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Gene research gets faster thanks to Aston University team

April 10, 2001

Aston University researchers have won a BBSRC research grant worth over £300,000 to study one of the most exciting areas of science today - biomolecular interactions. The Aston research team has invented a better, more effective method of randomising genes for laboratory research. Dr Anna Hine, who is leading the research and was the primary applicant on the bid, will be joined by Professor David Billington and Dr Andrew Sutherland to supervise two post doctoral researchers over three years of laboratory work. The work was seed-corn funded by Amersham Pharmacia Biotech.

In order to understand how the body functions on a daily basis, as well as how it responds to infections and disease, scientists study biological processes at the molecular level. Eventually, the resulting discoveries can be applied to create new therapies that doctors can use to manage and perhaps treat disease.

Vital in the study of most diseases is the fundamental interaction between proteins and their ligands (molecules that are bound by the proteins). A key area in protein/ligand interactions is the recognition of DNA, particularly by 'zinc finger' proteins. Zinc finger proteins are the critical component of many transcription factors (these are proteins that play a central role in switching genes on and off and in order to do this they must bind to a given sequence of DNA). In this case, therefore, the protein is the zinc finger and its ligand is the DNA sequence.

DNA is the genetic blueprint of life and is composed of four bases in an infinite variety of combinations. When this code is deciphered the information on the DNA is converted into amino acids, which are the building blocks of proteins. Each protein has a specific sequence of amino acids and some of these play a pivotal role in protein function. Individual amino acids within a protein may be exchanged by altering the DNA sequence of the corresponding gene. When this occurs two things can happen. Firstly the proteins may have no activity at all because changing the amino acids makes the protein stop working or secondly the new protein may recognise a different ligand - in this case a different sequence of DNA. This can have fundamental medical applications for the future such as switching off genes that cause some conditions.

But if scientists try to replace key amino acids one at a time the process will be endless. Instead, they use a technique called randomisation, which means that one or more amino acids can be replaced at once so that a library of proteins results. That library is then screened to find a protein that has an activity of scientific interest. Unfortunately, randomisation and screening techniques are time consuming and involve an exponential rise in the number of cloned genes required as the number of randomised amino acids increases. The Aston team's new method of randomising genes means, for example, that eight thousand different proteins can be made by cloning just eight thousand genes.

Once the library is created the proteins must be screened and the Aston researchers have also invented a new way to do this making the new method simpler, faster and more accurate than current methods. The remainder of the BBSRC grant will be used to develop this screening method, which has huge implications for the way in which scientists across the world screen other proteins to investigate interactions with their ligands as they are actually happening.

So what benefits will the team's research bring to science and medicine? Using existing techniques, scientists worldwide have been able to modify specific parts of zinc fingers to generate novel proteins that bind to new sequences of DNA. The team at Aston believes that their improvements to randomisation and screening will lead not only to more new zinc finger proteins, but more importantly to new ways of studying biomolecular interactions. The new zinc fingers may ultimately find application in anti-cancer and anti-viral therapies. Finally, the randomisation and screening techniques that they develop should be useful far beyond zinc fingers and DNA. In fact, they should ultimately be applicable to any protein/ligand pair.


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Aston University