Is THIS the "Essence" of Life?!

Essence of Life Found

The essence of life is the smile of round female bottoms, under the shadow of cosmic boredom.

- Guy de Maupassant

United States - Scientists from the Maryland-based Minimal Genome Project reported today in the US journal Science that they had pinpointed 300 genes that provide the minimum coded instructions to build an organism. But they insisted they would not attempt to create a living thing until pertinent ethical and environmental issues had been fully debated. - Reuters

Source: The Evening Post 11 December 1999

For an update on this project, see the final article on this page.

Do you think even a scientist REALLY believes that they've found the essence? [Perhaps I should have said "Do you think a scientist (especially a scientist) really believes..."] there IS an "essence" to life? Is it detectable? Through which clearly defined and agreed upon sense? Is it love? Reproductive capability? (See Living Dead: Ants and Infertile Humans Are Not Alive, but Parasitic DNA Is, According to a New, Universal Definition of Life further on in this section, and the article which follows it, The Origin of Life, for more on this possibility.)

The above illustration - a bottle containing the "essence" of life - appears on the paperback edition of Tom Robbins' curious and entertaining novel, Jitterbug Perfume. The paperback is published by Bantam Books. No one, however, seems to be given credit for the cover art - something I found to be more intriguing, even, than the book itself.

Scientists Identify the Spark of Life

by Mark Henderson

British scientists have discovered the gene that provides the spark of life, when an egg is fertilised by a sperm, in research that promises dramatic advances in fertility treatment and stem cell experiments. A 10-year study has revealed that the gene in sperm triggers the crucial process by which an egg starts dividing to form an embryo, solving a mystery that has confounded medical science for two centuries.

The breakthrough, by researchers at the University of Wales College of Medicine in Cardiff and University College, London, paves the way for improved therapy for infertile couples and treatments that use cloned stem cells to tackle Alzheimer’s, Parkinson’s and diabetes. Scientists believe it will eventually allow them to fertilise eggs using sperm that have previously been considered useless, and to transform success rates in therapeutic cloning.

Does this mean we'll be able to have kids?

It has long been known that fertilisation is followed by a surge of calcium but the molecules that start this process have remained elusive. "We’re thrilled to be at the forefront of such an exciting discovery," Professor Tony Lai, head of the Cardiff team, said. "The potential benefits to medicine are immense."

Mark Henderson is the Science Correspondent

Source: timesonline.co.uk Times Online 18 July 2002

What's Essential?

A Role for Junk DNA?

Junk DNA makes up nearly half of all human DNA, but many scientists have dismissed it as useless. A new study by scientists from the University of Michigan Medical School and Louisiana State University reveals some human LINE-1, or L1, junk DNA elements can jump to chromosomes with broken strands, slip into the break and repair the damage. Because L1s are so ancient and because they sometimes carry segments of genes with them when they jump to a new location, researchers now believe they have played an important role in human evolution by increasing genetic diversity.

Source: UPI

Some "Junk" DNA May Have a Function

It is a cliché of genetics that most of the genome is junk. The genes themselves constitute 2-3% of the DNA in a human cell's nucleus. Some of the rest regulates the genes, but most consists of stuff that is apparently useless or, worse, parasitic. Among the latter are the remnants of so-called retrotransposons.

A retrotransposon is a group of "freeliving" genes which reproduces by hiding in the chromosomes of its hosts, causing that host to copy it at the same time that it copies its own genes. Normally, it breaks out of its host chromosome after a time, to find pastures new. Sometimes, however, a retrotransposon forgets how to have a life of its own, and is just passed down the generations along with the host's genes.

Why such "endogenous" retrotransposons persist is a mystery. Natural selection would be expected to get rid of them. However, in a paper in Current Biology, Clare Lynch and Michael Tristem, of Imperial College, London, suggest an answer. They have been studying a retrotransposon that lost its independence to an early mammal some 70 million years ago. It is now found in that mammal's descendants, including humans, sheep, rats and mice. Dr Lynch and Dr Tristem think that its persistence, and the fact that its genes do not seem to have been damaged by random mutations, are due to the fact that it was "turned" at some point in the past, and is now assisting the hosts. In other words, it is no longer a parasite.

Retrotransposons are closely related to retroviruses, the most notorious of which is HIV, the agent that causes AIDS. One feature of some retroviruses is that infection by one sort can inhibit (by an unknown mechanism) the activities of others. Dr Lynch and Dr Tristem speculate that this retrotransposon's genes may have survived in mammals because the proteins they produce likewise protect cells from the activities of other retrotransposons. The poacher, in other words, has been acting as a gamekeeper since dinosaurs walked the earth.

