massive for research too?

LONDON "Scientifically it's a fantastic achievement. In terms of what we will know about what it takes to become an intracellular pathogen, it's the biggest achievement for decades," said Jo Colston, Head of Mycobacterial Research at the UK's National Institute for Medical Research, in response to the publication of the genome of Mycobacterium leprae in 22 February Nature.But at the end of 1999, the World Health Organisation (WHO) extended its deadline for the "elimination" of leprosy — meaning a reduction in the number of known cases to 1 in 10,000 within affected communities — from 2000 to 2005. The original deadline had been set in 1991 and a decade of 'elimination' strategies has led to a collapse in research funding for the disease. The European Commission, for example, awarded its last grant for leprosy research five years ago. Most mycobacterial researchers have sensibly moved over to studying tuberculosis.This would be fine if leprosy were really vanishing, but "the prevalence of leprosy is the number of people on register, and it's easily manipulated by reducing the length of treatment," Paul Saunderson, a consultant for American Leprosy Missions who spent 10 years on research with patients in Ethiopia, said this week. Treatment times for leprosy shortened dramatically with the introduction of multidrug therapy (MDT), which replaced the single drug dapsone at the end of the1980s. "What most people nowadays feel is the important figure is the case detection rate, which is related to incidence, which is actually very static," said Saunderson. Barry Bloom, Dean of Harvard Medical School and long-time researcher on leprosy, told BioMed Central "We could still use a drug that kills persistent organisms, but the problem is that infection is probably transmitted before people know they have it or seek treatment." Bloom would like to see progress toward a vaccine, which knowing the genome sequence could advance. "A vaccine would protect contacts and family members, as drugs appear not to be reducing incidence rates," he said.From 1985 to 1999 leprosy prevalence in the 32 most affected countries fell from 21 per 10,000 per year to just under 3 per 10,000, but case detection has hovered around 3 per 10,000 throughout the same period. "Despite the euphoria about decreasing prevalence and the elimination goal, there's actually disappointment that MDT doesn't seem to have stopped transmission," said Saunderson. "WHO still hopes that transmission is being stopped by early treatment but in most programmes where there's a lot of leprosy there are still a lot of children developing the disease, which implies they are still exposed, even though MDT has had good coverage.""It seems quite likely that people are infectious before clinical manifestations — like AIDS. It may be that people are infectious for quite a long time, two to three years, so maybe MDT is coming in after they've infected many of their contacts," Saunderson suggests. "The elimination goal has had some successes — the widespread use and political commitment to MDT. But it is probably slightly misleading us as to what is really happening with leprosy."So is what WHO calls its "final push" towards the 2005 deadline realistic? "Many people feel there does need to be a new breakthrough on research before we can do that final job of stopping transmission. Many of us don't like this term the 'final push', as that's compounding the mistake of talking about elimination," Saunderson said. He thus welcomes the sequencing of the leprosy genome, if it can give a new impetus to leprosy research.Etienne de Clercq, Chairman of the Medical-Social Commission of the International Federation of Anti Leprosy Associations, agrees: "With the elimination strategy, it was more or less felt that we had all the tools in hand, if not to get rid of leprosy, then really to control it. There was some feeling in the leprosy world that basic scientific research would be less and less necessary. So we saw a decrease in the number of scientific papers in leprosy. But over the past two years more and more people have become aware of the apparent limitations of MDT, and believe it is important to re-stimulate leprosy research."And the sequencing of the genome of Mycobacterium leprae has, indeed, caught the attention of mycobacterial scientists. M. leprae doubles so slowly that it takes up to a year to culture — in the nine-banded Armadillo or the footpads of mice because it can't be grown in tissue culture. Michael Glickman, a TB researcher at Albert Einstein College of Medicine in New York, said "One of the first goals of genome analysis is to derive conditions which will allow the organism to be grown in tissue culture.""This genome tells us what it takes to grow inside a cell — and that's basically all M. leprae does, you can't grow it in vitro," said Jo Colston. "So basically it seems to have got rid of everything it doesn't need. Which leads to interest in how it could have evolved.""It's also very important for research on TB. The interesting thing about the M. tuberculosis genome is exactly the opposite of M. leprae — it does much more than we anticipated it would be able to do." For example after the sequence of the M. tuberculosis genome became available 18 months ago "we found it had genes that would enable it to grow in an anaerobic environment… Now, by comparing it to the leprosy genome, we can say, this is all TB would need to do the basics, and it's got all this other stuff to enable it to be TB.""And as for leprosy itself, one thing