The synthetic genome

From Frankenstein’s monster through I, Robot to the lost young cyborg of Steven Spielberg’s AI, the idea of creating artificial life from inert matter has long inspired human imagination.

Last week that thrilling but unsettling goal appeared to have come a step closer with the announcement by Craig Venter, the maverick scientist, that his laboratory had constructed the world’s first completely synthetic genome.

He described how he had used laboratory chemicals to recreate an almost exact copy of the genetic material found inside a tiny bacterium - and was now attempting to slot it into an empty cell in the hope of creating a new life form.

For the layman, he compared his work with the building of a computer. His breakthrough was the equivalent of creating the software for a computer’s operating system. Now what he had to do was insert it into the computer itself - the empty cell - and “boot it up”.

What’s more, he announced, he was already working on the next stage of his great project. He would build an entirely synthetic organism, which he would then use to save the world from global warming.

For Venter, the showman of the world of science, the result could hardly have been better. Details of the breakthrough went around the world generating positive headlines. The prospect that a painless way of solving the problems of climate change might have been found was particularly attractive.

As the fuss dies down, however, questions remain. Has Venter really come close to creating a new life form? Will the benefits really be so powerful and clear cut? What might the acquisition of such godlike powers actually mean for humanity?

VENTER himself has long been a man of supreme immodesty. Since the 1990s he has scorched his way through the burgeoning science of genomics, leaving a trail of enemies in his path as he set about mapping the human genome.

The feelings he provokes are so intense that one profile in The New Yorker magazine from 2000 began with a quote from a string of fellow scientists, saying: “Craig Venter is an asshole. He’s an idiot. He is a thorn in people’s sides and an egomaniac.”

Venter’s first breakthrough was in developing what is now known as shotgun sequencing, a method for analysing the human genome faster and more cheaply than ever before.

At the time, however, it was unproven and too risky for the government-funded institution where he worked so, after many rows, Venter left and raised the money himself.

An instinctive entrepreneur, he might have expected to feel more at home mixing with fast moving risk-takers like himself, but instead the rows became even more intense. His first business partnership collapsed and his relationship with Celera Genomics, with whom he completed the genome, also proved tempestuous.

Even the publication of the genome itself proved controversial. Fearing that Venter would patent the genome and charge for access, a consortium of scientists launched their own publicly funded rival effort.

The race became so bitter that Bill Clinton, then US president, had to step in to negotiate a truce, with both teams agreeing to publish their findings simultaneously in 2001.

It was supposed to mark the end of hostilities but when Venter held a party his fellow scientists boycotted the event, leaving Venter glowering over a near-empty dance floor.

Soon after he was sacked by Celera. Insiders made clear the firm could no longer sustain such a huge ego.

Again Venter bounced back, using his £100m share of Celera’s stock to found the J Craig Venter Institute. It now has more than 400 scientists and staff based in Rockville, Maryland, and La Jolla, California. For Venter, however, perhaps its most priceless asset is that he controls it.

The years since then have seen Venter repeatedly in the headlines. Last June he announced success in transplanting the entire genome of one bacterium into another, effectively causing the recipient to change species.

Then, in September, he published his own genome, the first time any individual person’s DNA had been sequenced. It was perhaps a mixed blessing, revealing that Venter is at risk of Alzheimer’s, diabetes and hereditary eye disease.

For scientists the benefits of his institute’s synthetic genome are, however, much clearer. Although they have long been able to make synthetic DNA they have only been able to produce it in short lengths. This is because the chemical “bases” that make up the building blocks of DNA – adenine, thy-mine, cytosine and guanine – are very difficult to work with.

DNA chains are built from pairs of these bases all linked together to form the familiar “twisted ladder” shape. In the test tube, however, the chains become increasingly brittle the longer they get. This means that the largest synthesised DNA chain contained only 32,000 base pairs until now.

Dr Jim Haseloff, a Cambridge University expert in synthetic biology said: “The true breakthrough here is that Venter has built a DNA sequence containing 583,000 base pairs. There is a very good chance that if he can transplant it into a bacterial cell it will start working.”