Source: economist.com 4 September 2003

Unfinished Sequence - the Catch on 22

London - Publication of the sequence of chromosome 22 means that, for the first time since the Human Genome Project was proposed in the mid-1980s, researchers have an almost continuous sequence for a whole chromosome. There is, however, a catch. The published sequence remains "almost continuous" - there are still 11 irritating unsequenced gaps, accounting for about 3% of the sequence. When researchers call the sequence "complete", they mean they've gone as far as possible with routine methods.

Why do these gaps exist? Researchers on the Human Genome Project sequence DNA by isolating small pieces of chromosome inside bacterial clones or BACs which multiply to produce sequenceable quantities of the DNA segment. But, for various reasons, clones for certain sequences are simply absent from the collection of clones, or "clone libraries". According to Ian Dunham of Britain's Sanger Centre, the head of the team that sequenced chromosome 22, most of the gaps contain a sequence that is not stable in Escherichia coli or yeast. One gap does have a corresponding clone; but, for some unknown reason, researchers are unable to sequence it.

As Peter Little, of Imperial College London, puts it, many pieces of DNA "do really weird things when you try to work with them, and we have no idea why." Based on what he has seen in chromosome 22, Dunham speculates that missing sequences will tend to occur in certain regions of chromosomes: clustered at the ends, for example, with some gaps at the centres involving repeated sequences. "The good news is that we can now see how big the gaps are," says Dunham: they are between 50 and 150,000 base pairs. If an interesting gene is thought to be in one such gap, many strategies currently being developed could close these gaps. "It's a matter of fiddling - there is no reason to suppose these pieces cannot be done," says Little, adding that it would make very little difference to the overall list of genes on this particular chromosome.

Source: Nature Volume 402 2 September 1999

DNA Tests Could Solve Dispute over Columbus

by Emma Day

Madrid - In death as in life, it seems. Christopher Columbus could never stay in one place. The many journeys made post-mortem by Columbus, or Cristobal Colon as he is known in Spain, has led to doubt and confusion over his last resting place, with rival tombs claimed by authorities in Seville and Santo Domingo.

Two Spanish teachers, one a history professor with an interest in genealogy, have enlisted a prominent forensic science team to try to resolve the dispute with the help of DNA identification. "We have two Colons, or possibly even a third, buried in the church of La Cartuja in Seville," explained the professor, Marcial Castro, who teaches at a public school in Andalusia and is the driving force behind the project. Many historians have grappled with the whereabouts of the explorer's bones but Castro is apparently the first to come up with a workable solution to identify them. He is now seeking an answer through the skeleton of Hernando, an illegitimate son of Columbus's love affair with a woman from the Andalusian city of Cordoba.

Castro has asked Dr Jose Antonio Lorente, director of the Laboratory of Genetic Identification at the University of Granada to examine bones from Hernando's grave and try to match the DNA to bones from the various disputed Columbus burial sites. Lorente's forensic team usually works on criminal cases but has also tried to identify the bodies of people killed by Latin American dictatorships.

Whether Spanish and Dominican authorities will approve the project, and whether the Roman Catholic church will give permission for exhumation, is unclear. It is also uncertain whether sufficient nuclear DNA will be found in good enough condition to make positive identification of Columbus' remains. But Castro, who is working with Sergio Algarrada, a school colleague who teaches biology, is infectiously hopeful. The two are trying for results by 2006, the 500th anniversary of the explorer's death.

Columbus died an illustrious admiral in Valladolid, Spain, on 20 May 1506, having issued instructions that the should be buried in the Americas. But since no church of sufficient stature had been built there, he was laid to rest in a Franciscan monastery in Valladolid. Three years later, he was moved to a family chapel in the Carthusian monastery on the island of La Cartuja in Seville.

Castro said that in 1537, Maria de Rojas y Toledo, Columbus's daughter-in-law, received royal permission to move the explorer's corpse, and that of her husband, Diego Colon, to the Dominican Republic, to be interred in the newly constructed cathedral of Santo Domingo. But even this grave was to prove unquiet. In 1795, Spain ceded the island to France and decided that such venerable bones should not fall into the hands of foreigners. So they were moved to Havana, where they lay until 1898 and the Spanish-American War. At that point, the Spanish authorities decided they should be repatriated to Seville.

By then the controversy was already under way: an excavation of the Santo Domingo cathedral in 1877 unearthed a lead box inscribed with the words: "Illustrious and distinguished male, don Cristobal Colon." It contained 13 large bone fragments and 28 small ones, as well as a lead bullet that was thought to be from a wound the explorer suffered in his youth. Those remains are now buried at the Faro de Colon monument in the Dominican Republic.

