What Is Life?

by Paul Nurse

  I had serious heart disease. Within a couple of weeks of this unwelcome revelation I was anaesthetized and laid out in an operating theatre. The surgeon opened my chest and identified the defective blood vessels that were failing to supply the muscles of my heart with enough blood. He then harvested four short lengths of an artery from my chest and a vein from my leg, and plumbed them into my heart in such a way that blood could bypass the problem areas. A few hours later, I woke up, battered and bruised, but with a repaired heart.

  That operation saved my life. As well as the great skill and compassion of the medical staff who treated me, the success of the operation rested entirely on our understanding of what life is. Every step was guided by knowledge of the human body and the tissues, cells and chemistry within. The anaesthetist was confident that the drugs they delivered would make my brain lose consciousness in a reversible way. A solution was infused into my heart, which completely stopped it beating for some hours. It contained potassium at a concentration the doctors knew was just high enough to alter the chemistry of my heart muscle cells to make them relax. A machine stood in for my heart and lungs, oxygenating my blood properly and delivering it at the correct rate. During and after the operation, I was given antibiotics to keep infectious bacteria at bay. Without all that accumulated knowledge about life, the chances are I would not be writing these words today.

  As our understanding of life has grown we have acquired great new powers to manipulate and change living things. But we must wield these powers properly. Living systems are complicated, so if we interfere with them before we understand them well enough, we will get it wrong and could cause more problems than we solve.

  Throughout history, most human lives have been ended not by old age, but by infectious diseases. The attacks made by bacteria, viruses, fungi, worms and a host of other parasites and pestilences have claimed countless millions of lives, many of them before they leave infancy. The bubonic plague that swept around the world in the fourteenth century killed nearly half of all people in Europe. For much of history, death was a constant presence in daily life.

  That is not quite so true today. Where vaccines, sanitation and antimicrobial drugs are available, we have the tools we need to prevent, treat or contain a wide range of once-deadly infectious diseases. Even HIV, once billed by some as the next great plague, can now, with the right care, be treated as a stable chronic condition. After millennia in which healthcare relied chiefly upon superstition, vague explanations and a host of unproven and sometimes risky remedies, this transition is a truly miraculous change. It all rests upon our knowledge of life, generated by science, and then applied to the world.

  However, there is still a long way to go in fighting the ancient scourge of infectious disease. As I write these words in spring 2020, the coronavirus pandemic is spreading turmoil across the world. Like the disease caused by this coronavirus, COVID-19, many viral infections can be immobilizing, or even lethal. And although the outbreak of Ebola that ripped through West Africa in 2014–15 inspired the impressively rapid development of effective vaccines, such interventions are only helpful when they can get to the people who need them at the right time. In rich and poor countries alike, too many populations still lack good access to proven treatments. It is also astonishing that politicians in some developed nations should have ignored advice from scientists and experts and have weakened measures to deal with epidemics and pandemics such as these. This neglect has already led to grave consequences. Putting all this right should be an urgent priority for humanity.

  Those of us lucky enough to live in societies that provide good medical care should cherish the protection it affords us. It is a mark of a civilized society that medical care such as the heart surgery I received from the UK’s National Health Service is free at the point of delivery, regardless of the patient’s ability to pay. ‘Pay as you go’ healthcare systems punish the poorest, and risk-based insurance systems punish the most needy. And then there are those who wilfully criticize the safety and effectiveness of vaccines without adequate evidence. They should remember that rejecting proven, clinically approved vaccines is a question of morality. By doing so they are not just imperilling the safety of themselves and their families, but also that of many others around them by disrupting herd immunity and allowing infectious diseases to spread more easily.

  The battle with infectious disease is one that we will never wholly win, however. That’s because of evolution by natural selection. Since most bacteria and viruses can reproduce very quickly, their genes can also adapt rapidly. This means new strains of disease can emerge at any moment, and they are constantly evolving ingenious ways to elude or trick our immune systems and medicines. That’s why the rise of antimicrobial resistance is such a threat. It is natural selection in action and it is taking place before our eyes, with alarming consequences. Exposing bacteria to antibiotics without actually killing them off entirely, makes it more likely that they will evolve resistance to the drugs. That’s why it is important to take the right dose of antibiotics – and only when truly needed – and to finish the course of treatment you are prescribed. Not doing so may not only put your health at risk, but also that of other people. Just as dangerous, or even more so, are the farming systems that drip-feed low doses of these drugs to animals to make them grow faster.

  We are now seeing the emergence of strains of bacteria that can resist every intervention we can make; the diseases they cause are becoming untreatable. Resistant bacteria like this could cast medicine back in time, putting millions of lives at risk. Imagine a world where you or your family could be struck down by an incurable infection because of a scratch from a rose thorn, a nip from a dog or even a visit to a hospital. But we must not be fatalistic about this threat. Identifying a problem is the crucial first step towards solving it. We can and must use the antimicrobial drugs we do have more carefully; we can also design better ways to detect and track drug-resistant infections; and we need to develop potent new antimicrobial drugs and make sure the researchers who do this are well supported. We must use all our knowledge about life to solve this problem – our future may depend on it.