This event may be far closer even than Venter is saying. The paper published last week was actually written five months ago, since when it has been undergoing peer review by other researchers. In that time the research has intensified.

Dan Gibson, who led the research, and Hamilton Smith, the Nobel prize-winning biologist who worked with him, said: “We are now working towards the ultimate goal of inserting a synthetic chromosome into a cell and booting it up to create the first synthetic organism.”

What it means is that pretty soon we are likely to see the first truly synthetic microbes – and that will be sure to spark fierce debate. Some will accuse Venter of playing God. Others will raise fears of new bioweap-ons. The simple question is: just what will humanity be able to do with this new technology? ONE thing that is clear is that there is no chance of Venter’s techniques being applied to create synthetic human genomes. Or indeed of it leading to the halting of the human ageing process, as some scientists have speculated.

Mycoplasma genitalium, the bacterium on which Venter’s team worked, was chosen purely because it has a relatively tiny genome. Most bacteria have far more – typically up to 10m base pairs long, while fungi have around 38m and plants 115m. Mammals are thousands of times more complex again with humans having around 3 billion base pairs.

Professor Paul Freemont, head of molecular biosciences at Imperial College, London, said: “There are just 485 genes in Mycoplasma, while humans have 20,000. It is science fiction to think Venter’s work could give scientists control of the human genome.”

There are, however, many other possibilities, some of which were set out by Venter himself in a telling article published last autumn. He described how, in 2003, his team had synthesised the first artificial genome, of an obscure virus called phi-X174.

As news of the breakthrough got out, he was invited to a meeting with John Marburger, the president’s chief scientific adviser. Venter said: “We told him now we had achieved this goal, we could begin to move to creating new types of microorganisms that could be used in numerous ways, as green fuels to replace oil and coal, digest toxic waste or absorb greenhouse gases.”

Alongside these attractive benefits, Venter also set out a more sinister possibility. “We could now probably also syn-thesise any virus with a genetic code of fewer than 10,000 ‘letters’ of DNA in under a week in the lab, and larger viruses such as the Marburg or Ebola virus [both very unpleasant] in a month or so.”

For Marburger the implications were clear and, soon after, Venter’s research was put under scrutiny by the National Science Advisory Board for Biosecurity which oversees research deemed potentially dangerous.

In public, however, little was said about such fears. Perhaps the only clue came at a press conference when Hamilton Smith blurted out: “We could make the smallpox genome.” Venter later spoke of his relief when only one reporter repeated Smith’s reference to the “possibility of making deadly pathogens”.

It is a worry that plays on people’s minds. Literature and films are littered with the human race being imperilled by biological innovations that have spiralled out of control. Such fears will never go away. Synthetic biology is after all a powerful technology and, just like genetic modification, crossbreeding and every other method for altering the genetic make-up of other living things, can be used for good or evil.

For now, however, the biggest barrier for making any use of such techniques at all lies in our limited understanding of how DNA works.

The researchers who praise Venter’s breakthrough also warn that predicting how a given sequence of synthetic DNA will actually perform is a far harder task.

Jason Chin, who leads a synthetic biology research group in Cambridge, said: “DNA communicates with a cell by prompting it to make proteins, but we have a long way to go in understanding the relationship between a given DNA sequence, the proteins it generates and the final properties of an organism.”

So, for now at least, scientists will be limited to producing synthetic versions of DNA sequences found in nature and tinkering with them.

When will we see the benefits? The history of biotechnology is littered with other reminders that we may have to wait a long time. Stem cells, gene therapy and cloning were all great scientific discoveries but the practical benefits are taking much longer to emerge.

Venter’s ecological claims for his breakthrough have been greeted with cautious optimism by his peers. But they note that there would be significant regulatory hurdles surrounding the release of a new organism into the environment to overcome. The benefits would most likely not been seen within a decade.

For Venter, however, such cautionary notes are simply a challenge. His vision, he told Newsweek magazine last year, is of creating the first “trillion-dollar organisms” - patented bugs that could excrete bio-fuels, generate clean energy in the form of hydrogen and even produce tailor-made foods.

It is a startling vision of a brave new world, but it also sounds like a world that would be largely controlled by J Craig Venter.


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