Wetenschap - 9 oktober 2014

Viruses for precision medicine

Rob Ramaker

Wageningen chemists have designed and created an artificial virus. Copying the tricks employed by viruses will soon be helping to deliver medicines more precisely to specific parts of the body.

Illustration: Pascal Tieman

Photo below:  Sven Menschel

Food proteins, silk threads and gelatine are the kinds of material Renko de Vries usually studies. But last August, the associate professor of Physical Chemistry and Colloid Science published a very different kind of discovery. Together with a team of fellow researchers, he had designed and assembled a simple virus. This con-stituted a big step towards an ambitious goal: designing viruses capable of delivering medicines to specific parts of the body. 

This sounds like a strange idea. Thanks to pathogens such as HIV and Ebola, we are more inclined to associate viruses with diseases than with cures. Pathogenic viruses use our bodies to multiply and spread, for instance through symptoms such as sneezing or diarrhoea. They are too simple to carry out these tasks themselves. A virus is really no more than a piece of genetic material - DNA or RNA – wrapped in a coating of specialized proteins. Since viruses only have a handful of their own genes, they hijack our cells (and those of bacteria, plants and animals) in order to propagate themselves. In the course of evolution they have developed an extensive box of tricks to help them break into our cells. They often concentrate on one particular kind of cell. HIV, for example, likes to settle into the cells of our immune system in order to sabotage it from within. 

Copying tricks 

Scientists wonder how something as simple as a virus can penetrate our cells in such a sophisticated manner. Insight into the underlying mechanisms could, it is thought, help us to deliver medicines to a target in the body such as a tumour, the liver or the kidneys. The most common way of taking medicine to date is in the form of pills which dissolve in our bodies and spread through the parts of the body they can reach. Certain parts of the body, such as the brain, cannot be reached in this way. And some potentially useful drugs cannot be used because they are not soluble. An even bigger problem is that drugs are delivered to all sorts of locations where they are not required and where they can cause severe side-effects. 

De Vries hopes to be able to contribute to a solution to this problem on the basis of his study. In the article he published last August in the journal Nature Nano-technology, he showed that he has already succeeded in imitating one trick used by the virus. He managed to wrap a piece of genetic material or DNA in a protective coating of proteins especially designed for the purpose. Besides drawing inspiration for this process from natural viruses, De Vries also made use of a protein structure that is found in the thread of the silkworm. The coating that was formed protected the load being transported from being destroyed when the virus entered a hostile environment. And in fact the simple virus even proved capable of delivering its cargo right into cells. De Vries can now work on expanding the basic idea described in the article with new functions such as a module which determines the virus’s target location in the body. 

Gene therapy 

With his new delivery method, De Vries may be opening the door to new kinds of drug treatments. Experiments with gene therapy are going on elsewhere. In this kind of treatment, faults in our own genetic material are dealt with and corrected. Worldwide there are thousands of diseases caused by the fact that the patient inherited two faulty versions of a gene from his or her parents. Introducing a gene offers these patients the first hope of a cure. The problem is that the body sees a strange gene as an enemy, and then destroys it. A ‘virus coating’ would help to deliver a ‘repair gene’ to the target location. 

An artificial virus could contribute to gene therapy targeting cancer in a similar fashion. In tumour cells, genetic material is often badly damaged so that genes which inhibit the growth of cells, for example, no longer work. Or it might be a gene that forces damaged cells to self-destruct that is put out of action. A virus can introduce a new ‘suicide gene’, so that the tumour cell destroys itself.

At the moment, gene therapy mainly makes use of naturally occurring viruses. However, these viruses did not evolve for this purpose and have been the cause of a number of incidents in the past whereby patients died or contracted leukaemia. This led to stricter safety pre-cautions. Creating artificial viruses could be advantageous here, says De Vries: ‘The strength of the approach of creating viruses from scratch is that it gives you more understanding and control. When you fiddle around with natural viruses you often don’t really know exactly what you are doing.’

Another advantage is that the body has never seen these designed viruses before, so the immune system does not recognize them. Most natural viruses, by contrast, get cleaned up before they can deliver their precious cargo. What is more, natural viruses can only deliver a limited load, while such limits may not apply to an artificial one. 

At the moment, De Vries’s design only knows one trick so more functions will have to be designed before it can form a fully operable drug transport system. For instance, the virus will need to be able to recognize its target, whether a brain tumour or kidney cells. This can be achieved by adapting the ‘protein coating’ so that the virus itself recognizes where it needs to be. It is also possible to use key proteins which only fit the lock found in a particular kind of cell. De Vries can also call on help from nature to get the viruses in his lab to evolve in a controlled way, constantly making small random changes to the virus and then selecting the versions that are best at carrying out their task. 

Anaphylactic shock 

But it is not just with natural viruses that caution is advisable; there are safety issues surrounding the design of artificial viruses too. New structures could turn out to be toxic for the body, for instance: a possibility which needs to be ruled out at every stage. It is also important that the immune system does not respond to the virus. In the best case scenario, this could cause a mild allergic reaction, but a patient could also go into anaphylactic shock. A trial in English a few years ago led unexpectedly to organ failure. So artificial viruses still have a number of hurdles to take. Nevertheless, De Vries is optimistic about their potential and going full steam ahead with his research now that he is ahead of the field. The first pharmaceutical company has already expressed interest in collaboration. De Vries is convinced his idea of building new viruses from scratch is a solid one. ‘This is the first project I have ever had in which we have literally done what was in the project proposal,’ he says. ‘It just worked, without any significant changes of plan. That was a totally new experience.’



The price of life

Hightech healthcare comes at a price. In the Netherlands last year a cautious discussion blew up about how much it is acceptable to pay for an extra year of life. Innovative ways of delivering medicines in the body, among them gene therapy, will stimulate this discussion further. They are often complex and target one disease, making them very expensive. Glybera, the first gene therapy to be approved in Europe, immediately became the most expensive medicine in the world. One treatment for one person costs more than a million euros. The costs are extra high because only one or two in a million people suffer from the disease the drug targets, a shortage of lipoprotein lipase. Rare diseases which require continuous long-term treatment, such as Pompe disease and Fabry disease, are even more expensive.