No late surprises with systems biology

The business of drug discovery can be a big gamble. Therefore researchers will try any means to load the die in their favour. The present in vitro and in vivo developers now have better chances of turning a potential miss into a six by going the in silico way. This new approach is called systems biology. California-based Cellworks is the first exponent of this new technology in India. Sriram Iyer reports

In its present form, the process of drug development involves costs that may run into billions of dollars, and about a decade or more in time, from initial discovery to the final drug. A large number of potential drugs fail at various stages during these long years of hardcore research.

Phases in drug research

Traditionally, drug research involves in vitro (Latin: within the glass), and in vivo (Latin: within the living) methods. The in silico method, which basically refers to the fact that the 'experiment' is conducted within a simulation software, rather than in a test tube, Petri dish or human cell. When combined with traditional methods, this three-pronged approach allows molecules to fail early rather than late in the drug discovery path.

But with the advent of the in silico approach, these late surprises can be avoided to a great extent. Vidya Shankar, IT/BT Secretary, Government of Karnataka, has reportedly said, "The need to integrate drug mechanism and toxicity within the context of human cellular bio-chemical pathways makes new drug design and discovery a very challenging process and one that is very high up in the pharmaceutical value chain. Incorporation of emergent techniques like in silico based systems biology into the design of new molecules is a much needed innovation."

The set up consists of graphical user interface (GUI), an in silico platform software (also called computational backplate) and an ODE solver. "Systems biology is a virtual representation. It is like a map. It uses biology, mathematics and a lot of automation from the semiconductor industry," explains Taher Abassi, CEO, Cellworks. The technology is a physiologically aligned 'virtual experimental systems'. They are biological models of cell systems that can be used to analyse pathways in disease as opposed to normal conditions. This would enable an understanding of the effects of probable drugs on pathways within a cell and on cell systems. The virtual experimental systems are dynamic and can be customised for different cell types and come packaged with research based methodology protocols that can be tweaked at various levels for in depth analysis and research.

Advantages over in silico and in vivo

There are various reasons why the in silico approach scores over traditional research methodologies. "There is no transparency in which clinical trials are being carried out. There are a lot of effects that can't be monitored, e.g. depression in animals. Another handicap seen in many cases, while trying it on the cell is the fact that a cell is not representative of the entire effect that a drug/compound could have," Abassi points out. According to him, the approach enables researchers to qualify the biological target and associated toxicity at the nascent stage of discovery itself, thereby causing tremendous savings in time. In the highly competitive pharmaceutical industry, every year saved in drug research could translate into many million dollars, besides giving a first-mover advantage in the market. "People working in the lab do the same experiment three or four times to ensure that the results are more or less similar. With systems biology, it is enough to do it just once. For example, a knock out study in the normal process will take six to eight months. With this technology we can do it in just two days," says Abassi, emphasising the kind of difference that this technology could create in the field of drug discovery.

The technology is already in use in research labs across the world and has shown promising results. "Using Cellworks' virtual experi-mental platforms has revealed the different pathways and mechanisms by which uPA drug or genetic inhibitors affect cell migration, adhesion and attachment. The ability to understand drug mechanism to explain cancer cell death caused by our novel compounds indicates either-unaccounted drug targets by our compounds or novel, unpublished pathways by which uPA inhibition is causing selective cancer cell death. Using the predictive technology from Cellworks enabled me to perform 'what-if' analysis to test out new hypothesis," according to

Dr Fred Gorin, Professor Neurology, University of California, who has successfully deployed and used Cellworks' technology to develop new molecules in the area of oncology.

Indian labs are not far behind, but like any technology, the output depends on the quality of input. Dr Utpal Tatu, Associate Professor, Department of Biochemistry, Indian Institute of Science, Bangalore, has also used the technology on a few projects. He points out, "It is very reliable but dependent on the data that has been provided."

For the same reason of data constraints, Tatu also maintains that this cannot replace experimental science but can surely complement it. Cellworks is one among five to six companies in the world that have developed similar technologies on the same principle. Most of them, which include Intlos, Paulo Alto and G network Sciences, are based out of USA. Cellworks Research India (CRIL), the R&D centre of Cellworks, operates out of Bangalore and the present focus areas are oncology, inflammation, metabolic disorders, CNS and skin.

Multi-disciplinary skilled team

The good news is that it is not impossible to create the infrastructure and according to Abassi, all that is needed is a competent team consisting of experts in biology, mathematics, chemistry, computer science and automation. Which means, though it may not be possible for one team to focus on everything under the sun, there is space for more experts to team together and target on different areas that need equal attention from the pharma fraternity. The prevalent trial and error approach may not be in the best interest of anyone, especially in the sort of competition that is today. Indian CROs have already developed a global reputation for their competence in quick processing of research activities. Adapting technologies such as these will also help them to improve on the edge that we already have in terms of cost effectiveness. Therefore while systems biology may load the die in the researcher's favour, drug discovery remains a slippery path.

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