Confessions of a Molecular Biologist

I am a trained molecular biologist. Molecules, I was taught, are the fundamentals of functional biology, and understanding and studying them will eventually elucidate all living processes. This framework of knowledge is well founded: in 1953 Watson, Crick and Franklin showed us that genes have a structural reality, Max Perutz and John Kendrew showed how Oxygen is carried in the blood by binding to heme - and they let the world marvel at the structural complexity and beauty of these findings.
One of the most talked about advances in the last years was the development of AlphaFold. Based on work by David Baker, and carried on at Alphabet in collaboration with the European Molecular Biology Laboratory (EMBL) this work was awarded the Nobel Prize in Chemistry in 2024. AlphaFold enables scientists to predict the three dimensional structure of a protein given only the linear sequence. It was Max Perutz, notably, who founded the European Molecular Biology Organisation (EMBO) in 1964, the umbrella organisation to which EMBL belongs. These fundamental breakthroughs are so valued because they are the basis for research and development in - for example - the pharmaceutical industry. Pharma - broadly speaking - still operates on the structural and molecular view of life, health and disesase. Molecules need to be discovered that are functional, hit disease targets and have efficacy - and can be sold as drugs. This is how modern medicine and science views the world, investigates the world and intervenes in the world. It does so from a strongly structural and anatomical point of view. This is how I myself was taught and educated, too.

This is how I worked in the lab, on the basis of which I designed experiments from which we then published papers. And I know that this approach - broadly speaking - works. And it does work. I did it with my own hands, as did hundreds of my friends, colleagues, and collaborators. So what is my confession ? My confession is that I have, all this time, been deeply sceptical of this view. And as much as I look up to Perutz - who was a remarkable and compassionate man - and was inspired by the brashness of Francis Crick, by the quick wit of Sydney Brenner, and the towering intellect of John Sulston, who helped sequence the genome of C. elegans together with Brenner and Bob Horvitz, as much as my own education, my research and my day to day life was deeply set within the molecular world - I remained a sceptic. The pitfalls of success are that you think you are on the right track. Insulin works, lipitor works, penicillin and amoxycillin still work, Pembrolizumab, a humanised antibody used in cancer immunotherapy, works and generated ca. 25 billion US$ in sales last year. It is hard to argue against this Goliath collection of functionally active compounds. Yet… On January 1st 2025, my stepfather died of complications from Alzheimers disease. Most of us have heard of Alzheimers, and possibly know someone who has been inflicted with this disease. It is a complex form of dementia, with often severe impacts on the behaviour of the patient. There is of course a lot of research being done on the causes of this disease. Let me give you a very brief deep dive into the molecular aspects of Alzheimers: The first line of evidence points to a protein called Tau that is implicated in the aetiology of Alzheimers. It becomes hyperphosphorylated - too many phosphate groups are added to it - which impede its proper function. This then disrupts the microtubuli within the neurons in the brain. Intriguingly, the microtubuli are needed, among other things, to shuttle mitochondria within neurons. These organelles - mitochondria - are usually referred to as the ‘power stations’ of the cell, as they produce Adenosine Triphosphate (ATP), the energy currency of all cells. This is where things get interesting. In the classical, molecular view, the solution is clear. The mitochondria are needed to generate ATP. Neurons need a lot of energy or ATP, especially at certain locations within the cells - to which the mitochondria are constantly shuttled back and forth from. Seems logical, seems clear. Yet… What happens if you use mitochondria that don’t produce any ATP ? If you use mutant mitochondria that have lost only this particular ability, but are otherwise just as functional as normal ones ? Turns out - all is just fine. Neurons function totally normally, as they get their ATP from other sources. What then - if not to produce ATP - are mitochondria so vital for ? How come - if neurons can no longer shuttle mitochondria back and forth within the cells, do patients develop dementia ? Something doesn’t add up. Unless.. It is here where we need to step aside from what classical molecular biology has taught us. For mitochondria don’t just produce ATP - which is a molecule - but also generate an electrical potential - which isn’t. Is it possible that the real role of mitochondria at these positions within neurons is not primarily about supplying molecules - but rather to provide an electrical charge ? Why would this be so important ? And again we need to turn to a different discipline for a possible answer. To chaos theory or more precisely a phenomenon called ‘self organised criticality’: order at the edge of chaos. Neurons need to constantly be in a state in which they can be activated, for a brief period of time, before they, by their own accord, return to a quiescent state. In the parlance of neurobiology they need to fire (via a change in axon potential) and then be still. This axon potential is an electrical charge, and the “firing” of the axon is a change in the electrical charge or potential across the axon membrane. This state - being able to be activated as well as returning to an inactive state - is absolutely critical. And as it happens is only possible within a narrow margin of parameters. This is the “self-organised criticality” state mentioned above. This state needs to be maintained, always and at high cost. The charge emanating from mitochondria could well be instrumental in maintaining that state. Much more so than any molecule they produce. The journey doesn’t end here. For the mechanisms that generate the electrical potential within mitochondria operate at the subatomic level. We are now entering the quantum world. This is because mitochondria operate a sophisticated electron transport chain, the detailed description of which are well beyond the scope of what a particulate, molecular view of life can teach us. We are now firmly at the edge of current scientific knowledge. Quantum physics and molecular biology are still strange bedfellows and barely acquainted. The outlook here is truly fascinating. Through a series of steps the quantum world is connected to a cellular process that in turn is connected to a disease which results in memory loss and a personality disorder. Coming back to the world at our scale, what does this mean for an approach to treat Alzheimer’s disease? Can we rely on a purely structural and particulate, classical molecular biological framework, to begin to understand the true causes of Alzheimer’s and to then treat it? And is Alzheimer’s the only disease where the potential explanation lies outside the bounds of molecular biology? I firmly believe that the answer to both questions is no. We cannot and will not be able to fully understand diseases, health or life, by relying solely on what the bedrocks of science tells us we should be relying on. We will have to venture far into the unknown to begin to see what lies beyond molecules. Goliaths they may be, but conventional Pharma needs to be on the lookout for quantum David.