Hacking Darwin

by Jamie Metzl

  Although some parents will opt out of this process for ideological reasons or because they get excited together in the back seat of a hovercraft, sexual conception will come with costs. How many people will watch their neighbor’s child die from a preventable genetic disease before starting to blame the parents? Will they see these parents as the next “natural” heroes of Disneyland or as ideologues who took unnecessary risks that harmed their children?

  A test case for assessing how far prospective parents will go to prevent genetic abnormalities in their offspring has been carried out in Iceland in recent years.

  Babies with Down syndrome are born with an extra copy of chromosome 21, which can lead to heart defects, developmental and cognitive impairments, increased cancer and mortality risk, and other challenges. Nevertheless, many grow into happy, well-functioning adults who make meaningful contributions to the people around them and society at large. Most people with children, siblings, spouses, or friends with Down syndrome recognize them as the blessing they are.

  Since the early 2000s, Icelandic doctors have been required to inform expectant mothers that available screening tests, covered by the national health plan, can indicate with a high degree of certainty whether their future children will have Down syndrome or other genetic disorders. In the decade or so since these tests became available, nearly all the women who received a positive indication for Down syndrome have chosen to terminate their pregnancies.25 Iceland’s termination rate for pregnancies where Down syndrome has been diagnosed largely tracks many other countries. In Australia, China, Denmark, and the United Kingdom, for example, termination rates range from 90 to 98 percent.26

  With its raging, religion-infused abortion debate, the United States is in many ways an outlier among developed countries. When asked in 2007, only 20 percent of Americans believed parents should be allowed to terminate a pregnancy if their fetus “has a serious, but nonfatal, genetic disease or condition such as Down syndrome.”27 But 67 percent of Americans actually choose to terminate their pregnancies after Down syndrome is diagnosed.28 The contradictory figures show just how excruciating these decisions can be.*

  Critics of universal screening and termination of fetuses indicating Down syndrome raise very valid questions. Who is to say the life of someone with Down syndrome is worth less than anyone else’s? What possible moral criteria could be used to make such a determination? These deeply personal questions cut to the core of our very humanity. But these existential questions won’t necessarily be what prospective parents will be asking themselves when IVF and preimplantation embryo selection become the norm.

  If most mothers and parents in the developed world are already making the often-agonizing decision to terminate existing pregnancies where Down syndrome and other genetic disorders have been diagnosed, imagine what will happen when the choice being made is the less fraught decision about which among the fifteen or so early-stage embryos in a dish to implant? All of these early-stage embryos will be a prospective parent’s “natural” children, but only one or two of them can be chosen at a time to take to term.

  Doctors performing IVF in fertility clinics are already selecting embryos to reduce the chances of miscarriage. Would we really expect a prospective mother to be agnostic about which among her unimplanted in vitro embryos would be implanted if some might inherit debilitating and life-shortening diseases? Would we want it to be legal for prospective parents to affirmatively choose to implant a baby with Down syndrome or death sentence diseases like Huntington’s or Tay-Sachs if it were a choice?

  When writing this book, I asked on my Facebook page whether my friends would be willing to edit their preimplanted embryos to give their future children additional traits and capabilities. “As a mom with a kiddo with Down syndrome,” an old friend wrote,

  this is a tough dilemma. If I could have chosen, I believe I would prefer [my son] NOT have Ds [Down syndrome]. But our lives have truly been enriched by this diagnosis. We have a “second family” that is always there to help, no matter what. And he teaches me something new every single day. He’s one of the most fun and funny 5-year-olds I know. On the other hand, if I could prevent the struggles he has already faced and those that he will continue to face, I think I would want to prevent that. Every parent wants their kid to be happy and excel at whatever it is that creates that happiness.

  Saying that parents would not choose to implant embryos carrying Down syndrome is not at all to suggest that the lives of existing children with abnormalities like this are any less valuable than anyone else’s. But because parents around the world are already making the far tougher decision to terminate pregnancies when these kinds of abnormalities appear, it seems likely that parents will affirmatively want to screen out genetic diseases before their pregnancies even begin. Choosing from among preimplanted embryos in a lab will simply seem far less brutal than abortion.

  Governments and insurance companies—at least those in jurisdictions with rational health-care systems and where the abortion debate is muted—will also have significant incentives to encourage IVF and preimplantation embryo screening to avoid having to pay for lifetime care for what will come to be seen as avoidable genetic diseases.† A relatively simple calculation helps make this point.

