Target woman

October 7, 2005

Tuberculosis is no long-gone scourge but a deadly modern-day disease that is increasingly resistant to treatment. Anna Fazackerley meets a woman seeking new ways to attack the bacterium that causes TB

When Rachael Whalan started out in research, she was drawn to microbiology.

The subject could have taken her into a career in the food industry or research in an area such as bioremediation, developing plants that absorb noxious waste. But she wanted something more dramatic and more meaningful.

"I wanted to help save lives," she says simply.

The path she chose in the end was the study of tuberculosis. Though its name is familiar, people often assume that this is an old disease and no longer a particularly dangerous threat. They are wrong.

TB remains the leading cause of death due to a bacterial pathogen, and it infects about one third of the world's population, though few of the affected people will realise that they are carrying this potential killer.

"The World Health Organisation estimated that between 2000 and 2020, 1 billion people will become newly infected with tuberculosis, 200 million will become sick and 35 million will die," Whalan says. "Those are shocking statistics." And while the biggest problems are in Africa and Southeast Asia, wealthy Western countries such as Britain do not escape.

The disease attacks the lungs. In its active form, it is characterised by coughing, which often brings up blood. The body is generally unable to eradicate the bacteria. If the infection does not take hold, it will enter a dormant state and may reactivate when the carrier's immune system becomes weak through old age or from HIV/Aids.

"Most people know that this is a lung disease, but they don't realise quite how unpleasant it is," Whalan comments. "You really don't want to get it."

Whalan has been working as a postdoctoral researcher in the division of mycobacterial research at the National Institute of Medical Research for the past two years. Her team is working towards developing new drugs to fight TB - though she stresses that they are concerned with the very early stages of a long process.

They are answering an urgent need. There have been no new drugs for TB on the market for 40 years, and the disease is becoming resistant to the two main treatments available to doctors. The problem is exacerbated by the increased susceptibility of HIV/Aids patients and by the inadequate protection offered by the current vaccine.

"In the 1960s and 1970s, it was thought that the problems of TB control and treatment had been solved," Whalan explains. "When they realised it was still a problem, research had to be started up again from scratch, and that takes time."

The race to get things up and running is not helped by the nature of Mycobacterium tuberculosis , the bacterium that causes TB. This bacterium grows incredibly slowly, and Whalan estimates that it takes four times as long to do any research with it than with any other bacterium.

In essence, she is trying to understand how the biology of the bacterium works. Her group is looking for potential drug targets, but it is also trying to comprehend how the disease survives in the body. This means answering fundamental biological questions such as what individual proteins do.

When the bacterium enters the body, it has to switch on different genes that will express the proteins it needs to survive, and Whalan is attempting to get to the bottom of this process in order to come up with new strategies for stopping it in its tracks. Her group is focusing on protein kinases - enzymes that modify other proteins chemically by adding phosphate groups to them. The human genome contains about 500 protein kinase genes. Whalan says her team have isolated the protein kinases from Mycobacterium tuberculosis that they think are important for a virulent TB infection.

If they are proved right, then the ultimate aim would be to attempt to block the activity of these protein kinases. "When we find a target, it gets handed on to people at MRC Technology to do the chemistry. They screen our targets for inhibitory drugs. If they find something positive, it is then handed on again," Whalan explains.

It is a long chain, and any new drug will take many years to reach clinic.

But Whalan does not find this dispiriting. "Our job is to identify drug targets [rather than developing actual drugs]. It gets further and further away from us," she admits. "But I enjoy the part I do, and I like the fact that it is all part of a great big process."

Whalan's project complements the work of others in her group who are also investigating proteins, but she plans all her own experiments. Although she does not feel ready to work entirely on her own, she does enjoy considerable freedom.

Working in an MRC unit means that she can devote 100 per cent of her time to research without worrying about teaching. "That is definitely good," she says. "I'm a bit young to be teaching. I have supervised A-level students in the lab and that was good fun, but it was only for four weeks."

This is Whalan's first job since completing her PhD, and she is still unclear how her career will progress. With her molecular biology skills, she could easily cross over into working on another infectious disease, but TB clearly has her in its grip.

"If you want to become a specialist, it takes a long time to understand TB.

If you really want to know what you are talking about, you want to stay in the same field," she says. "It inspires me. It is such a big problem, and there is so much to learn."

Like most researchers her age, she is aware that she may have a string of short-term contracts and very little security ahead of her.

"In the early part of your career, you tend to move around every two or three years," she notes. "It is hard to get a permanent job. That is scary, particularly when you have done, say, two postdocs and want to settle down."

Her next move may be to experience life as a scientist in another country, although she finds the idea of Australia or New Zealand more tempting than the US. And, she insists: "I would come back!"

CV: RACHAEL WHALAN

Age: 28

Education 1999-2003: PhD in molecular microbiology at Warwick University

1995-99: Degree in biological sciences with intercalated year in molecular genetics, Warwick University

Research work

Currently on a Career Development Fellowship at the National Institute for Medical Research. Conducting research into Mycobacterium tuberculosis regulatory systems, specifically Ser/Thr protein kinases

2001: Laboratory demonstrator at Warwick University, teaching molecular microbiological techniques and theory to under-graduates

1998: research scientist at Health Protection Agency Centre for Emergency Preparedness and Response, Porton Down, Salisbury

Focus: TB
The traditional vaccination for TB - the Bacilli Calmette-Guerin vaccine - is ineffective in developing countries where HIV is rife. An alternative is urgently needed.

High-dose injections of a human antibody known as intravenous immunoglobulin have produced a considerable reduction in TB infection in mice, according to research from the MRC's National Institute of Medical Research in London.

Stephen Jolles, consultant clinical immunologist from the Royal Free Hospital, London, found that a single treatment of the antibody caused a long-lasting, 100-fold reduction in TB-causing organisms. "These are encouraging results because this type of therapy uses the existing immune response and is likely to be effective even with drug-resistant organisms.

The results suggest that further research in a clinical setting is possible," says Jolles.

Stop the spread

Before individuals infected with active TB reach the treatment stage, they will each infect about 10 to 15 people a year. They will usually only present to clinic after having done so. Researchers are looking at measures to control the spread of the disease.

MRC scientists in The Gambia have been carrying out a study monitoring the spread of TB among those infected and their immediate families. A database of 300 people with active TB and about 2,000 people in close contact with them provides ideal background information for the testing of a possible new vaccine. Currently known by its technical name, recombinant Modified Virus Ankara MVA 85A, the vaccine is in early stage trials in The Gambia, in partnership with a team from Oxford University, where it was developed.

So far the scientists have found that the vaccine stimulates a phenomenal response from key cells of the immune system known as T-cells. The response is much more striking in Gambians than in tests in Oxford. The next stage is to trial the vaccine in those with latent TB infection.

Immune questions

One third of the world's population is infected with TB, but only about 5 to 10 per cent will develop the disease.

Researchers from the London School of Hygiene and Tropical Medicine, in partnership with the MRC in Uganda, are comparing the immune response of people falling victim to TB against those who are protected against its effects, in an effort to understand disease processes. One recent study suggests that parasitic worm infections may make people more susceptible to the disease - possibly explaining why the BCG vaccination is ineffective in tropical regions with high rates of worm infection.

Becky McCall

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