I went to Medical School in 1987. It was an incredible experience, crammed full of learning from inspirational Professors at the peak of their careers. My stand-out memory is the first day of Gross Anatomy. Faced with dozens of cadavers in shrouds, fresh-faced students in crisp, clean white coats, and that smell – I couldn’t wait to get started. Such a privilege.
Each precious body had been donated to medical research, to help train doctors, nurses and physiotherapists. We stood next to our allocated body, four students in a group, and recited a modified Hippocratic Oath. We were to dissect the body over the academic year, 565 hours of dissection, in detail, covering all organ systems, blood vessels, nerves and the brain. Our bible for the year was Man’s Anatomy by Tobias and Arnold, in three volumes. Professor Tobias and Professor Arnold were the big beasts of Anatomy. We were in awe of them. They were known affectionately as PVT and JCA (behind their backs of course)!
Getting started was a hand-trembling affair, guided by this illustration. Skin preserved in embalming fluid is very tough. But once you’re in, you’re in – and the delights of the human body were ours to explore. Over the weeks and months, we committed to memory all the arteries, veins, nerves and bones (oh, my poor parents had that box of bones in their living room); using mnemonics to remember the long lists. For example, Peter And Paul Masturbated So Much Their Balls Shrank refers to the branches of one of the thoracic arteries (I wish I could remember which one)! I can remember, though, that this one refers to the twelve cranial nerves: Oh Oh Oh To Touch And Feel A Girl’s Vagina Very Happily (or something very like it). The point is, we were drunk on anatomy for that year. We were walking encyclopaedia of lists of body parts, our text books were marked in wax pencil (I still have one I used in 1987), and nobody would share the lift with us because the smell permeated our clothes and hair. We knew it and we didn’t care. We were doing something that not many people ever get to do. It would shape our lives in the future. Some would go on to be world class surgeons, some physicians, sports scientists, pharmacists. I decided on a career in research.
Who knows how a career will turn out. I didn’t even do Science at school. I was expected to study Languages at University. I’m grateful to a Biology teacher for showing me something different, and changing my life. She asked me to help her clear out the cupboard in the lab. What we didn’t find in there. And lurking at the back, in a dark jar, was the most gorgeous pig foetus. We changed the preserving fluid, to reveal the tiny, perfect animal; when was he put in there, kept for me to find? I was hooked.
And so, standing in the dissection hall, several years later, in the basement at Medical School, I knew I was in the right place. I grasped the scalpel with both hands and made the first cut. Nine months later, the Technician was standing over the cadaver we had been working on. It approaching the final Lesson – the brain. He used a tiny, whirring saw to remove the cranium. He revealed a clean, shiny brain in situ. In order to complete the study, we had to remove the brain, with all the cranial nerves in tact. I had the smallest hands and I put them on either side of the brain, inside the skull. I tugged gently and felt around the base of the brain, to free the nerves from their restraints. A little more tugging, and I had the brain in my hands. We prepared the dissection and made 1cm slices through the brain, sectioning it in cross-section. I have never forgotten that moment. And neither will countless other medical students. That brain, sectioned, preserved and displayed can still be seen in the Anatomy Museum at Wits Medical School.
Gross anatomy? I don’t think so. Stunning, wondrous anatomy, is more like it.
In general terms, we expect that people who ask our permission, who require our consent, will have the morals and ethics to respect our wishes and do the right thing. Recently however, I have seen a few examples where, frankly, the people concerned have the morals of a snake. I’ll say no more on that, but it prompted me to think more widely about these terms; ethics, morals, consent, permission.
In my own field of life science research, no research may be undertaken without a prior favourable ethical opinion. It used be ethical approval, which implied that a peer-reviewed process had taken place, and an important group of senior people had carefully considered the application and deemed it ethical to conduct the research. Now, it simply means that a committee has spent a few minutes of the agenda discussing the merits of the work, and no responsibility or blame can be put their way should the experiment turn out not to be ethical, either in its design or in the outcomes. A matter of semantics, perhaps, but important none-the-less.
Important because many of the subjects for my research are human volunteers who trust us, the scientists, to do the right thing. Now, I don’t want to put anyone off contributing to a research project; we do still need to do research using human subjects. But I do want to point out that the administration of the rules is not what it should be. To my knowledge, there is no enforcement of the consent. I have seen inspections. I have seen paper records. I know that biological material collected years ago is still lurking in the bottom of freezers in research laboratories. Consents and research records belonging to PhD students who have long-since moved on lingering on dusty bookshelves in study rooms. There is almost no way of knowing which material should be destroyed, ethical opinion and consents having long-ago expired. And that’s just in small university laboratories. Surely in large pharmaceutical and biotech organisations the record keeping and ‘policing’ of the research consents is more robust?
