Hacking Darwin

by Jamie Metzl

  To many religious people and others who believe in concepts of the spirit and soul, a human being is infinitely complex. For these people, even the most accurate medical tests cannot unlock the mysteries of the spiritual world or the deep interaction between humans and the divine. For those like me, who believe we evolved from microbes, humans are single-cell organisms gone wild over six hundred million years of random mutation and natural selection. We are not infinitely complex beings, just massively complex ones. There’s a big difference. If we are infinitely complex, we’ll never understand ourselves. If we’re only massively complex, there will come a time when the sophistication of our tools will outmatch our own complexity.

  We can understand simple organisms pretty well today because our advanced tools are increasingly a match for the complexity of their biology. Human biology, however, remains significantly more complex than our understanding of, or tools to manipulate, it. This won’t always be the case. As our knowledge and tools progress, our complexity will become as understandable with our tools of tomorrow as simple organisms have already become with our tools of today.

  To get a glimpse of how it will feel when the sophistication of our knowledge and tools begins to surpass the complexity of our biology and what that might mean, we only need to look at how quickly our understanding of single-cell and other simple organisms has grown.

  The C. elegans roundworm is the perfect example. Smaller at maturity than the size of a comma on this page, the standard mature C. elegans goes from birth to death in about two weeks, has a rudimentary nervous system with a brain, reproduces exponentially, and is probably the simplest living organism that shares many of its genes with humans. These qualities, along with its transparent and easily observable body, make these little creatures perfect research subjects and among the most studied model organisms in science.

  Over past decades, researchers have starved, chilled, and heated C. elegans as they look for the outliers; they have probed the roundworms with advanced microscopes, spun them around wildly in centrifuges, exposed them to antibodies, tagged them with laser microbeams to eliminate individual cells, profiled their proteins, and isolated and amplified their individual genes for closer examination.

  In 2011, a group of ambitious scientists came together to create the OpenWorm project, designed to network C. elegans researchers from around the world in a common effort to crack the code of how the C. elegans functions.23

  The C. elegans has exactly 302 brain cells, compared to about 100 billion for us (unless you did drugs in college or drink diet soda), that have been mapped in a connectome, a diagram of the switchboard of connections showing the worm’s brain at work. As an early step toward completely simulating the C. elegans as a virtual entity, the OpenWorm collaborators translated its neurons into a computer program used to animate a small robot, where the worm’s motor neurons, nose, and other body parts all had robotic equivalents.24 When booted up, the robot’s movements tracked those of an actual roundworm with surprising consistency.

  The OpenWorm Robot. Source: “Worm Robot Sneak Peek,” OpenWorm, YouTube, published July 21, 2017, https://www.youtube.com/watch?v=1wj9nJZKlDk.

  We have moved from little to deep understanding of how the roundworms function in the past few decades because the growing sophistication of our tools has enabled the growing sophistication of our knowledge.

  Getting from where we are now in our understanding of our own biology to the point where we will be the equivalent of the C. elegans relative to the sophistication of our knowledge and tools will require a map that is just starting to be built. The Human Cell Atlas is an open “coordination platform” that integrates data on human biology from around the world. This collection of “comprehensive reference maps of all human cells” will grow over time as research tools become more powerful and as researchers’ knowledge compounds.25 In these early days, the magnitude of the body’s complexity will tower over the capacity of our still relatively humble tools and our current limited knowledge. But why this will change can most clearly be explained in the graph on the next page.

  Our biology is about as complex as it has been for millions of years, but the sophistication and capacity of our tools is now advancing at exponential rates.

  The basic idea of exponential change is that innovation begets innovation. The more and better tools we develop, the more efficiently and effectively we organize ourselves and connect with each other, and the more ideas we have, the better positioned we are to devise even better tools, organize and connect more, and come up with even greater ideas. That’s why it took around twelve thousand years to go from the agrarian revolution to the industrial revolution but only a couple of hundred years to move from the industrial revolution to the internet revolution. Each technological revolution enables the next, and the time between each revolution becomes shorter and the impact bigger. Futurist Ray Kurzweil called this process the “Law of Accelerating Returns.”26

  In 1999, Kurzweil predicted that the entire amount of technological change achieved in the twentieth century would be achieved in only the first fourteen years of the twenty-first century. As innovations compound, he suggested the full twentieth-century amount of change will take only seven years starting in 2021. The same twentieth-century amount of change will take around a year a short while after that time. Ultimately, the equivalent of the full twentieth-century rate of change, equivalent to going from horse and buggy to the international space station, will take only months.27

  Since the invention of the microprocessor in the early 1970s, this acceleration has been fed by Moore’s law, the observation that computing power roughly doubles about every two years for the same cost, a trend that has continued for nearly half a century. It’s because of Moore’s law that we now expect our smartphones to be lighter and faster with each version, but that’s the least of it.

