Day 1 – stressing serendipity

By Professor Alistair Nunn, Director of Science, The Guy Foundation

It is sometimes difficult to untangle what came first in some stories. For instance, science fiction often builds amazing universes based on fantastical science, yet the origins of these ideas are usually derived from the emerging science of the day, yet, in turn, it can stimulate the generation of the very fantastical science it uses in future generations.  It could be said we are only limited by own imagination and as it turns out, the laws of physics, which many of us would love to over-turn, and indeed do in our heads. Who wouldn’t want someone to develop warp drive, or anti-gravity, or a cure for ageing, or perhaps even better, thought control of the TV? The world of quantum mechanics is a case in point. It has spawned innumerable best-selling science fiction novels, yet has led to the development of technologies that few of its founders could have imagined, but the incredible thing is that we still don’t actually know what it really describes.  Something that is embraced by the saying that “if you think you understand quantum mechanics, then you don’t”.  It is still a bit of black box – we can describe its shape, what it can do, even exploit its properties, but we still cannot really peep inside and go “ah”. Why is this relevant? Well, to paraphrase a quote used in Star Trek, at the quantum level there is no difference between biology and physics – something of which its founders, such as Schrodinger and Bohr realised a long, long time ago – even though they had probably never heard of Captain Kirk, or Picard or even the Borg and seven of nine.  Yet here we are today, working to mankind’s favourite pastime of “pigeonholing” – things have to be placed in a box, so we have biology, chemistry and physics, and apart from in a few rare cases, they  mainly inhabit different rooms in Universities and all scowl at the mathematicians, and each other. Yet they have far more in common that they think. So although the concept of “quantum biology” was discussed at the dawn of quantum mechanics in the 1920s, it never really took off, and even today it is only just beginning to make its mark – but with the difference that experimental data is indicating the biology may actually rely on it.

The story of how we got into it, is, perhaps one of classical curiosity-driven science where failure spawns adaptation, but is also an example of how being slightly outside the “system”, even if bits our “system” are firmly rooted in the reality of University-based science and commercial drug development (yup), led to the coming together of some minds that over numerous cups of coffee asked very simple deceptive questions like, “I don’t really buy the current theories, how does it really work”? Real science, as has often been said, is done when all the constraints are off, nobody is making any judgements, nobody is trying to make any money and one’s imagination can run riot where everything is on the table – and you must be prepared to be wrong.  Our story has its roots in trying to understand what disease really is, and trying to work out how natural products function as medicines. Our approach has been back to basics, often ignoring convention. This means going back to the origins of life and embracing the best model humanity has of the Universe (even if we don’t fully understand it), and that is quantum mechanics. Why? Well, much of modern science, and accepted wisdom, emerged through observation and because quantum mechanics is pretty counter-intuitive, folk tended to view the world through Newton’s eyes, as it is, well, sensible and pretty graspable. We were pretty much the same. Conventional biochemistry. Conventional pharmacology. Conventional  medicine. All in neat little boxes, easy to teach and put in a book.

Unfortunately, humans are still struggling to explain ageing (and thus, the origins of disease), how many drugs and in particular, natural products work (they bind to far too many things in a cell), and the biggies, consciousness, how life started (and what it actually is), and thus, perhaps are we alone in the Universe. Simply put, we seem to have not grasped some very big pieces of the puzzle. Don’t get me wrong, we have made some big strides, but I think we are beginning to realise that there is more to it. Take, for instance, the role of lifestyle and ageing. For years we thought we had cracked it with all our modern technology, but as it turns out, by far the most powerful medicine we have is a healthy lifestyle – why do with need clinical trials involving 1000s of patients to show an effect of some new “wonder” drug? Think on that.  Exercise should be a medicine, and as anyone in the physical education business will tell you, you can use N=1 to get a really good result. Take a very unfit individual, with all the markers of accelerated disease, such as a large waist, high blood pressure and glucose levels, and low good cholesterol, and get them to follow a healthy lifestyle with lots of exercise, and the transformation can be dramatic if they stick to it – even within a few months; a result that most drug companies would literally sack their CEO for. But perhaps what is less obvious is the link between exercise, intelligence and coordination, and the fact that the brain and musculature are intimately linked together. The computational power required, for instance, to throw or catch a ball, is immense. People often think that the mind and body are separate, they are not. Training in any sport is not just about the muscles, but the computer that enables it all to happen. When someone starts going to the gym, their first gains in strength don’t come from bigger muscles, but an improvement in the nervous system to coordinate and operate those muscles. We now know that muscle is an endocrine organ, and when used, it induces the brain to work better.

Lifestyle is hardly discussed at all during medical school, which is reflected in the number of slightly podgy GPs and nurses. Why is this? It doesn’t make any sense to me at all: exercise is equivalent to stopping smoking in terms of risk reduction, so it seems an obvious and total no brainer. This is a question we have been trying to answer, as have many others, but it certainly has its roots in “scientific idea inertia”, whereby the biggest hindrance to one idea is one that has become ensconced in professional opinion. Take, for example, mitochondria: this little endosymbioant kind of went out of favour for many years as people “discovered” genes and so on and thought that everything to be discovered about mitochondria had been, even to the point of mitochondrial toxicity becoming a by-word for off-target effects of many drugs. However, our little prokaryotic descendent has rather sheepishly come back into the fold as scientists rather reluctantly accept that it is rather important. As has their cousins, the gut microbiota. So was there something to be learnt here? Yup, again, history teaches us that as far back as the 19th century, and if we are honest, probably even back as far as the Roman and Greek civilisations, mankind had known about “what doesn’t kill you makes you stronger”. This biological process was given a name over 70 years ago “hormesis”, and explains a great deal of why exercise, calorie restriction, and even many plant compounds, make us healthier, and critically, why it improves our cognition. The mitochondrion is central to this process. In fact, without hormesis, we wouldn’t have evolved at all, as “stress” induces adaptation at all levels – especially the ability to process information, which does kind of define life. So the honest truth is that mankind may have got a little bit ahead of itself in thinking it had really grasped everything it thought it knew. One field where, perhaps this is less true, is the field of quantum mechanics, as anyone who is anyone in it realises we still have simply masses to understand and discover. So in this sense, as we don’t understand quantum mechanics, it could be said we simply cannot fully understand biology.