A second tomb found at the time was said to contain the bones of Luis Colon, grandson of Columbus; the Dominican authorities suggested that the Spanish had removed some other corpse by mistake.

To complicate matters still further, said Castro, in 1950 a history buff related to a family that bought the Carthusian monastery in 1839 turned up a body in the chapel where Columbus had once been buried.

Emma Daly writes for The New York Times

Source: International Herald Tribune Friday 24 May 2002

The Strange History of Bread

by I Bronowski

Before 8000BC wheat was merely one of the wild grasses that spread throughout the Middle East. By some genetic accident, the wild wheat crossed with a natural goat grass and formed a fertile hybrid. That accident must have happened many times in the springing vegetation that came up after the last Ice Age. It combined the 14 chromosomes of wild wheat with the 14 chromosomes of goat grass, and produced Emmer wheat with 28 chromosomes. The hybrid was able to spread naturally, because its seeds are attached to the husk in such way that they scatter in the wind.

For such a hybrid to be fertile is rare but not unique among plants. But now the story becomes more surprising. There was a second genetic accident, which may have come about because Emmer was already cultivated. Emmer crossed with another natural goat grass and produced a still larger hybrid with 42 chromosomes, which is bread wheat. That was improbable enough, and we know that bread wheat would not have been fertile but for a specific genetic mutation on one chromosome.

Yet there is something stranger. Now we had a beautiful ear of wheat, but one which would never spread in the wind because the ear was too tight to break up. And if it was broken, why, then the chaff flew off and every grain fell exactly where it grew. The bread wheat could only multiply with help; man must harvest the ears and scatter their seeds; and the life of each is dependent on the other.

In the Old World that happened about 10,000 years ago, and it happened in the Fertile Crescent of the Middle East. But it happened more than once. Almost certainly agriculture was invented independently in the New World, or so we believe on the evidence that maize needed man like wheat.

Source: Anderson Valley Advertiser date undenoted

Aunt Mom

by Smita P Nordwall

French officials are investigating the case of a 62-year-old woman who gave birth to a boy she said was fathered by her handicapped brother. The woman, identified only as "Jeanine," said she became pregnant using her brother's sperm and an egg from an American woman. A second child, a girl, fathered by her brother, was born to the woman who donated the egg.

Jeanine said both babies live with her and her brother, who is 52. The brother is blind and has been partially paralysed since he tried to kill himself in 1992. She said she did it to continue the family line.

Source: USA Today from wire reports date undenoted

Scientists Planning to Make New Form of Life

by Justin Gillis

Scientists in Rockville are to announce this morning that they plan to create a new form of life in a laboratory dish, a project that raises ethical and safety issues but also promises to illuminate the fundamental mechanics of living organisms.

J Craig Venter, the gene scientist with a history of pulling off unlikely successes, and Hamilton O Smith, a Nobel laureate, are behind the plan. Their intent is to create a single-celled, partially man-made organism with the minimum number of genes necessary to sustain life. If the experiment works, the microscopic man-made cell will begin feeding and dividing to create a population of cells unlike any previously known to exist.

To ensure safety, Smith and Venter said the cell will be deliberately hobbled to render it incapable of infecting people; it also will be strictly confined, and designed to die if it does manage to escape into the environment. More worrisome than the risk of escape, they acknowledged, is that the project could lay the scientific groundwork for a new generation of biological weapons, a risk that may force them to be selective about publishing technical details. But they said the project could also help advance the nation's ability to detect and counter existing biological weapons.

The project, funded with a $3 million, three-year grant from the Energy Department, will start as a pure scientific endeavor, but it could eventually have practical applications. If Venter and his collaborators manage to create a minimalist organism of the sort they envision, they will attempt to add new functions to it one at a time - conferring on it the ability, for instance, to break down the carbon dioxide from power plant emissions or to produce hydrogen for fuel. The more immediate plan is to try to puzzle out, and eventually model in a computer, every conceivable aspect of the biology of one organism, a feat science has never come close to accomplishing. Because all living cells are based on the same chemistry and bear striking resemblances to one another, that could shed light on all of biology. "We are wondering if we can come up with a molecular definition of life," Venter said. "The goal is to fundamentally understand the components of the most basic living cell."

The project is not entirely new. Venter launched an earlier version of it in the late 1990s while running a Rockville institute he founded called the Institute for Genomic Research. With his collaborators, he got as far as publishing a working list of the genes apparently required to sustain life in a single-celled organism called Mycoplasma genitalium, the self-replicating organism with the smallest known complement of genetic material. That work indicated that under at least some laboratory conditions, the organism could get by with only 300 or so of its 517 genes. People, by contrast, have an estimated 30,000 to 50,000 genes.

