John Rasko : Life Immortal

We have reached my fourth and final Boyer Lecture, a series this year devoted to the topic: "Life Re-engineered". So far, I’ve covered the fields of medical science I’m involved in. I focused on gene therapy in the first two lectures and turned to cell therapies in the third. Both of these technologies allow us to reshape the very basis of life.

I now want to bring these strands together to talk more generally about the ambition to re-engineer life. Biotechnology is a newish term — it was only coined a century ago — but this word expresses ambitions as old as humanity itself. In this lecture, I’m going to consider perhaps the ultimate ambition of biotechnology: the dream of immortality.

Here I have to admit that, as a scientist, I’m straying into waters less familiar to me — philosophical waters. Hopefully, I won’t get in too deep.

* * *

Let me start with a question: Where you are right now? Not geographically. Where are you in your life? Are you young, still deciding what to do with yourself, and what to believe? Or are you middle-aged, more established and more set in your ways? Or perhaps you’re retired, with time on your hands to dwell on your past and wonder what life’s all about.

Your life has an arc — a beginning, a middle and an end. But it began for you in the middle of your parents’ lives, at the point where their arcs converged. And if you have kids, you’ll repeat the process. Life proceeds in cycles linked up into a kind of fabric. Each of us is a stitch in time.

But, of course, the fabric unravels as quickly as we weave it. If you’re fortunate enough to live a long life, you’ll suffer the loss of those you love. Your parents, your siblings, your friends … maybe even your own children. And you’ll have plenty of time to worry, about your own mortality.

Humanity has always wrestled, with the problem of death. Why do we have to die? What’s the point of it? How can we live, knowing that our end will inevitably come? Is there anything after death? Can we transcend death or somehow cheat it?

In every society at every era, people have found ways to answer to these questions. Egyptian pharaohs spared no expense in building themselves pyramids and mastabas. These "houses for eternity," ensured their safe passage to the afterlife. Our cemeteries, shrines and cenotaphs do something similar.

But building monuments would be a waste of time if it wasn’t for the beliefs they express. Ideas of resurrection, of heaven and hell, and of an immortal soul, are all attempts to cope with the impermanence of life. Whether or not you actually believe in such ideas, you’ll admit they serve a vital function — they help us cope with the knowledge of death.

While recording these lectures, I’ve had an odd, but obvious, realisation: my voice will survive me. As you listen to this sentence, who knows, I could already be dead. While I like the idea something of me will go on indefinitely, it’s also unnerving. I feel like I’m already talking from the grave.

* * *

We each have to deal with our own mortality, one way or another. Some rely on religion, an afterlife, a benevolent god, or just the hope of "something beyond." Others cultivate a steadfast materialism — we turn to dust and that’s that. I suspect it’s much harder to stridently deny the existence of a hereafter when you’re staring death in the face. But most of us, most of the time, just avoid thinking about it.

Your view of death will also reflect your outlook on "life, the universe and everything." Many people see compelling evidence of the divine wherever they turn. Life is miraculous, a gift from God.

But, as a scientist, I’m always looking for physical causes and effects to measure and to manipulate. For me, life is a process set in train by the very nature of our molecules. These inanimate components are organised into our DNA, our cells, our organs, our bodies — our very being.

While there’s little room for wonder in a scientific manuscript, scientists are definitely not immune to it. On the contrary, scientific knowledge often provokes a sense of wonder. The more you learn about the complexity of things, the more astonishing they become. And the more you realise how little you actually know. The itch to seek absolute knowledge and certainty won’t ever disappear.

In the end, it’s a mystery. We just edge closer and closer to the ideal. It’s not a reason to despair so much as an incentive to try harder. Here, where understanding can take us no further, science rubs shoulders with surprising bedfellows. Albert Einstein put it this way:

The most beautiful experience we can have is the mysterious. It is the fundamental emotion that stands at the cradle of true art and true science … It was the experience of mystery — even if mixed with fear — that engendered religion.[1]

That’s a grand message, for sure. But it rings true. At their core, science, religion and art do seem like different ways of responding to the mysteries of our existence.

* * *

Two examples will take us into this zone of convergence, where we cannot help but feel a sense of unity with everything that lives. One comes from cell science, the other from genetics.

In the mid-nineteenth century, the great German pathologist, Rudolf Virchow, advanced the theory of cells. Its centrepiece was declared in Latin: "Omnis cellula e cellula." Which is to say, "all cells come from cells."

All life is based on cells, and all cells are derived from other cells, mostly by means of division. One cell gives rise to two, then four, eight, sixteen and so on. It’s one of the basic tenants of modern biology — so basic, even biologists often forget its implications.

