Curing the ‘two-bucket’ disease
In the second of the three highly commended articles for the Max Perutz Science Writing Award 2012, Sarah Caddy talks norovirus — its less-than-pleasant effects, why it’s so difficult to study in the lab, and how the key to tackling it might lie in developing drugs that target the human proteins the virus needs to survive.
One minute you’re feeling great, and the next the contents of your intestines are coming out of both ends. This is norovirus, the horrible cause of winter vomiting disease. One in twenty people in the UK suffer from the effects of this tiny virus every year. It is described as causing ‘mild gastroenteritis’ but if you have had it, you will know it is anything but mild. And aside from the individual trauma, it is a financial disaster to the UK. An estimated £100 million is spent by the NHS each year due to ward closures forced by norovirus outbreaks.
Surprisingly, norovirus is closely related to poliovirus, a virus on the brink of extinction thanks to international vaccination. So why haven’t we managed to eradicate norovirus yet? Why can’t we treat it? Is prevention ever going to be possible?
It turns out that norovirus is very elusive when trying to grow it in cells in the lab. No experiments have managed to make norovirus replicate naturally inside experimental cells. In contrast, polio was first grown in cells in a lab in 1948, allowing extensive research to be carried out. A polio vaccine was developed just four years later, and 2012 may be the last year that poliovirus exists.
So if norovirus can’t infect cells in a lab, what other options are there for research that might lead to control of the disease? The first investigations into norovirus involved a desperate bunch of volunteers, who would drink samples of filtered diarrhoea from infected people. This improved understanding of the transmission and effects of infection. In some people vomiting and diarrhea can develop within as little as 10 hours, whereas other people are surprisingly resistant to disease.
However, to be able to develop anti-norovirus drugs, we need to understand what norovirus does to individual cells in a human. Viruses cannot replicate by themselves, they have to get into cells to hijack the normal cell machinery. They then have to assemble their freshly replicated genes into a newly made protein coat, and escape out of the first cell before infecting the next. How on earth do noroviruses manage this? Studying disease in an entire human cannot even begin to tackle this question.
Norovirus research took a leap forward in 2003 when a similar virus was found to infect mice. Over 24 per cent of lab mice in Europecarry this type of norovirus, but only those with a deficient immune system get ill. Studying such mice, which get diarrhoea but interestingly don’t vomit, is giving many insights into the infection in humans. And helpfully, this kind of norovirus can infect cells in the lab. So that is what we work on. We can visualise the virus within cells using microscopes and we can manipulate specific viral genes and see what happens to infection.
We have also started to identify specific proteins in the hijacked cells that the virus needs to manipulate in order to survive and replicate. These cell proteins have the potential to become unusual drug targets.
Most drugs that treat infection by bacteria or viruses act by binding directly to the invading bug. They then block their action and with the help of the human immune system, the infection can be cured. However, resistance to anti-microbial drugs does develop. Norovirus in particular can mutate at an annoyingly fast rate. Any fortuitous mutations which stop the drug having an effect spread rapidly through a virus population. This is survival of the fittest at very high speed.
But what if drugs target key human cell proteins needed by the virus, and not the virus itself? Drug resistance takes much, much longer to develop in humans. The time from birth of a human to delivery of their own baby can be more than 50,000 times slower than the 12 hours it takes norovirus to get into cells and produce ‘offspring’. And our genes are replicated much more faithfully than those of norovirus.
This principle of developing drugs to target human cell proteins has already been applied to treating HIV — the promising new drug maraviroc binds a cell protein and blocks HIV getting into cells. Our lab aims to prove that a similar strategy can be applied to treating mouse norovirus first, and then the disease in humans.
So, hope for the future? The title of this article is a little fanciful; norovirus is unlikely to become treatable by the end of a three-year PhD. But every week, more information is gathered and published by norovirus researchers across the globe. And every piece of information learnt from molecular research brings scientists a step closer to developing anti-norovirus drugs. Wouldn’t it be nice if you could avoid that norovirus outbreak in hospital, or in your office, or on your cruise, simply by taking a tablet?