Many people know or love someone who suffers from a common disease for which there is no cure. My father had Alzheimer’s. As a journalist and editor, he’d worked with words all his life and had always been impeccably correct about his grammar. But soon after he retired, we noticed that he began to lose and jumble his words. After he died at the age of 77, we found notebooks in which he’d tried time and again to spell words correctly. On a scrap of paper, he’d practised my mother’s name and a birthday greeting. He must have been aware that the words were slipping away, at least in the beginning.
There was no cure for Alzheimer’s then, and there is no cure for Alzheimer’s now. Similarly, apart from surgery, there was nothing effective to offer my younger brother, who died with a brain tumour at the age of 33. Twenty years after his death, the same treatments are being offered to people with his type of tumour: surgery, radiation, and chemotherapy, all of which may delay the inevitable, but at a cost.
What makes a drug a success?
There was great fanfare recently for a new Alzheimer’s drug, lecanemab (brand name Leqembi), which was shown in a trial to reduce the rate of cognitive decline in people with mild impairment. The drug was hailed as “momentous” and “historic”, but it is expensive, has to be administered via fortnightly intravenous infusions, and requires multiple MRI scans due to the risk of potentially fatal bleeding in the brain. Moreover, it’s not even clear whether patients and their families will notice any benefit from the treatment, and there are serious questions about its value for women (a problem given that women are twice as likely as men to develop Alzheimer’s). Can this really be regarded as a success?
Set against the backdrop of the awe-inspiring technological advances that we hear about on an almost daily basis, I can’t help feeling shocked that we have so little to offer people with strokes, dementia, most cancers, brain injuries, multiple sclerosis, motor neurone disease, osteoarthritis, Crohn’s disease, Parkinson’s disease – the list goes on. Why has there been so little progress in medicine? After all, these failures come on top of decades and decades of research into these diseases. Why has it been so unproductive?
Unfortunately, most of the research into these diseases has been conducted on animals. In this sort of research, scientists try to reproduce the disease in animals and then test new drugs on these animals. Although we’re used to hearing about new medical breakthroughs as a result of animal research, the sad fact is that when these apparent breakthroughs are followed up years later, most of them come to nothing.
As I explain in my book Rat Trap, new scientific evidence shows that animal research doesn’t actually translate to humans as well as we thought, so we can’t extrapolate what is found in animals to humans with any degree of certainty. This uncertainty is due to species differences; even very small differences between animals and humans can lead to significant changes in outcome, which is obviously problematic when it comes to developing drugs.
When pharmacologist Dr Bob Coleman began his career with the pharmaceutical giant Glaxo, his arrival coincided with the discovery of some well-known drugs such as the bronchodilator salbutamol (marketed as Ventolin) and beclomethasone (Becotide). Much of the research into these drugs was conducted on animals, yet Coleman describes these successes as “lucky” because other research programmes underway at the same time within the company came to nothing. The reason for this, he writes, “is simply that experimental animals have always been unreliable in their predictive power for human efficacy and safety, providing useful information on some drug candidates but not on others”. This goes some way to explaining why over 90% of drugs that have been tested for safety and efficacy in animals go on to fail when tested in humans.
Reliability of animal testing
Even the few drugs that go on to be licensed for use in the general population can have unexpected and serious adverse effects once they are prescribed in large numbers. The arthritis drug rofecoxib (Vioxx) passed tests in several different animal species, yet it caused tens of thousands of excess cases of serious coronary heart disease in the US before it was removed from the market.
Likewise, troglitazone (Rezulin), approved in the US in 1997 for the treatment of diabetes, was withdrawn in 2000 after reports of death and severe liver failure requiring transplantation. Animal studies had not predicted troglitazone’s potential to cause serious adverse effects in humans, yet tests on human cells and tissues strongly indicate its effect on the liver. Had they been used instead of the animal studies, these tests would have given clear warning signs.
Human biology-based research
At Safer Medicines Trust, we believe that using human biology-based research is the best way to develop safe and effective treatments for patients. Such research has advanced by leaps and bounds over the last couple of decades and generates findings that are directly relevant to humans, making medical research much more reliable by cutting out the “middle mouse”. When you think about it, it makes no sense to investigate diseases in animals and then try to apply the findings to humans. It is much more sensible to study humans directly.
Scientists can now draw upon a range of innovative technologies that use human cells. Perhaps the most exciting of these is the “organ-on-a-chip” – a chip the size of a computer memory stick that contains microscopic hollow channels that can be lined with living human cells taken from an organ and through which blood, air, and nutrients can be pumped. Organ chips closely mimic the dynamic microenvironment that cells are exposed to within the human body and have been used to great effect.
In 2022, for example, a team led by Lorna Ewart from the biotech company Emulate used 870 liver chips to test 27 drugs that had been judged safe for human use based on animal study evidence but that had gone on to cause serious adverse reactions in humans, including liver failure and death. The liver chips were able to detect toxicity in almost seven out of every eight drugs that were toxic to the human liver, far outperforming tests in animals. How much harm might be averted if organ chips were used more widely in drug development and testing?
Computer modelling and artificial intelligence are also beginning to transform drug testing. An in silico software programme, DILIsym®, predicted that two migraine drugs (telcagepant and MK3207) would be toxic to the human liver, a prediction that led to their development being terminated even though animal studies had failed to raise any significant safety concerns. Had only animal studies been used, telcagepant and MK3207 may well have gone on to harm humans. Furthermore, DILIsym® predicted that a related drug, ubrogepant, would be relatively safe for the liver. This was confirmed in human trials and the drug was subsequently approved by the FDA. Such findings provide a glimpse of a much brighter future.
Studies of the human genome
As well as these awe-inspiring new technologies, we are now also able to draw on insights generated by studies of the human genome and microbiome, as well as tried and tested ways of gaining human data, such as clinical trials. These approaches generate information and insights about us, not animals; they can be used to directly understand and treat human disease and have the potential to reduce adverse drug reactions and bring medicines to market more quickly and cheaply. But transitioning away from a reliance on animal research also means that we can start to think differently and ask different questions. Most animal experiments try to “model” human disease at its advanced stages. By then, the disease has already got its claws into us: most people die from cancer because the diagnosis comes too late, when the cancer is already too far advanced. But imagine if we could detect disease at its very earliest stages and intervene then, when treatment is likely to be considerably less invasive and much more successful.
The NHS is currently running a large, randomised screening trial in which people without a cancer diagnosis are given a blood test that aims to detect the very earliest signs of many different types of cancer. This blood test was developed on the basis of research on human tissues and cells and, if successful, could be a complete game changer, especially for cancers that cannot usually be diagnosed until it is too late.
Likewise, in America, some individuals at high risk of Alzheimer’s disease are being closely monitored with regular blood tests, wearable technologies, and investigations of their microbiome in research that aims to allow scientists to detect the very first signs of a transition to Alzheimer’s disease. This creates the possibility of intervening early on with tailor-made programmes consisting of exercise, dietary changes, drugs, supplements, the removal of toxins, and lifestyle changes. Excitingly, evidence is beginning to emerge that such programmes can maintain and even improve cognitive functioning.
These remarkable new approaches have come too late for my father and brother, but they might benefit you and me, and perhaps our friends and relatives. This is modern medicine, and it’s based on human biology.
Pandora Pound, PhD, is a fellow of the Oxford Centre for Animal Ethics, an independent centre pioneering ethical perspectives on animals through academic research, teaching, and publication. The Centre comprises more than 100 academic fellows worldwide.