Using the first living thing on Earth as a model
By William J. Cromie
Gazette Staff
Jack Szostak is trying to make a living organism out of nonliving chemicals.
It would be a modest creature, a microscopic
bit of genetic material in a bubble of fat, capable of making copies of
itself and evolving into a more efficient form of life. The creature
would be modeled on the first, or one of the first, living things that
appeared on Earth about 4 billion years ago.
"We're trying to imagine the simplest possible
system that could get life started, then make it in our lab," said
Szostak, a professor of genetics who works at Massachusetts General
Hospital.
The best candidate for the first organism is
a bit of ribonucleic acid (RNA) enclosed in a plain capsule. RNA can
store information like a gene and reproduce itself. It makes up the
genes of viruses.
"We're concentrating on making such an
organism because, once it formed, most biologists agree that the first
single-celled creature would follow," Szostak explains. Neither plant
nor animal, such an organism would then give rise to creatures like
bacteria, algae, and amoebas.
Much the same thing could have happened on
Mars. Recently, NASA scientists announced that they may have found
signs of life in a 4-billion-year-old meteor knocked to Earth from that
planet. Szostak is skeptical about the finding, but he hopes that
robots or astronauts may someday bring back samples of living Martian microbes.
If such primitive Martians have the same
biology as early Earthlings, it would be "interesting, but relatively
boring," Szostak thinks. "But if they have a fundamentally different
biology, it would be fantastic! If life arose in different forms in
different places, it would tell us that life could evolve in multiple
forms all over the universe."
Good Progress Made
When Earth first formed about 4.5 million years
ago, it was volcanic-hot and battered by rains of large meteorites.
Most scientists believe life began shortly after the lethal impacts
stopped, and the planet cooled enough to allow water to exist. Fossil
evidence shows that primitive creatures, looking like today's bacteria,
existed around 3.8-4 billion years ago.
For 10 years, Szostak has been trying to
repeat hundreds of millions of years of evolution in his lab. He has
not yet shouted: "Eureka, it's alive!" But he claims to have "learned a
lot and made good progress."
A Nobel Prize-winning discovery by a colleague
started him down the road to lab life. In 1982, Thomas Cech of the
University of Colorado discovered that pieces of RNA living in a
single-celled animal can splice themselves out of larger RNA molecules.
That means RNA has the capability of doing chemistry on its own,
specifically, the chemical reaction involved in splicing. From there,
it's easy to assume that RNA can promote, or catalyze, other reactions,
such as reproducing itself.
"That made it much easier to think about the
origin of life," Szostak says. "Cech's discovery inspired me to think
of ways of making RNAs that could catalyze their own replication."
At the time, he was working with yeast,
studying how its genetic material reproduces itself when a cell divides
to make two daughter cells from one parent. "The lab techniques that
Cech used were not all that different from mine," he recalls. "I
thought there'd be a few interesting experiments I could do. Five years
later, my lab had completely changed focus from yeast to
self-replicating RNA."
Today, he and his colleagues are close to an
RNA catalyst, or enzyme, that copies other RNA molecules. If the
molecule being copied is another copy of itself, then he will have an
RNA enzyme that can be both the copier and the thing being copied.
"The way we do this is to harness the power
of evolution," Szostak notes. "Since we don't know how to design better
RNA, we have to evolve them. We're trying to evolve from an RNA that joins pieces of RNA to itself, to an RNA that copies itself and other RNA."
But evolving RNA like that on a newly formed
planet is a huge problem. Szostak calls it "the biggest challenge left
in our understanding of the origin of life."
RNA, like the DNA of which all modern genes
are made, is put together from four chemical units, or bases, plus
phosphate and a sugar. Some of these building blocks have been made in
labs, using gases and other elements thought to be present at the
beginning of Earth. But no one can figure out how to put these
ingredients together to make long RNA molecules.
On the young Earth, the construction may have
taken place in shallow coastal ponds that periodically dried up. That
would allow the necessary chemicals to concentrate on particles of
moist clay, or to be trapped in bubbles of fat.
One possible scenario cited by Szostak has
some of the ingredients forming in volcanoes, then being washed down
into ponds or shallow lakes by rain. The necessary compounds could also
have been formed in the air with the help of lightning, or been bought
to Earth by comets or meteorites.