Well, yes it is, and that results in a different problem. Large organisations who embark on long term research require consent from participants to be able to follow up on the outcomes of the research over a very long period of time, decades in some cases. With changes in technology, particularly in genetic research, where even five years ago the cost of this work would have prohibited it, that is no longer the case. Cost are down, through-put is up. In short, scientists can analyse more data, more quickly, at much lower costs. If the material already exists, if the methodologies are the same, there are also no start-up costs. Results could be coming within days. That means that if you volunteered ten years ago, donated a tube of your blood, approximately 10ml, and gave scientists permission to keep cells, plasma and DNA, they will still have all those bits of you in storage and on file.
I mentioned genetic research, for this is where I am most concerned. When you donated that small amount of blood all those years ago, you were probably young, in your twenties (most lab volunteers are), and too young to be showing any sign of disease. Your parents would have been young too; too young in most cases to have cancer or heart disease. You wouldn’t yet have had children either. And now, what if you are told that scientists have just worked out that your DNA shows a variation recently found to be associated with cancer – would you want to know? What would you do about it? Cancer cannot be treated if it hasn’t formed a tumour yet. This is the proposal of researchers, owners of these so-called ‘bio banks’, because original research is too expensive and largely unfunded. Would you still give your consent for your material to be used?
I believe that material collected more than five years ago should either be destroyed or re-consented. Yes, that will cost money, but it keeps science honest and transparent. It makes sure that scientists’ personal ethics and morals are not tested. It introduces a check that the material we think is there, has been stored correctly and will be useful in the research. Very often, biological material degrades over time and is useless. Better then to destroy it.
And finally, I must reveal here that I never allowed my cells or DNA to be stored. I have never used my own blood, cells or DNA in any experiment I have conducted. I do not want to know that I have a particular genetic variation. Until scientists are clever enough to re-program my genetic material, there are some things not worth knowing. Of course, there are some conditions for which there are extremely good genetic tests, and with the correct counselling, it is very helpful to do these tests. But these tests have made the transition from research to clinical application. We can’t change what has gone before, but we can make sure that we are informed about the future. Research must be done, human biological material must be used for research wherever possible. Don’t take ethics, morals, consent and permission for granted in science, or anywhere else for that matter.
Animal experimentation is always a sensitive subject, whichever side of the fence you sit. When I started out in medical research, almost twenty-three years ago, animals were used in all sorts of experiments, from radical surgical therapies to shampoo testing.
I personally witnessed some horrors in the name of science. It was fascinating stuff though, particularly the work done on developing novel surgical strategies for strokes, heart attacks and bone regeneration after motor vehicle accidents. I can’t say that I enjoyed seeing rabbits being used to test shampoo or make-up, and I’m happy that this rarely happens these days. I fully support campaigns against animal testing.
But, I also support those pioneering scientists who over the years have used animals big and small to test their hypotheses and make huge strides in science and medicine.
For example, life-saving surgery performed daily in many hospitals, putting a stent in a coronary artery, a main blood vessel supplying the heart, following a heart attack, would not have been developed if not tried in animals first. This surgery saves hundreds of lives every year. People who go on to live very productive lives after heart attack. Surely this is a good thing?
More recently, I have seen groundbreaking work carried out in genetically modified mice. These mice have been bred without a particular receptor (simply put, this is a grabber for chemicals such as drugs), which is believed to be key in addiction. This work describes how people are genetically pre-disposed to becoming addicted to cocaine or heroin. And it will help to provide strategies for treating a lost generation drug of addicts across Europe. The cost benefit of this treatment runs to millions of Euro’s.*
There is sometimes an argument for using alternatives to animal testing. I always prefer to use non-animal experiments. In fact, I have not worked with animals in twenty years, preferring instead to recruit human volunteers for my research. This is more difficult than it sounds. It often involves drawing repeated small amounts of blood from which I prepare DNA, the genetic material of life. And volunteers are understandably concerned about what scientists might do with that information. Consent is not required for animal experiments.
But ethics is required for types of experimentation. Morals and standards on ethics are required at all times. Public scrutiny is key to this as well, which is why I think it is important to talk openly about the work we do on animals. It is not sufficient to say that a committee of academics and vets approved the work, therefore it’s OK to do it. No, scientists must be called to account at all times.
