Bioengineering's big worries

Synthetic biology could lead to great technological advances, but it's not going to be an easy ride.

Some believe that it will be possible to bolt new functions onto existing bacteria such as the widespread escherichia coli. At the JCVI, researchers such as John Glass believe they need to go one step further and build genomes from scratch. They think the genome of E coli is too complex to work with: instead they aim to build an organism with the smallest possible genome needed to live in the hope that it will be easier to control.

So far, Glass and colleagues have developed the ability to take the genome from one bacterium and transplant it into another, replacing the original. In the process, it takes on all the properties of the bacterium that provided the transplanted genome. And they have constructed, using chemical synthesis, the genome of a bacterium that they aim to transplant into living cells. The genome they constructed is that of an existing microbe: mycoplasma genitalium. But that was simply to ensure that the path to the first living organism with a synthetic genome would be easier.

"We won't be able to use mycoplasma for production, but it is a good testbed," says Glass.

Ultimately, they will transplant built-to-order genomes designed on a computer and create new species in the process. Although some view the JCVI's plans as creating life, this is more about redesigning it.

Professor John McCarthy, director of the Manchester Interdisciplinary Biocentre, says: "There is an important distinction between making the DNA synthetically and creating a living organism. The DNA strands represent the blueprint for the cell but they are not the cell themselves."

Taking the easy route

At first glance, the idea of creating DNA synthetically and implanting it in a cell seems to break new ground. But that is not the case, argues Pam Silver, director of the Harvard University graduate programme in systems biology. She points to the genetic engineering that has been done already. The first gene made artificially was assembled in the 1970s.

"We have engineered biology for 25 years," says Silver. The difference with the latest wave of engineered organisms made using what is called synthetic biology is not an individual tool or technique. "Synthetic biology is about making biology easier to engineer."

What has happened is that a number of techniques and approaches have come together to form a new engineering discipline. Philipp Holliger of the Medical Research Council's laboratory of molecular biology points to a reversal in the way that scientists look at biology. "Traditional biology looked at what is and asked: why? Synthetic biology looks at things that never were and asks: why not?"

It is the "why not" aspect of synthetic biology that is likely to make it the successor to genetically-modified food and nanotechnology in the list of potentially destructive technologies in the public imagination. Scientists working on synthetic-biology projects are keen to avoid the fate of genetically-modified food in Europe - effectively denied a market.

The safety of synthetic biology is rarely out of the conversation at public-outreach meetings held to discuss the technology and its future. Second-generation biofuels will use bacteria and plants altered using synthetic-biology techniques. In the case of Agrivida, researchers have designed a protein that, when heated, will switch from dormant into a powerful enzyme able to break down the tough cell walls of maize leaves, or stover. LS9 is altering E coli to convert sugar into petrol. These organisms could improve the efficiency of biofuel production, reducing competition with land needed for food. But that is not the only public concern.

Campaigners are worried about genes from modified plants crossing over into their un-engineered analogues and bugs that escape from their biorefineries and coat the land with a patina of petroleum. Governments are concerned about the potential applications of the technology for terrorism and possible misuse by home 'biohackers'.

At the same time, governments are encouraging research boards to look at defence applications. In June, US under secretary of defense for acquisition, technology and logistics John Young wrote to the Defense Science Board to request that it set up a task force on the military applications of synthetic biology. "Novel applications, which combine traditional and new research areas, suggest new interdisciplinary fields that will have important defense applications," he wrote.

It is for these reasons that pressure groups such as Canada-based ETC Group want a moratorium on applied synthetic biology. "It is a dangerous path to go down," says Jim Thomas, research writer at ETC. "Nobody knows how to assess synthetic biology products in the environment: that has just not been done.

"I think at this point, the work is extremely speculative. And there is the potential for escape. There is no work whatsoever looking at the biosafety impact of synthetic biology. You see what are glorified breweries being built in rural areas and there will be thousands of these across the landscape. You have an organism that converts cellulose into jet fuel. If that escapes then we have the potential for a real nightmare."

Researchers such as Silver do not see themselves as creating new problems. Quite the opposite: synthetic biology is attracting graduates because of what it might make possible. "Synthetic biology has really captured the imagination of students," she says.

For good and evil

Although Silver's research is primarily focused on medicine, a couple of years ago students in her lab "wanted to do something big" for the environment. The answer was to investigate biofuels. The Harvard group is looking beyond the second generation of biofuels, which remain based on carbon. "Our long-term goal is to create a microbial solar cell," she says.

Can the disparate views of campaigners such as Thomas and synthetic biology researchers be reconciled? As Alexander Ninfa of the University of Michigan points out: "Every technology has applications for good and evil."

