Author(s): Carolyn Butchers and Neha Karl, BioStrata
Publication Date: 04th October 2016
Crystal structure of human SAMHD1, a cellular protein that blocks HIV-1 replication that Kate Bishop’s group is studying.
Crystal structure of human SAMHD1, a cellular protein that blocks HIV-1 replication that Kate Bishop’s group is studying.

Now in its fourth year, BioBeat, founded by Miranda Weston-Smith, is a collaborative platform for entrepreneurs and leaders in the biotech industry. BioBeat’s annual Movers and Shakers report honours women in biobusiness who are setting the pace in the life science sector and delivering extraordinary success in their field. In the run up to this November’s BioBeat16 event, we speak to some of 2015’s Movers and Shakers to explore how they’re transforming today’s challenges into tomorrow’s opportunities.

In the first Q&A blog of this series, we speak to Kate Bishop, Group Leader at the Francis Crick Institute, who conducts research into HIV replication which may lead to new therapeutic treatments. Her group studies how the enzyme SAMHD1 prevents viral DNA synthesis in white blood cells, and whether modulation of this enzyme could block HIV propagation. Kate talks to us about the benefits of collaboration when translating fundamental research into therapeutic applications.

Tell us a bit about your background. How have you arrived at where you are today?

After completing a PhD in virology at the Medical Research Council’s National Institute for Medical Research, I undertook a postdoctoral position at King’s College London. In 2004 I was awarded a Royal Society Dorothy Hodgkin Fellowship and then received a Wellcome Trust Career Development Fellowship following that. In 2008 I became a Group Leader at the National Institute for Medical Research, which now forms part of the Francis Crick Institute.

Can you tell us a bit about the work that you do, and how it can be used to bring benefits to human health?

My group studies retroviruses, the family of viruses that HIV belongs to. We do fundamental research into understanding how these viruses replicate, and study how they interact with cells at a molecular level. By understanding the virus biology, our goal is to develop new and better drugs for HIV therapy.

On the one hand, lentiviruses like HIV are examples of retroviruses we try to prevent replicating. But retroviruses can also be used beneficially as gene therapy vectors and our work may suggest ways to manipulate them for therapeutic applications. Retroviral vectors have been used to successfully treat immunodeficiency in children, however many of these patients subsequently developed leukemia. Better knowledge of the replication process should lead to better targeting and improved safety.

Retroviruses are also helping us understand other cellular processes. For example, the function of one of the viral proteins we work on is to destroy cell proteins that would otherwise get in the way of virus replication. The virus hijacks the cell’s own regulatory system to get rid of proteins that aren’t normally degraded. Surprisingly nothing was really known about some of these cellular proteins until we found that retroviruses targeted them for degradation. So we decided to find out what these proteins do, and why the virus would need to target them. It turns out they’re actually quite fundamental to cell performance!

By using the virus in this manner we’re finding out so much about cellular processes. I started my career thinking I’d find a cure for HIV – but in fact retroviruses are really useful tools to probe our cells and the activities that go on inside them. We’re beginning to understand genetic disorders because we’ve been able to study their mechanisms using these viruses.

You’re currently collaborating with GSK on SAMHD1 drug screening. Could you tell us a little about the work you’re doing with them?

Pharmaceutical companies are realising that in order to identify and develop new HIV drug targets, you need to understand more about the basic cell biology. They’re increasingly interested in collaborating with researchers like myself to get a handle on this. The Francis Crick Institute and GSK have set up a collaboration and I am one of the researchers involved.

Many HIV drug targets are nucleotides, and pharmaceutical companies like GSK are trying to target enzymes that manipulate these DNA building blocks. GSK have extensive chemical libraries that inhibit these enzymes. Because the restriction factor SAMHD1 is also an enzyme that targets nucleotides, we’re working with them to understand the enzyme better and to see whether we can use these compounds in cells to interfere with viral replication.

We also study an HIV protein of which very little is known, and whilst we think its job is to degrade a cellular protein, we don’t know what it is. GSK are helping us identify this target, which could open the door to a whole new area for drug development.

What are the challenges facing the field?

Retroviral therapies are often very expensive. Whilst they’re used in economically developed countries they’re not affordable in the developing world where they’re needed most. One of the major challenges is to develop stable, affordable drugs that only need to be taken once a day.

Having said that, retroviral therapy has come a long way and is being rolled out across Africa. However, this means we have to be very wary about drug resistance. At the moment most drugs target the same proteins in the virus, so if you develop resistance to one drug, you become resistant to a whole family of drugs. For this reason, developing new targets is extremely important.

Secondly, there is not yet a cure or vaccine for HIV. The problem is we don’t really know what we need to do to cure it. Because of the way the virus replicates – it actually inserts itself into the cell – the only way to get rid of the copy in the genome is to kill off the cell. What’s more, the virus can use cells to hide itself away, and once you take the patient off treatment, the virus bounces back. To fight the disease it’s essential we identify all of the cells that become infected and work out how the virus replicates in these cells – this is something we’re trying to do.

You were involved with a scheme that paired MPs with scientists. What did you learn from that experience?

Science affects so many of the decisions that are made in parliament, yet many MPs don’t have a scientific background. The scheme, run by the Royal Society, helps MPs by putting them in contact with scientists who can bring expert insight on these issues, and it gives scientists the opportunity to ensure science is on the agenda.

Not only is it important for MPs to hear scientists’ voices, I think it’s very important for scientists to understand the parliamentary process and how we can make our voices heard. The scheme allowed me to spend a week in Westminster, to sit in on some of their meetings and attend Select Committee meetings, to understand how parliament works. I discovered that because MPs have to deal with such a broad range of issues, they have very little time to be briefed beforehand, so it’s really important experts get their message across in a precise and efficient way.

How is BioBeat helping your research?

I think it’s very important for people in fundamental research, like myself, to talk with people in industry and those further downstream, as it helps us understand what we need to do so that something translational comes out of our research. These conversations also help those in industry understand how the basic science develops, as well as the bottlenecks we face.

For me, BioBeat is about having a community where you can discuss your research and consider how you can get the most out of your work; to discover the side routes beyond your own research path that can benefit others. I think this is particularly true for developing bio-based research tools.

For example, the viral proteins we study degrade proteins in our cells. If you take a little bit of the protein that’s being targeted for degradation, and attach it to other proteins you’d like to target, we can use the retroviral proteins to get rid of these proteins. With development, we may be able to turn on degradation at specific times which others may be able to use as a tool for their own applications.

Where are you taking your research? What are your goals?

From a research perspective I’d like to find new protein targets that interfere with HIV propagation and understand how they do this. I think there’s a whole new pathway that the virus has to overcome, that’s waiting to be discovered. If we find out what it is, we may be able to use it to get in the way of retroviral replication.

I hope to turn some of our work into useful tools that can be used by other researchers to study other diseases. Retroviruses are small, compact packages that are quite easily modified, which makes them perfect tools to get into cells and perform tasks – there’s a great deal of potential there!