, to see both the patient's relative state of health and any predisposition for other conditions or disorders.

Some of the most exciting developments in the field of diagnostics and therapeutics are occurring in the adjacent fields of genomics and bioinformatics. By now we have become accustomed to the impact that transistors and computer software have had in our lives, but we should be prepared for the revolution on the horizon with regard to monitoring patients and the drugs they may be able to take. At the root of this revolution is the ability we now have to know by name all of the genes that make up our cells. This is important because by knowing their sequence we can develop technologies that allow us to follow the changes in each one of these genes as cells are modified in health and disease.

Summary points

• Gene expression can be followed by DNA microarrays

• Gene expression provides a robust snapshot of what has occurred in a cell

• Expression profiles will improve diagnostics

• Future uses of DNA microarrays will allow drugs and drug regimens to be personalised

• Doctors will be offering gene expression profiles to some patients in the next three years

Pattern matching as a diagnostic tool

In the past five years researchers have found that they can stick DNA to glass and record the level of gene expression in human cells. As we begin to know the tens of thousands of genes that exist in our cells we are becoming able to develop detailed monitors of what is going on in cells. DNA microarrays have been used to study changes in plants and yeast and to analyse many different types of human cells.¹,² Researchers who have recognised the power of this detailed information have begun to take snapshots of cells under a variety of conditions such as tissues during development, different tumour cells, and cells exposed to drugs.^3–5 We are only now beginning to understand the importance that these snapshots may have in monitoring patients' responses to therapeutic interventions and improving efficiencies of drug discovery. Doctors working with mathematicians and physicists have recognised that the capabilities that allow one's ear to tell the difference between a spoon hitting a glass and a bell ringing are sophisticated ways in which we in everyday life do pattern matching. Researchers have recognised that much less sophisticated pattern matching which can be done by computers is still powerful enough to be able to help compare the complex patterns that come back from such microarrays.

Comprehensive target profiling

Over the next few years, as large databases are built that contain the profiles of cells under different conditions, it will become possible to build up objective measurements of various disease states. These techniques are likely to help pinpoint patients who have recently had acute health crises, such as heart attacks and strokes, and monitor how long ago and how severe these were. The profiles provided by such DNA microarrays may have a greater impact on health as a result of the benefits that drug discoverers could gain by having clear indications of which drugs may have side effects or interact with other drugs. It has already been shown that it is possible to treat cells with compounds and compare the resulting patterns of gene expression with patterns previously obtained when treating cells in known ways, thereby identifying which proteins or targets the compound is altering. Such in vitro target identification should greatly improve the inefficient methods by which we currently develop drugs. Because animal testing of compounds is expensive, time consuming, and has other negative aspects, DNA microarrays are likely to improve the efficiency of drug discovery by supplementing the information obtained by traditional animal testing.

The use of DNA microarrays is still in its infancy. In the next three to five years, however, the direct impact of these DNA microarrays is likely to enter the doctor's office as some of the harder diagnostic puzzles may be solved using this technology. As with the steam engine—which started out being used for very specific stationary jobs and ended up leading to the combustion engine that fuels most of our modes of transport—there is little doubt that DNA microarrays will come to be used in many diverse applications and will enter more and more parts of clinical practice.

Competing interests: None declared.

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ROSETTA INPHARMATICS

Microarray

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MARTIN HASWELL

New forms of diagnosis will become possible