Biology and engineering don’t mix. This is one of the most outmoded and outdated concepts in science that is slowly being overturned as more and more biologists seek engineering solutions to understanding living systems. Of late, the all-important field of therapeutics in medicine is a major concern that has hopped onto the mathematical and simulation bandwagon for a quicker ride to plausible solutions.
Certain topics in experimental biology sometimes just don’t add up. In such cases, an engineer’s perspective is often of great value. The Chemical Engineering department at the Indian Institute of Science hosts a laboratory that does just that – it bridges the gaps in biology with some engineering tools. The Therapeutic Engineering or TE lab headed by Prof. Narendra Dixit uses mathematical modelling and computational simulations to answer questions in biology that often cannot be addressed through actual, physical experiments.
One of the overarching goals of the TE lab is to understand the interactions between an invading organism such as a virus and the host immune system. In working towards this goal, the lab thrives on an amazingly diverse array of projects that span topics from vaccine design to viral evolution to drug efficacy in treating diseases. The main organisms that the lab has focussed on in more than a decade of research are the Human Immunodeficiency virus (HIV) and the Hepatitis C virus (HCV), though they also work on topics related to tuberculosis and typhoid.
A significant part of this group’s work on HIV revolves around a radical method to combat the virus – by turning its greatest weapon, a high mutation rate, against it. Prof. Dixit’s team have determined that HIV survives on a razor-thin edge in terms of mutation rates. It needs to maintain a high enough rate of mutation to develop resistance to the dynamic immune system and new drugs, but it also needs to curb mutation rates from crossing an ‘error threshold’. The ‘error threshold’ is the rate at which accumulated mutations jumble up the genome with so many meaningless changes that the viral genome loses its identity. The lab’s simulation studies have shown that a 2 – 6 fold increase in HIV’s current mutation rate would be enough to push it over the error threshold. One of the ways this can be done is by using a class of drugs called ‘mutagens’ – currently in clinical trials to treat HIV – to induce hypermutations in the viral genome for error catastrophe to occur.
“But that’s not all we work on”, says Prof. Dixit. “There is growing evidence that HIV strains in India are less virulent and exist in higher concentrations in their hosts than those from US. We also have ongoing projects on viral evolution to explore trade-offs and the implications of such patterns on epidemiology”, he adds. The lab also works on the evolution of the Hepatitis C virus (HCV) to describe and quantify how new mutants arise and drug resistance is developed. Estimating rates of mutant generation could help in designing optimal combinations of drugs for maximum effect against HCV-associated liver diseases. Recent work on the efficacy of therapeutic strategies against HCV has resulted in two important publications for the lab – theoretical explanations for why interferon therapy sometimes fails to clear HCV infections and why certain classes of anti-HCV drugs act in synergy with each other.
In the study on interferon therapy, Prof. Dixit’s team showed that HCV interaction with the interferon signalling network causes bi-stability in the system. Such a bi-stable system can lead to two outcomes: one, a stable state where interferons are effective in clearing the HCV infestation; or it can stabilise under conditions where the virus persists in a chronic infection that cannot be easily dislodged. The model offered a plausible explanation for the occurrence and stochastic nature of interferon-resistant HCV infections. Furthermore, it also showed that direct acting antiviral drugs administered at the right time in the right doses could push cells towards a stable condition that allows interferon-mediated virus clearance.
The work on drug synergy aimed to explain the puzzling phenomenon that a certain class of drugs called “entry inhibitors” or EIs seemed to act synergistically with many other classes of antiviral drugs used to treat HCV infections. The study established that the heterogeneity in the number of targets in infected cells is what contributes to anti-viral drug synergy. What this means is that when the targets of two drugs are present at different levels in a cell population, the drugs exhibit synergy irrespective of their mechanisms of action. “Target heterogeneity seems to be an important factor that needs to be accounted for while designing drug combinations. It doesn’t matter what you target, it looks like the drugs will act in synergy if their target levels vary from cell to cell!” says Prof. Dixit, who also adds that this phenomenon could apply to other infections or even cancer.
Apart from the immense amount of work on HIV and HCV, the TE lab’s interests also span signalling mechanisms in Mycobacterium tuberculosis (MTb), the causal agent of tuberculosis. Current projects have focussed on signal transduction networks in this organism that allow it to evade its host’s immune system. The lab also works on the rates and mechanisms of viral escape from the immune system, which Prof. Dixit hopes will help in designing better vaccines for a variety of diseases.
At Prof. Dixit’s lab, the operating paradigm is that a given biological process can be converted into a mathematical model. Analyses of these problems often provide answers that may not be obtainable or even obvious through experimental investigations. In conclusion, the TE lab with its mathematical and computational approaches to biological questions could provide reasonable solutions in cases where time, effort or money preclude biological trials. Engineering tools in biological baskets indeed!
About the lab
Narendra Dixit is an Associate Professor, heading the Therapeutic Engineering Lab at the Indian Institute of Science, Bangalore.