So how did we get into the quantum world? Serendipity and experimental failure. We have been studying how natural products, such as cannabidiol, modulate mitochondrial function, in particular, morphology. This was because we believed that one way to approach explaining how many natural products might work is to start with the mitochondrion, as, even if these compounds have multiple targets, a huge amount is known about the role of the mitochondrion. One of the big questions we wanted to ask was if our compound of interest does modulate mitochondrial function, does it, in the cell, end up there? Several scientific papers, and our own data, suggested it might – as did a whole pile of other literature for other natural products, suggesting that this could be a common mode of action. As I have a background in detecting things using fluorescence, I looked at its structure and thought it must. We threw it into a spectrofluorimeter machine, and hey presto, it fluoresced in the UV. Great! We thought we had discovered something unique, alas, after further digging in some very old literature, which everyone had forgotten about, we discovered we weren’t the first to do this. In fact, someone had even gone as far as to suggest phytocannabinoids might be sunscreens. Alas, nothing new in the scientific world, but it was very reassuring that we were not alone. Anyway, we had the bright idea of trying to use its fluorescence to track it through live cells. Once we had found a laboratory to help us, we set up the experiment and promptly discovered it was quenched, and then realised, which goes to show something about how prior education can blinker you, that the cell was actually full of UV fluorescent compounds. This was a revelation.  Since we had won some time on the microscope, we tried something else, which I had always wanted to do, and that was to image mitochondria using NADH fluorescence, and then study its lifetime decay (a very quantum effect) to monitor bioenergetics in response to our cannabidiol. Alas, we promptly cooked/bleached the cells, even though we were using 2 photon, which in theory should minimise the input of energy. We realised we were doing this as the mitochondria changed shape after taking only a few images, suggesting the light itself was having an effect (any fluorescence imaging expert would simply say “novice error!”, but so would have any quantum physicist: you cannot observe something without altering it). So we lowered the power of the laser, which helped, but of course reduced the image quality. But this got us really thinking.

We had heard of quantum biology, and after a crash course in quantum physics, realised that there was a lot more to this light effect than met the eye. In fact it was fundamental to how the Universe worked. We then went back into the literature and discovered a whole heap of stuff, including finding that someone in the 1920s had discovered that cells produce very low intensity photons called “biophotons”, which if you think about it, is a perfectly logical as electrons can emit photons and life, as they say, is simply about an electron looking for a home. This then led us straight back to another thing we had been interested in – electromagnetic fields, as mitochondria produce huge ones, and we were well into theories about proton gradients and thermal vents (in particular, Nick Lane’s work). Another delve into the literature uncovered lots of data showing that folk had been investigating how cells use them, and can be influenced by them, for many years. There were even theoretical papers suggesting that mitochondria could be communicating with other parts of the cell using both photons and electromagnetic fields. And of course, in quantum physics, the interaction of photons with matter and fields is all fundamental stuff, as photons, electrons, and even whole molecules, exhibit wave-particle duality.

So we are now trying to put this altogether into a coherent theory, starting at the beginning, which has been helped by more recent theories involving the origins of life using UV light and basic thermodynamics. To us, this kind of makes sense, as almost all of the most fundamental molecules in the cell, ranging from DNA, to NADH and most of the vitamins, as well things like cholesterol, all absorb UV light and can dissipate its energy and many are involved in redox reactions (transfer of electrons). So how does this help with medicine? Well, we figure that as life must be based on quantum effects at some level, it may well provide us with a much greater insight into the origins of life, how it works, and critically, why it degrades over time leading to ageing, disease and, sadly our ultimate demise as we dissipate our last. Just as modern medicine was born with working out how the basic bits of the body knit together, and the underlying physiology works, we may have to go deeper to actually understand what life is at the quantum level, and in doing so, may well be able to understand why it stops, and just maybe, how we might control this process.  It may take a few years, but if we don’t look, how can we possibly know? One of the key things in all of this is the emergence of intelligence, or the processing of information as a fundamental quantum-thermodynamic principle, which is why the Foundation is not just interested in it from the medical point of view, but also how it might be applied, say, in sport. Top levels sportsmen and women epitomise, perhaps, the definition of living in optimal health, a phenotype that emerges from a lot very, very hard practice. And what is practice? Well, it is the repeated application of the appropriate kind of stress to induce a training effect, resulting in constant improvement to do the task – in effect, hormesis. A process that may have kick-started a bunch of UV sensitive molecules back on the Hadean earth into something resembling life because they incorporated information to accelerate entropy, the driving principle in our Universe, which follow basic mathematical principles, including natural selection. Darwin could not have possibly thought where his thinking would lead. However, I will finish not with a Darwin quote, but one from Chuck Yeager: “Just before you break through the sound barrier, the cockpit shakes the most.” It could well be that embracing quantum mechanics could shake the biological tree to its roots, and who knows what fruit will fall out of it.