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Biology by design part two – how synthetic biology could revolutionise everything from medicines to energy

8 August 2012

In a series of articles we are highlighting the work of some of the leading synthetic biology researchers in the UK. Here we profile Professor Polly Roy of the London School of Hygiene and Tropical Medicine and Professor Martin Warren from the University of Kent.

Making test-tube viruses to deliver better vaccines

Viruses can only reproduce by high jacking the cellular machinery of the organisms they infect. By redesigning virus genomes in the lab so that they are deficient in key genes researchers hope to render viruses unable to replicate in order to deliver better vaccines.

  • Current vaccines for viral diseases are developed by killing or inactivating live viruses.
  • Using the tools of synthetic biology researchers could design new viral genomes missing key genes. These could confer immunity but would be unable to replicate outside of the lab.
  • Research could also allow scientists to design better vaccines which would allow clearer distinction between vaccinated and infected organisms.

In order to develop immunity to a disease, we first need to be exposed to the microbe that causes it. Vaccination works by presenting the immune system to with a dead or inactivated version of a disease-causing organism like a bacteria or virus. However there are drawbacks to this approach. New research is using synthetic biology to design viruses which cannot reproduce outside of the lab which could be used as improved vaccines for important diseases of both people and animals.

Professor Polly Roy
Professor Polly Roy

A research team led by Professor Polly Roy of the London School of Hygiene and Tropical Medicine has recently reconstructed a Bluetongue virus (BTV) in a test tube. The virus is responsible for an important disease (Bluetongue) of livestock that is transmitted by midges. The disease has a high mortality rate (up to 70% in sheep) and has a severe economic impact on European agriculture. Since 1998 the geographic range of BTV has been extending Northwards in Europe where it is now endemic. In 2007 Bluetongue was first detected in the UK and there are fears that it could become a more regular threat to the UK.

Professor Roy and her team synthesised the Bluetongue virus's gene and protein building blocks separately and then combined them in the right order in order to produce a functional virus particle. Then, to check whether they had been successful, they infected some midge cells with the newly synthesized virus.

Professor Roy explains: "By virus standards Bluetongue is quite architecturally complex and it has a relatively difficult genome to work with, so assembling it in a test tube was a significant challenge. No one had been able to get such a complicated virus to assemble outside a cell before. When we injected the virus particles that we had assembled in the test tube into some midge cells they started behaving and replicating just as we would expect a wild virus to do. This was a really exciting moment. What had previously been a complex of proteins and other molecules whirred into activity and started making copies of itself."

Currently, Bluetongue vaccines are produced by chemical treatment of virulent viruses to inactivate them. These vaccines are effective at preventing the disease, but it is difficult to tell the difference between animals that have been vaccinated from those that have recovered from an infection. This makes controlling outbreaks much more difficult.

By using the tools of synthetic biology researchers hope to rebuild viruses to particular specifications and so design new vaccines with useful properties. Developing a vaccine that is tagged with a marker, for example, would make it easier to tell the difference between animals that have been vaccinated and those that have suffered a disease. The team also hopes to deliver more effective vaccines for bluetongue than are currently available. They could achieve this by either producing a virus like particle which triggers an immune response but does not contain any genes or by designing a virus deficient in certain genes which could raise an immune response but would not be able to reproduce outside of the lab.

Professor Roy was recently awarded the General President's Gold Medal for science, one of India's most prestigious academic awards for her work on viruses, including bluetongue.

New sources of vitamin B12

Professor Martin Warren hopes to engineer plants that can produce a vitamin which is essential for brain and blood health.

  • Only bacteria can produce the important vitamin B12
  • Some people, especially vegetarians and the elderly suffer problems from B12 deficiency.
  • Scientists hope to make it easier to get enough of the vitamin by transporting the pathway for producing the vitamin into plants and making it more efficient.

We rely on plants to supply virtually all of the vitamins which we need to keep us healthy. But plants cannot make one important vitamin B12. Deep in evolutionary history, the machinery to make this key nutrient never made the leap from bacteria to more complex organisms.

Professor Martin Warren
Professor Martin Warren

This prehistoric quirk has important consequences today. Vitamin B12 has a key role in the normal functioning of the brain and nervous system and for the formation of blood. Most people are able to get enough vitamin B12 in their diets by eating meat, fish and dairy, however people who are on strict vegetarian diets are prone to vitamin B12 deficiency and this can lead to anaemia, neurological disorders and developmental problems in unborn babies.

Vitamin B12 deficiency is also a problem in the elderly and research suggests a link between a lack of the vitamin and the breakdown of the brain seen in Alzheimer's sufferers.

Professor Martin Warren and his team at the University of Kent want to take the complex biological pathways which some bacteria use to make the vitamin and transfer them into other organisms, like yeast and plants. At present vitamin B12 supplements are produced industrially through a bacterial fermentation process but scientists want to see whether they can make this more efficient or produce plants that contain the vitamin.

Vitamin B12 is the largest and most complicated vitamin that we know of. Thirty different enzymatic steps are required along the production line to produce the finished vitamin and scientists have been puzzling over how all of the pieces fit together for over 50 years since its structure was first revealed by the famous scientist Dorothy Hodgkin.

This complexity means that an awful lot of genes are involved in encoding for all of the different enzymes. Unlike older forms of genetic engineering where a couple of genes might be transferred from one organism to another, engineering an organism that can produce vitamin B12 from scratch requires a whole series of genes to be combined and inserted into a cell in a very specific order.

Transferring entire biological pathways across the large evolutionary distance that separates a bacterium from yeast or a plant is a considerable technical challenge but Professor Warren and his team are confident that it can be achieved.

Plants have the advantage of possessing a secondary ring of DNA within cellular compartment, which in essence behave like bacteria within the plant. The scientists will transfer the vitamin production pathway into this plastid DNA, increasing the complexity of the system to try to maximise vitamin production within the bounds of the plant's biology.

What is synthetic biology?

Synthetic biology is the science of designing, engineering and building useful new biological systems which have not existed before in nature.

Using our ever-increasing understanding of genetics and cell biology synthetic biologists are able to design complicated biological parts, systems and devices to act as sensors, tissues or to produce useful chemicals. These technologies could deliver advances in a wide range of fields including medicine, biofuels and renewable materials.

A synthetic biology approach offers incredible promise but also poses many ethical, legal and even existential questions for the scientific community, policymakers and for all of us to think about. Some of these questions were explored in a public dialogue carried out by BBSRC and the Engineering and Physical Sciences Research Council in 2010.

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