  As healthcare has improved and the threat posed by infectious diseases has been gradually pushed back, average life expectancy has crept steadily upwards. But as people live longer, they have had to confront a host of unpleasant non-infectious conditions of ill health, including heart disease, diabetes, a range of mental health conditions and cancer. Their fundamental causes are old age and unhealthy lifestyles. Globally, they are all on the rise, and they create big challenges for both sufferers and the scientists who want to understand and treat them.

  Consider cancer – it is actually not one disease, but many. Every cancer is different, and each incidence changes with time, so that an advanced cancer is often a bit like an ecosystem in its own right, containing many different types of cancer cell, each containing different genetic mutations. Once again, this is the work of evolution by natural selection. Cancers begin when cells acquire new genetic changes and mutations that cause them to start dividing and growing in uncontrolled ways. They flourish because they have a selective advantage: they can monopolize the body’s resources, grow more than the non-mutated cells around them, and ignore the body’s ‘stop’ signals.

  Some of the most promising new approaches to cancer therapy have been informed by our improved understanding of life. Cancer immunotherapies, for example, seek to educate the body’s immune system to recognize and attack cancer cells. This is a smart approach because the immune system can launch extremely precise assaults on cancer cells, while ignoring healthy cells nearby. New treatments are also emerging from work that my colleagues and I started on the cell cycle of the lowly yeasts. Drugs that bind to and inactivate human versions of the CDK cell cycle control proteins are now used to treat many women with breast cancer. Four decades ago, I had no idea that work on the cells of yeast would eventually lead so directly to new cancer treatments. Because cancer is an inev
itable result of the cell’s capacity to adapt and evolve, we will never entirely eliminate it. But as our understanding of life gets better we will increasingly be able to spot cancer early and treat it more effectively. I am confident there will come a time when cancer no longer arouses fear, as it still does today.

  If we want to accelerate progress in tackling cancer and other non-infectious diseases, decoding the information in our genes provides important new ways forward. When the first draft DNA sequence of the human genome was shared with the world in 2003 it promised to open the door to a new future of preventative medicine. Many of those involved looked forward to a world where any individual’s genetic risk factors could be accurately calculated at the moment of birth, including predictions about how those risks would interact with lifestyle and diet. But realizing this aim is very challenging, both scientifically and ethically.

  That’s partly because of life’s profound complexity. Few human characteristics behave like the clear-cut characters of the pea seedlings that Mendel studied in his garden. The diseases that are caused in a similar way, by defective versions of single genes, include Huntington’s disease, cystic fibrosis and haemophilia. Together these diseases cause a great deal of suffering and pain, but they each affect relatively small numbers of people. Most common diseases and disorders, including heart disease, cancer and Alzheimer’s disease, by contrast, have more multi-factorial triggers. They are caused by the combined influences of many individual genes which operate and interact with each other and with the environments we live in in complicated and hard-to-predict ways. We are starting to unravel the intricate chains of cause and effect that intertwine our nature and our nurture, but all progress is hard-won and slow.

  This is an area where understanding Life as Information comes to the fore. Researchers are now amassing extremely large collections of data – some of them containing gene sequences, lifestyle information and medical records gathered from up to millions of different people. But making sense of such large data sets is difficult. The interactions between genes and environment are so complex that the researchers who study them are stretching the limits of presently available techniques, including new approaches such as machine learning.

  Useful insights are emerging, though. It is now possible to use genetic profiling to identify people with an elevated risk of suffering heart disease, or becoming obese, for example. These can be used to give advice about lifestyle and drug treatments that is tailored to individuals. This is good progress, but as the ability to make accurate predictions from our genomes gets better, we must think hard about how this knowledge should best be used.

  Accurate genetic predictors of ill health pose particular difficulties for medical systems that are funded by personal health insurance. Without strict controls on how gene information can be used, individuals could find themselves being deemed uninsurable and denied care, or charged unaffordably high insurance premiums through no fault of their own. There are no such problems with medical systems that provide care that is free at the point of delivery, since they will be able to use advances in genetic predisposition to predict, diagnose and treat disease more easily. That said, this is not always easy knowledge to live with. If genetic science advanced to the point where it could make a reasonably accurate prediction of when and how you are most likely to die, would you want to know?

  Then there is deciphering the genetic factors that influence non-medical factors, such as general intelligence and educational attainment. As we learn more about genetic differences between individuals, genders and populations, we must make sure these insights are never used as the basis for discrimination.

  Advancing in parallel with the ability to read genomes is the ability to edit and rewrite them. An enzyme called CRISPR-Cas9 is a powerful tool that functions like a pair of molecular scissors. Scientists can use it to make very precise cuts in DNA, in order to add, delete or alter gene sequences. This is what is referred to as gene-editing, or genome-editing. Biologists have been able to do this in simple organisms, such as yeast, since around 1980, which is one of the reasons that I have worked with fission yeast, but CRISPR-Cas9 vastly improves the speed, accuracy and efficiency with which DNA sequences can be edited. It also makes it much easier to edit the genes of many more species, including human beings.

