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Opinion

Of mice and men


Immunology needs a major overhaul to remain relevant. It's time for a study of the immune system on a grand scale, something akin to the Human Genome Project.


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Credit: iStockphoto

The immune system is just as important as the cardiovascular or nervous systems. If your immune system goes haywire, you're in deep trouble.

Yet, for many years, it has been a black box. That situation has changed dramatically over the past few decades with enormous progress in basic immunology, but very little of this knowledge is being applied medically. Immunologists still can't define what constitutes a healthy human immune system.

We know a lot about what the system can do and should do, but do not have a test that can yet identify whether it is working correctly. Such a test would be more complicated than, say, a cholesterol test, but it would serve a similar vital function: providing clinicians with an easy-to-understand readout of the health of the patient.

That way, trouble could be spotted early and interventions taken when necessary. Cholesterol tests are a good model because they're proactive. We need a similar, proactive test for immune function that lets physicians and patients know when a big problem lies ahead.

If such a test were developed, it might help reduce the burden of the almost 90 known autoimmune diseases and the 120 known immune deficiency diseases. More recently, immune dysfunction has been found to play a role in big killers such as Alzheimer's disease and atherosclerosis, the inflammation and hardening of the arteries that causes heart disease.

These diseases could be handled better if we had a deeper understanding of how the human immune system works and what goes wrong with it.

Much of the lack of progress in human immunology is due to the tremendous success of inbred mice as a scientific model. As a result, the whole field is severely tilted toward studying mice, with some 80% of articles published in immunology journals involving rodents, not people. Yet the mouse is a poor clinical model.

Sure, the thousands of immunology studies conducted on mice have provided, and continue to provide, major insights into how the mammalian immune system functions. Yet mice aren't people, and the mouse immune system does not accurately mimic our own. More than 65 million years of evolution separate mice and men, a vast divide. Researchers can regularly cure cancer and autoimmunity in mice, but almost none of those cures work in people.

Here's one example: Recently, an antibody developed as a cancer therapy showed outstanding results in laboratory mice, leading to human trials. But after hundreds of millions of dollars and two large human studies, only 14 % of patients showed any benefit. Everyone involved with this therapy had great hopes for it. Dozens of similar examples litter the drug development landscape.

Part of the solution is that some of the money should be funnelled into explicating the differences between human and mouse immunity. Defining this gap would be incredibly valuable. Another part is to begin a Human Immunology Project focussed on defining immunological health, taking some important cues from the Human Genome Project. In the 1970s, human genetics was a limited field with little ability to inform medical care. But after a huge investment in sequencing and cataloguing the human genome, genetics is now at the centre of our search for cures.

A large-scale Human Immune Project could work similar wonders. Such a project would focus the field on people instead of mice. The project would create or ease access to large banks of blood samples from clinical trials. And it would encourage researchers to mine them for critical information on immune function in healthy and ill people.

As a step toward that goal, I've helped organise the Human Immune Monitoring Core at Stanford University. Clinicians running human trials are encouraged to send patient samples to the facility. We also aim to combine data from dozens of such studies to uncover previously unrecognised similarities between diseases.

Immunology has always held the potential to be clinically useful across a broad spectrum of devastating diseases, but it's going to take a serious rethinking of the whole field to achieve that potential.

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Mark Davis is the director of the Institute for Immunity, Transplantation and Infection at Stanford University. This is an edited extract from the Bulletin of the Howard Hughes Medical Institute in Maryland, USA.