The project fell by the wayside when Venter and Smith launched Celera Genomics Corporation, the Rockville company that raced publicly funded researchers to a tie two years ago in compiling draft maps of the entire human genetic complement, the genome.

Venter resigned from Celera early this year in a dispute over its future direction. He is financing a series of new initiatives, including the Institute for Biological Energy Alternatives, the entity that will house a revived project to build the artificial organism. The $3 million Energy Department grant, awarded recently, will pay for a staff of about 25 to pursue the project over three years, though Venter and Smith acknowledged it could take longer. Smith, widely considered one of the world's most skilled at manipulating DNA, will direct the laboratory work. The project will begin with M genitalium, a minuscule organism that lives in the genital tracts of people and may or contribute to some cases of urethritis, an inflammation of the urethra. The scientists will remove all genetic material from the organism, then synthesize an artificial string of genetic material, resembling a naturally occurring chromosome, that they hope will contain the minimum number of M genitalium genes needed to sustain life. The artificial chromosome will be inserted into the hollowed-out cell, which will then be tested for its ability to survive and reproduce.

Ari Patrinos, a senior Energy Department administrator who will help oversee the project, said the organism was an attractive starting point to create a "minimal genome" because it is so minimal already. "We know even the simplest of cells is incredibly complicated," Patrinos said - too complicated, at least so far, to understand completely. "This is a case where we're trying to cheat a little bit, to take the smallest and simplest and make it smaller and simpler."

The project raises philosophical, ethical and practical questions. For instance, if a man-made organism proved able to survive and reproduce only under a narrow range of laboratory conditions, could it really be considered life? More broadly, do scientists have any moral right to create new organisms? A panel of ethicists and religious leaders, convened several years ago at Venter's request, has already wrestled with the latter issue. The group, which included a rabbi and a priest, concluded that if the ultimate goal was to benefit mankind and if all appropriate safeguards were followed, the project could be regarded as ethical. "I'm less worried about the minimal genome project taking off and creating some kind of monster bug than I would be, partly because I have a sense that the scientists are aware of the possible risks of what they're doing," said Mildred Cho, a bioethicist at Stanford University who was chairwoman of the ethics panel.

Scientists don't usually announce their experiments in advance, but Venter said he felt this one needed to be brought to the attention of policymakers in Washington, since it could create a new set of tools that terrorists or hostile states might exploit to make biological weapons. "We'll have a debate on what should be published and what shouldn't," Venter said. "We may not disclose all the details that would teach somebody else how to do this." Venter and Smith acknowledged the theoretical risk of creating a new disease-causing germ, but said they would take steps to ensure against that. One of the first genes they'll delete is the one that gives M genitalium the ability to adhere to human cells. Many of the 200 genes to be deleted will be ones that confer the ability to survive in a hostile environment, so that the end result will be a delicate creature, at home only in the warm nutrient bath of a laboratory dish. Even if the organism were to escape stringent confinement and enter the environment, Smith said, "it's a dead duck."

Justin Gillis is a Washington Post staff writer

Source: The Washington Post Thursday 21 November 2002 © The Washington Post Company

The Bradford Bug That May Be a New Life Form

by Roger Highfield

A strange life form has been identified in Bradford. Genetic analysis reveals that the organism is so bizarre and unlike anything else seen by scientists that perhaps it should be placed in its own category of living things. The creature, first discovered in a small industrial cooling tower on the outskirts of the city, could qualify for a new "domain" in the tree of life - where a domain is a bigger category than a kingdom or a phylum.

The "giant virus", dubbed the Mimivirus, or "mimicking microbe", because it was first mistaken for a bacterium, inhabits amœbae and is more than twice as big as any other virus so far found. At about half a millionth of a metre across - around the size of a small bacterium - it is one of the few that can be seen under a light microscope. Two research teams in the Marseille School of Medicine, led by Prof Didier Raoult and Prof Jean-Michel Claverie, have "read" the genetic code of the organism and found a number of genes previously thought to belong only to more complex life forms. The size and complexity of the Mimivirus genetic code - which is 1.2 million "letters" long, at least 10 times larger than the code of a typical virus - "challenges the established frontier between viruses and parasitic cellular organisms", they report today in the journal Science.

