Hope in mesothelioma research

A personal and professional perspective by JHMRF research award recipient and organic chemist Professor Adrian Dobbs.

Some newsletter readers may have met Adrian at one of our AMD events in Leeds. A lovely, personable man and hugely dedicated to mesothelioma research, here is what he wrote for us, and for you.

I should begin with a confession.  I am a chemist.  I studied chemistry.  Worse than that, I like chemistry!  That is usually a conversation killer, so congratulations if you are still with me.  I like mixing things together and seeing what happens – perhaps I missed my true calling to be on the Great British Bake Off! And fortunately, they don’t (often) go bang, as in school chemistry.

I graduated in 1992, and enjoyed the subject so much that I studied for a PhD in organic chemistry, graduating in 1996. I was then very excited to take up a research position at the Université catholique de Louvain, in Louvain la Neuve, just outside Brussels in Belgium. Belgium is a fantastic country, and I cannot recommend it highly enough. I thoroughly enjoyed living there for two years. Everything in my life was great at this point; I had never heard of asbestos.

After I had been living in Belgium for a couple of months, my parents came out to visit me for the first time, driving over via the relatively newly opened ‘Le Shuttle’ through the ‘Chunnel’.  I thought that they looked tired, but put this down to them both being retired and a long drive.  However, during their 5 day stay, my dad never quite got back to his usual self, and a short while after returning home to London, decided to see his GP, who referred him for a few tests. Nevertheless, provisional plans were in place for future visits to Belgium in 1996.

These never happened. It turned out that the reason for my Dad’s tiredness/breathlessness was  fluid in his lungs, which they removed by means of a drain. This happened many times. Then they started asking the question – casually at first – had he ever worked with asbestos? ‘No’ came the reply from my father.  But when he was working, he had been a charted civil engineer, working on many projects including the Hallamshire Hospital in Sheffield. As he thought about things, he remembered that – while still an apprentice – he has been on site visits to the GPO tunnels under the Holburn region of central London, and the workforce had been spray-lagging the tunnels with a mixture of cement and asbestos – despite the thick clouds in the tunnels, none of the men wore any face/nose protection.

Then came the phone call from my parents – long distance of course as I was still in Belgium. “Your dad has been diagnosed with mesothelioma.”  “With mee-zo… what?” At the time none of us knew what this meant or the implications. While we cannot ever fault or complain about the care he received through the NHS and later South Bromley Hospice Care and St Christopher’s Hospice, the one thing no one ever said was the implications on life expectancy or that it was a terminal disease. I believe the only comment he received was that it would ‘affect his life expectancy’ but little more than that.

Being relatively ‘geeky’, I was really interested in this new ‘thing’ that was really taking off in 1996-7 called the ‘internet’ and used it to find out what I could for my Mum about mesothelioma – we didn’t tell my Dad everything we learnt, but information was generally scarce.  The one excellent piece of information we had was a small booklet by Mavis Robinson, a MacMillan nurse, I believe associated with JHMRF.

I am an only child, and in due course, I was able to leave my position in Belgium and return to the UK and to live at home with my parents during my Dad’s last few months, before he passed away in July 1998.

I have always loved university life, and have never truly left university – even some 26 years after originally going up to King’s College London in 1989. Over the years, I have developed my own independent research group, working in the field of organic chemistry – that is making molecules – and always with the purpose of addressing medicinal problems. However, one nagging doubt always remained at the back of my mind – why had I never got involved in any mesothelioma research?

The answer was simple – where do you start?  Let me give you some background to medicinal chemistry. Nearly all drugs on the market, for any condition, have somewhere in their history, as a starting point a compound from nature. This often comes from folklore.  For example, aspirin originated from a compound found in the bark of the willow tree; many modern painkillers are derivatives of extracts from poppies, including morphine. Ephedrine, first isolated in 1923 from a plant long used in traditional Chinese medicine was the foundation for the development of the anti-asthma agents salbutamol and salmetrol.  Rhubarb extracts have led to some modern laxatives. And so the list goes on. Chemists need a starting point for their work, and for mesothelioma, there was no such starting point.

All that changed in 2009, with the report of a compound, termed JBIR-23, by a group of natural products chemists in Japan. They claimed that this natural product showed some (albeit not great) ability to kill mesothelioma cancer cells. What a break through – our starting point! We attempted to start work looking at this molecule straight away, our chemistry-heads racing with possibilities about how this compound may work and how we could try and develop it.

However, drug discovery is an expensive business! We were very fortunate that the JHMRF saw the possibility in this compound, and we entered into an agreement with them, and one of their major benefactors, the sadly deceased Steve Lee, to fund initial research into this compound. We initiated a collaboration with Dr Peter Szlosarek at Bart’s Cancer Institute in London, who would test all the compounds that we made against the mesothelioma cancer cells.  Our work involved making chemical compounds. We pass these to Bart’s for testing – they tell us if the compounds are any good or not (that is, were they effective at killing the cancer cells).  They also test the compounds against healthy human cells, to check they there are unlikely to be side effects. We use this information to design more compounds, make them, get them tested, and so the cycle goes on, until hopefully we reach a point where we have a small number of compounds we can progress to studies outside the test tube and into animals in the first instance.

To an extent, this is where luck plays a part in the whole process, in that you hope that you can find those ‘perfect’ compounds as quickly as possible. Unfortunately, we are still in that cycle of manufacturing and testing – mainly limited by limited resource and not enough manpower – universities cannot throw 20 chemists at the problem in the same way that the big pharmaceuticals can.  On the other hand, even if it is slow progress, at least we are looking at potential new developments for mesothelioma, which the pharmaceutical firms on the whole are not.

In January 2013, I moved to my current position as Professor of Organic & Medicinal Chemistry at the University of Greenwich, on their Medway campus near the Chatham dockyards – itself a hotbed of asbestos with a terrible legacy of asbestos-induced diseases. Our work has really gathered pace since being a Greenwich, and the University is very supportive of this. Even more exciting, since the discovery of JBIR-23, three more natural products have been isolated which also show good levels of anti-mesothelioma activity. We are now looking at all of these compounds, with the idea to see if there are any common features in their chemical composition or ‘make-up’ which may give clues to their mode of action, and which we would incorporate into more efficient agents, but without harming normal healthy cells in the body.

The University of Greenwich has been very supportive of our work in this area, and featured it as part of their Alumni fundraising campaign in Summer 2014, with the aim of raising sufficient funding to cover the costs of the chemicals and other laboratory consumables for a new PhD student starting in our laboratory in October 2014. More generously, the JHMRF agreed to match fund penny-for-penny the money raised by the Alumni campaign, which now stands at several thousand pounds, with money still coming in. Further, the University supported a fundraising initiative on behalf of our mesothelioma research at the first Action Mesothelioma Day in Medway in July 2015.  Our local Medway MP Tracey Crouch is visiting our laboratories on 12^th December as part of her interest in campaigning for mesothelioma victims in Parliament.  For those who use twitter, you can follow our progress at @MesoUoG.

Dr Kate Hill and all from the JHMRF have been fantastic in supporting our work, and recently visited us at Greenwich to meet the new PhD student, Perry Devo and to see our laboratories.

I cannot express how exciting a time it is for us in this research. The drug discovery process is a long and arduous one, with no guarantees ever of success; it is the literal ‘needle in a haystack’ in terms of finding that correct chemical structure  that will do what you want it to do, without harming the rest of the body. As I write this, I cannot offer any promises that we will ever make it.  What I can do, however, is assure you that every penny we have received from our generous supporters is used to further our knowledge and understanding of mesothelioma.