[Paleopsych] NS: Alive! The race to create life from scratch

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Alive! The race to create life from scratch
      * 12 February 2005
      * Bob Holmes

    YOU might think Norman Packard is playing God. Or you might see him as
    the ultimate entrepreneur. As founder and CEO of Venice-based company
    ProtoLife, Packard is one of the leaders of an ambitious project that
    has in its sights the lofty goal of life itself. His team is
    attempting what no one else has done before: to create a new form of
    living being from non-living chemicals in the lab.

    Breathing the spark of life into inanimate matter was once regarded as
    a divine prerogative. But now several serious and well-funded research
    groups are working hard on doing it themselves. If one of them
    succeeds, the world will have met alien life just as surely as if we
    had encountered it on Mars or Europa. That first alien meeting will
    help scientists get a better handle on what life really is, how it
    began, what it means to be alive and even whether there are degrees of
    "aliveness". "We want to demonstrate what the heck life is by
    constructing it," says Packard's business partner and colleague Steen
    Rasmussen, a physicist at Los Alamos National Laboratory in New
    Mexico. "If we do that, we're going to have a very big party. The
    first team that does it is going to get the Nobel prize."

    Although the experiments are still in the earliest stages, some
    people, especially those with strong religious beliefs, feel uneasy at
    the thought of scientists taking on the role of creators. Others worry
    about safety - what if a synthetic life form escaped from the lab? How
    do we control the use of such technology?

    Finding a way to address these worries will have benefits beyond
    helping scientists answer the basic questions of life. The practical
    pay-offs of creations like Rasmussen's could be enormous. Synthetic
    life could be used to build living technologies: bespoke creatures
    that produce clean fuels or help heal injured bodies. The potential of
    synthetic organisms far outstrips what genetic engineering can
    accomplish today with conventional organisms such as bacteria. "The
    potential returns are very, very large - comparable to just about
    anything since the advent of technology," says Packard. And there is
    no doubt that there is big money to be made too.

    Only a few research groups have explicitly set themselves the goal of
    making a synthetic life form (see "Race for the ultimate prize" -
    bottom). Most are adapting bits and pieces from existing organisms.
    ProtoLife's plans are the most ambitious and radical of all. They
    focus on Rasmussen's brainchild, which he has nicknamed the Los Alamos
    Bug. Still but a gleam in its creator's eye, the Bug will be built up
    from first principles, using chemicals largely foreign to existing
    creatures. "You somehow have to forget everything you know about
    life," says Rasmussen. "What we have is the simplest we could dream

    To achieve this radical simplicity, Rasmussen and his colleagues had
    to begin with the most basic of questions: what is the least something
    must do to qualify as being alive? Biologists and philosophers
    struggled to answer that question for decades (New Scientist, 13 June
    1998, p 38). However, most now agree that one key difference - perhaps
    the only one - between life and non-life is Darwinian evolution. For
    something to be alive, it has to be capable of leaving behind
    offspring whose characteristics can be refined by natural selection.
    That requires some sort of molecule to carry hereditary information,
    as well as some sort of process - elementary metabolism - for natural
    selection to act upon. Some kind of container is also needed to bind
    these two components together long enough for selection to do its

    Containment, heredity, metabolism; that's it in a nutshell. Put those
    together in the simplest way possible, and you've got the Los Alamos
    Bug. But every step is completely different from what we're used to
    (see graphic - the four stages shown are described further in "The Los
    Alamos Bug" - below).

    Take containment, for example. Terrestrial life is always water-based,
    essentially a watery gel of molecules enclosed within an oily
    membrane. Modern cells move nutrients across this membrane with the
    help of an array of different proteins embedded in the membrane. The
    Los Alamos Bug, however, is completely different. For a start it is
    oil-based, little more than a droplet of fatty acids. "Instead of
    having a bag with all the good stuff inside, think of having a piece
    of chewing gum," says Rasmussen. "Then you stick the metabolic
    molecules and genetic molecules into the chewing gum, so they are
    attached on the surface or sitting inside the chewing gum."

The bare necessities

    The container is the easy part. The next step - heredity - is where
    most efforts to create synthetic life get bogged down. The challenge
    is to create a molecule complex enough to carry useful genetic
    information, which can also replicate. In modern organisms DNA has a
    whole army of enzymes to help it replicate its genetic information -
    far too complicated a process for the Bug. Instead, Rasmussen plans to
    use a molecule called peptide nucleic acid, or PNA. It uses the same
    "letters" of genetic code as DNA, but has two forms, one soluble only
    in fat, the other also attracted to water. Rasmussen hopes to put
    PNA's dual nature to use in a rudimentary form of replication (see

    The Bug's metabolism has also been pared down to the minimum. The
    researchers plan to "feed" it with chemicals that can be converted
    into fatty acids. If enough are produced, the droplet will grow and
    divide into two. A similar metabolic process turns PNA precursors into
    functional PNA.