  The internet revolution has given us virtually unlimited access to information and to each other, and a network of thousands of educated people linked and working together to solve the same series of problems is way more than a thousand times more creative than the sum total of each of us working alone. Collaborating with artificial intelligence (AI) agents, this networked group of people has the potential to be many times more innovative than the thousand people merely connected to each other. As AI capacities grow, a future form of superintelligence may become more sophisticated than all humans put together, and new possibilities for remaking our species and our world will emerge. Over time, hard things will become easy, and today’s complex things will become, relative to the tools and capacities we have to understand them, simple.

  Collectively as a species, we are today moving along the spectrum, from laying the technological foundation for human genetic engineering to finding preliminary applications to imagining what might be possible in the future to making that imagined future real. Even the legends of our past are strangely becoming our new realities. The idea of humans merging with animals, one of our most ancient human mythologies, is a perfect case in point.

  The word chimera comes from a Greek word meaning she-goat. In Greek mythology, the Chimera was a hybrid of different animals, usually a lion with a goat head and sometimes with a snake tail. In the Iliad, Homer described a “thing of immortal make, not human, lion-fronted and snake behind, a goat in the middle.”28 In Dante’s Inferno, Geryon represents a medieval version of the Chimera, “the monster with the pointed tail… The face was as the face of a just man…and of a serpent all the trunk beside.”29 Many ancient cultures shared this idea. The Chinese Qilin, a mythical creature with the neck of a giraffe, the antlers of a buck, and the scales of a fish, allegedly marks the birth and death of important rulers. The Indian Ganesh is the son of the gods Shiva and Parvati, with the head of an elephant and the body of a man.

  More recently, chimeras have come to mean any creature that is composed of parts from multiple plants or animals, a concept that has moved from fiction to fact.

  Nearly a
hundred years ago, insulin removed from cows was first used to treat diabetes. Extracted dog, pig, and cow insulin made it possible for humans to live with diabetes and saved countless lives for decades until E. coli bacteria could be genetically modified to produce human insulin at scale.

  Over three decades ago, doctors started using pig and cow valves when repairing human hearts. Although this process was somewhat controversial among some Jews, Muslims, and Hindus,30 the use of decellularized animal aortic valves has become a mainstay of cardiovascular transplant surgery, even for many Jews, Muslims, and Hindus. The benefits simply outweigh the risks.

  Scientists have had greater success using animal heart valves for human transplantation than full-organ, animal-to-human transplants. In 1984, California surgeon Leonard Bailey and his team famously transplanted a baboon heart into Baby Fae, a child born with hypoplastic left heart syndrome, a rare congenital heart defect. Although a small number of additional animal-to-human transplants have been attempted since, all of them proved unsustainable after being rejected by each person’s immune system.

  But although Baby Fae tragically died within a month, the procedure opened the door to progress in human-to-human organ transplants, which have proven far more sustainable than animal-to-human transplants, that saved hundreds of thousands of lives since. These transplants, however, have two major problems. First, the human body is fine-tuned to reject alien DNA, so people getting transplants need to take immunosuppressant drugs for the rest of their lives, which puts them at risk for other ailments. Second, the United States and many other countries face a tragic shortage of donated organs.

  As of August 2017, there were more than 114,000 people waiting on organ-transplant lists across the United States. Twenty people die every day while waiting for a transplant. This chronic and deadly organ shortage should, theoretically at least, be solvable with policy changes alone.31 A single donor can donate as many as eight organs, meaning that he or she could potentially save up to eight lives. But that’s not what’s happening. In the United States, 95 percent of people support organ donation, but only 54 percent are registered donors.32 A far smaller percentage actually ends up donating because family members can be conflicted about organ donation at the emotionally challenging moments when the decisions are made.

  Because the prospects for getting more humans to donate their organs are still poor in the United States and many parts of the world, scientists have been exploring how new technologies like CRISPR-Cas9 can be used to make animal to human organ transplants more feasible.

  Of all domesticated animals, pigs are the most important potential source for transplants, because we already breed a lot of them and because their organs are similar in size and function to ours. But harvesting organs from pigs has at least two big problems. The first, the human body’s natural immune response, is extremely serious but has been made more manageable over past decades with both the steady advance of new immunosuppressant drugs and by preliminary efforts to edit the animal genes most likely to be rejected by humans.33 The second problem, the risk of pig and other animal viruses infecting humans after transplants, is also starting to be overcome.

  Pigs carry active viruses called porcine endogenous retrovirus, which scientists have given the unfortunate acronym PERV. These viruses can be extremely dangerous and even deadly to humans, particularly those whose immune systems are already suppressed by drugs. Until recently, PERV was essentially a deal-killer for pig-to-human transplants.

  Now, however, a group of Harvard scientists is using CRISPR-Cas9 to edit the genome of pig embryos in multiple locations simultaneously to create pigs with their PERVs rendered inactive.34 Clinical trials for transplanting gene-edited pig kidneys and pancreases to humans are likely to begin soon, potentially saving thousands of human lives per year.

