by Jamie Metzl
Shinya Yamanaka’s miraculous 2006 innovation was that the four Yamanaka factor genes could reprogram these specialized cells back into stem cells. The epigenetic marks from the adult cells were being removed, similar to what happens when a child is conceived.
You probably remember from childhood that when a starfish loses one of its arms, a spider loses one of its legs, or a lizard loses its tail, those appendages can often grow back. You probably also remember from every U.S. Civil War movie you’ve seen that humans don’t have the same opportunity. Being able to look deep into the cells of the regenerating animals, however, has enabled scientists to figure out that their cells are reverting halfway between their specialized and stem versions to recreate the arms, legs, or tails. Following the injury, their relevant cells revert back enough to regrow but not so far back to forget what they need to grow into.
With this in mind, scientists started to wonder what would happen if they used Yamanaka factors to turn older, specialized cells into younger versions of the same types of cells, rather than all the way back to stem cells. The genes could conceivably stay the same, but the epigenetic instructions telling the genes how to function would change. Remarkably, partially reprogramming adult skin cells in a dish to become younger skin cells worked.47 And if individual cells could be made younger, some hypothesized, wouldn’t it be possible to use the same type of approach to make entire organisms biologically younger?
The first time that scientists tried this, all of the mice died awful deaths as their adult tissues lost their specialized identities and cancers proliferated. But Salk Institute researchers wondered if the idea was right and just the dosages were wrong. After experimenting for five years trying to find an effective but nonlethal dose, they figured out a way to genetically engineer mice with extra copies of the Yamanaka factor genes that could only be expressed when the mice received a specific activator drug in their drinking water.
After multiple efforts with this moderated, partial reprogramming strategy in mice with progeria, a disease causing rapid cellular deterioration and premature aging, the scientists hit pay dirt. The mice treated with this partial epigenetic reprogramming looked better, had better tissue function, and lived 30 percent longer than other mice with the same disease. “Our study shows that aging may not have to proceed in one single direction,” Salk Institute researcher Juan Carlos Izpisua Belmonte said at the time. “It has plasticity and, with careful modulation, aging might be reversed.”48
There are many dangers and pitfalls ahead when considering cellular reprogramming to slow and ultimately reverse human aging, but this research points the way toward epigenetic reprogramming as a way of turning back the clock for all animals, potentially even us. As with the senolytics, finding drugs that do this will be more feasible than genetically engineered hacks, but this work too has already begun. Big pharma companies like GlaxoSmithKline, Eli Lilly, and Novartis are jumping into the epigenetics treatment field.
But wait, as the 1970s Ginsu knife commercial goes, there’s still more.
In the seventeenth century, eminent British scientist Robert Boyle hypothesized that “replacing the blood of the old with the blood of the young” might help make significant life extension possible. It seemed a crazy idea to many people, but the first real efforts to test this hypothesis came in mid-nineteenth-century France. Parabiosis, a term coined by researchers in the early 1900s to describe the burgeoning efforts to decipher animal biology systems by cutting open two different animals of the same species and sewing them together, comes from the combination of the Greek words para, meaning next to, and bios, meaning life. In the 1950s, Cornell animal husbandry professor and gerontologist Clive McCay sewed an older and a younger rat together and found that the older rat’s bones became stronger, hinting that Boyle could have been right. Parabiosis remained, however, a rather cruel way of doing research, even among scientists comfortable with the inherent but often necessary cruelty of animal studies.
The modern age of parabiosis began in 2015, when a husband and wife team of Stanford researchers published a high-profile paper describing how, when parabiotically paired with younger mice, the older mice healed faster and had better liver function than other older mice not Siamese-twinned to anybody.49 Since then, a slew of studies have shown that when old and young mice are joined, the older ones get functionally younger in many ways and the younger ones get functionally older. The paired older mice’s hearts get healthier, new neurons are formed in their brains, their memory improves, their spinal cord injuries heal faster, their muscles become stronger, their hair thickens,50 and they move back into their parents’ house and put rock-and-roll posters back up on the walls. Just kidding about the posters, but multiple parabiosis studies suggest that the paired young mice in many ways become old, and the old ones in many ways become young.
There are many theories about why this happens, most involving stem cells and other elements of the younger rodents’ blood plasma rejuvenating the older partners. To prove this point and demonstrate that parabiosis wasn’t just about mice and rats, Stanford’s Tony Wyss-Coray injected human umbilical cord blood into older mice and showed that something in the human cord blood was improving the mice’s success at memory tests.
The race is now on to figure what factors in the blood are catalyzing changes like these and how these factors could be isolated as a treatment for aging and its associated diseases. Wyss-Coray’s company, Alkahest, for example, is testing whether older Alzheimer’s patients will see their condition improve after being infused with matched plasma taken from young donors. Once the rejuvenating elements within blood plasma are more successfully identified, isolated, and cultured, we may well see in the near future antiaging treatments designed to enhance these capacities.