One of the reasons why the JCVI wants to simplify the genome of bacteria is to deal with one of the fears about trying to harness living organisms as biorefineries. Glass notes that mycoplasma genitalium is much tougher to deal with than E coli. The latter has a much larger genome that contains a number of redundant genes that help the bacteria survive difficult conditions and react to sudden changes in food supply and temperature.

Members of the JCVI team believe that by shrinking the genome further to create a new species of bacteria, they can make it more controllable. They will also take out genes that manufacture a key amino acid that the organism needs. Amino acids are the building blocks of proteins. The organism would be fed on a diet that contains this essential amino acid. Without it, they could not function. It is a step that might not be necessary.

"It has happened where genetically enhanced organisms have been released, to deal with oil spills, for example. They have been competed out of existence, out of action by existing organisms," says Holliger.

Experiments by Professor Richard Lenski of Michigan State University showed that a colony of bacteria could evolve the ability to metabolise different foods - even in the case of a restricted-genome organism, it might be possible for those that escape to evolve new functions. However, it took 20 years for the new metabolism to appear in Lenski's culture: it would be a rare event that allowed a novel feature to appear quickly enough to support a fragile artificially designed organism in the wild. But is that enough to convince the public of the safety of pushing the design of bacteria further?

Brian Wynne of the ESRC centre for economic and social aspects of genomics at the University of Lancaster says synthetic biology "does raise
a new set of social and ethical concerns".

Wynne adds: "It raises questions about the forms of regulation that we have devel--oped since the Second World War. Is risk assessment enough for managing the issues that fields like this are generating?"

For Thomas, much of the problem is that exploitation can lead to shortcuts. With biofuels, he cites the problems of the current generation that are produced from food crops (see 'Feeding the power', p50). Although not the only cause of rising food prices, the Gallagher report for the UK's Renewable Fuels Agency claimed that biofuel incentives created by the European Union were a major contributor.

By moving the focus to non-food crops and the waste from food production, second-generation biofuels received greater approval from the report. However, Thomas counters that even these fuels will have consequences: "The assumption is that it is using waste. It isn't. Normally, the waste gets ploughed back into the soil. It lets the soil lock up carbon and prevents erosion. With second-generation biofuels, you will see increased erosion."

Professor Arthur Ragauskas of the Georgia Institute of Technology and the first Fulbright distinguished chair in alternative energy technology at Chalmers University in Sweden, disagrees that all of the waste needs to be ploughed back in and that research is ongoing into the need for biomass to maintain fertility: "There are people
at Oak Ridge [National Laboratory] who have experimental plots to determine how much biomass needs to stay on the land and how much can be taken off."

In the case of medicines, synthetic biology may have an impact on local economies. Work is progressing on the synthesis of the anti-malarial artemisinin using bacteria (see 'Unlocking life's secrets', p64). But social scientists from the University of Nottingham point to this production as possibly disrupting the production of artemisinin in China from natural sources.

The result is that the benefits of synthetic biology in biofuels are difficult to quantify without understanding how the applied technology will fit into the economic environment. But, in the hope of achieving wider public approval, social scientists want to take the debate over synthetic biology closer to the science.

Getting the public's approval

Biologists in the UK have noted that the research councils are encouraging them to include ethicists and social scientists in programmes to try to thrash out potential problems with public acceptance.

The model being adopted by the UK research councils is based on that used for nanotechnology. Government officials and scientists believe that the work undertaken by the Royal Society to investigate claims and counterclaims over nanotechnology was broadly successful.

"It is vital to recognise the importance of maintaining public legitimacy and support. In order to achieve this, scientific research must not get too far ahead of public attitudes and potential applications should demonstrate clear social benefits," wrote Andrew Balmer and Paul Martin of the University of Nottingham in their report commissioned by the Biotechnology and Biological Sciences Research Council (BBSRC) and published last month.

The open question is whether it is the research that is in question or the application when it comes to synthetic biology. And the problems are not just those of perceived dangers, but of technologies that promise much but fail to live up to expectations.

Wynne says: "When there is a lot of pressure to translate into technologies faster and faster, it does raise some important questions. We can see how the competitive world of science allows us to be pushed towards the exaggeration of promises. People are more cautious. They say haven't we heard these promises before? People are responding with a certain amount of scepticism."

The public uses what Wynne calls "evidence-based opinion" - they have seen it all before in fields such as gene therapy, which once promised much. The problem is, it seems, for public support to continue, the promises must be believable and the dangers unbelievable. If that balance shifts too far in the direction of risk, it becomes impossible to make use of the research.

For synthetic biology to avoid becoming the son of genetically-modified foods, science and industry will have to work hard to maintain public support.

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