Hacking Darwin

by Jamie Metzl

  It is a very long way from synthesizing the genome of a single-cell organism, which hasn’t yet fully happened, to doing it for the twenty-one thousand or so protein-coding genes in the human genome but, as the Chinese proverb goes, a journey of a thousand miles begins with a single step. As Stanford synthetic biologist Drew Endy told NeoLife in 2018, “We want to make modellable biological systems that we understand and can use as engineers to rebuild the living world… I have to imagine that one day we’ll be routinely building human genomes for any purpose that anyone can advocate for.”41

  Mommy? A DNA synthesizer machine. Source: Seth Kroll.

  As computing power increases and the cost of producing an entire human genome decreases, the walking pace will speed up. Lao-Tzu, the purported originator of that Chinese proverb twenty-five hundred years ago, would have needed about three hundred hours to walk that thousand miles. Today, Lao-Tzu’s descendants can go a thousand miles in twelve hours by car, four hours by train, two hours by plane, and three and a half minutes in an orbiting spaceship. A journey of a thousand miles still begins with a single step, but travel speeds can accelerate pretty quickly from there.

  The Genome Project-write (GP-write), one notable example of this accelerating change, seeks to raise $100 million to synthesize the full human genome, starting with synthesizing the genomes of simpler organisms but continually moving up the complexity chain toward creating human genetic code.42 “What we’re planning to do is far beyond CRISPR,” George Church said at the time. “It’s the difference between editing a book and writing one.”43

  If funded and even minimally successful, this initiative will help scientists better understand the complex genetic and broader systems biology ecosystem. In the longer term, this understanding will help future generations manipulate, engineer, and ultimately create life. The transformation of human life into information technology will proceed apace: reading, writing, and hacking. Given these aspirations, it’s no coincidence that Church’s 2012 book is titled Regenesis. Our religious traditions have a three-letter word for the entity that writes the book of life.

  The computing, machine learning, AI, nanotechnology, biotechnology, and genetics revolutions all have different names today, but these different technologies are currents converging into one megarevolutionary tidal wave, washing over what it means to be a human being. If we ride this wave, the only limit for how far we can go is, perhaps, our collective imagination.

  Geneticist Christopher Mason of Weill Cornell Medical College is already, for example, working on what he calls a “ten-phase, 500-year plan for the survival of the human species on Earth, in space, and on other planets” and collaborating with NASA to “build integrated molecular portraits of genomes, epigenomes, transcriptomes, and metagenomes for astronauts, which help establish molecular foundations and genetic defenses for long-term human space travel.”44 The spaceship of our genetic future is already loading at the dock.

  That is why when we traveled in our time machine described at the start of this book, the baby we brought back to today from a thousand years ago was pretty much like us, but the baby we brought back from a thousand years in the future was healthier, stronger, smarter, and more robust than most of us are today. It’s also why that baby, if we feed and nurture her, will also very likely live significantly longer than any of us do today.

  Chapter 7

  Stealing Immortality from the Gods

  In the world’s oldest surviving literary work, King Gilgamesh of Uruk can’t stop grieving the loss, and stressing over his own mortality, after his best friend Enkidu dies prematurely. “Must I die too?” he weeps. Siduri the tavern keeper warns Gilgamesh that “the life of man is short. Only the gods can live forever,”1 but Gilgamesh, undeterred, sets out on an epic journey to seek the secrets of the gods and the key to immortality.

  He finds the immortal man Utnapishtim, a Mesopotamian Noah who survived a great flood after being instructed by the god Enki to build a boat and fill it with animals.* After much coaxing, Utnapishtim finally tells Gilgamesh where at the bottom of the sea to find a magical, youth-restoring “wondrous plant.” Gilgamesh locates the plant and is taking it home when it’s stolen by a sneaky snake. The snake becomes young again, but with no way to get a replacement, the humbled Gilgamesh heads home, finally accepting his own death as inevitable.

  Like Gilgamesh before his enlightenment, I have long wondered how it can be that our lives form such a brief arc, shifting so quickly between two crying moments at the hospital. What cruel hoax determined that our muscles start to lose their fiber when we are only in our twenties, that most of our bodily functions peak in our late twenties, that our chance of death doubles every eight years beginning at age thirty, and that our cells begin losing their ability to repair dangerous mutations starting at around forty? I am not alone.

  For as long as humans have been around, we have struggled with our mortality. Even if it forces us to take stock of our aspirations while we have the capacity to achieve them, mortality is at best a mixed blessing.

  Lacking the tools to fight back, our ancestors could never really suppress the drive to steal immortality from the domain of the gods. That’s why so many cultures have been obsessed with extending life and overcoming death.

  In the Old Testament, Methuselah was the one who beat biology. According to Genesis 5:27, Methuselah lived to the ripe age of 969. Because the Bible doesn’t say much else about Methuselah, we don’t how he did it but are told that his forebears lived between 895 and 962 years, so genetics is a good guess. Regardless, Yahweh seems to have changed his mind when he says a few verses later in Genesis 6:3, “My Spirit will not put up with humans for such a long time, for they are only mortal flesh. In the future, their normal life span will be no more than 120 years.”