    Although most of the design is still on the drawing board or in the
    earliest stages of experimentation, the team has made most progress
    with the Bug's metabolism. "If you look at the individual pieces, they
    are all sort of demonstrated in the lab. But if you put everything
    together, not yet," says Liaohai Chen, a biochemist at Argonne
    National Laboratory near Chicago, who heads Rasmussen's experimental
    team. If all goes according to plan, these three components -
    container, genome and metabolism - should fit together to provide all
    the essentials for Darwinian evolution.

    In October 2004, Rasmussen landed a large grant from Los Alamos to
    begin making the Bug a reality. "I can't promise that we'll have it in
    three years, but I can guarantee that we'll have good progress," he
    says. The biggest problem may be coordinating the copying of the PNA
    and the metabolism of the fatty acid precursors so that replication of
    the genome proceeds at the same pace as the growth of the droplets.
    "Almost always when you put processes together there are
    cross-reactions, things that your theories won't tell you about."

Life support

    Another fledgling research programme, known as Programmable Artificial
    Cell Evolution, or PACE, could provide the solution to this
    coordination challenge. Packard and Rasmussen are collaborating with
    PACE, which is focusing some of its attention on Rasmussen's design. A
    key idea behind PACE is to deliver precise amounts of particular
    chemicals to synthetic cells at specific places and times using
    computers to precisely control the flow of tiny amounts of chemicals.
    For example, a computer could use sensors to monitor the rates of PNA
    replication and fatty acid production in Rasmussen's experimental
    system, then deliver the correct amounts of each precursor. That would
    let researchers work out the kinks one by one in a controlled,
    programmable setting, providing something rather like a life-support
    machine that helps artificial cells through the critical steps towards
    becoming alive. "Once we have our hybrid unit, then we can
    successively withdraw the machine to approach a stand-alone cell,"
    says John McCaskill, a chemist at Ruhr University in Bochum, Germany,
    who heads the PACE programme.

    In this way the PACE team plans eventually to evolve its way towards a
    self-supporting artificial cell. To do that, though, the team will
    need a way to recognise the system's first tentative steps down the
    pathway to life. But how do you recognise something faintly lifelike,
    when it looks nothing like the life we know?

    Look for the footprints of adaptation, says Mark Bedau, a philosopher
    who specialises in the boundary between life and non-life. Bedau is on
    leave from Reed College in Oregon to work with Packard at ProtoLife.
    If something is evolving then it should be generating adaptations -
    novel solutions to the problems of the world. And those new solutions,
    however subtle and incremental, become the foundation from which
    evolution takes its next steps. Adaptations which confer some
    advantage should last longer and spread faster than other variations.

    Bedau is developing statistical tests which will pick up these kinds
    of patterns in unfamiliar life forms. But since the PACE project has
    not yet begun lab experiments, he does not know whether the tests can
    detect the glimmerings of real life. However, he has road-tested them
    on a system that works in a similar way, namely human culture.

    In 2002, Bedau and colleague Andre Skusa sifted through more than five
    years of US patent records, counting the number of times each patent
    has been cited as a basis for later patents. They found that a few
    patents - such as the one enabling a web browser to display an ad
    while loading the main page - were cited far more often than one would
    expect if the differences found in the number of citations for
    inventions were random. These key innovations are the equivalent of
    biological adaptations such as opposable thumbs. "That gives you
    reason to think it should be possible to do the same kind of thing in
    chemical systems which are not yet alive but might be on the path to
    being alive," says Bedau.

    Using tests like these, the PACE team hopes to see its hybrid
    gradually become more and more lifelike. But at what point would it
    actually become alive? Perhaps at no particular point, says Bedau, who
    thinks it is quite possible that the living and the non- living are
    separated not by a clear, distinct line but by a wide grey area in
    which the Bug is partly but not totally alive. "There are shades of
    grey, and I imagine measuring how dark the grey is," he says. "Our
    conception of what life is will evolve as we learn more and acquire
    the ability to make things that are more and more alive."

