“We can use man-made components and integrate them into the machinery of life”
Chemists have added synthetic letters to bacterial DNA. Study leader Prof Floyd Romesberg explains how this could expand the genetic code to make proteins never before seen in nature
What is the genetic alphabet?
All information that encodes the diversity of life is stored in DNA. The genetic alphabet has four letters [known as ‘bases’] –G, C, A and T – and a critical property of that alphabet is that it forms base pairs [the rungs of the ladder in the DNA double-helix]. So G always pairs with C, and A always pairs with T. The four letters are what encode the information. You can translate the code into proteins, which perform all the functions of a cell.
How are your two synthetic letters different from natural ones?
Natural bases are hydrophilic, which means they’re soluble in water. Our synthetic bases are hydrophobic, so they are insoluble in water. Our bases are oil-like, so they don’t pair with the natural ones because oil doesn’t like to mix with water. Let’s call our bases X and Y. If X and Y pair with each other, it would give us six letters in total.
After adding synthetic letters to DNA in a test tube, and inserting them in bacteria, you’ve now managed to get the microbes to keep your ‘unnatural base pairs’. Could any cell use synthetic bases?
We think so. We’ve shown there’s nothing magic about a natural base pair, and that chemists can use any force available in nature – in this case, the fact that water and oil don’t mix – to underlie the same type of thing in any organism. This is one of the things my lab is working on right now, specifically we’re working with human cells.
Can cells read and decode DNA with synthetic bases?
That’s what scientists call transcription of DNA into RNA, and translation of the RNA into proteins. Yes, it works. Part of the point of doing all this was just to demonstrate that we could. A lot of
people think the molecules that make life are different from those that are part of things that are not living. We’ve shown that’s really not true. We can use synthetic components and integrate them into the machinery of life just fine.
How could synthetic letters be useful?
Traditionally, drugs have been small molecules, but in the last 20 years there’s been growing success with proteins. But proteins are composed of only 20 little amino acid building blocks and a lot of them are pretty boring. There are certain types of functional groups of atoms that medicinal chemists have had success with in small molecules, but they aren’t present in proteins. So we could develop proteins that have unnatural functionalities to make better drugs. That’s the short-term goal.
Now the second, long-term application: instead of getting bacteria or human cells to make a protein to use elsewhere, couldn’t we make the cell create proteins it uses for itself? So we could evolve bacteria that use unnatural proteins to do new things. Maybe they eat oil to help clean up spills, or maybe we could develop bacteria that you inject into a person and they localise to certain tissues, then secrete a drug. The potential applications are only limited by your imagination.