  In time, we can expect new therapies based on gene-edited cells. Researchers are already making cells that are resistant to specific infections, such as HIV, or using them to attack cancers, for example. But for the time being, it is extremely reckless to attempt to edit the DNA of early stage human embryos, which would result in genetic changes in all the cells of the person born, and those of any children they might have in the future. At present there is a risk that gene-based therapies might accidentally change other genes in the genome. However, even if only the desired gene is edited, those genetic changes could also cause hard-to-predict and potentially dangerous side effects. We simply don’t yet understand our genomes well enough to know for sure. There may come a time when this procedure is deemed safe enough to free families from certain genetic diseases, like Huntingdon’s or cystic fibrosis. But using it for more cosmetic purposes, like creating babies with enhanced intelligence, great beauty, or high athletic ability is another matter altogether. This area entails one of the most thorny of today’s ethical concerns about the application of biology to human life. But although talk of using gene editing to make designer babies is mostly hot air at present, many parents-to-be will have to contemplate some challenging issues in the years and decades to come, as scientists develop more powerful abilities to predict genetic influences, modify genes and manipulate human embryos and cells. All these issues need to be discussed by society as a whole, and they need to be discussed now.

  At the other end of life, advances and developments in cell biology are providing ways to treat degenerative diseases. Take stem cells, for example: these are cells that the body maintains in an immature state, rather like those present in an early embryo. The key property of stem cells is their ability to divide repeatedly, to produce new cells that can then go on to adopt more specialized properties. A growing fetus or a baby contains large numbers of stem cells, since they have a constant requirement for new cells. But stem cells also persist in many different parts of the adult body long after it has stopped growing. Many millions of your body’s cells die or are shed every day. That’s why your skin, your muscles, the lining of your gut, the edges of the corneas in your eyes, and many other tissues of your body contain populations of stem cells.

  In recent years scientists have worked out how to isolate and culture stem cells and to push them to develop into specific cell types – nerve, liver or muscle cells, for example. It is also now possible to take fully mature cells from a patient’s skin and treat them in such a way that they turn back the developmental clock, reverting to a stem cell state. This raises the exciting prospect that it might one day be possible to take a swab from inside your cheek and use the cells to generate almost any other cell in your body. If scientists and doctors can fully master these techniques, and can establish that they are safe, they could potentially revolutionize treatment of degenerative disease and injuries and revolutionize transplant surgery. It might even become possible to reverse currently incurable conditions of the nervous systems and muscles, like Parkinson’s disease or muscular dystrophy.

  This progress is part of what has inspired bold predictions, many of them emanating from firms based in Silicon Valley, of a fast-approaching future in which it will be possible to arrest or even reverse ageing. It is important to keep these claims grounded in practical reality. Personally, I will not be opting to cryopreserve my brain or body when my time is up, in anticipation of a highly unlikely future time when I might be resuscitated, rejuvenated and kept alive into perpetuity. Ageing is the end product of the combined damage, death and pre-programmed shutdown of a body’s cells and organ systems. Even for those in fine health, skin becomes less elastic, muscles lose
tone, the immune systems becomes less responsive, and the power of the heart gradually weakens. There is no single cause for all this and it is, therefore, very unlikely that there can be a straightforward fix. But I have little doubt the decades ahead will see life expectancy creeping on upwards and – importantly – the quality of life improving in old age. We will not live for ever, but we could all benefit from ever more refined treatments that use combinations of stem cells, novel drugs and gene-based therapies, as well as healthy lifestyle practices, to revive and regenerate many parts of elderly and ailing bodies.

  The application of biological knowledge has not only revolutionized our ability to mend broken bodies, it has allowed humankind as a whole to flourish. Beginning around 10,000 bce, the world’s population leaped upwards when our ancestors started farming. They didn’t see it this way at the time, but this was achieved by our human ancestors applying the principles of artificial selection to domesticate animals and plants. A much larger and more reliable supply of food was the reward.

  Compared to the prehistorical surge, the world’s population has grown even more dramatically within my lifetime: it has nearly tripled since I was born in 1949. That means nearly 5 billion extra mouths that must be fed each day, with all that extra food being produced on roughly the same area of agricultural land. The Green Revolution, which started in the 1950s and 60s, was key to making this possible. This involved developments in irrigation, fertilizers, pest control and, most importantly, the creation of new strains of staple food crops. In contrast to breeders throughout history, the scientists involved were able to leverage all that had been gleaned about genetics, biochemistry, botany and evolution towards the production of novel plant varieties. It was astonishingly successful and generated new crops with significantly higher yields. This hasn’t been an entirely cost-free exercise, however. Some of today’s intensive farming practices have a damaging effect on the land, farmers’ livelihoods, and on other species that share the environment with food crops. The amount of food wasted every day is a scandal that must also be solved. But without that major injection of biological knowledge into farming practice last century, millions more would starve every year.