The scientists who do this work conduct their experiments under the strictest conditions and scrutiny. Far from being hidden away, animal experimentation is a transparent necessity of science. The public has the right to know what experiments are being done in their name.
The problem is that there are some people who are so passionate about not using animals for science and research, that they endanger the lives of others. And that means that we cannot always talk about it openly. It’s a conundrum to which I don’t have a solution, just a plea to both sides. Maintain a dialogue, keep an open mind. Be respectful of each other. Scientists, especially in the UK, who use animals in their research are not evil people, taking over the world. I admit, there are less scrupulous researchers in other countries, but here in the UK, animal-lovers and concerned campaigners should be re-assured that the work is done with the very best intentions, in the best facilities, under the tightest regulations and conditions.
The sad fact is, that animal models are still needed for progress in many human diseases. Whilst it is true that whole animals such as mice or rabbits do not adequately represent the whole body situation in human beings, animal organ systems and cells are extremely useful for science and research. Non-animal models such as immortalized cell lines derived from humans, can only answer one question at a time, because these cells are taken outside the body and are not subjected to the same complex environment.
My mother died of cancer. She died from a form of lung cancer, for which there is no cure. She was sixty-six years old. She was too young to die. If scientists wanted to test drug, or design an experiment to better understand the disease, I would be all for it. Wouldn’t you?
*Note: please understand that I cannot describe experiments in detail or identify scientists here.
If you search for ‘statin and cancer’ on the public science and medicine database you will find 1,774 articles dating back to 1976. So, why was there a dramatic headline splashed across the newspaper last week? It’s not like we don’t already know about statins. They’re taken by millions of people around the world to reduce cholesterol by blocking something called the mevalonate pathway. This is a metabolic pathway involved in cholesterol production. Blocking this pathway reduces the production of cholesterol. This effect is simplified in the figure below. It’s like re-directing a stream of water.
Much of our understanding of of statins has come from work in animal models, looking at the reduction in cholesterol levels in the blood. In the lab I worked in we investigated the effect of two commonly prescribed statins on a protein made in white blood cells, which is a sign of inflammation. We showed that this sign of inflammation was decreased in response to these statins when the cells were treated with a substance known to mimic the effects of infection. As a result of these experiments, we considered another use of statins in blood vessels. They could be used to reduce inflammation inside the arteries of people with cardiovascular disease. The only current accepted, clinical use of statins is to lower the circulating fat (lipids) in the blood, which can be deposited in arteries causing heart attacks and stroke.
What’s the connection between inflammation and disease?
We have known for about twenty years that the underlying pathology in cardiovascular disease is rampant inflammation in the arteries. This is often due to fatty deposits, which cause red blood cells to clot in the arteries. A number of cells migrate to the region and release chemicals, which contribute to the inflammatory reaction, much like you might see if a wound becomes infected. Other causes of inflammation are viral infections, like influenza.Inflammation in the arteries happens over a long time and there are multiple signs in the blood. Testing for it is complex, which is why a doctor will often consider a full medical history when making a diagnosis.
I mention this because it is also known that markers of inflammation, like C-reactive protein in some cancer patients are only slightly increased. Two clinical trials looking at the use of statins, the PROVE-IT Study and REVERSAL Trial (reviewed by Salam, 2004) showed a reduction in C-reactive protein in people taking statins. For scientists, inflammation presents a wonderful environment for experimentation.
What about statins and cancer?
The author of the report in the newspaper, Dr Carol Prives and her team work with p53 a well known tumour suppressor gene found in many but not all cancers. The research referred to last week is in its very early stages. Dr Prives reports that the mevalonate pathway is significantly upregulated in tumours containing the p53 mutation. They do not say that statins have an effect on these tumours, merely that the same pathway of action of statins is implicated in p53-containing tumours (Freed-Pastor et al, 2012). This is interesting because it represents another line of research – to look at the effect of statins in these tumours. But it should be remembered that cancer cells outside of the human body, such as those used in laboratory experiments, are often derived from people who had cancer and died a long time ago. Their cells have been immortalized and are continually cultured for use in experiments. The disadvantage of this is that sometimes it does not represent the true tumour response. The advantage, however, is that the cells are always the same and experimental data can be compared over time and between laboratories, unlike if we use different people (or animals) each time.
