In Conversation with Siddhesh Kamat

How would you describe your research to a high-school student?

Lipids is a topic of interest taught alongside molecules like sugar and amino acids. It is one amongst the essential biological molecules. The textbook typically only states out its functions such as an energy provider, controlling the entrance and exit of substances in and out of the cell while playing a key role in the cell membrane. Apart from these functions, lipids also play a role in signalling across different organs and this class of lipids are referred to as bioactive lipids. Our research spans across a few main topics like finding where these lipids exist in the body, how these lipids are synthesised or broken, and the way their signalling is controlled across the biological processes occurring in the body. Currently, our team is studying biology while also developing technology to detect, quantify and measure lipids since it is hard to do it otherwise. We do this using mass spectrometry and use this technique to detect low abundant lipids in biological systems.

What exactly is cell-signalling?

Cell-signalling in brief is the process of communication within the cells. Considering the example of immune cells, the communication within the innate cells and the acquired cells is modulated by signalling lipids. It “tells” a certain type of cells to respond in a particular manner and another set in another way. It basically orchestrates the entire process.

What inspired you to study lysophosphatidylserine (lysoPS) keeping in mind the fact that it is one amongst the lesser known lipids to exist?

LysoPS was rare when we started exploring it; rare because there were few tools to study it. Our work started because of the curiosity to know where it is found in the body, what role it plays, what diseases it is prevalent across and so on. Now that we had the opportunity to explore it, we have found that it is responsible for several diseases in humans. It is found in every tissue in the body and there are dedicated enzymes which synthesise it and degrade it as well. It is a finely tuned system in the body and we are beginning to understand how to leverage this in therapy.

Are there any know genetic mutations that affect lysoPS signalling pathways in humans?

LysoPS activates the immune system. It directs the immune system to clear off everything. And once the task has been accomplished, the lipid is degraded by enzymes. If there occurs a mutation in the enzyme that degrades this lipid, there is an accumulation of lysoPS in the body. This leads to neurodegeneration, autoimmune conditions. Hence, it is essential for the body to have mechanisms to turn this enzyme on or off. Defect in either of these functions gives rise to diseases.

Are there any known genetic mutations that affect lysoPS signalling pathways in humans?

In the brain, the enzymes which make this enzyme or degrade this enzyme- both cause neurodegenerative diseases. Mutations to the enzyme which forms this lipid causes Hereditary Spastic Paraplegia, where the affected person is paralysed in the lower limbs. On the other hand, mutations to the enzyme which degrades this lipid causes PHARC- polyneuropathy, hearing loss, ataxia, retinitis, pigmentosa and cataract. These are the diseases in the brain that we know of. There are also polymorphic mutations to different receptors which causes different autoimmune diseases. These lipids are also linked to psoriasis- autoimmune condition where the affected person has dry skin, and arthritis.

What were some experimental models and techniques used by your team for this research work?

My lab is a “chemical-biology lab”. We develop chemical tools to study biological systems and functions. We use mass-spectrometry based lipidomics to study and measure the lipids present in the body. We use animal models, cell cultures to study the same. We purify enzymes and study them recombinantly in test tubes and develop drugs which inhibit these enzymes. My lab has also designed lipid probes which essentially fish out all the proteins the lipids interact with.

What were some challenges you faced along the way?

We faced challenges in every way. Synthesis of this lipid is not an easy task; it takes about 15-20 steps to make it. Generating mouse models was also took us about a couple years since doing this in India is quite trivial. Mass-spectrometer is an expensive instrument and writing grants to receive them also posed a challenge. Hiring the right people for the right job also took us quite some time.

How do you view lysoPS research influencing broader fields of lipidomics and systems biology?

When my lab started, we were interested only in measuring lysoPS. We wanted to see if we can measure lysoPS, can we generalise this to other lipids as well. From our research, we were able to develop broader lipidomics platforms. In terms of systems biology, we are now at a stage where we are beginning to understand and starting to explore how the lysoPS levels in one tissue influence another tissue. If we can establish connections on how lysoPS can communicate between tissues, maybe we can start building a platform to start understanding this in more depth.

What is one piece of advice you would like to offer young researchers?

I like to view research analogous to cricket. It is not a one-day (ODI) game; it is going to be like a five-day test match. There are going to be several struggles, failure is common as well. Irrespective of all this, you must have it in you to persevere and play this game. Secondly, choose something that you like doing which will keep you occupied for at least 15-20 years down the line. Last but not the least- choose wisely. Do not choose your topic based of what your supervisor recommended you to do. Let it be your passion and your calling. All the best!