Abstract
Interview by Rona Williamson
Steve Bloom was born in Kent in 1942 and received his undergraduate medical training at Cambridge University, Cambridge, UK. His House Officer, Senior House Officer and Registrar posts were undertaken at The Middlesex Hospital where he also received an MRC Clinical Research training Fellowship. He moved to the Royal Postgraduate Medical School at Hammersmith Hospital as a Consultant Physician in 1974 where in due course he became Professor of Medicine. His roles have included Deputy Director of the Department of Medicine, Chairman of the Academic Board, Director of the Endocrinology Clinical Service and, Director of Chemical Pathology (renamed Metabolic Medicine and later Investigative Medicine), Chief of Service for Pathology and Chief of Service for Endocrinology and Diabetes. Having stepped down from his 10-year tenure as Head of Division of Investigative Science in 2007, Steve now holds a dual role within Imperial College London as Head of Division of Diabetes, Endocrinology and Metabolism and Chair of the academic Section of Investigative Medicine and also as Head of Clinical Chemistry at Imperial College Healthcare NHS Trust. His research work over the years falls into five related categories: endocrinology clinical research, physiology and pathology of gut hormones, control of insulin release and insulin resistance, role of neuropeptides in organ control and the role of neuropeptides in CNS regulation of appetite and related hypothalamic functions. He currently leads a research group investigating hypothalamic appetite control systems and gut hormones. This group’s discovery that oxyntomodulin reduces appetite offers a potential new treatment for obesity and in 2005 Steve cofounded spin out company ‘Thiakis Ltd’ to commercialize these findings. In 2008, Wyeth Pharmaceuticals successfully acquired Thiakis for a reported £100 million (milestoned). He has published over 1000 original papers (as well as numerous review articles) in journals such as Nature, J. Biol. Chem., PNAS, JCI and NEJM. In the past Steve has been a member of the Main Scientific Board for AstraZeneca and advisory boards for Upjohn and Novartis. In 2012, Professor Sir Steve Bloom was awarded a Knight Bachelor for Services to medical science.
You are currently Head of the Division for Diabetes, Endocrinology & Metabolism at Imperial College London, UK. What has been your greatest achievement to date in this role & what do you hope to achieve in the future?
The establishment of an active research group looking to solve one of the world’s most important problems, the pandemic of obesity, has been most rewarding. It is proven to be very difficult to find good leads for the medical treatment of obesity but after a 25–30-year period of research I think we have succeeded in identifying the satiety inducing gut hormones as being the best way forward. We found that they were naturally elevated following the only successful way of treating obesity, surgical gastric bypass. It is likely that this elevation of satiety gut hormones after bypass is in fact the way the bypass works. Having discovered this, then the endocrine unit team could get to work on turning these peptide hormones into efficient drugs. In the future, our hope is that we can set up another spin-out company, which will apply this in a commercial way, testing gut hormone analogs in the clinic for efficacy in humans.
What inspired you to specialize in the field of obesity research?
Obesity was clearly the main cause of the disease – which as a clinician I saw the most of – Type 2 maturity onset diabetes. There is at present a world pandemic of obesity and as a consequence, a ‘pandemic’ of diabetes. Maybe >90% of patients with diabetes only have it because of their excessive body adiposity.
Obesity is considered to be one of the greatest burdens on the NHS; increasing the risk of Type 2 diabetes, heart & liver disease & also increasing the risk of some cancers. What role do you think that education plays in the prevention of obesity & what more is needed to educate people on the dangers of this disease?
It is often not effective just to advise patients to eat less and take more exercise. Their response is to feel tired and sit down and because we have instructed them on which foods to eat, they tend to feel hungry and eat more. Although there is clearly a necessary educational point in advising people concerning their diet and their need for exercise, it fails in many people. There is a distinction between the over-achievers in social class one who mostly do seem to manage and, in social classes three, four and five, the people with slightly lower self-esteem who have greater difficulty in overcoming the desire for a little pleasure in life and who tend to get much more obese.
Although education is clearly limited in its effect, what we do not know is if we did not try to get people to be thinner would they in fact be fatter still? Is our population at risk of being even more obese if we gave up on the effort to instruct in diet and to give opportunities for more exercise?
Orlistat is the only obesity therapeutic currently available in the UK. What effect do you feel its introduction has had on the field of obesity & what remains to be addressed?
In my opinion Orlistat, a lipase inhibitor causing some malabsorption of dietary fat, is not a very effective agent. Side effects of orlistat, which include crampy abdominal pain due to malabsorption of foods and the need to use toilet facilities much more frequently, impacts on the patients quality of life. Unfortunately, people on Orlistat, knowing that fat in the diet is going to cause them digestive trouble, have a tendency to stop the tablet on the day when they have a birthday and start again the day after.
Only approximately 1% of patients remain on Orlistat at the end of the year. The weightloss is not very great, perhaps about 4 pounds total, and you have to keep on taking the tablet just to keep that weight off. You do not lose anymore. Although it is a help and can be useful when initiating diet and showing people that they could get on top of their weight problem. It is not a very effective long-term therapy for those recalcitrant many who, somehow, seem never able to lose any weight.
The identification of the naturally-occurring peptide hormone oxyntomodulin as an appetite suppressor has led to its potential as an obesity therapeutic. How did your research initially identify the role of oxyntomodulin & what are the major obstacles still to be dealt with before we can see this research translated into an available therapeutic?