One of the defining characteristics of a virus is that it is unable to make proteins independently, instead relying on the cells it infects to manufacture its proteins and thus reproduce. But the Mimivirus contains a number of genes for protein translation. It also contains genes for DNA repair enzymes and other proteins, all typically thought to be trademarks of cellular organisms. The Mimivirus - which so far has only been found in Bradford - appears to represent a new family of "nucleocytoplasmic" large DNA viruses that emerged with the first life on earth some four billion years ago, said Professor Raoult. After much debate among his team, "for the first time we have enough genetic information to conclude that there is a fourth domain of life", he said. "If this is true, this is revolutionary."

The other three domains of life are the eukaryotes, which have cells that contain a nucleus, and the prokaryotes, unicellular organisms that are divided into the bacteria and archæa. The family tree drawn up by Professor Claverie shows that the Mimivirus is no more related to the eukaryotes as it is to bacteria. "This organism is as old as all the rest of living organisms," he said.

However, Dr Dave Roberts, head of microbiology at the Natural History Museum, London, was "deeply sceptical" that the Mimivirus deserves to be placed in its own domain, though he agreed that it did mark a new family. "There are a lots of odd things turning up in the microbial world all the time," he said. "It is a fascinating paper and very exciting. The virus seems to link to a group prior to the appearance of the three domains we currently recognise. But we are not convinced that the tree of life is still a branching structure when you get that deep."

The giant virus has not so far been linked with disease.

Roger Highfield is the science editor of The Telegraph

Source: portal.telegraph.co.uk 15 October 2004

What Is Life? Can We Make It?

by Philip Ball

Two years ago American scientists created life. Or did they? It all depends on what you mean by life. More specifically, it depends on whether you are prepared to regard viruses as living entities. Viruses have genes, and they replicate, mutate and evolve, all of which sounds lifelike enough. And in August 2002, a team at the State University of New York (SUNY) announced that it had made a virus from scratch, by chemistry alone.

What this meant was that, for the first time since life began over 3.5 billion years ago, a living organism had been created with genetic material that was not inherited from a progenitor. To what did the SUNY researchers choose to award the honour of being the first synthetic organism? They selected a virus that scientists have spent decades trying to eradicate, a cause of human disability and death: polio. If you think that sounds unwise, so did some biologists. Craig Venter, former head of the privately-funded US human genome project conducted by Celera Genomics, called the work "irresponsible" and claimed that it could hurt the scientific community.

To Eckard Wimmer, who led the SUNY team, this alarming choice of target was the whole point. If they could do it, so could bioterrorists. Wimmer's group did not apply any great technical wizardry: they simply looked up the chemical structure of the polio virus genome on the internet, ordered segments of the genetic material from companies that synthesise DNA, and then strung them together to make a complete genome. When mixed with the appropriate enzymes, this synthetic DNA provided the seed from which the infectious polio virus particles grew. It was so simple that some researchers claimed it could be done by undergraduates.

Making viruses from scratch is just one of the potentially devastating capabilities of a new field of science called synthetic biology. Most biologists cling to the belief that theirs is a pure science, an exploration of the world "out there" - far removed from the moral dilemmas of applied science and technology. But synthetic biology tells us that biology is no longer an immutable aspect of the world.

In a sense, that is nothing new: several of the most contentious moral issues which science has generated in the past decades have hinged on the question of whether, or how much, we should tamper with biology. Every genetically modified organism (GMO) is in some degree synthetic, a product of the human manipulation of genetic material. The same can be argued of genetic clones, and perhaps even of embryos made by in vitro fertilisation. But synthetic biology aims for much deeper levels of intervention than, say, simply adding a herbicide-resistance gene to a plant's genome. Synthetic biology regards living organisms - at the most basic level, single cells - as assemblies of parts that can be reassembled in new ways, or redesigned, or indeed built from scratch, perhaps with completely different materials. It is not about tinkering with biology, but about what exactly biology is, whether alternative biologies are possible, and whether we can remake life just as we can redesign cars or houses.

Bigger benefits, bigger risks

There are some powerful arguments for why we might want such new forms of biology. Some researchers believe that synthetic biology could solve the energy crisis, transform manufacturing into a green technology or rid the world of infectious diseases. It could allow us to combat lethal viruses and tumour cells on their own terms, using their own tricks and weapons. It could deliver new drugs and provide cheaper means of making existing ones. Yet if ever there were a science guaranteed to cause public alarm and outrage, this is it. Compared with conventional biotechnology and genetic engineering, the risks involved in synthetic biology are far scarier. Whether you approve of them or not, GMOs are more like patients with an organ transplant than Frankenstein's monster. There is no sense in which genetic engineers are "making life" - but that is what synthetic biologists propose to do, if indeed they have not already done so.

