Professor Luke O’Neill on marvel molecules and being a scientist

Professor Luke O’Neill of the School of Biochemistry and Immunology talks to Trinity News about the exciting discovery of a molecule that could help treat a variety of inflammatory diseases.

Science HeaderNew research led by scientists at Trinity has uncovered a molecule that could lead to new treatment of inflammatory diseases including multiple sclerosis, Alzheimer’s, Parkinson’s, gout, asthma, diabetes and Muckle-Wells syndrome. This marvel molecule, called MCC950, is capable of blocking a compound, called NLRP3 inflammasome, which is a key driver of inflammatory diseases. This could lead to new, non-invasive treatments for these diseases. The research, resulting from a collaboration of six institutions, has just been published in the journal Nature Medicine.

Inflammation links all these diseases. Could you tell me more about this?

I’ve always worked on inflammation as a process. It’s very important because the body repairs itself through inflammation, and it also happens through infections, so a cut on your hand will get red and painful and so on. The trouble is that process goes out of control for some unknown reason, which is really the puzzle we work on, in diseases like MS, arthritis, Alzheimer’s and diabetes. They all involve the same cells or molecules going out of control. The big mystery is why: we still don’t know why. What we have learned is the nuts and bolts of what goes wrong. We’ve always known one main process would become dysfunctional and the diseases differ in the part of the body that is affected.

So we knew there was a main pathway and then this NLRP3 inflammasome was discovered in 2001 by a Swiss lab and it turned out to be a driver of many of these diseases. It drives an inflammatory signal called i01 and I had worked on that since 1985. We’ve got to a point now where we have a drug that might actually interfere with this pathway.

This marvel molecule was already known. Is that right?

This marvel molecule was discovered and made by the drug company Pfizer. Chris Gable, who was working for Pfizer, found it could block i01- the consequence of the pathway- but he didn’t know the mechanism. Then Pfizer dropped it. We know it went into humans and was pretty safe and [that] they saw signs of efficacy in arthritis. Then our job in the lab was to show it blocked NLRP3. I got that idea because I knew NLRP3 had been discovered by this stage and that it was really important for all these diseases. [Dr] Rebecca Coll led the whole thing while she was a postdoc in my lab. We discovered it could block this pathway perfectly and got fantastic results. What really got us going is that it worked on three completely independent systems and, if you’re a scientist, you love independent lines of evidence: it worked on the MS model, on a model of infection and then, thirdly, it worked in a very rare human disease called Muckle-Wells syndrome, where patients get arthritis, liver inflammation and skin rashes. We could cure the mouse model and suppress the inflammation in blood samples from patients. I knew at that moment: this is extremely exciting. That’s what provoked us to try Nature Medicine and after some toing and froing it was accepted. It’s very tough to get into, worse than Time magazine!

Why is there such a dire need for new medicines in the first place? Is it due to lack of research?

It’s because discovering a new medicine is more difficult than climbing Everest backwards! The reason is the body is so complex. Many drug companies spend billions of dollars trying to discover new medicines and fail, because drugs often have side effects, the model systems we use are not perfect and a drug might work for one person and not another. It’s extremely expensive, time consuming and difficult to get to the point of having a new medicine, but the ultimate reason is we don’t know what causes these diseases and that’s why we need to do research. There are tens of thousands of people committed to this and the good news is we are making progress. Our work in College is part of that and we’re adding a little piece to the puzzle. Our dream is that we might have found one of the key pieces.

How long will it take for this to become a medicine and what will your next steps be?

The timelines won’t be that long because it’s been tested in humans already. First we’ll look at acute inflammation such as gout, where you can give someone the drug for a week with less worry about side effects. Chronic diseases are the problem: if you take a tablet every day and it has some side effects that could be very damaging. We’re looking at 2 years at least for diseases like Muckle-Wells and, for other more complex diseases like MS, 5-10 years.

Our model at the moment is to form our own company. We’ve made derivatives of the Pfizer molecule and we’re trying to get patents on those.

Drug companies often come under attack in books such as Bad Pharma by Ben Goldacre. What do you think of this?

Great book. One of his main gripes is that they don’t publish negative data for commercial reasons. He’s right: we need to publish negative data. Another issue is their overzealous concern about intellectual property and secrecy. You’ve got to have good regulation. Ben [Goldacre] is a key champion of more regulation in the sector, which is a good thing. Ultimately this is about trying to benefit patients and treat these diseases. There’s no doubt that you’ve got to be fair and honest, disclose negative results and be less secretive. As academics, we’re in the business of discovery, so we depend on drug companies to help us, and then the venture capital people to invest in companies. But we’ve got to be aware that these are businesses, they’re not charities.

And in science in general it’s very important to publish negative results. Do you agree?

Absolutely. The publications racket is disastrous. Our profession is under threat because who would want to become a scientist at the moment, with the pressure to perform? It’s horrific. We need to change the whole publishing system. When I was a student, one paper every three years was a big success, and that’s the way it should be because discovery is very difficult. I worry about the publishing business and the pressure on young people. There are fewer jobs as well, which makes it even worse, and the big elephant in the room is lack of reproducibility, which is driven partly by rushing things and leaving things out. This is a big problem now, which is growing, and if that continues the whole edifice could collapse.

So do you think open access publishing is the way forward?

Open access for definite. I think we need to reconfigure the profession and reevaluate what success means. Success isn’t publishing three crappy papers that nobody can reproduce. Success might be to publish three well-done, control papers that are negative, because that’s science as well. Our expectations on young scientists are too high: one good paper in a PhD is a success.

Leading on from this, what advice do you have for students who are thinking about pursuing a career as a scientist?

I wouldn’t want to be discouraging. It’s one of the greatest jobs you can ever have, but it’s up to us as the leaders to look after young scientists more and care for them, otherwise the system is threatened. But in our lab our mission is to discover things that will be relevant to human diseases. The joy of discovery is what drives us forward and if you can combine that with making a difference, that’s what makes it very appealing as a profession.

Do you think science communication is important for researchers and why?

Essential. It’s a recruitment policy. To get people to become scientists you have to get them interested and they might decide to join the effort. Secondly, you have to tell the taxpayer what you’re doing because they’re funding you. But the main reason is just the joy of it: because I’m a huge Beatles fan, I could easily stand up and talk about the Beatles as well! If you have an enthusiasm, it’s a great honour to be an academic in a sense, because you have a captive audience.

So do you think enthusiasm is the key?

Enthusiasm, excitement and passion. If you’re not going to be enthusiastic about it, you’re going to put people off. The danger with this is that you’re going to dumb it down and it’s going to become a show. It can’t become entertainment either. It’s in a strange interface between entertainment and information and complexity. I do think the minimum requirement to be a lecturer has to be interest and passion and enthusiasm and to convey that somehow. Humour is a great way, I think, to convey things to people. Another thing that has been shown is that people will never remember a fact you give them or a piece of information, they’ll remember how they felt. So if you can provoke some sort of emotion or feeling to people, then they are going to remember that.