that is unique to the disease is that it invades nerves — Schwann cells — so it has some unique capacity, and maybe the genome will show what that is" said Colston.Stewart Cole of the Institut Pasteur in Paris, the leader of the M. leprae sequencing project, said other obligate intracellular pathogens had been sequenced, including Rickettsia and Chlamydia, but neither showed gene decay on the same scale. "Probably about 25% of the genome of the typhus agent [epidemic typhus is caused by Rickettsia pronazekii] is dead, but the sequencers were unable really to prove that. They couldn't identify any genes in there, but at the same time they couldn't identify any pseudogenes. Whereas we had the TB sequence to compare with." This showed a multitude of TB genes in M. leprae that are unused — Cole concludes that genome decay in Rickettsia is not on anything like the same scale as M. leprae.Already, "the leprosy sequence has enabled us to do two things," Cole said. "One is, we've been able to identify genes that look like they're specific to M. leprae, at least for the present. We will try and produce the proteins for some of those… and see if they are recognized by the immune system. If they are, we'll look at whether they can be used as diagnostic antigens for improving diagnosis in paucibacillary patients… And there is a group of 200 or so proteins that seem to be confined to M. tuberculosis and M. leprae, so these genes could be responsible for highly specific functions associated with pathogenic mycobacteria, and would be potential drug targets. The main interest here would be for TB."So what use can the leprosy genome be for leprosy itself? According to Paul Nunn, Disease Coordinator for Tuberculosis and Leprosy at the WHO-based Special Programme for Research and Training in Tropical Diseases (TDR), "The contrasts between leprosy and TB are very revealing. In TB we have a clear-cut test of disease — the sputum smear. Now there may be all kinds of problems with it, but nevertheless if you've got a positive smear you've got infectious TB. So there's a clear-cut, specific if not very sensitive test for disease. Second, we have a test for infection, the tuberculin skin test, which may not be 100% reliable, but it's quite good enough for most purposes." But in leprosy all there is a clinical observation, of lightened, insensitive skin patches. "And therefore vastly more is known about the epidemiology of TB than is known about the epidemiology of leprosy."Given the controversy over the high incidence rates and possible early transmission of leprosy, as outlined by Saunderson, a key aim will therefore be to develop a specific and sensitive molecular diagnostic test. And TDR will be putting a lot of its money in that basket."One approach that's being taken is to select out sequences of 10–15 peptides that might be useful, get a selection of hopefully unique peptides and put them together, and by using a soup of these get a test that's both specific and sensitive," said Nunn. "This is already being done in one or two places, but with the genome it's going to be very much more efficient to do so."How long would it take? "This is a complete guess, but I'd say at least 3–4 years." And how much would it cost? " Well we're talking in the region of $1–2 million." And what's TDR giving? "It depends on what we receive, but we're hoping for around $1 million a year for this."Vijay Pannikar, manager of TDR's Steering Committee on the Chemotherapy of Leprosy hopes the genome can be used to look at resistance to rifampicin, one of the main components of MDT. "This is something we are a bit worried about. We've been using MDT for the last 15 years, and cured more than 10 million patients with that. And the main drug is still rifampicin. It is likely that eventually a resistant strain will emerge. And we want to keep a watch on it. But the current methods are too slow… the mouse footpad takes about a year to get a result. But I believe with the genome information we can do it within a few days.But the great problem is not reaching everyone with MDT, Pannikar believes. "Still in Africa there are large areas where patients are undetected; and in our opinion the delay between onset of the disease and detection is still about three years, which we need to close.""Globally we should reach 1 in 10,000 prevalence before 2005," Pannikar believes. "But still some countries will be left out, and within other countries there may be some areas totally left out. For example: Angola — most of the country is inaccessible; the Democratic Republic of the Congo; Brazil is a large country, and huge areas like Amazonas with only 2 million people — there's a problem of accessibility; Madagascar." "And in India the problem is very big. There are 35 states in India, and it's only in 12 states that leprosy is really endemic, but these 12 cover 90% of the problem."The leprosy genome project was launched with initial funding from the Victor Heiser Trust of the New York Community Trust for research and training in leprosy and tuberculosis, while Barry Bloom was chair of the Scientific Advisory Committee. "They agreed to invade their capital [against their rules] to allow this project to get funded. The Trust people were heroic and really trusted the scientists to use their relatively small funds wisely. They are heroes," Bloom said.

massive for research too?

. The decay of its genome mirrors an unfortunate collapse in interest in leprosy research, while disease incidence stays stubbornly high.

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