Building known viruses from the genome up is one thing, but some researchers are redesigning DNA itself. "I suspect that in five years or so, the artificial genetic systems that we have developed will be supporting an artificial lifeform that can reproduce, evolve, learn and respond to environmental change," says Steven Benner, a chemical biologist at the University of Florida. Benner is no stranger to the controversy that this is likely to excite. Sixteen years ago he organised a conference in Switzerland that pre-empted the new field of synthetic biology. It was to have been called "Redesigning Life." "The conference title raised such a furore that it had to be changed to 'Redesigning the Molecules of Life,'" says Benner. "People were convinced that the original title would incite riots."

The idea of "playing God" is beside the point here - the notion that God cobbled organisms together from nucleic acids and proteins like a chemist experimenting in the lab should be offensive to any theistic faith. In fact, one of the brightest prospects of synthetic biology is that it might allow us to begin exploring how life began, which in turn could force us to take a less sentimental view of what we mean by life in the first place. There is nothing very spiritual about DNA and proteins, the "stuff of life." To chemists they are just beautifully ingenious molecules. If there does turn out to be anything special about these chemical building blocks which makes them uniquely suitable for sustaining life (and this is by no means clear), it will be for prosaic reasons such as their chemical stability, not because of any vitalistic magic.

What is life, anyway?

Life is not embodied in its molecular building blocks, but it is a characteristic of the way in which they interact. It may be that you could create life from a completely different pool of constituents, just as a computer can be made from ping-pong balls running down tubes, instead of silicon chips. Despite the hype of the human genome project, life's grandeur does not reside in a filament of DNA. The truth is that life does not have an objective, scientific meaning. Even scientists sometimes fail to recognise this, wasting much ink in trying to come up with an airtight set of criteria that a living organism must meet. They typically invoke such characteristics as the ability to reproduce, grow, metabolise, evolve and respond to the environment. They will fret about whether a living entity must have boundaries, or whether a computer program or a planet can be "alive."

The futility of all this was recognised 70 years ago by the British virologist Norman Pirie, who wrote: "'Life' and 'living' are words that the scientist has borrowed from the plain man. The loan has worked satisfactorily until comparatively recently, for the scientist seldom cared and certainly never knew just what he meant by these words, nor for that matter did the plain man. Now, however, systems are being discovered and studied which are neither obviously living nor obviously dead, and it is necessary to define these words or else give up using them and coin others." It is natural that a virologist like Pirie should understand this, because viruses are nature's reminder that there are no boundaries between the animate and inanimate realms. No one knows whether to call viruses living or not. Their genes are sometimes, as in the case of polio, encoded not in DNA but in its sister molecule RNA, and they cannot reproduce autonomously: they must infect a host organism and borrow its cellular enzyme machinery to make copies of themselves.

So it remains a moot point whether by creating viruses synthetic biologists have made life. But that ambiguity is likely to disappear in the next few years. Viruses inhabit a grey area, but bacteria are clearly alive: they are single-cell organisms that sequester raw materials and energy from their environment and replicate on their own. No one has synthesised a bacterial cell chemically yet, but it is not far off. The technology for synthesising strands of DNA chemically - by stringing together their four distinct molecular building blocks, or nucleotides, one by one in specified sequences, like combining words to make sentences - is on the verge of being able to generate sequences of one million or so nucleotides. That is long enough to construct the genome of some bacteria - the smallest known bacterial genome, that of the Mycoplasma genitalium, contains just 517 genes, encoded in a genome of 580,000 nucleotides.

Craig Venter, who now heads the Institute for Biological Energy Alternatives in Rockville, Maryland, believes that Mycoplasma genitalium could point the way to a "minimal genome": the smallest complement of genes that can support a viable organism. One way of finding out what is essential and what is an evolutionary luxury is to strip out genes from the bacteria one by one and see if the cells survive. Another option is to make the pared-down genome from the bottom up, by chemical synthesis of DNA, and see if it can be brought to life - that is, used as the blueprint for making an organism. Last November, Venter reported the synthesis of the complete genome of another virus, a bacterial pathogen called phi X. In contrast to the polio virus genome, which was patched together over many months, Venter's team made the phi X genome in just a few days, demonstrating how quick this DNA technology has become.

Redesigning cells

The odd name of Venter's institute testifies to his desire to use a bacteria-building technology to solve important practical problems. He is being funded by the US department of energy to explore the redesign of bacteria as hydrogen-generating organisms. Some natural bacteria produce hydrogen, but they are neither robust nor efficient enough to provide an abundant natural source of this clean fuel. Venter hopes that, either by transforming existing microbes or by creating entirely new, synthetic species, he can design microbes that make hydrogen for power generation.

