This post was contributed by Dr Clare Sansom, Senior Associate Lecturer in Birkbeck’s Department of Biological Sciences.
Dr Vitor Pinheiro (right) and Professor Nicholas Keep, Dean of the School of Science
The first of two Science Week talks on Wednesday 2 July was given by one of the newest lecturers in the Department of Biological Sciences, Dr Vitor Pinheiro. Dr Pinheiro holds a joint appointment between Birkbeck and University College London, researching and teaching in the new discipline of synthetic biology. In his talk, he explained how it is becoming possible to re-design the chemical basis of molecular biology and discussed a potential application of this technology in preventing contamination of the natural environment by genetically modified organisms.
Synthetic biology is a novel approach that turns conventional ways of doing biology upside down. Biologists are used to a “reductionist” approach to their subject, breaking complex systems down into, for example, their constituent genes and proteins in order to understand them. In contrast, synthetic biology is more like engineering, a “bottom-up” approach that tries to assemble biological systems from their parts. Pinheiro introduced this concept using a quotation from the famous US physicist Richard Feynman: “What I cannot create, I cannot understand”. Synthetic biologists often use vocabulary that is more characteristic of engineers or computer scientists: words like “modules”, “device” and “chassis”.
All life on Earth is dependent on nucleic acids and proteins; the former store and carry genetic information, and the latter are the “workhorses” of cells. They are linked through the Central Dogma of Molecular Biology which states, put somewhat simplistically, that “DNA makes RNA makes protein”. The information that goes to make up the complexity of cells and organisms is held in DNA and “translated” into the functional molecules, the proteins, via its intermediate, RNA. The mechanism through which the biology we see now arose – evolution – is well enough understood, but it is not yet clear whether evolution had to create the biology we see today or if it is a kind of “frozen accident”. There is, after all, only one “biology” for us to observe. But synthetic biologists are trying to build something different.
DNA is made up from three chemical components and structured like a ladder: the rungs are made up of the bases that contain the information, and sugar rings and phosphate groups make up the steps. All three components can be chemically modified, affecting the physical properties and the potential for information storage of the resulting nucleic acid. Any modifications that do not disrupt the natural base-pairing seen in DNA and RNA can be exploited to make a nucleic acid that can exchange information with nature. And if the enzymes that in nature replicate DNA or synthesise RNA can also be exploited to synthesise and replicate these modified nucleic acids, that process will be substantially more efficient than chemical replication. Modification of different components presents different re-engineering challenges and different potential advantages. Sugar modifications are not common in biology and are expected to be harder than nucleobases to engineer. On the other hand, they are expected to increase the resistance to biological degradation of the modified nucleic acid. These synthetic nucleic acids have been generically termed “XNA”.
Pinheiro, as part of a European consortium, led the development of synthetic nucleic acid in which the natural five-membered sugar rings had been replaced by six-membered ones. They are more resistant than DNA to chemical and biological breakdown, and have low toxicity, but are poor substrates for the polymerases that catalyse DNA replication and RNA synthesis. Further, he has harnessed the power of evolution to create “XNA polymerases” through a process called directed evolution. In this, hundreds of millions of variant polymerases are created and those that happen to be better able to synthesise the selected XNA are isolated. The process is repeated until the best polymerases are identified or isolated polymerases have the required activity.
These synthetic nucleic acids, however, still cannot be involved in cell metabolism and this is a current research bottleneck that prevents the development of XNA systems in bacterial cells. An alternative route towards redesigning biology would be to modify how information stored in DNA and RNA is converted to proteins: redesigning and replacing the genetic code. The exquisite fidelity of the genetic code depends on another set of enzymes, tRNA synthetases, which connect each amino acid to a small “transfer” RNA molecule including its corresponding three-base sequence or codon. This allows the amino acid to be incorporated into the right place in a growing protein chain. In nature, almost all organisms use the same genetic code. Synthetic biologists, however, are now able to build in subtle changes so that, for example, a codon that in nature signals a stop to protein synthesis is linked to an amino acid, or one that is rarely used by a particular species is linked to an amino acid that is not part of the normal genetic code.
Any organism that has had its molecular biology “re-written” using XNA and non-standard genetic codes should be completely unable to exchange its information with naturally occurring organisms, and, therefore, would not be able to flourish or divide outside a contained environment: it could be described as being contained within a “firewall”. It would therefore lack the risks that are associated with more conventionally genetically modified organisms: that it might compete with naturally occurring organisms for an ecological niche, or that modified genetic material might spread to them. If, or more likely when, these “genetically re-coded organisms” are released into the environment (perhaps to remove or neutralise pollutants) they will not be able to establish themselves in a natural ecological niche and will therefore pose negligible long-term risk. The more such organisms deviate from “normal” biology, the safer they will become.
