Dr Zam Cader
This profile is taken from the MRC Annual Review 10/11, Perspectives, which tells the stories of MRC scientists who made some of the most compelling research discoveries of 2010/11 by thinking about research problems from a new angle.
Clinician scientist at the MRC Functional Genomics Unit, Oxford.
Zam has found the first gene to be directly linked with a typical form of migraine, which points the way to effective new treatments for the condition.
As an MRC clinician scientist, Zam divides his time between being a consultant neurologist at the John Radcliffe Hospital in Oxford and doing research on the genetics of neurological disorders at the MRC Functional Genomics Unit. It’s a balance that works well for him:
“If you have an academic turn of mind then there’s nothing better than being able to see the patients for whom you’re doing the research. It gives you an immense sense of satisfaction that you’re directly addressing some of the problems that they talk about, especially when there aren’t good treatments available. You’re right there at the frontier.”
Zam’s research aims to discover genetic changes that cause nerve conditions, find out why they are causing the condition and investigate ways of intervening in this process to develop new treatments. In particular, he looks at the genetic basis of migraine.
“Migraine is perhaps one of the most dismissed disorders,” explains Zam, “people think that it’s just a headache, but it affects 14 per cent of people worldwide, so it’s a huge health burden. It’s a severe, pounding, type of headache that can last for a couple of days and quite often beyond that, and sometimes you get warning signs with it, things like flashing lights and zig-zag lines, which is what we call migraine with aura.”
Genetic detective work
Until recently, the genetic causes of migraine were unknown. But in 2010, Zam struck gold by discovering a direct link between migraine and a mutation in the gene responsible for making a protein called TRESK. He says:
“Before our study, scientists had been looking really hard but they hadn’t actually pinpointed a gene linked with migraine, they had only found migraine-associated genetic markers. Often these markers were located in areas of DNA between genes – and understanding how these non-gene regions increase susceptibility to getting migraine was always going to be a challenge. So finding a damaging mutation directly in the TRESK gene was a real breakthrough.”
The TRESK gene is responsible for making a type of ion channel. Ion channels are pores in the membranes of nerve cells which let electrically charged particles in. The movement of electrically charged particles allows nerve cells to generate electrical impulses and send signals to other nerve cells. Through studies in frog eggs and human brain tissue samples, Zam and his team showed that the TRESK ion channel can control the excitability, or electrical activity, of nerve cells in a part of the brain called the trigeminal ganglia. This has long been known to be the central place in the brain which is activated during a migraine headache.
The scientists found the TRESK mutation by looking for ion channel gene mutations in a migraine sufferer with a strong family history of migraine with aura, which is a type of migraine known to have genetic causes. When they looked at all the other members of the person’s family, they found that those who had the TRESK mutation suffered from migraine and those without the mutation did not – strong evidence of the gene’s involvement.
Curb your excitement
“The discovery was a major step forward in understanding what migraine is. We found out that patients who have a TRESK mutation have certain neurons that become more excitable, more prone to be triggered, and thereby set off a migraine headache attack,” says Zam.
“It’s getting very exciting now because the discovery of the TRESK mutation, and the heightened nerve excitability allows us to immediately start thinking of ways of tackling migraine by bringing the excitability back down again.”
And the new knowledge stemming from this discovery has the potential to help all migraine sufferers, not only those who have the TRESK mutation, Zam explains: “The trigeminal ganglia are very much at the centre of the migraine headache, whatever the cause. So if we can reduce the excitability of that area of the brain, we can potentially improve the symptoms or even prevent all types of migraine.”
Towards the clinic
Zam's team is now working with MRC Technology, the company which commercialises MRC-funded discoveries. They are about to begin a drug discovery programme to find small molecules which can alter the effects of TRESK and reduce the excitability of the neurones which cause migraine, ultimately leading to new drugs for the condition.
Of the progress he has made, Zam says: “One of the reasons why I went into neurology is because when I started - and to still a large extent now - it’s a big black box of unknowns, with patients who are hard to treat. If my research ultimately makes a difference to the patients that I see, to bridge some of that gap between what they want from their doctor and what neuroscience can provide, I think that’d be great.”
Watch a video of Zam talking about his work
Published October 2011