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INSERM Transcriptome Platform Nantes Head Jean Lger on Myochips

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At A Glance

Name: Jean Léger

Title: Centre National de la Recherche Scientifique; Transcriptome Platform Nantes; Senior Research Scientist

Background: PhD, Nuclear Physics from Swiss Polytechnic School of Technology in Z rich, Switzerland — 1965; PhD in Biochemistry from Orsay in France — 1971

Age: 63

Jean Léger was appointed to a research fellowship at the Centre National à la Recherche Scientifique in 1972, where he joined a laboratory of the French National Institute of Health headed by P-Y. Hatt and B. Swynghedauw. Léger’s work focuses on understanding the molecular and functional bases of normal and pathological striated muscles using biochemical, immunological and genetic approaches. For 20 years, his laboratory at the Faculty of Pharmacy in Montpellier produced monoclonal antibodies to identify and chart different sarcomeric components, such as myosin subunits and dystrophin in diseased human skeletal and cardiac muscles.

Léger is currently in charge of a scientific team at the Faculty of Medicine and INSERM U533 dedicated to functional genomics in neuromuscular and cardiovascular diseases. He heads a regional technical platform for transcriptomal studies using custom DNA chips.

You spoke on the first day of the conference about muscle dedicated chips. What was the core of your lecture?

I tried to show it was possible, using muscle-dedicated chips — genes preferentially expressed in heart — to isolate biomarkers in heart failure. I think the big difference with many people is to say that pan-genomics is not necessary, when you consider specialized cells, like cardiac cells.

What method did you use to narrow down your choice of genes to study?

It was long work lasting a few years. We selected the genes using subtractive methods, comparing normal heart tissue with diseased tissue. With that you probably have interesting diffentially expressed genes and genes expressed in the corresponding tissue.

Afterwards, when you have the gene collections, you apply that onto chips and take different patients with heart failure — you take explanted heart from people who received a transplantation because of acute heart failure — we analyze the gene expression in different patients. We have done that recently in 47 different patients. Using statistical analytic methods, we can detect those genes with expression higher than biological noise. With that, we analyzed roughly 7,000 genes. It finished with roughly 70 to 90 genes of interest. One percent of the genes were really significant [of heart-specific genes].

What is the next step relating to the chips?

We have made chips with the 7,000 genes. We now have to establish if these 70 to 90 genes are really biomarkers in many different situations, and afterwards we have techniques in which we will use them.

Afterwards, we will see if the corresponding proteins are dysregulated or not, during the onset of heart failure. One of our objectives is to anticipate that.

Heart is really difficult to work on, because you have no access to the tissue. Either you have explanted material or endocardial biopsies — very small amounts of tissues that are very difficult to control. In the future, if these markers found in heart tissue are interesting, we have to look to see if these markers are present in blood.

And predict heart failure?

In a way. One of the main reasons to do this job is to understand how it occurs, and we hope that one day it will have application. But we must not say that. I am sure that from [the research] we will learn something.

That is one of the challenges today — our clinician colleagues will try to force us to try to apply genomics to their work. But I think there is still a gap.

How large is the field for the genomics of cardiovascular disease?

As I showed in my talk, I think the two epidemics in cardiovascular disease are heart failure and atrial fibrilations — both concern about one million hospitalized people in the United States per year. To detect the early signs of that will help, because there are existing drugs that can be applied to that to slow onset.

Around 20 researchers are working on this. There are people that are clinicians, some are biochemists, and some are bioinformaticians — that is a must, that is a key word of this new functional genomics. You need to do intensive data mining and use databases in connection with statistical techniques for this deluge of data.

What is your background?

It is very complicated. I was a nuclear physicist at the beginning. I have two PhDs, one in nuclear physics and one in natural science.

It was a long way. I started in nuclear physics, in mechanics, and I wanted to move because rapidly I saw that I was not interested in this complicated physics, so I moved to biology.

I have been working for the last 30 to 35 years on muscle disease — striated muscle disease — there are two parts to my laboratory, one part works on cardiac diseases and the other works on muscle diseases — dystrophies. I am a specialist on two molecules, myosin and dystrophin. Dystrophin is one of the main molecules involved in Duchenes muscular dystrophy, it was discovered 10 to 15 years ago. I was involved in that with other people.

In your estimation, are muscle chips widely useful in your field?

Yes. We made what we call myochips or cardiochips — they’re the same because they are both similar striated muscle — but at that time most of the [commercial manufacturers] are really hesitant to do that because they believe that the market for these chips is not large enough, but I think they made a mistake. Not because of the market, but because of science. They are able to put 35 to 40 thousand different genes on the same chips, but they put them only once.

In science, when you make only one measure of something, you have only one chance out of two to make a mistake, so you have to have replicates and so on. I think it’s a big mistake.

We make [the chips] in our lab with two robots from Amersham.

Have companies shown interest in your chips?

Today several scientists are trying to select interesting genes, but when the gene is selected and we publish our selection, in the next few years these [manufacturers] will take over the job for us.

The industry quality is not the same as academy quality. We try to do our best, but we don’t have the amount of money and possibility as industry, but in terms of science it is sufficient.

There is a small starting company in France that we are interested in, but for years I have been in contact with different companies — essentially American — but most of the American companies like to work only with Americans. They speak exchanging information, but to go further is difficult.

Do you expect the chip to come into use by clinicians?

I bet it will not be our chips, but sub-products of our chips, in about five to 10 years. But it will have a much more simple form. Nothing can be too complicated in chip technology. To have correct experimental points, the measurement costs roughly between €300 and €500, and that is too much for current applications.

Drug companies? Are they interested in your laboratory’s work?

Yes, they are interested. I was largely supported by Aventis in cardiovascular [research], but such companies change their strategies very often.

What is in the future?

What we do now is a much more applied program in heart — it’s a follow up of heart transplantations. We have started such a program involving genomics, transcriptomics, but also proteomics approaches.

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