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WHO Goodwill Ambassador's Newsletter For The Elimination Of Leprosy

INTERVIEW: Leprosy under the Microscope

When a basic scientist discusses leprosy, he tells it like it is - especially Koichi Suzuki.

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M. leprae bacilli taken from female chimpanzee, Haruna

Dr. Koichi Suzuki works at the Leprosy Research Center at Japan's National Institute of Infectious Diseases, where he is chief of the laboratory of molecular diagnostics in the department of mycobacteriology. He is a basic scientist, a civil servant and he is also disarmingly frank.

How long have you worked in leprosy?

I joined the research center around 10 years ago. Until then I wasn't directly involved in leprosy research, although I had an interest in leprosy. I was working in immunology and other fields.

What got you interested in the disease?

Seeing a cluster of M. leprae bacteria under the microscope and thinking, "Can these tiny organisms really be responsible for such a terrible disease? Maybe there's something I can do." Also, I was curious how one type of bacteria could induce such a variety of clinical manifestations of leprosy.

What did you bring to the field of leprosy research?

Since I had a background in molecular biology, I felt that if we introduced the newest molecular biology techniques we might make some progress. The problem is it's not possible to culture M. leprae in vitro. That means you can't genetically modify it, which means you can't use the latest techniques. It makes progress difficult.

How far has our knowledge come?

We know the genome sequence of M. leprae, but have yet to confirm the function of individual genes biologically, for the reason I've just given. We know the major components - the proteins, the cell wall lipids. But we still know very little about what role the genes perform, what other minor components there are and how important they are.

Why can't M. leprae be cultured?

Because M. leprae has such a small number of genes - about half the genes of M. tuberculosis, which it resembles - it is not able to survive on its own and thus has a high dependency on its host. But just what factors are needed for its survival we don't yet know.

The transmission route of leprosy has yet to be determined. True?

We have yet to discover a means of demonstrating the transmission route. Infection occurs quite some time - years, in fact - before the onset of disease, yet we have no means of demonstrating how and when. Nor are there any good laboratory animals for this purpose. With leprosy, it is generally believed that infection occurs in infancy, through the respiratory organs, as with TB. However, it's possible that a baby being cared for by someone with lesions might be infected when bacilli from the lesions enter its body through the chaffed skin of the baby's hands.

Why do some people get infected, and others not?

Like all other infectious diseases, it largely depends on their immune system, their nutrition level, their overall physical condition at the time. Another factor is genetic predisposition. For more and more diseases, we are finding the responsible gene. Where leprosy is concerned, based on genetic background, there will be people who are easily susceptible to infection when exposed, and those who are not. That said, I doubt the existence of a "leprosy susceptibility gene". The bigger factor is how many bacilli are involved and how many repeated chances they have to infect. A single exposure to many bacilli could lead to infection; on the other hand, a very small amount of bacilli entering the body daily probably would not, as the immune system would be able to cope.

It can be years after infection before someone develops the disease. What triggers its onset?

As I mentioned earlier with regard to infection, there are a couple of factors: one is genetic, which can't be helped; the other is changes in one's physical state that create conditions favorable for the bacteria to multiply. We don't yet know why someone would develop leprosy 20 or 30 years after being infected, but there must be a number of factors that disturb the immune system. This is true not just of infectious diseases, but of autoimmune diseases and diseases such as cancer as well. Over the years, a lot of things enter the body that are bad for it. That's why the possibility of developing cancer increases the older we get. On the other hand, it also implies that a person won't necessarily develop a disease by the end of life, even with these factors and infectious agents.

What do researchers find interesting about M. leprae?

M. leprae has a very distinctive genetic makeup. The number of genes is very small; however, the number of pseudogenes - genes thought no longer to have a function - is extremely large. Normally these non-functioning genes are eliminated from DNA; but in M. leprae a lot of them remain. They account for nearly half of the M. leprae DNA, the highest among all known bacteria. Gene researchers want to know why these pseudogenes stick around and don't get eliminated. There is an interesting possibility that they have some other function.

Another point of interest is that M. leprae lives inside the host's macrophage. The macrophage is the immune reaction's director of operations; its job is to ingest bacteria and to launch an immune reaction. Yet M. leprae survives and multiplies in its enemy's command center. It tricks the immune cells into doing nothing. It's an extremely adroit mechanism.

M. leprae tricks the immune cells into doing nothing. It's an extremely adroit mechanism.

If you could understand how this mechanism worked, what could you do?

M. leprae is a typical intracellular pathogen that parasitizes in the host macrophage. If we could understand this parasitization mechanism, we would be able to design or at least seek a new treatment. It might also be possible to develop a drug delivery system that mimics M. leprae parasitization, enabling us to insert a drug that would kill the bacilli before the disease develops. We'd like to steal the mechanism and use it against M. leprae.