You won’t see wealthy older people with sorry younger ones stitched to their sides any time soon, but popular culture is already catching on to this trend. In the popular HBO comedy Silicon Valley, a wealthy tech CEO pays a young man he calls his “blood boy” to transfuse his blood straight into the older man. In the not-too-distant future, however, we might well see more people transfusing blood plasma from others or even storing their own blood for self-transfusions later in life.*
In the medium term—as super-ager studies like Nir Barzilai’s continue to identify specific genes and genetic patterns that make a given person statistically more likely to live longer and healthier—parents having children using IVF and embryo selection will be able to implant embryos with the best genetic chance of living healthier longer. Not long after that, parents will have the option to genetically alter their preimplanted embryos to further increase these chances. There may be evolutionary trade-offs in making this decisions that would need to be weighed, but people, as we’ve seen, will want their children to be optimized for a long and healthy life.
As we live longer, the chance that some of our many parts will break down from overuse will become greater, even if our stem cells can remain as active as we age as they were when we were young. But we will have a widening set of tools to fight back over the coming decades—nanobots scouting through our bodies looking for things to fix, biological 3-D printers building replacement parts to implant, and other genetic tools to turn our own biology into machines upgrading our software and hardware from the inside out.
All of this work to expand the human health span will be sped up significantly if we as a global community invest more, and more smartly, in understanding aging and countering its more pernicious effects. In 2017, for example, the U.S. National Institutes of Health only spent only $183.1 million of its overall $32 billion budget, one-third of one percent, on aging biology, far less than the many billions it spent on cancer, arthritis, diabetes, and hypertension.51 Even within this small base, the National Institute on Aging spends over half of its budget on Alzheimer’s disease. Cancer, arthritis, diabetes, hypertension, and Alzheimer’s are all terrible conditions that must be addressed, but eliminating any one of them entirely
won’t extend most of our health spans by all that much because they are all correlated with age. The older we are, the more likely we are to get all of them. That’s why the return on investment for the overall population would be significantly greater if we invest relatively more than we are today in understanding and treating aging itself, rather than in each of its many cruel manifestations.
University of Illinois at Chicago researcher Jay Olshansky and his collaborators tried to calculate the cost savings to society of pushing back the average age at which we are afflicted with the multiple diseases of aging. Based on their 2013 study, intervening to slow the aging process and push back the onset of the multiple diseases of aging by 2.2 years across the U.S. population would result in a whopping $7.1 trillion in savings over a fifty-year period.52 Put another way, if extending health span across the population proves as possible as it now appears, the anticipated savings could not only pay for a Manhattan Project that targets aging but also cover repairing all of America’s decaying infrastructure, provide universal preschool for every American child, and provide clean water to virtually everyone on earth.*
Massive life extension will not be easy, and there will be obstacles before us we cannot yet see. Because the oldest person to ever live was 122, for example, we don’t know if there is some type of deadly disease we’ve never heard of that humans will get at age 123. But with biology becoming ever more malleable, the prospect of at least continuing the rapid expansions in health and life span we’ve seen over the past century into the next seems very real. Making the same forty-year leap from a global average life span of about thirty in 1900 to around seventy in 2000 will be tough because growing global prosperity has already so significantly reduced the infant and child mortality rates that suppressed the 1900 numbers, but this kind of continued growth is not impossible.
The first step would be to help lower infant mortality and increase overall health and longevity in the most vulnerable parts of the world, particularly in sub-Saharan Africa and South Asia. Even if that is achieved, most of us will still want longer and healthier lives.
Over the past century, average life expectancy in the United States has increased by about three months per year. With all the budding technologies I’ve described, we might be able to increase that rate to four months, then five, then six months per year. If life expectancy could be made to consistently increase faster than people age, then we would reach what Ray Kurzweil calls “life expectancy escape velocity” and basically be immortal. This is great in theory, but I seriously question we’ll ever get there in our current time-limited bodies. This book is about hacking our genetics, which will certainly be possible. Even so, I’m doubtful we have enough wiggle room in our biology to make biological immortality possible.
But maybe our biology could become less of a limiting factor if we merge in new ways with our machines. It’s not too far-fetched to imagine that, someday, we’ll be able to digitize and disembody our brain function. If we see ourselves as code, then perhaps, our code could be transferred to a new form, perhaps a robotic body or integrated with a new form of disembodied semi-consciousness. This type of disembodied snapshot of a mind may or may not still be us, but it could at least afford some level of limited immortality. As unappealing as this may sound to some, it will be considerably more appealing to many than being eaten by worms or scattered over the Himalayas.
Immortality in our current biological form will very likely prove impossible for us but, as Gilgamesh finally realized at the end of his epic quest to live forever, perhaps our immortality as a community comes from each of us contributing all we can to the greater good of society. Perhaps the best investment we can make in our immortality is to have a child, write a book, help save the environment, or contribute positively to our communities and cultures. To make more of that possible, why not do all we can to extend our healthy lives as much as our biology and technology can allow?