Your body is made up of cells — perhaps a few dozen trillion, give or take.[2]All those cells can be traced back to one single cell, the fertilised egg that your parents had fun creating. But let’s not stop there. We can trace the origins of your parents’ cells, and those of their parents, backwards through time, generation upon generation, to the first humans. Then further backwards, down the evolutionary tree, to where all the forked branches converge, at the trunk, three-and-a-half billion years ago.

At the end of this regression, there was something resembling a single primordial cell, the origin of all life. And where did that first cell come from? Now you’ve bumped into a great mystery — the biological equivalent of the Big Bang.

Perhaps this first flicker of all life arose in deep-sea thermal vents or some murky molecular soup, battered by comets. The transition from molecules to a thriving, primeval life required countless gradual steps in natural experiments that took eons. In any case, those first cells propagated and evolved. Snowballing complexity allowed the adaptation of different cells to an ever-increasing number of settings. And life spread over the Blue Planet.

Now let’s approach this question of connectedness through the prism of genetics. Just as all living things are unified by their cellular origins, they all share a common genetic code. Across all the many branches of evolution, life stores its information in DNA and uses the same molecular mechanisms for transmitting and reading it.

Every plant, every animal and every bug on the planet has a common language! Not only is the language of DNA something we share with all living things, we also share much the same genetic information. For instance, although the actual percentages may vary (depending on definitions of similarity), we share about 96% of our genes with chimpanzees, 85% with mice, and 60% with bananas.[3]

Measures of genetic similarity allow us to work out at what point in the evolutionary tree distinctive branches split off. The fact we share so much of our genetic make-up with chimps shows that we’ve not been evolving separately for very long. We probably shared a common ancestor only 7 million years ago.

Of course, we’re more distantly related to other creatures, but even the simplest, like bacteria, are our cousins. Life is one enormously extended family!

* * *

I began by reflecting on our mortality and our endless struggles to deal with it. Beliefs in the immortal soul and the afterlife are solutions to this problem. But if we consider life as a whole — as we just did — the problem of mortality simply melts away. In the face of death, humans dream of immortality, but life itself is already immortal. On this planet, life is already four billion years old and counting. Even if we humans end up destroying ourselves — whether through global warming or a nuclear winter — life in some form will go on without us.

Since we have the big picture in view, I should mention something else. Aside from humans, no other creature on earth has a problem with death. No doubt, suffering and fear feature in the lives of most animals. But they don’t have a concept of their own mortality, so they don’t have that to worry about it.

The fear of death, like the dream of immortality, is uniquely and utterly human. It’s the unfortunate consequence of being able to reflect on yourself and the nature of existence.

On the other hand, because we’re intelligent enough to have a problem with death, maybe we can also do something about it. For the first time in the history of life, there is a creature now able to re-engineer life at its most basic level. An animal has gained the ability to direct the course of its own evolution. And possibly — who knows? — solve the problem of death.

* * *

As I mentioned earlier, science, religion and art have their differences. But, ultimately, they draw from the same well. For example, I give you the Greek god Prometheus. He was an important character in Greek art and mythology. The trickster god, he stole fire from the heavens and gave it to humans. Which makes him the legendary source of human technology. In modern parlance, he was a titan of applied science.

While the religion that gave birth to him died out long ago, he has remained an inspiration for painters, poets, sculptors, filmmakers and composers — including Beethoven, who wrote his only full-length ballet with Prometheus in mind.

But I know Prometheus best as the poster boy of regenerative medicine. Countless articles on stem cell research begin with his story, focussing on its most gruesome episode.

To punish Prometheus for stealing fire, the king of the gods, Zeus, bound him to a crag in the Caucasus Mountains. Each day, an eagle would swoop down and feast on Prometheus’s liver. And, each night, his liver would regrow in time for the eagle’s return.

This story is emblematic of regenerative medicine because the liver really does have a remarkable ability to repair itself. But many doctors and scientists have argued that the Prometheus myth is more than just an emblem. They take it as evidence that the ancient Greeks actually knew about the liver’s regenerative powers. If so, then they glimpsed a natural wonder that would not be scientifically verified until the late nineteenth century — a wonder that stem cell research is only just beginning to explain.

I’m not convinced the ancients did actually know about liver regeneration. After all, Prometheus, like all other Greek immortals, could regrow any tissue.

That said, I’d hate for stem cell scientists to forget about Prometheus. There is something very appealing about how the Greeks imagined their gods. Prometheus and his kin are not disembodied spirits. They’re flesh-and-blood creatures whose vital powers have been pushed beyond all limit. They are inspiring beacons for regenerative medicine.