So, there is a long way to go before we can say that millions of lives will be saved by taking statins. But, according to one cardiologist, the real importance of statins is longer life, and that’s a good thing, whichever way you look at it.
Education is the most powerful weapon which you can use to change the world. -Nelson Mandela
I am often asked why I left South Africa, and 16 years on and I honestly don’t remember the exact reason. I know my husband and I were fortunate to receive an excellent education in South Africa and attended University there too. We wanted to be citizens of the world, to use our education where it was needed. I’m pleased to say that for the most part, we have been successful in this. No matter what happens in life, nobody can take away your education.
Thandulwazi* means for the love of knowledge in Zulu. Wouldn’t it be great if all pupils could go to school with those words in their hearts? Instead, as the post-grad assigned to supervise them, I see students in the final year of their science degree, who are working so hard to complete coursework, study for exams and write a dissertation, that they seem to have forgotten that they chose science for the love of knowledge. They started university full of excitement and promise and over the three years have been worn down to just wanting to get a 2:1. Some, of course, will always be enthusiastic and will want to know more than the syllabus dictates. They are challenging and fascinating people.
I had a brief exchange with Erika-Check Haydn, from Nature News, about the challenges UK universities are facing as they attempt to produce biomedical scientists equipped to face the changing environment of research. They are only just up to speed with basic molecular biology techniques. Now, the technology companies are saying we need to train bioinformaticians. These are scientists who will spend their post doc jobs sitting at a computer, nowhere near a lab, analysing millions of digital data points. Where’s the thandulwazi in that?
So much of the data produced in experiments today is digital i.e. there is no physical picture of the result for us to examine.The peer-review process of publication in reputable journals should be able to put the data through the ringer, but sometimes the work is so specialist it can be difficult for outsiders to follow. The very nature of digital data is that it can be amended. The pressure to publish is a constant threat to researchers, and it can mean that research questions may not be stringently tested. I’m not saying that is what happened in the following examples but, questions will be raised if the data cannot be reproduced independently. While 2011 saw some incredible scientific breakthroughs, from the colour of meteorites to the secrets of aging (in mice, at least), it also saw two low points in science reporting.
Two research papers are in question at this time. The first is the finding that a murine leukaemia or related virus (MLV) was detected in patients with chronic fatigue syndrome. However, as the number of samples was limited and the data not reproducible, the authors had no choice but to retract their publication. That’s not to say they aren’t right. They simply need to find another way to prove it to their peers.
The second paper is more topical. Its focus is stem cell lineage and it was published in the journal Blood. The researchers acknowledge that some of the data may not reflect the published data analysis. This paper, was published in 2008 and cited 13 times in other papers. It could be argued that although there were errors in assembling the manuscript for publication, the authors stand by their findings and the interpretation thereof.
So, where does that leave the rest of us, struggling through to try and publish our blood, sweat and tears? I think it leaves us a little tainted in the public eye, and we must work harder to make sure our science stands up to rigorous scrutiny by our peers. As research funding decreases, the strongest research questions and protocols will rise to the top. Let’s hope that exciting research, and the love of science, does not drop away altogether.
*The St Stithian Foundation was set up to provide support for a Saturday school called Thandulwazi for pupils struggling to find a way complete their school education. It also supports teacher training. The Thandulwazi Trust is a Maths and Science Academy based in Johannesburg, South Africa.
Testing Treatments, by Imogen Evans, Hazel Thornton, Iain Chalmers and Paul Glasziou, is aimed at the informed patient and explains how new medical treatments are researched, and how that relates to the experience of the patient being treated. The book strikes a tone that is halfway between academic text and pop science, and might seem intimidating to some, but the regular summaries of key points and personal stories mean that the reader will soon find themselves gripped.
The book takes a long view over history, covering scurvy treatments in 1747 right up to cancer trials of the present day, advocating a partnership approach between patient and doctor, and includes calls to action for professionals, patients and policy makers to ensure that questions are asked and information is shared. The reader is encouraged to look sceptically at the need for treatments and screening, and to try to see through marketing and media hype.
Ben Goldacre provided the forward to this edition, and the book continues in the spirit of his work – accessible without being over simplistic. I would have liked to have more detail, but I’m not sure how that could have been achieved without losing the ease of understanding. There is an extensive list of further reading and references at the back of the book for the reader who would like to know more, and I didn’t personally feel that the scientific knowledge was shied away from in the text. Perhaps a scientist would disagree, but I went away feeling that I knew much more about the subject and that I would be a more informed patient.