  Most babies born with early onset genetic diseases spend around three weeks in the neonatal intensive care units of hospitals at an average cost of $3,000 a day or around $60,000 each, and the costs often go up rapidly from there.29 The mean additional annual cost in the United States for treating cystic fibrosis is $15,571. Because the average life span for people with cystic fibrosis is thirty-seven years, the lifetime additional health-care cost for a person with cystic fibrosis would be nearly $600,000. Considering that there are thirty thousand people in the United States with cystic fibrosis, the total additional annual expenditure on cystic fibrosis alone is about $467 million.30 The same calculation model arrives at a lifetime total cost of $100 to $150 million for treating the thirty thousand Americans with Huntington’s disease and $850 million for treating the roughly two hundred thousand Americans with Down syndrome.31* All of these costs are necessary investments in people’s loved ones, who deserve every opportunity to reach their potential and enjoy the lives they have, and no price can be set for ameliorating the suffering of even a single human being.

  And yet we do make these choices every day through our institutions. If America deployed its full gross domestic product toward curing or treating a particular disease, chances are we could make significant progress. We don’t make this investment because we are indifferent to this one disease but because societies require balancing different, valuable interests against each other to function. For preimplantation embryo screening to become accessible to everyone, therefore, the social benefits would need to outweigh the financial and other costs.

  If screening all the embryos in the United States for a range of genetic disorders prior to implantation could be done for one dollar less than the total cost of treating for life all the people born with those disorders, society would come out ahead economically while reducing overall levels of pain and suffering. Dividing the total annual cost of treating all these diseases by the total number of babies born each year in the United States gives us a preliminary guess of the point at which every prospective parent could receive IVF and preimplantation embryo screening at no additional cost to society. A rough “back of the envelope” calculation helps make this point.

  Around four million children are born in the United States each year. Assuming that two percent of them are born with genetic diseases, that would mean eighty thousand children.32 If each of these children had a genetic disease equivalent in cost to the additional roughly $600,000 spent for lifetime care for a person with cystic fibrosis, that would mean spending an additional $48 billion over the next thirty-seven years. If we created an embryo-screening bond to bring forward this future expenditure to apply it today, we’d have about $16,500 to spend on IVF and PGT for each Americ
an woman wanting to have a child.† If we included in our calculations the costs of many other genetic and partially genetic diseases that show up later in life—like diabetes, Alzheimer’s, and certain cancers—the $16,500 figure would go up farther.

  IVF in the United States is an incredibly expensive procedure, usually costing between $12,000 and $30,000 a round. Because couples go through an average of three cycles, these costs quickly become prohibitive to most Americans.33 But the cost of IVF is far lower in other countries. In Turkey, it costs around $8,500; Britain, $8,000; Spain, $5,600; Mexico, $4,000; Korea, $3,000; and Poland, $1,200.34 In Israel, where IVF without limit is covered by the national health plan for women under forty-five, national IVF rates are growing at double digits, success rates are high, and costs for medical tourists from abroad are low.35

  If the cost of IVF and embryo selection in the United States remains high, parents of even moderate means have the ability to go elsewhere for these services. As IVF and embryo screening become the norm, however, prospective parents around the world will increasingly demand these services be covered under their health plans, competition among IVF providers will force prices down, and access and quality and our understanding of what the preimplanted embryos’ genes are saying will go up.36 The consumers, medical providers, and insurance company and/or government payers will all be incentivized to want the same outcome.

  Forward-thinking employers are already coming along. In 2014, Apple and Facebook announced they would cover the cost of egg freezing for their female employees. This was condemned by a number of prominent women as a ploy to trick women into deferring motherhood and keep working.37 More people, however, including Facebook’s Sheryl Sandberg, saw it as an inevitable step toward empowering women with more reproductive options.38 Since then, many companies, including Amazon, Google, Intel, Microsoft, Spotify, and Wayfair, have followed suit. More recently, companies such as Starbucks, Facebook, Uber, and NewsCorp have begun covering IVF as part of their employee health plans. According to a survey conducted by FertilityIQ, women working for companies that provide IVF benefits felt a significant bump in their loyalty to their employer.39 As more employees demand this type of coverage, the best and most competitive employers will provide it.

  The intersection of inexpensive and ubiquitous genome sequencing, IVF, embryo selection, and shifting cultural attitudes and financing models will propel more of us to make babies in the future very differently than how we have to date. What we’ve done in the back seat will itself take the back seat because parents won’t get the benefits of genetic selection if they conceive their children through sex. This coming shift away from natural conception would be likely if our understanding of the genome was only advancing linearly, but it is inevitable in light of the exponential progress being made in understanding our genes and how they are expressed.40

  Assessing how much we can ultimately learn from the extracted and sequenced cells taken from preimplanted embryos during PGT requires us to ask even bigger questions about what genes do and how important they are in determining who we are.

  *About 3.5 billion years ago, the first single-cell microbes split into two branches: bacteria and archaea. Some biologists make the case for a third branch, eukarya.

  *A small number of recent studies suggests that mutations putting people at risk for Mendelian conditions are present in about 15 percent of the population. If so, this would change our assessment of the risk these mutations pose and possibly also increase the financial incentives for better understanding and potentially addressing them. Because humans generate tens of additional mutations when generating sperm or egg cells, it is also possible, though less likely, the Mendelian diseases could develop in a child whose parents were not carriers of a particular mutation.

