Blood, sweat and toil all part of the job

Prof Chandy is scientific director of NTU's new infection and immunity research programme. His own research focuses on potassium channels in the body that can be targeted to treat diseases such as severe dry eye and diabetes.

Q: You've won awards for your research on auto-immune diseases, which include rheumatoid arthritis and childhood diabetes. And last year, you were one of the world's most highly cited scientists, according to Thomson Reuters' report on the world's most influential scientific minds. But you originally wanted to be a medical missionary. How did you get started in science?

I'm from southern India and I studied medicine at the Christian Medical College in Vellore, India. After medical school we had to serve a two-year bond, usually at a mission hospital, but I was given the opportunity to do a research project.

At the time, young men came into the hospital with a damaged heart valve needing massive cardiac surgery. Normally, such valve damage is the consequence of a throat infection but none of these patients had any evidence of such an infection. One of my professors told me - you're a smart guy, go find out why this is happening to these people.

So I went and did my research, and we found that a viral infection may trigger an immune response which attacks the heart valve. So I started thinking about auto-immune diseases, and wondered if there was a common mechanism that underlies the different diseases. I was 25 years old then. I did this calculation that if a busy doctor sees about 50 patients a day, and I worked until I was 75, I would serve about 100,000 people. But if I could find a common mechanism for the auto-immune diseases, I could potentially help about 700 million people affected by the diseases.

Q: One of your first breakthroughs came in 1983 when you found that a type of white blood cell - T cells, which control the immune system - has channels that can be blocked to stop auto-immune diseases. Your own blood cells appeared on the cover of an issue of the prestigious scientific journal Nature in 1984. Can you tell us about the breakthrough?

I had arrived at the University of California, Irvine in the United States to study auto-immune diseases. I met a guy called Professor Michael Cahalan, who was studying proteins called ion channels in giant squids' nerves.

He was using a new technique called the patch-clamp which allows the measurement of teeny electrical currents carried by ions as they go in and out of cells.

But that year, there was a weather phenomenon called El Nino which caused the waters of the Pacific Ocean to get really hot, and all of the squids disappeared. He had all this fancy technology and nothing to study.

We knew that when immune cells meet foreign invaders like bacteria and viruses, calcium and potassium ions go in and out of the cells, but we didn't know how. I asked him if the patch-clamp technique could be used to study immune cells.

I'll always remember the day - May 24, 1983. When I finished work, I stuck myself with a needle and collected some immune cells, and we used his method to measure electrical currents carried by ions in human immune cells.

That allowed us to show, for the first time, that immune cells had ion channels and, if we blocked them, we could prevent the cells from activating. In February 1984 we had a Nature paper, and cells from my blood were on the journal's cover.

Q:You believe blocking some of these channels is a better way of curing auto-immune diseases?

Auto-immune diseases can be stopped with immunosuppressant drugs, but these cause serious side effects because the drugs compromise the immune system's function in protecting against infections and cancers.

There are about one trillion T cells in our bodies. At first they are naive but, after they battle a foreign invader, some cells become central memory T cells that remember the specific invader.

When these central memory cells meet the same invader again, they reproduce to mount a faster and stronger immune response.

But if repeatedly challenged, some of them become effector memory T (TEM) cells instead, which are very aggressive and play a critical role in the development of auto-immune diseases. If TEM cells attack joints, you can get rheumatoid arthritis; if it happens in the pancreas, you can get Type 1 diabetes.

If we can create drugs to selectively silence these TEM cells by blocking their unique channels, we may be able to treat auto-immune diseases without compromising the rest of the immune system. That would be a significant advantage over existing drugs.

Q: You've found channels that can be targeted to treat obesity, diabetes, fatty liver disease, and liver, kidney and lung fibrosis, which is the thickening and scarring of connective tissue. One of the drugs you found also had encouraging results against psoriasis, a skin disease, from a human trial last month. Can you elaborate?

Potassium channels are the largest family of ion channels in the immune cells, with 76 genes in humans. The diversity of the potassium channels in the different physiological systems, coupled with their important roles, makes them excellent targets.

The Kv1.3 channel, for example, plays a critical role in TEM cells. Genetic and pharmacological studies suggest that Kv1.3 can be targeted to treat obesity, Type 1 diabetes, multiple sclerosis and rheumatoid arthritis.

I found a drug, ShK-186, from a sea anemone which blocks this Kv1.3 channel, and results from a trial in patients with plaque psoriasis, a skin disease, showed it was safe and produced significant improvement in the disease.

The KCa3.1 channel plays an important role in central memory T cells, macrophages, which "eat" foreign invaders, and other cells. My group developed TRAM-34, a drug which inhibits this channel.

In animal studies, the drug effectively suppresses atherosclerosis, a disease in which plaque builds up in arteries, the liver, kidneys and lungs, and it also reduces damage to neurons after a stroke.

Q: You've had a lot of help from animals in your research. Can you elaborate?

I was thinking about how to design a drug that blocked the channels when a young scientist, Dr Christine Beeton, sent me a scientific paper about how a 43-year-old woman in the United States, who had the auto-immune disease multiple sclerosis (MS), was bitten by a scorpion in 1982.

Over a two-week period, all of her MS symptoms disappeared, and that lasted for two months. Dr Beeton asked me, what if the scorpion venom was blocking your Kv1.3 channel? I was really sceptical but we tried, and not just with scorpions but also other venomous creatures.

While we were doing this, I was giving a talk and this marine biologist, Professor William Kem, came to me and asked why I was so land-biased. We started collaborating and, with other investigators, discovered ShK-186.

Q:Your wife is a psychiatrist and was your classmate in medical school. What is this competition you have with her?

(Laughs) She's been working for 35 years, and has served about 85,000 people.

I've published a bunch of papers but served zero people.

I keep telling her, some day, I'm going to blow you out of the water when my drug is approved and used for auto-immune diseases!

This article was first published on June 14, 2015.
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