But as we shift our understanding of biology from something fixed, fated, and inevitable to being as readable, writable, and hackable as our information technology, we will need to stop fetishizing chance, rationalizing death to give meaning to life, or ascribing to spiritual mysticism those forces of mortality that we will increasingly comprehend.
The genetics, biotechnology, and longevity revolutions will challenge our current conceptions of what it means to be human beings. And we humans—with our frailties and superstitions, our primate brains, predatory instincts, and social systems honed over millions of years, and our limited biological capacities functionally merging with our seemingly limitless technologies—will need to figure out how to navigate the awesome ethical challenges just around the corner from where we now stand.
*For those who still think the Bible is an original work…
*I’ve always wondered why people who believe in the “intelligent design” theory of evolution are not asking why our designer, if he or she is so intelligent, gave us so many fragile individual parts.
*Centenarians are people who live to be age one hundred and beyond.
*This is not a self-help book, but if you want to live longer and healthier, I recommend that you incorporate as many of the lessons of Dan Buettner’s blue zones as you can: exercise or at least get moving every day, find your spiritual center and special purpose in life, decrease your stress level, switch to a mostly plant-based and not-too-high-calorie diet, invest in your social and family life, and stop drinking too much alcohol. I would also be remiss, or at least in trouble, if I did not mention that my brother Jordan has written a fantastic book on the systemic health benefits of exercise: Jordan Metzl, The Exercise Cure: A Doctor’s All-Natural, No-Pill Prescription for Better Health and Longer Life (Rodale, 2013).
†As someone addicted to my morning cup of hot chocolate and deeply passionate about salted caramel soufflé, even I can’t in good faith sign on to such a restrictive regimen.
*Alter completing a nineteen-hour ultramarathon in the rain forest of Taiwan, someone back at my Taipei hotel told me I must be getting paid a lot of money to participate in the race. He was incredulous when I told him I actually paid an entrance fee.
*Today, red blood cells can be stored for only ten years. But more easily stored cells like skin cells could probably be frozen indefinitely then thawed in the future and induced to become blood cells that could be used in self-transfusions. I explore this possibility in my novel Eternal Sonata.
*To address the time-lag issue of spending tomorrow’s savings today and add an additional incentive for progress, big countries like the United States could offer health span bonds.
Chapter 8
The Ethics of Engineering Ourselves
Our history provides some wonderful examples of humans using technology to cure diseases, enhance our potential, explore the cosmos, and preserve our planet. We also have many examples of our using technology to kill and enslave each other, sow dissent, and destroy our surroundings. Our tools are agnostic. The variable is the values we individually and collectively apply when figuring out how we’ll use them. The same will be true for the incredibly powerful tools of the genetic revolution. How we understand and apply these tools will significantly determine our future as a species. Each and all of our answers to the core questions of the genetic revolution will add up to the future trajectory of our species.
There are no easy answers to the critical questions of complexity, responsibility, diversity, and equity the genetics revolution will raise, but a better understanding of the ethical issues at stake is a critical first step.
We humans are each massively complex biological systems embedded in and constantly interacting with the even more complex ecosystems around us. Each of our genes performs multiple functions and interacts with other genes in ways we still don’t fully understand. Even when we identify a gene that’s doing something bad in one context, there’s often a very real possibility the same gene is helping us in some other context.
We’ve seen that people who
inherit a copy of the sickle cell mutation from each of their parents often suffer terribly from the disease. Those who inherit only one copy don’t have sickle cell disease but can often possess a very significant natural resistance to malaria. Eliminating the sickle mutation from humans would end the suffering of sickle cell disease but potentially increase the suffering from malaria. Perhaps we could solve that problem by creating a more effective malaria drug, or we could use a gene drive to decimate the population of mosquitoes that transmit malaria.1 But if we wiped out too many mosquitoes with a gene drive, we’d face the potential danger of crashing the ecosystems in which they live and doing even more damage to ourselves.
Each of these steps solves a particular problem but, for all we know, creates a new problem requiring an even greater intervention and so on down the line. It’s like the old Peter, Paul and Mary song we used to sing at summer camp:
I know an old lady who swallowed a cow
I don’t know how she swallowed the cow
She swallowed the cow to catch the goat
She swallowed the goat to catch the dog
She swallowed the dog to catch the cat
She swallowed the cat to catch the bird
She swallowed the bird to catch the spider
That wriggled and jiggled and tickled inside her
She swallowed the spider to catch the fly
But I don’t know why she swallowed that fly
Perhaps she’ll die.2
Given that we still have so little understanding of how we function relative to the complexity of our biology, some ethicists argue, wouldn’t we be better off not even attempting to play the role believers assign to god? As the conservative bioethicist Leon Kass wrote in the report of the George W. Bush–appointed U.S. Commission on Bioethics: