Michael Coleman on modern toxicology
As a postdoctoral fellow, Michael Coleman sought to reduce drug toxicity in patients using research based on various animal- and human-based models. When he did eventually succeed in producing a therapeutic regimen that reduced the toxicity of a sulphone drug, dapsone, he was struck by the relative uselessness of the animal models.
The following interview is with yet another courageous scientist, by the name of Michael Coleman. We use the word “courageous” because Dr Coleman is clearly a forward-thinking toxicologist, who is prepared to challenge the status quo. However, as will be seen from the interview, there are limits to how far one can mould the system from the inside. The science of toxicology is clearly undergoing a major transition — from the old to the new. Antidote’s mission is to accelerate that transition.
Antidote Europe (AE): Could you tell our readers about how and when you became interested in non-animal work in your career?
Michael Coleman (MC): I spent my years as a postdoctoral fellow trying to design therapeutic strategies that might reduce drug toxicity in patients. This required a programme of using various different animal and in vitro animal and human-based models. I was eventually successful in producing a therapeutic regimen which reduced the toxicity of a sulphone drug, dapsone. However, it struck me during the work that the animal models used were not very predictive of the human situation and that the in vitro human-based work was ultimately more instructive. Subsequent work aimed at improving the model has borne this out for me in my field. Clearly every scientist working in life sciences may not have had my experience, but it strikes me that designing human-based models is the ‘Formula 1’ of life science research, in terms of intellectual challenge in method and technique development. Nothing is taken for granted — it’s like having to build your own racing car from scratch: indeed, the sheer enormity of this challenge I find irresistible.
AE: There is a fundamental need in our society to reliably assess the risk to human health and the environment of chemicals. The chemicals industry and our regulatory authorities have for years relied mainly on animal studies to provide this data. Modern toxicological methods look set to moving away from using animals, but the change is taking place painfully slowly. Why do you think this is the case, and could the change have happened much sooner?
MC: If this were an easy problem to solve, it would have been fixed many years ago. As scientists, we are as fractious and conservative as most people are and we resist what we often see as unjustified change. Doctors resent what they perceive as interference in their clinical judgement and civil servants do not welcome wholesale changes in bureaucratic procedure. People also invest large chunks of their lives in particular beliefs and methods, so they will defend them to the last. In addition, in vitro technology with human tissues has not had anything like the investment and interest that animal work has, so progress is slow. Real beacons in this area in the UK are the investments in non-animal work carried out by replacement charities in the UK, most notably the Humane Research Trust and the Lord Dowding Fund. These charities have been almost alone in funding work in the replacement, non-animal area in the UK, anyway. Without expertise, funds and the political will to find and invest in superior methods things will grind on in what feels like geological timeframes. There are some areas where replacement of animals is actually a reality, such as in the area of eye research at the University of East Anglia. All scientists are searching for perfect methods and we should not compromise on this search, so we need a level playing field for funding. It was easy for the guy on his horse to laugh at cars in the 1890s burping and wheezing along the road. By 1905 a V-8 Darracq could exceed 105mph. Given will and money, we can solve any scientific challenge and fairly quickly, too.
AE: Could you comment on the statement: “The main reason that such animal studies persist is because 20th century regulators are struggling to comprehend 21st century toxicology”. Would you say that “classical” toxicologists and modern day molecular toxicologists are worlds apart?
MC: I think that it is not a case of lack of understanding on either side, it is more a case of entrenched positions. Animal-based workers reject the positives of non-animal work and it is also important to point out that non-animal workers are very sceptical of animal work also. There are many instances where established systems that depend primarily on animals are not always predictive of human toxicity. This is beyond doubt, as the numbers of failed drugs testifies. There is room for classical and molecular toxicology in solving the problems of prediction in toxicology. Both skill-bases are not only relevant, but they are essential. Molecular toxicology generates enormous amounts of data, rather like mining 100 tons of ore in one sitting. The problem is finding the diamonds. The basics of the area of toxicology remain the same in this situation and are applicable, where change in structure leads to change in function. We have to work together on this and money should be available to groups who are willing to pool expertise and bury hatchets (obviously get the metaphorical hatchets in the ground first, of course…).
AE: The EU chemicals programme, REACH, entered into force in June 2007 and will require extensive animal testing in order to fulfil the regulatory requirements of this directive. Although there is scope in REACH for the implementation of non animal methods, regulatory authorities estimate that it will take at least 10 years, and in some cases, much longer, for full replacement of animal tests to occur. Taking acute toxicity as an example, could you propose a rational testing strategy – not involving the use of animals – that could be put in place immediately?
MC: Drug/toxin/chemical testing is two things: ‘Where does this stuff go?’ as well as ‘What does it do when it gets there?’ If we start with the second of those questions, we now have many ways of monitoring cell health, like the way you would monitor a car engine-oil, antifreeze, emissions, noise etc. We can watch what a cell does when it is set a task and we can see how its structures are standing up under the strain of imposed stresses. We can then compare this information from a new compound to known toxins and we can gain a handle on what a new chemical will do to a cell. Cells differ like cars do and we can grow cells which represent every organ in the body. Some will be more susceptible to damage compared with others. The final hurdle is the first question above, that is the whole body- ..‘where does this stuff go?’. This is obviously where we need to know where a chemical might go in the body: it might sit in the plasma, or head to the brain, or never even enter the body. Pro-animal testers point out the difficulty of testing this aspect of testing but it can be fixed, in that chemicals have rules like everything else, physiochemical rules. Essentially, if you tried to wash your dinner plates without detergent, the fat will sit on the surface of the water and they will never mix without detergent. Similarly, drugs and chemicals will go to certain areas of the body according to their degree of ‘fattiness’. We can predict this by making calculations based on their structures. We compare this with known human data and we can make a pretty accurate stab at where the chemical will go in a human. So we can do both….where does it go and what does it do, in human cellular systems.
AE: An often heard criticism of using human cells to study chemicals is that they cannot predict the systemic (whole body) response, and therefore animal studies are indispensable. How would you comment on this statement?
MC: See above.
AE: What thoughts not covered in this interview would you like to share with our readers in your closing remarks?
MC: Ultimately, we are at the ‘horseless carriage’ stage of development with in vitro-human based tests. The European Community is not helping with this problem, as it puts ill-directed political pressure on the development of testing procedures, along the lines of ‘test 30,000 chemicals by next Wednesday, or else!!’. This poorly thought out political strategy means that we will have to test them all twice: once with animals and eventually with human systems. The EU are promoting tests which purport to be replacement, but they are not, as they involve animal cells. Studies have shown that 95% of driving in towns is in a straight line. So a three-wheeled car will model most automotive testing situations adequately except for the remaining 5% of driving, that is, the corners. The history of drug development is littered with such ‘corners’ and I feel that we should be avoiding them in the REACH process and that only political expediency is governing the use of animal DNA to test effects on humans. Human-based systems should receive adequate investment for all our futures and our children’s futures.
