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Devangshu Datta: It's in the 'super' genes

Gene-scrambling techniques developed in the synIII project could be used to make new synthetic strains of yeast and medicines

Devangshu Datta  |  New Delhi 

Devangshu Datta

Synthetic biology took a giant step forward recently when an international team managed to synthesise an artificial yeast chromosome. This process had been carried out earlier with bacteria, but yeast is more complex. Yeast cells are similar to that of plants and animals. Human beings share many of their genes with yeast.

The team was led by Jef Boeke, who is the director of New York University's Langone Medical Center's Institute for Systems Genetics. It involved collaborations between nine universities and institutes scattered across the US, China, Australia, Singapore, and the UK, as well as the aid of an army of students drawn mainly from Johns Hopkins.

The design and insertion of a functional, entirely artificial gene into an eukaryote could eventually lead to the redesign of micro-organisms to produce new medicines and biofuels. The team used computer-aided design to build a fully functioning chromosome, which they named synIII.

This was a variation on the natural yeast chromosome III , the shortest of yeast's 16 chromosomes. The entire yeast genome was mapped in 1996 in a similar collaborative effort. SynIII was successfully created and inserted into brewer's yeast (Saccharomyces cerevisiae).

It took seven years to construct synIII. The artificial chromosome contains some 273, 871 base pairs of DNA, much less than its native yeast counterpart, which has 316,667 base pairs. Boeke's team made over 50,000 alterations to its genetic base, removing repeating sections of some 47,841 DNA base pairs and junk DNA, including base pairs known not to encode for any particular proteins, and "jumping gene" segments, which can randomly mutate. Other sets of base pairs were added or altered to help researchers label DNA as synthetic or native. The synthetic DNA pairs were assembled by students who then swapped them for native DNA sections, under the guidance of Professor Srinivasan Chandrasegaran from Johns Hopkins.

DNA is composed of four letter-designated base molecules, A (adenine), T (thymine), G (guanine), C (cytosine). These are combined and repeated in the famous twisted double helix chains. Yeast shares about a third of its genes with humans.

This project successfully manipulated yeast genes without any apparent loss of function. The artificial chromosome was replicated and reproduced through 125 generations. This proved the iteration was stable.

The team of 60-odd scientists developed new techniques for scrambling genes and also investigated changes in various environmental factors. The students would make long chunks of DNA and then these would be added to the yeast. This method of replacement, part-by-part, may be more easily used with complex organisms.

Given that the yeast genome has been mapped as long ago as 1996, the next goal is to scale up and use similar synthesis on the entire yeast genome with its 16 chromosomes. The gene-scrambling techniques developed by this project could be used to make new synthetic strains of yeast and develop new products and medicines. Apart from bread and wine, a couple of anti-malaria and anti-hepatic drugs are developed from yeast itself. Biofuels with higher yields could also be developed from yeast.

The ability to replace natural chromosomes with engineered ones could lead to many further advances. For example, there have been experiments that suggest that immunity to virus attacks could be developed by changing some genetic code. It might be equally possible to create organisms designed to spread diseases.

One of the more speculative possibilities is the revival of extinct species. If a full sequencing of an extinct animal's DNA is available, it might be possible to use this technique to replace natural chromosomes in a close living relative. For example, an elephant could be used as the base for trying to grow a woolly mammoth.

Of course, synthesising one yeast chromosome is just the beginning. The yeast synthesis created a chromosome with less than 300,000 base-pairs. The smallest human chromosome is chromosome 21, with 48 million base pairs and we have a total of over 3 billion base pairs, while yeast has about 12-13 million. It would also be necessary to make male and female variants if scientists were dealing with higher animals or plants. Each of these represents difficulties of major dimensions but there is no apparent reason why the problems could not be solved.

In the long run, it may be possible for human beings to insert "super genes" into their children, to give them resistance to disease, or better oxygen consumption patterns, or resistance to diabetes, HIV, and so on. If such technologies exist, it will unquestionably be tempting to use them. Such a scenario would mean changes to the human race itself.

It may be a far distant future and sound like science fiction. But the first genome sequences occurred in the mid 1990s. The first synthetic chromosome - a bacteria called Synthia - was demonstrated in 2010. The yeast synthesis is a big jump in capacity. The pace of discoveries is accelerating.

The US Defence Advanced Research Projects Agency (DARPA) is pouring money into synthetic biology. The Living Foundries programme from DARPA is supporting a wide range of experiments in these areas. By 2015, DARPA will be spending $28 million per annum on this sort of research. This could mean more breakthroughs at the basic level.

In Aldous Huxley's Brave New World, human beings are cloned, classified and divided into castes for specific qualities. Some version of that future could be edging a little closer. There is nothing in our social systems or legal jurisprudence to provide more than the broadest of benchmarks for dealing with such situations.

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First Published: Thu, May 01 2014. 21:48 IST