Curing diseases modern medicine has left behind

THEY say it is like having boiling metal injected into your veins. Melarsoprol, the only available treatment for advanced African sleeping sickness, is a toxic mixture injected intravenously every few days for four weeks. Developed in 1941, it is an arsenic compound dissolved in polyethylene glycol, and has long been known by those who administer it as “arsenic in antifreeze”. As well as being agonising, the drug scars veins and can cause blood vessels to collapse. Without melarsoprol, sleeping sickness is fatal, yet the treatment itself kills 1 in 20.

It’s a familiar tale of woe. Almost all tropical diseases, from malaria to Leishmaniasis, are neglected by modern medicine. “It’s extremely depressing,” says Michael Ferguson, molecular biologist at the University of Dundee in the UK. “The sad situation is that the introduction of new treatments for tropical diseases is incredibly slow because the pharmaceutical industry isn’t looking for them.”But now, small teams led by Ferguson and a few other groups of like-minded academics around the world are making a determined effort to find a way round the impasse. By bringing together a variety of disciplines and adapting commercial methods, they hope to come up with a set of safe and effective modern medicines designed to save the lives of the world’s poorest people. “No one’s done it before,” says Ferguson, “Our goal is to come up with drugs that are significantly safer, more selective and more efficacious.”It is not going to be easy. Creating new drugs is notoriously expensive and time-consuming and, with tropical diseases, the financial incentive isn’t there for big drug companies who stand no chance of recouping their investment. It can take up to 10 years to develop a new treatment from initial research to clinical trials and final approval. And it certainly doesn’t come cheap. A team led by Joseph DiMasi at the Tufts Center for the Study of Drug Development in Boston estimated last year that the average cost of bringing a new drug to market was $802 million (Journal of Health Economics, vol 22, p 151).Whereas the average healthcare budget per person per year in the US is approximately $4000, in sub-Saharan Africa it is less than $20 per person per year, dropping to practically nothing in some rural areas. Small wonder then that most western drug companies concentrate their efforts on producing big-earning drugs for impotence, obesity, Alzheimer’s and the like. Meanwhile the World Health Organisation (WHO) estimates that 1 million people worldwide die each year from malaria, while safe and effective treatments remain as elusive as ever.This failure to deliver decent treatments to the world’s poorest people is all the more frustrating because there is no shortage of basic research on tropical diseases and the parasites that carry them. Teams have discovered dozens of chinks in the parasites’ molecular armour that could be targeted with drugs. And at the other end of the drug development spectrum, bodies such as the World Health Organization and the World Bank are ready and waiting to fund clinical trials for promising new drugs.Between these two extremes lies a yawning gap: finding drugs that hit the target and working them up to the point where they can enter clinical trials. Until now, no one has come up with a way of bridging that gap in the drug pipeline. This is where Ferguson and others like him come in.Ferguson is in the process of setting up a new Centre for Interdisciplinary Research at his university. Due to open later this year, it will focus on diseases caused by insect-transmitted protozoan parasites such as those that cause sleeping sickness, Chagas disease and Leishmaniasis. His aim is to develop the candidate drugs that show the most promise in lab and animal tests, which can go forward to clinical trials. To find these leads, Ferguson has borrowed a technique more usually employed by multinational drug companies: high-throughput compound screening, or HTS.After buying a commercial library of compounds and a robotic screening system, Ferguson can test 100,000 compounds against a chosen target. If, for example, he finds a protein that helps the parasite survive or infect its host, they will be able to search for a chemical to stop the protein in its tracks.HTS has one major advantage over other drug development methods. The library of compounds will include some 2500 licensed drugs. So an existing drug might do the trick except that no one has thought of using it for this particular disease before. “If we get a fantastic hit from one of these compounds, it could prove a short-circuit to a treatment,” says Ferguson. One example is eflornithine, an effective drug against sleeping sickness that was originally designed as an anticancer drug. Aventis, the company that discovered it, gave some $25 million to a WHO programme to help combat the disease, but so far the distribution of eflornithine has been confined to trial areas.Dundee is one of just three academic centres in the world bringing industrial technologies to bear on neglected tropical diseases – similar projects are being developed at the Walter and Eliza Hall Institute (WEHI) in Melbourne, Australia, and at Harvard University.In Melbourne the screening robots were switched on last year with some ambitious targets: “We’ve got two screening projects to develop lead compounds which we plan to complete within 12 months,” says Ian Street, who leads the drug screening team. He has developed a network of collaborators, among them Bill Charman, a professor of pharmacology at Monash University.If one of the centres succeeds in producing a promising lead compound, they would likely work with the WHO on further development and eventually animal and human trials. But even then, there is no guarantee any will make it to the clinic. “We shouldn’t underestimate the challenge facing these centres,” warns Robert Ridley, head of the Tropical Disease Research Programme (TDR) at the WHO. “Over the last 30 years the number of new classes of compound that became drugs is quite small.”This sort of technology is not cheap; the HTS system alone costs some $2 million to set up. Whereas the WEHI project is largely government-backed, Ferguson is relying on charities and research councils, but he reckons he’s done his sums: “We’re smaller, we’re cheaper and we don’t have to pay any marketing people.” He plans to operate on a budget of just $10 to $20 million over a five-year period, with a view to coming up with up to two potential drugs.Because these projects don’t fit within the traditional academic framework, getting the money together hasn’t been easy. “It can be like fighting with one hand tied behind your back,” says Alan Fairlamb, Wellcome principal research fellow at Dundee, “In order to obtain funding you need to get research published in high-quality journals; drug discovery doesn’t work like that.”As for the drug companies, Fairlamb believes they still have a place. Most of the bigger ones already put resources, albeit limited ones, into treatments for malaria and TB. And smaller generic drug companies, particularly in Asia, are in a good position to manufacture tropical medicines. “If we can offer the industry high quality leads for development, they will be under pressure to take them on.” Ferguson is more cynical: “It depends on how [the drug companies] are feeling about PR at the time.” Nevertheless, even small successes will be an improvement on existing treatments. For African sleeping sickness, that could mean an end to arsenic in antifreeze.(Source: From issue 2482 of New Scientist magazine, 15 January 2005)