* * *

In fact, the ancient Greeks imagined many ways to escape death. When Achilles was born, his mother tried to make him immortal by dipping him in the river Styx. Waters of life and fountains of youth flow in the myths of many cultures.

We’ll never drink from them, but maybe one day we’ll invent a medical equivalent. In terms of life extension, it’s worth remembering just how far we’ve already come. At the turn of the twentieth century, the average lifespan was 30-odd years worldwide. Nowadays it is 80-or-more years in wealthy countries like our own.

But in some places, like Sardinia and Okinawa, people commonly live past 100. This raises a fascinating question: What’s the longest time anyone can live for? It’s a controversial issue even among scientific authorities. We can’t be sure what the natural human age-limit is or even whether there really is an upper limit.

As we grow older, our body accumulates mutations and damage at the molecular level, leading to progressive deterioration. This brings an increased risk of all sorts of diseases — like arthritis, cancer and Alzheimer’s — and these in turn increase the threat of dying.

Some argue, if disease and cellular damage were effectively remedied, then we might all live indefinitely. If you follow this train of thought to the end, you’d be tempted to conclude that ageing is itself a disease and therefore something we might cure.

There is a growing biotech industry devoted to this very idea. Everything from supplements to gene therapy is offered as an antidote to death. Those who peddle such products — life extensionists — may talk a lot about science. A few of them may even be scientists, but they’re mostly quacks in white lab coats, selling the age-old dream of immortality.

Science and faith may have a common source, but they shouldn’t be confused. They’re very different activities. Charlatanism mixes myth and knowledge, magic and medicine. It’s a dangerous combination.

* * *

Blood has always been a potent symbol of life. As a haematologist, a blood doctor, I’m curious about how this depiction was conjured from human imagination.

The ancient Romans prized the blood of their fallen gladiators. Rather than see it spill out onto the ground, they’d collect it fresh. Spectators would drink this blood to augment their own life-force.

A still more grotesque story concerns Pope Innocent VIII. In 1492, while on his deathbed, he tried a desperate remedy. A physician drained the blood from three 10-year-old boys and gave it to the pontiff. If the story is true — and it probably isn’t — this was the first ever blood transfusion. Apparently, it didn’t go well. The Pope and the boys all died.

The restorative power of blood was depicted in art and religion long before there was any scientific evidence for it. Dracula, everyone’s favourite vampire, occupies an interesting place in this historical transition from myth to medicine. Bram Stoker wrote his gothic gem at the end of the nineteenth century. This coincided with the increasing medical credibility of blood transfusions. Indeed, it’s an important part of the novel. At night, Dracula drains the blood of his young victim, Lucy, and during the day, Professor Van Helsing uses blood transfusions to save her life.

In Bram Stoker’s novel, it’s as if myth and medicine are fighting each other for the right to control blood’s life-giving power.

The restorative ability of blood may not be a complete fantasy. Some experiments have shown blood plasma from young animals may confer health benefits on older animals. We don’t know if the same applies in humans and what side effects it will have, but some clinical trials are underway.

* * *

Life extensionists will try anything, based on a whiff of science. One idea is to apply the ultra-low temperatures used routinely for cell storage to the recently departed. I expect you’ve heard that Walt Disney is lying frozen in a vat of liquid nitrogen under the Pirates of the Caribbean ride at Disneyland. It’s an urban myth, I’m afraid. Walt’s body was cremated. So the only Disney on Ice is the ice-skating spectacular touring the world.

But soon after Walt’s death in the mid 1960s, a Californian man really was the first to be cryopreserved. And he remains in liquid nitrogen to this day. He now has hundreds of frozen friends, all of them awaiting a time when they can be revived and cured of whatever killed them. I’m pretty confident that won’t ever happen.

Science can pursue more plausible paths to life extension. My own areas of research, gene and cell science, could arouse cautious optimism. I’ll take them in turn.

Stem cell research brings with it the promise of regenerative medicine. The idea is to use stem cells to supercharge the body’s own regenerative powers or else to grow replacement tissues and organs in the lab.

One day we might be able to extend your life in the same way we extend the life of a car, by replacing parts as they wear out and break down. With a car, it remains "the same" even if you replace all of its parts — just as long as the vehicle identification number is maintained. Who knows, maybe we really will need barcodes for humans.

But we’re a long way from finding out. In my third Boyer lecture, I defended regenerative medicine as a very exciting field of research. To date, its progress has been slow and its achievements modest. The hype surrounding stem cells far exceeds its medical reality — in an alarming way.