  But why stop there? If using insulin made from genetically engineered bacteria and yeast was a step up from using animal insulin, wouldn’t transplanting an entire human organ grown outside a person’s body from a person’s own cells be better than transplanting a gene-edited animal one? What if we could grow human organs inside animals for transplantation? Making this possible would be no easy feat, but a significant first step has been made to produce chimeric embryos generated from cells of one type of animal grown in another.

  Scientists at San Diego’s Salk Institute injected different levels of human stem cells into fifteen hundred pig embryos until they finally found a human cell that integrated into the pig cells. Another team inserted mouse pancreatic cells into rat embryos that grew into mouse pancreases inside the rats, which were then successfully transplanted back into mice to treat diabetes. This work was then followed up by an announcement in February 2018 that a team from the University of California, Davis, had developed sheep embryos with 0.001 percent human cells.35 Just like with the rats and mice, hacking the sheep embryo to shut off its ability to grow a particular sheep organ and replace it with inserted human genes instructing it to instead make a human version of the same organ type is starting to seem like a real possibility.

  Growing human organs in other species will not happen tomorrow, but if it becomes possible for an individual person to have an organ grown inside an animal using his or her own genetics, people needing replacement parts because of illness or the ravages of age will quickly overcome any squeamishness they may have about crossing the human–animal barrier. Governments will be hard-pressed to prevent people from having replacement parts grown in animals.

  The possibility of inserting animal DNA into the human genome imagines a future that science is fast making real. The science already exists to relatively easily place a single fluorescent protein from jellyfish into humans that can make a person glow under UV light. If scientists find a single gene or two that make naked mole rats completely resistant to cancer, for example, might we want to splice versions of that gene into humans using CRISPR or some future gene-editing tool? Integrating whole genetic systems like those that give dogs special hearing abilities, eagles amazing vision, or dolphins sonar would be a lot more complicated and not possible any time soon. But the transition of biology into yet another domain for human engineering will, over time, blur our sense of where science fiction ends and science begins.

  The possibilities for this type of engineering are vast because all life operates according to different manifestations of the same genetic components. It will someday be possible to even create new human traits and capabilities from scratch, using new combinations of these same genetic building blocks.

  The exploding field of synthetic biology uses computers and laboratory chemicals to write new genetic code that nature never imagined and make organisms do things they weren’t previously programmed to do. Some of its early applications include current efforts to culture meat in a lab, engineer oil-secreting bacteria, manufacture yeast with spider DNA to make ultra-light silk stronger than steel, or induce bovine collagen to make nonanimal leather. Synthetic biology is being used to create renewable microbes to produce acrylics for paints and custom engineer inexpensive synthetic sugars for biofuel. The preliminary list of these types of synthetic biology applications is almost endless. This science and the industry associated with it are exploding as synthetic biology tools become more easily accessible.

  These new life forms are being created from readily accessible genetic parts. The International Genetically Engineered Machine (iGEM) Foundation, for example, provides a free collection of DNA sequences encoding for a particular biological function that can be “mixed and matched to build synthetic biology devices and systems.”36 The BioBricks Foundation, established by MIT and Harvard researchers, provides synthetic gene sequences for free,37 making ordering genetic sequences about as easy for a researcher as dropping by Home Depot is for a builder. The ease, accessibility, and flexibility of these tools are empowering a synthetic biology revolution where all sorts of useful products, including computer chips, appliances, and clothes, could be grown through engineering bio
logy.

  The commercial implications of this revolution are massive. It is estimated that the global synthetic-biology market will grow from around $3 billion in 2013 to about $40 billion in 2020, with a projected global compound annual growth rate of 20 percent. Not surprisingly, China is expected to be the world’s fastest-growing market for synthetic biology products.38 According to leading biologist Richard Kitney, synthetic biology has “all the potential to produce a new major industrial revolution.”39

  As the global population rises, our climate continues to heat, and new and unforeseen challenges arise, these types of precision gene-editing-based synthetic biology applications will become essential for our survival. Our growing dependence on synthetic biology in our lives will pave the way for greater acceptance of synthetic biology in ourselves. This process, too, has already begun.

  In 2010, the maverick scientific entrepreneur Craig Venter announced that he and his colleagues had synthesized the full genome of a bacteria called Mycoplasma mycoides and placed it into the empty membrane of another bacteria—creating the world’s first synthetic cell.40 This wasn’t just editing an existing cell, like getting a bacterium to produce insulin, but building life from scratch. For people concerned that biologists were “playing god,” this was Exhibit A. Six years later, Venter’s team announced they had pared down the genetic code of their synthetic cell to a much smaller number of essential genes required to keep it alive. As a first step in a never-ending process of creating and rewriting the code of life, this was a major achievement.

  “Recent leaps in the biosciences, combined with big data analysis, have led us to the cusp of a revolution in medicine,” Venter wrote in a December 2017 Washington Post editorial. “Not only have we learned to read and write the genetic code; now we can put it in digital form and translate it back into synthesized life. In theory, that gives our species control over biological design. We can write DNA software, boot it up to a computer converter and create unlimited variations of the gene sequences of biological life.”