    The moment when a blob of molecules becomes a fully living, evolving
    being is at least several years off. "Even our optimists wouldn't put
    a time horizon much sooner than 10 years for that kind of
    achievement," says Packard. Indeed, sceptics wonder whether the Los
    Alamos Bug and its ilk will ever yield anything useful. "It's
    certainly interesting from the conceptual point of view," says Pier
    Luigi Luisi, a biochemist at the University of Rome 3 and an expert on
    synthetic life. "But nature with nucleic acids and enzymes is so much
    smarter, because these are products that have been optimised over
    billions of years of evolution. To pretend to do life with simple
    chemistry is a nice ambitious idea, but it's probably not going to be
    very efficient."

    Still, if Packard, Rasmussen and their colleagues do someday succeed
    in creating synthetic life forms, they will have opened the door to a
    world of new possibilities. "We are breaking the last barriers between
    us and living technology," says Rasmussen. "That's going to be a very
    big thing. It's going to happen, no doubt about it."

    Among the most obvious payoffs could be organisms custom-designed to
    break down toxic compounds or produce useful chemicals such as
    hydrogen fuel. More conventional organisms can be genetically modified
    to do these tasks, but as Rasmussen points out, "the problem is these
    guys have evolved for billions of years. They're extremely versatile,
    and it's very difficult to keep them on task." An artificial organism,
    on the other hand, could in principle be built to do nothing but the
    task at hand, yet still have the evolutionary flexibility to adapt to
    changing conditions.

    Packard hopes that this controlled adaptability could lead to even
    greater things. He envisions living pharmaceuticals that deliver drugs
    to us in an intelligent, adaptive way, or diagnostic life forms that
    could roam our bodies collecting information and watching for signs of
    a problem. The ultimate goal would be machines that repair themselves
    as living beings do - even computers that can handle incredibly
    complex calculations while coping with inevitable errors, just as our
    bodies tolerate errors and failures within our hundreds of billions of

    If life is all about the ability to evolve and adapt, then living
    technologies always have the potential to surprise us with unexpected
    new strategies that can take them beyond our control. But then again,
    that risk is nothing new. We already grapple with it when
    contemplating what would happen if robots or artificial intelligence
    were to get out of hand and in evaluating the safety of genetically
    modified fish, crossbred potatoes or even introduced rabbits. Indeed,
    for the foreseeable future, synthetic life probably poses much less of
    an escape risk, because the early versions, at least, will be so
    fragile and require so much life support. That means the safety of
    synthetic life is something to keep an eye on, not to be frightened
    of. "There isn't going to be some precipice we're going to fall over,"
    says Bedau. "We'll be slowly inching our way down, and we'll have lots
    of opportunity to turn around."

    As well as concerns about safety, synthetic life raises some profound
    ethical and religious issues. "Just the fact that you're making life
    from scratch will give some people pause. They will think that's a
    prerogative that humans should never take," says Bedau. If humans can
    create life on their own, doesn't that remove one of the last deep
    mysteries of existence, in effect prying God's fingers from one of his
    last remaining levers to affect the world?

    Not necessarily, say theologians. "We are fully a part of nature, and
    as natural beings who are living and creating synthetic life, we are
    in a sense life creating more life, which is what's been going on in
    evolution for 4 billion years now," says John Haught, a Catholic
    theologian at Georgetown University in Washington DC. "And that does
    not in principle rule out that God would still be creating life using
    natural causes - namely us - which is the way in which theology
    understands God as always operating in the world."

    One thing seems certain; synthetic life will provide philosophers with
    plenty to chew on right from the start. Until now, efforts to come up
    with a good definition of life have been hampered by the fact that we
    are trying to generalise from just one example, the life that arose
    here on Earth. Having a second form, completely independent and based
    on different chemistry, should give a new perspective on this age-old
    question. And knowing what did or did not work in the lab, may also
    help us understand the origin of life - the first version, that is -
    on Earth.

The Los Alamos Bug

    Containment This relies on the fact that oil and water do not mix. The
    components of each individual Bug are contained by a droplet of fatty
    acids, suspended in a watery solution enclosed by a test tube. Each
    fatty acid molecule has a negatively charged head which is attracted
    to water and which faces out into the watery environment, and a
    water-hating oily tail facing inward.

    Heredity Instead of DNA the Bug has short stretches of peptide nucleic
    acid, or PNA. Like DNA, PNA is made of two intertwining strands
    containing the genetic "letters" A, T, C and G. And like DNA, the
    sequences of letters on these stands complement each other. A pairs up
    with T and C pairs with G.

    The strands have a peptide backbone which does not carry an electrical
    charge, so will dissolve in fat. This means that the molecules of PNA
    prefer to face the inside of the fatty acid droplet, like crumbs
    embedded in the surface of a piece of chewing gum.

