SAN DIEGO, Calif. — Scientists are taking the first steps toward creating alternative life forms — organisms
that use a genetic code different from the one used by all other creatures on earth.
Such organisms, bacteria to start with, would have novel chemical units in their DNA and synthetic building
blocks in their proteins. Scientists hope that such organisms can be used to study biochemical processes in
new ways and to produce new medical or electronic materials that cannot now be made by living things.
The research goes well beyond current genetic engineering, which involves reshuffling the ordinary
components of DNA or proteins into new combinations or moving DNA from one organism to another.
Adding completely new elements to DNA and proteins is essentially rewriting the genetic code, the
fundamental language of life. As such, it is likely to raise new ethical and safety issues, though there has been
no controversy yet because the work is still 5 to 10 years from any practical use.
"We're not trying to imitate nature; we're trying to supplement nature," said Dr. Floyd E. Romesburg, an
assistant professor of chemistry at the Scripps Research Institute here. "We're trying to expand the genetic
code."
So far, scientists are nowhere near creating truly novel life forms. They have been able to get only one
unnatural protein building block at a time substituted for a natural one. And no one has been able to get
unnatural DNA to function in living cells, although progress has been made in test tubes.
Despite life's vast diversity, all creatures — from yeast to humans, from microbes that live in near-boiling
water to those that tolerate freezing temperatures — spell out their genetic instructions using the same four
DNA chemical units, known as bases, which are represented by the letters A, C, G and T. Different three-letter
combinations specify amino acids, which are strung together like beads to make the proteins that carry out
most functions in a cell. With rare exceptions, all living things use the same 20 amino acids.
The genetic code, then, is a language of four letters used to make 20 words. Despite the limited vocabulary,
those words can be used to make the huge variety of sentences and paragraphs that characterize life.
But what if there could be additional genetic letters and words? That, scientists say, would allow organisms to
be even more versatile, just as some languages have sounds or express concepts not found in English.
[...]
Scientists say creatures with a truly different genetic code would essentially be alien life forms. Indeed, one of
the aims of the research is to see what kinds of life may be possible outside earth.
"We can't think of any transparent reason that these four bases are used on earth," said Dr. Steven A. Benner, a
professor of chemistry at the University of Florida, "and it wouldn't surprise me in the slightest if life on Mars
used different letters."
The scientists working on the creation of novel organisms say that for now at least, there is no chance that the
microbes will run amok. The bacteria created so far that use an unnatural amino acid have to pick up the
synthetic component from the medium in which they grow. If they escaped into the wild, they would die or
revert to using a natural amino acid. [...]
Efforts to expand the genetic code have drawn new attention with the publication of two papers in the journal
Science on April 20. Both are from scientists at the Scripps Research Institute. [...]
One of the papers presented a variation of the error-causing theme.
Scientists introduced a genetic change that crippled an enzyme involved in correcting errors in protein
formation. That allowed an unnatural amino acid to be taken up at 24 percent of the locations in all the
bacteria's proteins where the amino acid called valine was supposed to go. The work was led by Dr. Paul
Schimmel at Scripps and Dr. Philippe Marlière of Genoscope, a French research institute, and Evologic, a
biotech company.
The second Scripps paper took a different approach. Instead of substituting a new amino acid for one of the
20, the scientists introduced a 21st amino acid. And instead of widespread substitution, they put the new amino
acid in a specific spot of their choosing. They did this by creating special molecules to deliver this amino acid
to the cell's protein-making machinery.
This work was led by Dr. Peter G. Schultz, a chemistry professor who is also director of the Genomics
Institute of the Novartis Research Foundation.
Some experts said the work paved the way for introducing more than one new amino acid into bacteria and
doing so with a precision previously unobtainable. "I would say it's a major, major advance," said Dr. Uttam
RajBhandary, a molecular biologist at M.I.T., who is doing similar work.
But if scientists are going to add new amino acids this way, they have to specify where in the proteins these
new amino acids should go. So they must put the genetic code for the new amino acids into the bacteria's DNA
at the right spots.
There is only one problem: there is no sequence of DNA letters that encode for amino acids that nature has not
encountered before. With four DNA bases, there are 64 possible three-letter combinations, called codons,
which can specify an amino acid. But 61 of them are already used for the 20 natural amino acids. (There are
duplications; for instance, six different codons specify leucine.)
When the cell encounters one of three remaining codons that do not specify an amino acid, it stops building
the protein. Dr. Schultz picked one of those codons as the code for his new amino acid.
But this approach has an obvious problem. What if the bacteria's DNA naturally contains this codon at spots
where protein formation really is supposed to stop? If the 21st amino acid were inserted instead at such spots,
erroneous proteins would be made that could kill the organisms. [...]
[I]f scientists want to introduce many new amino acids, new codons will be needed. That is why they are
trying to add letters to the genetic alphabet. If DNA consisted of six bases - say, A, C, G, T, X and Y - there
could be 216 codons instead of 64.
Such artificial DNA bases have been made by Dr. Benner in Florida, Dr. Romesburg at Scripps and Dr. Eric T. Kool, a chemistry professor at Stanford. Besides fitting into the double helix of DNA, each artificial base must
pair with only one artificial counterpart, just as A always pairs with T, and C with G. Such pairing is essential
for accurate DNA replication.
Dr. Benner in one case managed to use an artificial DNA base to produce a protein with an unnatural amino
acid — but only in a test tube. It has been extremely difficult to use natural enzymes to replicate DNA that
contains artificial bases, even in the test tube. And when artificial DNA is introduced into organisms, the
organisms invariably die.
But Dr. Kool is confident that he will achieve replication, at least in the test tube. "In 5 to 10 years, we'll have
an alien replicating system," he said.
Additional papers discussing some of these questions
may be viewed by clicking the following links:
"Planets and Life: The emerging Science of Astrobiology", Eds:
W. Sullivan, J. Baross, 2007, pp. 537-544
"Instruments, Methods, and Missions for Astrobiology XIII, SPIE, vol. 7819, pp. 1-12
by M. Moser; James Prudent
Nucleic Acids Research, 31(17), 2003, 5048-4053
reverse transcriptase from Human Immunodeficiency Virus-1",
by A. Sismour; S. Lutz; Jeong-Ho Park; M. Lutz; P. Boyer; S. Hughes, and S. Benner
Expert Opinion Biol. Ther. 2005 5(11), 1409-1414