Such practical applications are not the only reason for wanting to identify a minimal organism. One of the prime motivations behind synthetic biology is to understand how natural cells work. While this has arguably been the objective of molecular biologists for over 100 years, only recently have they been forced to accept that decoding genomes - reading out the sequences of nucleotides in an organism's DNA - is not going to supply the answer. For all the talk of "reading the book of life," the sequencing of the human genome (completed in draft form in 2000) tells biologists as much about the way human cells function as a pile of engine parts tells the mechanic how a car works. The question is how the parts fit together, and how they interact with one another. This is now being addressed in the discipline known as systems biology.

Systems biologists think of cells as circuits, rather like the electronic circuits of silicon chips. The individual components are genes and proteins, and they are "wired" into networks in which specific elements regulate the behaviour of other components, for example by switching them on or off. Most genes encode the instructions for making particular protein molecules, each with a definite role in cell function. One gene might regulate another gene by generating a protein that binds to the other gene and prevents it from producing its own protein. Biologists are now mapping out this network of interactions, providing them with circuit diagrams of cells. They are finding that many of the motifs familiar from electronic engineering, such as feedback loops, switches and amplifiers, appear in gene circuits too. That is why systems biologists are as likely to be computer scientists or electrical engineers as molecular biologists.

It was inevitable that, once this engineer's view of the cell began to emerge from systems biology, the engineers would start asking what they always ask: what can we make? If cell circuits can be broken down into gene modules that perform well defined functions, what happens if the modules are rewired? Can one design new modules from scratch?

The first demonstration of this thinking came four years ago, when Princeton researchers Stanislas Leibler and Michael Elowitz designed an oscillator gene circuit and plugged it into the genome of E coli, the bacteria that live in our guts. The experimental techniques involved in such a manipulation are tried and tested: biotechnologists have been splicing foreign DNA into genomes for over two decades, using a method called recombinant DNA technology. But until then, no one had thought of making a module that did something as physics-like as oscillate. What does it mean for a genome to oscillate? In Elowitz and Leibler's module, which they called a repressilator, three genes switched each other off in cyclic succession, so that the cycle of gene repression repeated with a steady rhythm like a game of pass the parcel. The researchers designed one of the genes so that it also triggered the cells to produce a protein that glowed green when light was shone on it. They found that E coli cells fitted with the repressilator module blinked on and off periodically, like tiny living beacons.

As researchers heard at the first conference on synthetic biology at MIT in June, there is now an expanding toolbox of gene modules that can be wired into cells to alter and control their behaviour. In April, Ron Weiss and collaborators at Princeton described E coli cells equipped with population-control modules, so that the cells committed suicide if their population density rose above a certain level. The synthetic module includes genes that make the bacteria emit a chemical, so that they can "smell" how many other cells are in their vicinity. If this "smell" gets too strong, a killer gene is activated that causes the cell to die. Programmed behaviour like this could be exploited to turn bacteria into environmental sensors that spot and signal the presence of toxic chemicals.

Some researchers consider these reprogrammed cells to be like wet micro-robots that can be directed towards useful tasks by downloading genetic instructions into their genomes. It may be possible to fit such cells with safety circuits to prevent their unwanted proliferation in the wild - they could be programmed to die if they were to escape from some highly controlled environment, or could even be fitted with genetic "counters" so that they would become incapable of dividing after a specified number of generations. But it is not clear yet how secure such measures would be. Because of the random mutations that occur during any process of cell division, some of Weiss's cells evolved to escape the population-control mechanism.

As well as rearranging and redesigning the molecular components of life, synthetic biologists are introducing completely new materials into biology. When it comes to making organisms, nature is endlessly inventive, but it is remarkably conservative with its basic building blocks. Just about all proteins are constructed from only 20 different types of amino acid: each protein molecule is a distinct permutation of these ingredients, strung together in a chain and then usually folded up into a compact shape. Similarly, the genome of every organism in existence contains just the four nucleotides of DNA (except for RNA-based viruses, which are a minor variation) arranged in different sequences. There seems to be no fundamental reason why biology has to use this limited palette - it is simply that, just as with some industrial processes, changing the set of components is too costly to be worthwhile. But scientists have now made bacteria that can use new, non-natural amino acids in their proteins, and non-natural nucleotides in their DNA.

Similarly, the genetic code - the correspondence between nucleotides and amino acids, which enables protein structures to be encoded in genes - is essentially identical across all of biology. But it is now possible to change the code: to make cells that perform the DNA-protein translation in another language from the one employed throughout the course of evolution. The book of life, in other words, is written not in stone but in soft clay, and we can wipe it clean and start again. How would a bacterium fare if its genetic code was entirely different? Would it evolve more quickly, or in unexpected directions? Could it breed with natural bacteria? We may soon find out.