Do you think it will be possible to eradicate leprosy some day?

I think that once the number of people with leprosy falls to a certain level, then the number will keep falling. Children have a chance of being infected in high endemic pockets, but even there, should case numbers decline, they will keep on declining. On that basis, the disease will eventually disappear. If you think about it from M. leprae's point of view, unless it is transmitted to many different hosts, it's not going to survive. But it will take time. We must also pay attention to possible natural reservoirs of M. leprae, such as other primates and wild armadillos.

Are we going to see a leprosy vaccine?

As a scientist, I understand that creating a leprosy vaccine or brand new drugs or diagnostic tools are interesting research subjects to get funding for and to publish preliminary reports on. But in reality, it would be difficult to test a leprosy vaccine in clinical trials because of the very long incubation period of the disease and because of the geographical location of endemic areas and of people affected. Also, we do not have any animal models to run a phase 1 study. Although such basic science is important from a scientific viewpoint, when I consider the current situation, I am not sure whether it is a good idea to allocate large amounts of funding and human resources for vaccine research. Continuing the current efforts of the leprosy program may be the most cost-effective strategy to make use of limited resources.

What about a faster treatment regimen?

One of the concerns is lepra reaction. Reaction occurs when the bacilli are killed, flooding the system with broken-down components. In response, a strong immune reaction takes place. If we want a treatment with no reaction, then maybe we should use a drug regimen that is actually a little less strong than MDT, and kill the bacteria slowly over three to five years, for example. That way, there may be no reaction. But the length of treatment must be balanced against such considerations as the quality of life.

Are there any areas you would like to see more emphasis on?

Treating everyone with MDT who needs it, when they need it, is very important and must continue. But I think we ought to be doing more for people after the infectious disease has been treated. I would like to see more emphasis on helping people with disability. Compared to the ongoing strategy for regisering patients and treating them with MDT, I feel that care for the disabled is less organized and less scientific, and relies largely on the efforst of individual caregivers. I think we could adopt a more scientific strategy to help them - for example, by providing guidelines for making a certain type of sandal for people who have a particular problem with their toes. I understand this kind of order-made medicine is not easy to supply, but I feel our efforts should shift to that direction in the future.

Will developments in regenerative medicine help people affected by leprosy?

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Scientists at work in Dr. Suzuki's lab

Regenerative medicine is making a lot of progress. In the past, it was accepted that neurons don't regenerate. Yet data is now emerging that they do. A lot of big names are working on this; it's state-of-the-art medicine. It's also one of the most expensive areas of research. Since most people who would benefit from its applications are in developing countries, however, it may be some time before the fruits of this research reaches them.

Would you advise young researchers to go into leprosy?

If they are clinicians looking at patients, and want to go overseas as part of international cooperation, that is one thing; but as a basic scientist, who thinks M. leprae is interesting and wants to study it, I have to say it will be difficult for them to find a place to do this and attract funding. To focus only on leprosy as a career would be a risk. That said, academic science must have freedom, and I hope that creative young talents challenge whatever interests them. But if I really had their interests at heart, I would have to point out that in the scientific world, it is only research published in the best publications that is evaluated highly. From that point of view, I am not sure that leprosy research is a promising field for everyone to study. Nevertheless, I hope that basic research for leprosy can be sustained by creating research facilities supported by grants and other resources.

Does leprosy research have wider implications?

I like to think that the results of the research we are doing now, when looked at from a long-term perspective in a global context, will have applications in other medical and biological fields. Similarly, a breakthrough in a different field could lead to a big advance in leprosy medicine. But if people aren't still researching leprosy in 10 or 20 years' time, then we won't be able to take advantage of these breakthroughs. We need at least one center of excellence in leprosy research in the world to continue basic research. But it shouldn't be for leprosy alone. Ideally, it would cover four or five different areas of research, to act as a stimulus.

You spend a lot of time looking at M. leprae. What are your feelings toward it?

You will often hear researchers say, "I really like my bacterium! It's the cutest of all!" I find M. leprae fascinating. Over time, as is the case with other bacteriologists and their bacteria, I have come to like M. leprae more and more. I view it not so much as an opponent, but more as a rival with whom I'm engaged in a good conversation. "Better watch out," I'll say. "One day I'll get the better of you."

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PROFILE: Dr. Koichi Suzuki

Dr. Suzuki is Chief, Laboratory of Molecular Diagnostics, Department of Mycobacteriology, Leprosy Research Center, National Institute of Infectious Diseases, Japan