The peptide hormone oxyntomodulin was first identified as affecting the oxyntic cells in the stomach, that is, suppressing gastric acid secretion in the later stages of the digestive process when gastric acid secretion was no longer required. It engendered excitement as a possible reason for duodenal ulcer formation that is, if you did not have enough oxyntomodulin release to switch off your acid properly, you developed an ulcer.
We established a method for measuring oxyntomodulin and showed it was indeed released after meals. When given to animals it caused a surprisingly big weightloss, this then led us to investigate it further. It seemed to cause weightloss not just by inhibiting food intake but we found it also increased the rate at which you expended energy and therefore was far more powerful than any straight appetite inhibitor. Naturally, the body tends to defend its existing fat supplies when one eats less and so, normally, as a consequence, energy expenditure goes down. Oxyntomodulin inhibits appetite and energy expenditure goes up. This gives a much better weightloss. We tried oxyntomodulin injections in human volunteers over a 4-week period and achieved considerable weightloss with no side effects. We therefore felt that oxyntomodulin was a potential winner.
Unfortunately oxyntomodulin had to be given by injection three-times a day before meals, which was obviously rather impractical. We thus felt that an important unit objective was to try and develop an analog of oxyntomodulin, which was longer acting and therefore more able to help obese people. Making a long-acting analog proved to be quiet tough and we had to test a very large number (500 or more) before we found one that was suitable for developing as a therapeutic agent with daily injection.
You founded the company ‘Thiakis Ltd’ in 2004 to develop novel medicines for the treatment of obesity & comorbidities. Can you provide us with some background information on TKS1225 & what progress is being made on the commercialization of this compound & the company as a whole?
Obviously in a capitalist society, if you want to develop a drug it is much easier to do it inside a biotechnology company where all the rules can be properly followed. We therefore set up “Thiakis Ltd” in order to exploit our oxyntomodulin analog. We coded our analog peptide TKS1225. We then had the tough job of raising capital venture money (at least £10 million was needed), then testing our analogue for toxicity in animals as well as developing a proper manufacturing process to make sure that it was stable and safe to administer to man. We ran a Phase I clinical trial in human volunteers, the purpose of which was to test if oxyntomodulin was safe, and indeed it was, very safe. At that point, we approached larger pharmaceutical companies to undertake the much more difficult, longer term, multinational human clinical trials. At the end of 2008 we successfully sold the company to Wyeth for £100 million in milestone tranches.
At the beginning of 2012 you were awarded a Knight Bachelor for your work in the field of obesity & diabetes. Do you feel that the recognition of your achievements has helped support & draw attention to your work at Imperial College?
Yes, the award was very nice for the unit as it showed everybody that attention was paid to research and from a personal view point the University has allowed me to stay on for another few years so I feel it has been quite helpful personally too.
What will be the major focus of your teams work at Imperial for the next 5 years?
Having developed a first generation long-acting oxyntomodulin, we are now working flat out to develop an even better one, with much greater potency and which would only need to be administered once a week. We have got our work cut out, as this is not so easy. We have had a breakthrough in the last year and it is all looking extremely promising. We are also actively interested in developing a second agent that could either work on its own or be additive with the oxyntomodulin and this second agent goes by the name of peptide tyrosine tyrosine (PYY).
PYY is another gut hormone, which also switches off appetite. It works naturally in conjunction with oxyntomodulin, so having a two-peptide injection would make a great deal of sense. All we have to do is develop equally long-acting analogues of PYY. The research for the next 5 years is well planned.
Is there a particular area of research you are interested in working in that you currently are not?
One of the things that have come out of developing analogs of these two gut hormones has been the effect of a small amino acid change on the whole structure. This turns out to be much more subtle and yet of much greater importance than one might anticipate. To illustrate the effect of such a small amino acid change, perhaps changing a leucine to an isoleucine makes the analog work much less well, however if at the other end of the molecule one has a glutamine rather than a glutamic acid, another small change, then the leucine to the isoleucine change now becomes helpful, in spite of the fact that these amino acids are perhaps 20 residues apart in a straight chain amino acid peptide. It does not fit preconceived notions but if you think of the molecule as having a whole molecule vibration or dynamic movement between different shapes it has possible to regard a change in one place as affecting a change in another, a bit like when you are playing the violin, the strings can be made to vibrate in different ways according to length and position of damping.
I would absolutely love to have the time to work more on this because I think it tells us something fundamental on the nature of proteins.
Finally do you have any words of advice you would give a young researcher entering the field of endocrinology & metabolism?
Well my first problem with giving advice is I am not quite sure what endocrinology is. It is the release of a hormone into the bloodstream to act at a distance – sure. That was the original definition of a hormone. Unfortunately, it turns out that many different things work in this way, for example the entire cytokine family controlling the immune system and many cancers have to induce blood vessel formation and this is due to local hormonal actions and so on. Therefore, every tissue depends on the local action of things released into the surrounding fluids. Basically everything is endocrinology or put it another way, quite which bit of it should we describe as ‘endocrinology’ is unclear. When I have solved that problem, I will be able to give scientists entering the field proper advice.
A number of members of my family have gone into science and to them I say, “this is going to be a very tricky career.” Only one in 100 PhD students become a lecturer and it depends on their idiosyncratic discovery of new things, ability to get grants and on bosses that are friendly rather than exploitative. My advice might be “do not”; however, the future depends on people with enough courage to risk everything in order to make fundamental discoveries as, only that way will mankind move forward.
Disclaimer
The opinions expressed in this interview are those of the interviewee and do not necessarily reflect the views of Expert Reviews Ltd.
Financial & competing interests disclosure
The author is grateful for grant support for his current oxyntomodulin and PYY research from the UK Medical Research Council. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.