As a result, we see the rise of stem cell clinics offering unproven therapies. They have plenty of patients knocking at their door — desperate people who believe stem cells will cure them and who can’t wait any longer for mainstream medicine.

The hype surrounding stem cells not only encourages pseudo-science, it also encourages fraudulent science, even within the world’s best medical institutions. To hear more about this, check out the podcast of my third lecture.

What about gene therapy? Does it offer a solution to ageing? Again, research in this field is encouraging but still in its early days. We know that constant cell division during our life leads to the accumulation of damage to our DNA. At the ends of our chromosomes, we have "tips" — called telomeres — protecting them from erosion. They’re a bit like the plastic ends of your shoelaces. As your cells divide and your chromosomes are copied, the telomeres get shorter and shorter. It’s a molecular equivalent to the fraying of old shoelaces, which is in turn linked to disease and ageing.

In recent years, we’ve learnt how to lengthen telomeres. We’ve done it in mice and it does seem to delay some effects of ageing and prolong life. No one knows whether the same trick will work for humans.

But that hasn’t stopped some people claiming the fountain of youth is already flowing. In 2016, the CEO of one biotech company took herself to Columbia for some telomere lengthening. She returned to the US with the news that her cells were now biologically younger. Indeed, 20 years younger. That would be a world’s first, if it was true. Instead of promoting rigorous scientific research, the only thing achieved was to promote her company’s sales of anti-ageing concoctions.

If you’d like to learn more about gene therapy, including the problem of do-it-yourself genome hacking, please listen to the podcast of my second lecture.

* * *

I’ve already talked about the ancient myth of Prometheus, which has inspired many stem cell scientists. I’d like to end by revisiting "The Modern Prometheus." That’s the subtitle Mary Shelley gave her masterpiece of science fiction, Frankenstein, which this year celebrates its 200th anniversary.

I’ve mentioned Frankenstein more than once in my Boyer lectures. That’s because my main theme is illustrated by the novel: the promises and the dangers of biotechnology. So far, I’ve focused on Shelley’s monster. Now I want to look at the moral of her story. Beyond the electrical rekindling of life, Frankenstein is a cautionary tale. It makes us reflect on medical ethics.

The usual way of reading the novel is to judge Victor Frankenstein guilty of much the same crime as Prometheus: excessive ambition and hubris. Where Prometheus stole the fire of invention from the gods, Doctor Frankenstein steals the secret of life from Nature. In both cases, we humans acquire a power we don’t have the wisdom to wield.

Shelley’s lesson is this: If science makes it possible for us to engineer life in our laboratories, or even create it from scratch, that doesn’t give us the right to do so. In other words, we should resist the temptation to "play God."

It’s an appeal for scientists to reign in their ambitions and set moral boundaries on what they do. It’s an appeal for caution and humility.

I certainly think this is a lesson worth heeding. In my lectures, I’ve underlined the need for medical science to proceed with caution and with the best interest of patients in mind. I’ve also pointed to the dangers of scientific arrogance, and visited some of the darker sides of science. Scientists, like everyone, make mistakes and show moral flaws. Hopefully, I’ve not dissuaded you from my firm belief in the great virtues of biomedical research.

But there is another lesson to learn from Shelley, one that hasn’t been widely recognised. Dr Frankenstein realises his own hubris just as his creature opens its dull yellow eyes. A feeling of mortal dread fills him and he flees from the lab.

This is his second big mistake. Dr Frankenstein rejects his creature, refuses to care for it, refuses to consider what it needs or what it sees through its yellow eyes.

Dr Frankenstein lacks the courage, imagination and — most importantly — compassion to take responsibility for what he has created. He can’t face living with this creature of his own making. In Mary Shelley’s book, this seems to be a moral failure even worse than hubris.

It’s a very different moral message, but it’s just as important. Especially now. For we may not have gained the power to create life from scratch, but we are learning how to bend it to our will.

We’ve already invented unnatural beings that evolution could never have created. In centuries past, they might’ve been called Monsters. From test-tube babies to human GMOs, we are re-engineering what it means to be human. If we find a cure for death, we’ll have fashioned a creature more outlandish than anything yet seen.

The warning against hubris only takes you so far. It’s like a guard standing at the threshold of the new. Crossing that threshold will demand a search for other guiding principles.

In the fields of gene and cell therapies, we have already crossed many thresholds, with more in view. We may not fully understand the consequences of what we’ve done for generations to come.

To sustain the future we’re inventing, we’ll need courage, imagination and — most importantly — compassion.