Drugs From Worms

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by Barry Shell
Illustration by Aaron Bihari

A surprising discovery

There’s a promising new treatment for psoriasis and eczema being developed. Its active ingredient? A drug discovered by an SFU graduate student as he studied roundworm parasites in soil.

This is a new approach in an area where not many new compounds are in development. Doctors are always looking for better alternatives to cortisone-based skin creams because cortisone tends to thin the skin and cannot be used for long periods of time.

Cases of dermatitis are on the rise. Allergies are up. Asthma is worse than ever. Hay fever, Crohn’s disease, inflammatory bowel disease (IBD), and diabetes are just some of the disorders caused by an overactive human immune system. Forty or 50 years ago only one in 10,000 people were affected by IBD; now it’s more like one in 250. Why?

One explanation is that we’ve become too obsessed with cleanliness – that our immune system needs exposure to dust and dirt when we are young so that our bodies can learn to tolerate all the tiny foreign things that set off our defences. Fifty years ago growing children were exposed to many more environmental irritants than they encounter in today’s sanitized and disinfected culture. But that theory could be wrong. Perhaps new chemicals in the environment are responsible, and our immune systems are overreacting to such stimulants. Nobody knows for sure.

Vancouver-based biologist John Webster has another idea.

Doctors are always looking for better alternatives to cortisone-based skin creams because cortisone tends to thin the skin and cannot be used for long periods of time.

His theory began at SFU in the 1980s when he was a professor of biology studying the classic symbiosis of the soil nematode Heterorhabditis and the bacteria Photorhabdus luminescens. The bacteria are dormant in the nematode, but when the worm enters an insect larva, the bacteria kill the insect, digest it, and create a sterile incubator and food source for the worm to reproduce.

To understand this peculiar symbiosis, Webster filled his lab with rows of petri dishes, each with a wax moth larva, a bit of moistened filter paper, and about 500 nematodes. The worms, barely visible to the naked eye, look like tiny white fibres in a drop of water. After a few days the infected dead larvae would turn bright red. The rest would die and rot. “Infected larvae would be clean and mould-free,” recalls Bruce Leighton, Webster’s lab technician from the time, “and they had a distinctive smell.” Not unpleasant, the odour permeated the entire lab.

At the time Webster and his team were searching for the best nematodes for agricultural pest control, but one of Webster’s graduate students became fascinated by something else. Genhui Chen wanted to find the antibiotic chemical used by the bacteria to keep the dead moths fresh for almost two weeks while the worms inside lived and reproduced safely. Originally from Hunan, China, Chen was a keener intent on learning English. According to Leighton, whenever he heard a new expression, such as “brown bagging it,” Chen would repeat it constantly for days until he mastered it. “It was fun watching the books on Genhui’s shelf change over a period of years as he went from pest management and nematology to microbiology, then biochemistry, and finally pharmacology,” says Leighton.

After years of research Chen and Webster ultimately discovered a handful of potentially valuable new antibiotics from the symbiosis – including hydroxystilbenes, isoflavonoids, and anthraquinones. At this stage Webster and Chen, together with SFU chemist Jason Li, formed a company called Welichem Technologies Ltd. to commercialize their discoveries. Subsequently in 2000, the company morphed into Welichem Biotech Inc.

In routine screening the scientists soon learned that many of their biologically active molecules blocked an enzyme that activates T-cells. They realized that a potentially more important feature of the nematode-bacteria relationship was their ability to chemically modify the insect’s immune system. Considering that over millions of years humans have evolved together with their own parasites, Webster thought that these natural compounds might affect the human immune system too.

“Perhaps we need parasites like nematode worms to modulate our innate immune systems and suppress the apparently ad hoc occurrence of autoimmune diseases,” he says. But nobody wants to be infected with worms, so Webster and his colleagues have been isolating the chemicals that parasites use to influence the immune system of their hosts.

In fact, some people do take worms to cure themselves of disease. David Pritchard, an immunologist-biologist in Nottingham, England, infected himself with hookworm larvae after noticing that natives in Papua New Guinea do not suffer much from autoimmune-related illnesses such as asthma, hay fever, and allergies. It is common in the tropics for most people to be infected with hookworm. In low numbers such parasites do not cause problems, and Pritchard’s research has shown that they do indeed blunt their host’s immune system for mutual benefit. In a 2006 study, participants were amazed to find their allergies disappeared after ingesting only 10 hookworms, not enough to make them sick.

“ John is looking for drugs in weird places where others don’t normally look.” Many drug companies are fastidiously collecting plants from rainforests with the hope of discovering new pharmaceuticals ... but few are looking at parasitic nematodes that live in the soil right underfoot.

Welichem researchers have now identified several compounds from nematode-infected moth larvae that modulate the human immune system that are in various stages of drug development and testing. The most advanced is WBI-1001, now in Phase II trials as a skin cream for psoriasis and eczema. The cream seems to partially down-regulate the immune system, and two-thirds of the patients that applied the test cream experienced improved skin.

“To try something with a completely new molecule and get positive results very early on in clinical development – this is something we don’t see often,” says Montreal dermatologist Robert Bissonnette, one of the doctors conducting the trials. He cautions, however, that longer trials with thousands of patients are still needed before the new skin cream can be approved.

Cam Oehlschlager, a retired SFU chemistry professor who worked with Webster back in the 1980s, says, “John is looking for drugs in weird places where other people don’t normally look.” Many drug companies are fastidiously collecting plants from rainforests with the hope of discovering new pharmaceuticals, he adds, but few are looking at parasitic nematodes that live in the soil right underfoot.

Through Welichem’s unique drug discovery platform called Symbiochem®, which is based specifically on the symbiotic relationship between nematodes and bacteria, the company continues to develop new drug candidates. “We don’t live in isolation,” says Webster. “All of nature and biology are interconnected in a complex ecology, including us.” He believes that the human immune system response to parasites can have positive effects, including a reduction in autoimmune diseases. The idea is to work out how to get the benefits without having to eat the worms.

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