    This gives the molecule unusual mobility. In its usual double-stranded
    form, with its two peptide backbones facing outwards, a PNA molecule
    is completely fat-soluble, so it will sink into the oily centre of the
    Bug's droplet. But above some critical temperature, the two strands of
    the PNA double helix separate spontaneously. When this happens, the
    bases, which bear a slight charge, are exposed and attracted to the
    Bug's watery environment.

    So these single-stranded PNA molecules should then migrate to the edge
    of the droplet where the backbone can remain in the oil while the
    bases interact with the water outside.

    This mobility provides the handle needed to control replication. The
    plan is to supply the Bug with short bits of single-stranded PNA
    precursors, just half the length of its tiny genome. If a
    single-stranded PNA gene on the Bug's surface encounters two of these
    "nutrient" PNAs with the right base sequences, it will pair with them
    to form a double-stranded PNA molecule. This should then sink down
    into the droplet, where conditions favour the joining-up of the two
    "nutrient" fragments into a whole strand.

    Eventually, the double-stranded molecule will dissociate once again
    and its two strands drift back to the surface where each can pick up
    new partners - a rudimentary form of replication.

    Metabolism The third essential part of the Bug's life - metabolism -
    has also been pared to its barest minimum. The researchers plan to
    "feed" the Bug with fatty acid precursors. These will have
    photosensitive molecules attached their charged "head" ends. These
    photosensitive caps mask the charged head, making the molecules
    completely fat soluble. This means they will tend to collect within
    the Bug's droplets.

    When light strikes the photosensitive cap, it breaks off, exposing the
    negatively charged fatty acid head, which migrates back to the surface
    of the droplet. Eventually, so many new fatty acids will be produced
    that they will not all fit on the surface and the droplet will split
    in two to create a larger surface area.

    The Bug will also be supplied with inactive PNA precursors bound to a
    photosensitive molecule. Once again, when light strikes this
    photosensitiser, it breaks off to release the active PNA fragment.

    Effective metabolism also requires one more step to prevent the
    photosensitive molecule, once broken off, from re-sticking to the
    fatty acid or PNA and so deactivating it once again. The PNA genetic
    material prevents this by acting as a rudimentary wire, conducting
    electrons to neutralise the photosensitiser. In this way, the Bug's
    "genome" plays an active role in the metabolic process.

    Evolution If all goes according to plan, these three components -
    container, genome, metabolism - should fit together to provide all the
    essentials for Darwinian evolution. As the Bugs grow and reproduce,
    corralled in a test tube, natural selection should favour PNA base
    sequences that pair up and split off fastest, and also conduct
    electrons most efficiently to the photosensitisers.

    Synthetic slaves Artificial organisms could be custom-built for
    particular tasks:

    break down toxic compounds

    produce useful chemicals such as hydrogen fuel

    act as "living pharmaceuticals", delivering drugs in the body in an
    adaptive way

    be tiny diagnosticians, roaming our bodies, collecting information and
    checking for problems

    become part of machines that can repair themselves as living beings do

Race for the ultimate prize

    THE Los Alamos Bug has some stiff competition in the race to be the
    first artificial life form, especially since some of the entrants are
    taking much more conventional routes to that goal.

    At the Institute for Biological Energy Alternatives in Rockville,
    Maryland, Craig Venter, leader of the private group that sequenced the
    human genome, and colleague Hamilton Smith are trying to create a new
    life form by extracting the genome from an existing bacterium and
    replacing it with a synthetic genome stripped down to a bare minimum
    of genes (New Scientist, 31 May 2003, p 28).

    Because this approach leaves most of the cell's machinery intact,
    Venter's team is widely expected to be the first to succeed, perhaps
    within a few months or years. (Uncharacteristically, Venter is not
    talking to the press about this project.) However, Venter's new
    organism will end up looking very much like existing life.

    And at the University of Rome 3, Pier Luigi Luisi is working on the
    "minimal cell project". Starting with a simple membrane-bound vesicle,
    Luisi's team plans to gradually add in off-the-shelf enzymes and other
    cellular components until they assemble the simplest possible working

    Across the Atlantic at Harvard University, Jack Szostak has been
    working on a synthetic life form just as simple as Rasmussen's Los
    Alamos Bug, but using more familiar chemistry. Szostak's design calls
    for a tiny membrane-bound vesicle containing little more than an RNA
    or RNA-like molecule with a special talent: that of catalysing its own

    The problem is that no one has yet developed an RNA capable of
    replicating more than just a small part of itself. Szostak predicts
    success is probably 10 or 20 years off. "I've been saying that for the
    last 10 or 20 years," he says, "and it's still true."

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