  For the ancient Chinese, who spent centuries trying to generate elixirs of life, the secret was the famous lingzhi, the supernatural mushroom of immortality allegedly found high in the mountains. For the Indians, amrita, also known as soma, was a drink made of an elusive, mountainous plant that, according to the Rigveda holy text, let a person live forever.

  The advent of the Scientific Revolution in Europe brought a new rationality and new hope to humanity’s search for immortality.

  In 1896, a Russian-born French doctor, Serge Voronoff, set sail for Egypt after studying for years with the Nobel Prize–winning father of transplant medicine, Dr. Alexis Carrel. Witnessing how the bodies of Egyptian eunuchs seemed to be wasting away, Voronoff concluded that their lack of testicles was denying them the glandular secretions their bodies needed to maintain vitality. Drawing on what he had learned from Carrel about the possibilities of grafting body parts between humans, Voronoff came up with the creative idea of splicing monkey testicles into human males to supercharge glandular secretions and cure all sorts of diseases, increase vitality, and extend life. “The sex gland,” Voronoff wrote in 1920, “pours into the stream of the blood a species of vital fluid which restores the energy of all the cells, and spreads happiness.”2

  By 1923, Voronoff’s procedure was in such demand that a special reserve needed to be set up in Africa to contain all of the captured male monkeys awaiting castration to fuel this increasingly popular and massively expensive procedure. After the men with the monkey testicles grafted into their scrotums failed to see much improvement, Voronoff doubled down on his claims. If the monkey donors and the human recipients of the grafts were matched by blood type, he asserted, the humans could live to 140. When none of these claims materialized, the procedure fell from grace.

  Monkey testicles were out, but a whole slew of magical procedures and potions—from sewing goat testicles into a person to drinking special “elixirs of long life”—flooded the market at the turn of the twentieth century. All were eventually discarded when they didn’t work. Then a strange thing happened. Even though none of the magic potions were doing much of anything, the average human life span started to increase at a faster rate than ever before.<
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  For most of our history, the average human life span has been painfully short. There were lots of ways for our nomadic hunter-gatherer ancestors to die. If you didn’t die in childbirth or of the countless infections and diseases in your early years, chances were relatively high that some type of accident or predator or conflict would eventually get you. That’s why the average life span for early humans was only about eighteen. In spite of all the advances, the average life span in Roman times was a mere twenty-five. By 1900, it was only forty-seven in the United States, by then one of the more advanced countries in the world.

  Average life span doesn’t mean that the wise elders of Roman times were twenty-six and everyone in the United States a hundred years ago dropped dead at forty-eight. It means that, if we add up the number of years everyone lives in a given era and divide by the number of people, we arrive at the average. So, if two children are born the same day but one dies immediately and the other lives to eighty, their collective average life span is forty. If infant mortality is high, average life span across the population is low, even if decent numbers of people are living long lives.

  But over the course of the twentieth century, advances in health care, sanitation, workplace safety, public health, and nutrition both pushed up the average life span like never before and massively increased the number of old people per capita in the population. Today, the average life span is 71.4 globally, 79 in the United States, and 85 in Japan, even though it is still only around 50 in many of the poorest African countries.

  This increase in average life expectancy in the developed world over the past century averages out to about an additional three months per year. The number of people living past 100 has increased by almost two-thirds in the United States and quintupled in the United Kingdom over just the past three decades. Japan, which recorded only 339 centenarians in 1971, today has over 75,000. Pew estimates the global population of people living past one hundred will increase from around 450,000 today to nearly 4 million in 2050.3

  As the possibility of living longer has become our new reality, our expectations of how many years constitute a full life have changed.

  It’s a good bet that the families of early humans who had died in their forties on the African savannah never felt they’d been robbed. At that time, living to forty was pretty good in light of all the dangers that could cut short someone’s life. Today, losing someone in their forties feels like a crime against potential. But when someone dies today in their nineties, an extremely rare occurrence for our ancestors, most people feel it’s about right. When asked in 2013 how long they wanted to live, 69 percent of Americans offered numbers between seventy-nine, the current average American life expectancy, and one hundred, with a median age of ninety.4 “For everything there is a season,” Ecclesiastes says, and the season of life feels to most people like it ought to last around ninety years.

  But what if more people were living healthy lives to 120 or 130? Would people whose parents, spouses, and friends died at ninety feel like their loved ones had lived a full life or would they feel as robbed as we do today when someone dies at sixty? Would we benchmark longevity based on how long our grandparents lived or instead expect to live about as long as our neighbors and friends? There is nothing magic about the eighty-year life; it’s just what we happen to know now at this particular point along the continuum of our evolutionary trajectory. When that changes, so will our expectations.