How worried should we be?

New ethical questions raised by science tend to fall back fairly quickly on old templates. And the notion of creating life is an ancient template indeed: Mary Shelley was fully conscious of the legends she evoked, since her father William Godwin was the author of Lives of the Necromancers, with chapters on Paracelsus and Faust. Paracelsus's instructions for making the homunculus, an "artificial man," were drawn from the same mythic well that produced the Golem of Jewish cabbalistic fable. When science intersects with cultural myths as profound as this, the ensuing debates tend to get shaped by undercurrents of which the participants are often unaware.

There is greater continuity between Mary Shelley's tale and modern biochemistry than is often appreciated. The dream of a chemical creation of life was very much alive at the turn of the 20th century, and was announced more than once in the newspapers. In 1899, biologist Jacques Loeb discovered that sea urchin eggs could be made to produce larvae by treating them with inorganic salts, without the need for fertilisation by sperm - "artificial parthenogenesis," as Loeb called it. The Boston Herald hailed this as the "Creation of life: Lower animals produced by chemical means."

Three years later, Loeb was being compared to Frankenstein. He did little to dispel such notions, claiming that "We may already see ahead of us the day when a scientist, experimenting with chemicals in a test tube, may see them unite and form a substance which will live and move and reproduce itself." Nor was this an idiosyncratic position: Darwin's champion Thomas Huxley maintained that the biological goo known as "protoplasm" was sure to be put together some day by chemists. "I can find no intelligible ground for refusing to say that the properties of protoplasm result from the nature and disposition of its molecules," he insisted. By 1912, the president of the British Association for the Advancement of Science confirmed that scientists were on the threshold of "bringing about in the laboratory the gradual passage of chemical combinations into the condition which we call living." The dream has always been too seductive to relinquish.

The image of the Promethean scientist whose quest for knowledge unleashes destructive forces beyond his control might be a romantic distortion of the way in which science works, but synthetic biology surely provides more cause than biotechnology or nanotechnology ever have to worry about a runaway catastrophe. And synthetic biologists themselves admit as much - they are already showing deep concern about the directions their nascent discipline could take. The most immediate fear is that catastrophe could be engineered. Last November, the CIA issued a report, "The Darker Bioweapons Future," which cited the SUNY work on the polio virus and cautioned that the advances that are driving synthetic biology could also lead to biological agents with effects "worse than any disease known to man." The report hinted at the need for "a qualitatively different working relationship between the intelligence and biological sciences communities."

Scientists would, of course, prefer self-regulation. Already, scientific journal editors have taken it upon themselves to delete from papers details that could be judged as posing security risks. The American Society for Microbiology asked an author to remove a description of how a lethal natural toxin could be modified to boost its potency 100-fold. Some feel that such measures do not go far enough; others fear that they are already a threat to academic freedom. Certain precautions ought to be routine: for example, some companies that synthesise DNA sequences now check their orders against the genome sequences of known pathogens. But the industry remains barely regulated; biologist Roger Brent of the Molecular Sciences Institute in California has suggested that DNA synthesis might in future require a licence. The nightmare scenario, however, is that synthetic biology could generate a "hacker" culture analogous to the internet - except that the viruses which hackers designed would be real, not virtual.

George Poste of Arizona State University, who weathered several scientific controversies as chief science and technology officer of the pharmaceuticals giant SmithKline Beecham in the 1990s, fears that synthetic biology is poised to fall foul of the fantasy of a zero-risk culture. While the problems this new science might address, such as the spread of diseases ranging from Aids to Sars to malaria, have come to be regarded by society as business as usual, public concern focuses on the extreme, rare disasters that new technologies could precipitate. According to Poste, a powerful technology like synthetic biology whose implications are extremely hard to predict requires "a framework for navigation, not prescriptive controls." But Poste acknowledges that some of the risks of this field are real. He has suggested how a "risk factor" for new scientific developments might be estimated on the basis of their possible benefits, dangers and unknowns. When the risk factor exceeds a given threshold, this would act as an alarm signal.

Whichever path is taken, Poste believes that "biology is poised to lose its innocence" - the price that is always paid when science becomes technology. Some might argue that this innocence was forfeited years ago with the development of the recombinant DNA techniques that enable genetic engineering. But we would be wrong to regard synthetic biology as "the same thing, only more so." The field should bring real benefits, and it poses real dangers. It will also signal a new relationship with nature, one that will uproot some treasured, if confused, notions about what "nature" and "life" mean.

Source: prospect-magazine.co.uk August 2004