  †I use the word palatable here because although abortion could address the risk of some Mendelian diseases, it would not be reasonable or desirable to use it to address every Mendelian disease risk.

  *Ohio, Indiana, and North Dakota passed laws in 2017 making it illegal for doctors in those states to perform abortions on embryos because of a Down syndrome diagnosis. If we see an uptick in the number of babies born with Down syndrome in those states over the coming years, we will know that laws like this work. If not, we can assume prospective parents have found alternative ways to have their reproductive wishes expressed.

  †In the irrational U.S. health-care system, where people change insurance providers around every two years, these incentives are decreased.

  *The more common genetic disorders have higher aggregate costs because more people have them. But costs for treating these disorders can also go down because of economies of scale. Some of the five thousand rarer, treatable single-gene-mutation diseases are extremely expensive because they are so rare that it can take a lot of time and energy to figure out the problem and how best to address it.

  †This is [48 billion (dollars) divided by 37 (years)] divided by 80,000 parents.

  Chapter 2

  Climbing the Complexity Ladder

  The genetic revolution has provided us with new ways of understanding ourselves that our ancestors could hardly have imagined. Trying to explain to someone twenty thousand years ago that humans are made of code would have been far beyond what their life experiences had prepared them to absorb. But despite our great and often well-founded faith in science, we would be well-advised to maintain the same humble appreciation of the world beyond our grasp as animated our forebears. Even our single-gene-mutation diseases, the clearest and simplest perspective targets for human genetic engineering, should encourage our humility.

  Reliably linking single gene mutations to specific genetic diseases represents decades of hard-won progress. But this story is more complicated than it first seems. Because many of the genes linked to particular genetic diseases have been found in people showing symptoms of those diseases, researchers don’t know as much as they should about other types of people who might carry similar genetic mutations but who don’t get the particular diseases for one reason or another, perhaps because they have some other gene or genes protecting them. That’s why it’s very likely that the more people—all types of people, not just those showing symptoms of particular diseases—we sequence, the more we will come to recognize the complexity of even seemingly simple genetics. We will learn that we are all genetic mutants in one way or another, carrying mutations that might cause diseases in some but not others.

  Our complex and interactive genetics exist within the even greater complexity of our multiple biological systems, the epigenome, transcriptome, proteome, metabolome, microbiome, and virome among them. Our composite individual biology is then embedded within the broader context of our environment.1

  That’s why, after an early stage of euphoria a decade or two ago, many scientists have more recently become more cautious about our time frame for understanding our genetics and the other interacting systems within and around us. We’ve made enormous advances with inexpensive, fast, and accurate genome sequencing, but our ability to collect data has not yet been matched by an equal ability to understand the data we are collecting. “We’ve made the mistake of equating the gathering of information,” Boston University bioengineer James Collins told Nature, “with a corresponding increase in insight and understanding.”2

  As our species always has, however, we balance this justifiable humility about technology with our inherent, Promethean hubris, and for good reason. Each of the complex biological systems within us will be increasingly decodable, our genes foremost among them.

  Because tackling the human genome in one swoop is an impossible task, geneticists are working their way up the complexity ladder by trying to understand the biological systems of simpler and faster-breeding model organisms like yeast, fruit flies, roundworms, frogs, mice, and zebra fish, all with many gene and biological systems similar to ours. Because all living beings share a common ancestor, the genetics of these creatures are more or less like that of humans, d
epending on when we split from them. Humans and fruit flies, for example, share a common ancestor from around seven hundred million years ago. We split with mice, our far closer relatives, a mere eighty million years ago, which explains why both of our species love cheese (just kidding). For this reason, we share 60 percent of our DNA with fruit flies but 92 percent of our DNA with mice.

  Unfortunately for them, these relatives of ours have taken the brunt of our genetics research. In the early days, they were bombarded with harmful radiation to mutate their genes and see how various genetic changes led to particular physical outcomes. Today, a wide range of genetic tools are used to knock out genes in model organisms, and laboratories around the world genetically engineer mice and other animals to help study various diseases or traits.* Slowly but consistently, these processes are moving us toward better understanding how complex biological systems like ours function.

  For years, researchers like Eric Davidson, a biologist at the California Institute of Technology, have been working to show how the complex biological systems of model organisms can be increasingly understood. Davidson systematically knocked out multiple proteins controlling the expression of genes in sea urchins and monitored how each change altered the other proteins and gene expression. With this information, he and his team are painstakingly developing a dynamic map of how many different proteins and genes interact in an effort to draw basic principles for the overall biological system of the sea urchins. There is still a lot of work to be done, but Davidson describes his work as “a proof of principle that you can understand everything about the system that you want to understand if you get hold of its moving parts.”3