  Even if our perception of biology is malleable, we don’t really know how malleable our actual biology of aging could potentially be. But the new tools of the genetic and biotechnology revolutions are giving us a fighting chance to keep pushing the limits of both our total life spans and our health spans, the vigorous periods of our lives.

  As a first step in exploring how long we might eventually be able to live, we need to understand what aging is.

  For a process that people understand so well intuitively, aging is remarkably complex. Scientists can’t agree on a uniform definition of aging because aging is not one thing. It’s probably a combination of many different systems in the body all decaying at different rates. Some scientists have thought of aging as a series of changes that make an organism more likely to die, others as a progressive decline in its ability to do things, others as an increase in inflammation levels or oxidative damage in the body, and still others as a decline in the body’s ability to activate the stem cells needed to keep cells in good repair.

  Whatever the best definition, aging is the leading cause of death among humans because the diseases that kill us most are all diseases of aging. Heart disease, cancer, and chronic lower respiratory disease account for over half of all deaths in the United States and are three of the top four causes of death globally. These chronic diseases have become a relatively greater threat to us as we’ve learned to better handle the infectious diseases that plagued so many of our ancestors. Because the chronic diseases correlate with age—the older you are, the more likely you are to get them—curing any one does not help all that much. If one disease of aging doesn’t get you, another one soon will. Eliminate all cancer from the United States, and life expectancy only goes up a little more than three years. This leads to the conclusion that if we really want to extend our healthy life spans, we’ll need to start worrying relatively less about countering each disease of aging and more about slowing aging itself.

  Given the maddening number of parts and systems within the human body, addressing individually the special and unique aging process of each system of our body might prove impossibly difficult.* But if aging is significantly a unified experience with some central mechanisms governing the whole process, conceivably there ought to be a way to slow the aging of an entire organism, including each of its parts. A first step toward assessing if this is the case would be to find ways to measure systemic aging.

  Everyone ages differently and at different speeds. We all know people who are chronologically young but still seem or look old. We also know people who are old but seem young. At least superficially, that’s the difference between chronological and biological age. While chronological age measures the number of years since our birth, biological age seeks to assess the many genetic and environmental factors that make us age differently.

  If I look at your driver’s license, I can easily tell you how old you are. By knowing how old you are, I can make a pretty good guess about how healthy you are and how much longer you will live. But I won’t be able to tell you how relatively young you are for your age or how long you might live compared to other similarly situated people of the same chronological age without more information about your personal health status.

  While chronological age is straightforward and easy to measure, biological age is not. You may seem younger than you are, but we’d need to be able to measure your biological age before and after any kind of antiaging treatment to determine whether this intervention is actually working.

  Since the 1980s, researchers have been working to define what this type of benchmark for biological aging might look like. More recently, the American Federation for Aging Research, AFAR, established a goal of identifying a biomarker of aging that could accurately predict the rate of aging, measure the general aging process instead of the impacts of disease, be repeatedly testable without harming the person, and work both in laboratory animals and humans.5 Achieving this is easier said than done. Biomarkers of aging likely include a dizzying and often overlapping list of genetic, metabolic, and other factors that are extremely difficult to measure and, even when measured, are tough to assign specifically to aging.

  Recently, however, researchers are starting to make more progress. Studies have suggested that epigenetic markers measured in blood,6 the length of the genetic “caps” at the end of chromosomes called telomeres,7 walking speed,8 observable facial aging,9 and many other factors are preliminary biomarkers of aging that could, in the future, come together to help us solve the riddle of biological aging. The California start-up compa
ny BioAge Labs is using AI to make sense of the sequenced DNA from and metabolic analysis of blood cells to identify complex biomarkers of aging in the blood. Blood stored for decades in European blood banks, where the biomarkers and the life and death record of the blood donors can be matched, is proving a uniquely valuable resource.

  Being able to measure biological age will help us assess efforts to manipulate it, but we’ll still need to look for clues about how long we can live and what we would need to do to live longer and healthier.

  The good news for thinking we might be able to overcome today’s mortality limits is that, within limits, evolution doesn’t seem to care much how long we live.

  If our ancestors had faced a problem of too many babies being eaten by predators, our offspring might have eventually been selected with exoskeletons like lobsters. If too many parents were being eaten and not able to care for their children, our infants would have eventually become as self-sufficient as loner Komodo dragon babies, who scurry away after hatching to avoid being eaten by their mothers, or the Lambord’s chameleons of Madagascar, who hatch each season all alone because the entire adult population dies off after the females lay their eggs.

  If grandparents, on the other hand, who were around far less in the early days of human development, got devoured by predators, it would be sad for the family and community but probably not have had a huge evolutionary impact on our species as a whole. Elders are and have always been incredibly useful and important carriers of traditions and critical life lessons—and some smaller proportion of elders were likely needed to look after children while mothers were out foraging for food—but evolution was largely unaffected by whether most lived forty, fifty, or eighty years. The capabilities of babies and parents are essential to human evolution, grandparents less so.10