Due to limitations of time and lab equipment,
Szostak skips this part and starts with trillions of pieces of RNA in a
solution. In living things, RNAs are made of varying sequences of the
four bases; RNAs that do different jobs contain different sequences.
"In our lab," he explains, "we start with lots of random sequences and
try to find the rare ones that do something interesting, like catalyze
a chemical reaction."
After selecting such promising RNAs out of
the dilute soup, his team uses a system of directed evolution to make
them work more efficiently. This involves putting in mutants, or
changing the sequences slightly, then selecting the best sequences over
and over until effective catalysts are found. Such evolution-in-glass
yields molecules that fold up into three dimensions and serve as
catalysts necessary for RNA copying.
Another life investigator, Gerald Joyce of
Scripps Research Institute in California, worked out the same
technique. Szostak and Joyce shared the 1994 National Academy of
Sciences Monsanto Prize in Molecular Biology for this achievement.
With the help of this technique, Dave Bartel,
a former student of Szostak's, succeeded in making an RNA enzyme that,
under the best of conditions, joins together six RNA units or bases.
"This really was a great breakthrough," Szostak comments.
Bartel, now at M.I.T.'s Whitehead Institute
for Biomedical Research, showed for the first time that an RNA enzyme
can do the same reaction done by proteins in more organized forms of
life. "Now that this has been shown, all we have to do is use evolution
to make it work better. By this means we should be able to get
self-replication," says Szostak.
In today's world, protein enzymes assemble
hundreds of thousands of chemical units into complex molecules needed
for everything from growing a toe to thinking a thought. RNA enzymes
have now been relegated to a minor role.
"The important point here is that protein
enzymes came later because RNA-based cells evolved a way to make the
first proteins," Szostak points out. "So one of the big projects in my
lab is to evolve RNA enzymes that carry out all the steps needed for
protein synthesis."
Putting It Together
A naked RNA molecule can't copy itself. It
needs to be enclosed in a thin envelope, a bubble of fat, that keeps
out harmful substances while letting in beneficial ones. Virtually
every modern cell has such a protective covering, a soft armor of fat
and protein complete with entry and exit ports. Surely, the first
membranes were much simpler, but no one knows how and of what materials
they were made.
"Surprisingly, few people are working on this
problem," Szostak lamented. "Once protected by a membrane, RNA could
evolve much more quickly."
Nature now constructs proteins from amino
acids, small molecules made principally of carbon, hydrogen, oxygen,
and nitrogen -- elements present when Earth first formed. Various
researchers have created amino acids from combinations of these
elements dissolved in sea water solutions. Stanley Miller at the
University of California, San Diego, for example, passed electric
discharges (to simulate lightning) through such mixtures and produced
13 of the 20 amino acids essential for building proteins.
Building on such experiments, Szostak has
made an RNA molecule capable of bonding amino acids together. The next
step is to link them together into so-called peptides. Put peptides
together and you have proteins.
"It's an exciting advance," he says. "I'm
sure we're not too far away from building small proteins with the help
of RNA enzymes."
Down By the Sea
Szostak does not champion the idea that life
began in hot springs on the ocean floor where a primitive one-celled
creature, called an archeon, was recently discovered. Its genes show
that it shares a common evolutionary heritage with us, but not with
bacteria. The consensus is that both archeons and bacteria came from a
common, even simpler creature. But even this one-celled organism is far
more complicated than the first living thing.
"A lot of evolution had to occur before RNA,
working alone, could have evolved into a cell like this, complete with
genes and proteins," Szostak believes.
Viruses are the only organisms that now have
genes made of RNA. DNA took over that vital function very early in
evolution, even before the ancestors of archeons and bacteria.
"We believe life on Earth started with RNA
molecules that stored genetic information and catalyzed the chemical
reactions needed to make proteins," Szostak says. "Hundreds of millions
of years later, the two functions became specialized. DNA now stores
the genetic blueprints that make an organism an amoeba or a human.
Proteins catalyze all of life's chemistry, including the replication of
DNA that passes from parents to offspring."
Details of how Earth went from an RNA to a DNA
world are lost forever in the natural record. All traces of the origin
of life have long been destroyed by chemistry, geology, and the biology
of more complex, more voracious creatures.
"Our only hope of reconstructing life is via
laboratory experiments," Szostak says. "If we make something everyone
agrees is alive, that would provide a plausible scenario for the great
event. But, because the trail is billions of years cold, we'll never
really know for sure if we're right."