SAN DIEGO (CNN) — For the first time, scientists at the Scripps Research Institute have shown it is possible to alter DNA, the genetic alphabet of life, and still have a living organism that passes on the genetic information.
Scientists added two new “letters” to the four-letter DNA code of a bacterium. They reported their findings this week in the journal Nature.
“This is the first experimental demonstration that life can exist with information that’s not coded the way nature does (it),” said Floyd Romesberg, associate professor of chemistry at the La Jolla-based research institute.
Medicine can greatly benefit from this discovery, Romesberg said. There’s potential for better antibiotics and treatments for a slew of diseases for which drug development has been challenging, including cancers.
The findings also suggest that DNA as we know it on Earth may not be the only solution to coding for life, Romesberg said. There may be other organisms elsewhere in space that use genetic letters we have never seen — or that don’t use DNA at all.
“Is this alien life? No,” he said. “Does it suggest that there could be other ways of storing information? Yes.”
How they did it
For their genetic experiments, Romesberg and colleagues used molecules, called X and Y, that are completely different from the four building blocks of DNA.
Normally, the genetic code consists of four nucleotide bases: adenine (A), cytosine (C), guanine (G) and thymine (T). In DNA, guanine always pairs with cytosine and adenine with thymine.
Each pair is held together by hydrogen bonds, meaning the negatively-charged part of one molecule attaches to the positively-charged part of another through a shared hydrogen atom. James Watson, Francis Crick and Maurice Wilkins shared a Nobel Prize for the insight that these molecules form a double-stranded helix shape.
The X-Y bond is very different: These molecules are hydrophobic — like oil, they do not dissolve in water.
“The forces underlying the new pairing are completely different than that which nature used,” Romesberg said.
First, researchers synthesized about 300 different genetic variants that could be potential carriers of information. They finally ended up with X and Y molecules that, in a test tube, looked like they replicated well.
Even trickier was introducing these molecules into a cell and getting that cell to reproduce with the unnatural DNA molecules.
“This feat was far from simple,” University of Texas at Austin biologists Ross Thyer and Jared Ellefson wrote in an accompanying commentary article in Nature.
Scientists used the bacteria Escherichia coli to demonstrate that X and Y can be successfully passed on from one generation to the next. E. coli is an easy organism to introduce foreign DNA into, Romesberg said.
Critical to the process was a transporter protein, which would insert X and Y into the cell by assembling itself into the membrane of the cell.
Scientists inserted a gene that codes for the transporter protein into the cell. Then they gave it an element of DNA with the X and Y molecules.
One of the most remarkable aspects of the experiments is that the bacteria reproduced about 23 times, passing down the X and Y genetic molecules, and remains completely healthy, Romesberg said.
The process of assembling the transporter protein does slow down bacteria growth, but Romesberg and colleagues have found that they can reduce that effect by inducing less of this protein. They have reduced the delay to almost zero.
“This work represents an important transition from artificial systems to living organisms and it lays the groundwork for some really exciting research,” Thyer said in an e-mail.
Thanks to this study, it is now possible to have a cell that has not just two genetic base pairs, but three. That means there’s more information in it.
“We need to be able to retrieve within a cell that increased information that’s stored,” Romesberg said.
You may recall from biology classes that genes from DNA get transferred to RNA, and proteins are based on the code for RNA. The next step in Romesberg’s research is to make proteins that have never been made before, using unnatural genes.
Proteins have become important in drug therapies, Romesberg said.
Traditional drugs are small molecules, which have to be made synthetically, one at a time. But proteins, which can be large and complex, are made by cells in a very short period of time.
“Because they’re in a living cell, you can use techniques of evolution to evolve the proteins of interest to have properties that you want them to have, that might make them better drugs,” Romesberg said.
Unfortunately, in nature there are only 20 possible building blocks — called amino acids — possible for proteins.
But if scientists can use the unnatural information stored in cells as the Nature paper describes, they may be able to create proteins that never existed before. The new technique makes it possible to create up to 172 amino acids to build proteins.
Romesberg has started a small biotechnology company to explore these issues.