[Paleopsych] NS: Alive! The race to create life from scratch
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Tue Jul 12 19:30:07 UTC 2005
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
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."
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
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
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 -
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
break down toxic compounds
produce useful chemicals such as hydrogen fuel
act as "living pharmaceuticals", delivering drugs in the body in an
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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