by Jamie Metzl
In 1998, University of Wisconsin developmental biologist Jamie Thomson and Johns Hopkins University’s John Gearhart, both leading human embryonic stem cell researchers, described to CNN the many miracles stem cells might unleash. They could, Thomson and Gearhart claimed, be used to repair spinal injuries, heart-muscle cells after heart attacks, and organs damaged by disease or radiation; spur insulin-production to treat diabetes and brain cells to secrete dopamine to treat Parkinson’s disease; and to genetically alter blood cells to resist diseases like HIV.5
The idea of using embryonic stem cells to deliver these kinds of miracles enthralled many around the world but terrified others. Embryonic stem cells are, as their name implies, derived from embryos. These embryos, in nearly all cases, are unimplanted embryos from fertility clinics. For those believing life begins at conception, these early-stage embryos in petri dishes were people. If so, destroying discarded embryos to support cutting-edge research—even to discover life-saving treatments—was nothing short of murder. America’s right-to-life movement quickly targeted stem-cell biology.
“Suddenly, stem cells are everywhere,” Time magazine reported in July 2001.
Once relegated to the depths of esoteric health journals, the microscopic clusters have made their way to the nation’s front pages…[and] become the political cause du jour in Washington. The debate surrounding the cells threatens to rend traditional alliances, challenging our comprehension of life and leaving some abortion opponents in a very uncomfortable spot: Is it possible to protect the strict boundaries inherent in the “sanctity of life” and still harvest these cells to help the living among us?… [S]ome pro-life advocates have likened using stem cells for research to what Nazi doctors did during World War II. But these cells also hold great promise for millions of ailing patients and their families.6
Caught between scientific advancement and his conservative base, and between the conflicting views of different members of his own cabinet, U.S. President George W. Bush split the difference. On August 9, 2001, he announced a ban on federal funding for research involving newly created human embryonic stem-cell lines. This meant that the seventy-one stem-cell lines that met the U.S. government’s criteria that were already in use by researchers could still be accessed. Any researchers using new or other human stem-cell lines, however, could not receive U.S. government funding.
The Bush administration’s Solomonic effort pleased no one. For advocates of stem-cell research, limiting the number of available stem-cell lines only slowed essential research likely to save and improve countless lives. For many opponents, the use of any embryonic stem-cell lines violated the sanctity of life and was an abomination. Some U.S. researchers decamped to countries like Singapore and the United Kingdom to continue their research with fewer restrictions. Activists in New York and California countered the Bush administration restrictions by creating well-funded, state-based researched support organizations, the New York Stem Cell Foundation and the California Institute for Regenerative Medicine.
But then a discovery in a somewhat obscure Japanese research institute blew open the doors of stem-cell research and transformed our concept of biological plasticity forever.
Most of us think of biology as a process that moves forward linearly. We start as a single cell and then grow into complex beings. We are born, we age, then we die. But nature sometimes hides its tricks in plain sight. We wouldn’t expect to make perfectly fresh cheese from old milk, but it seems perfectly normal to us that two thirty-year-old adult humans can have a child who is born zero years old, not thirty or sixty. Clearly, our cells already have a way of resetting the clock.
In the 1950s, Oxford biologist John Gurdon was thinking about how certain animal cells seem to rejuvenate themselves. He wondered if cells already specialized—as skin or liver or other types of adult cells—might retain a latent ability to revert to their predifferentiated state. To test this hypothesis, he replaced the nucleus of a frog egg cell with one from a fully mature and specialized frog cell. After a series of these (literally) adulterated egg cells failed to do much of anything after being inseminated with frog sperm, a few, miraculously, became fertilized and healthy tadpoles were created. Gurdon proved that any adult cell, under the right circumstances, had the innate ability to go back in developmental time to become the equivalent of an embryonic stem cell.
Gurdon’s incredible discovery opened researchers’ minds to the possibility of cells behaving like Benjamin Buttons, but didn’t provide a blueprint for how to make that happen. Japanese veterinary researcher Shinya Yamanaka was determined to find it.
As a child in Osaka, Yamanaka enjoyed taking clocks and radios apart and putting them back together. After beginning his career as a surgeon, his frustration that he was unable to heal some of the worst diseases facing his patients inspired him to seek a deeper understanding of cell biology. He went back to school to get his PhD in pharmacology, with a particular focus on mouse genetics. When he learned of Jamie Thomson’s work generating human stem cells and John Gurdon’s findings on how nuclear DNA can be reprogrammed, he set his heart on deciphering the hidden potencies of cells.
After years of painstaking research, in 2006 Yamanaka and his team discovered that proteins encoded by just four “master genes” could turn back the clock and transform any adult cell back into a stem cell. Just as a stem cell could differentiate itself forward in developmental time into a skin, blood, liver, heart, or any other of the two hundred types of human cells, these Yamanaka factors could revert any skin, blood, liver, or other type of cell back into the equivalent of an embryonic stem cell. He called these induced pluripotent stem cells, or iPSCs. Yamanaka deconstructed the cell and showed how the biological clock could tick backward.
Yamanaka and Gurdon won the 2012 Nobel Prize because their discoveries have the potential to revolutionize much of biology—including how we humans create eggs.
In 2012, Japanese cell biologists Katsuhiko Hayashi and Mitinori Saitou announced they had used the Yamanaka factors to reprogram adult mouse skin cells in a dish into iPS cells. They then added more chemicals to turn these stem cells into egg and sperm progenitor cells, the precursors of eggs and sperm. After they placed the same artificial cells into mouse ovaries, the cells matured into eggs. When they put induced sperm precursor into mouse testes, these cells matured into sperm. These induced eggs and sperm were used for mouse IVF, resulting in perfectly healthy baby mice. Even though the success rate for these iPSC-generated sperm and eggs in IVF was extremely low, this was a spectacular breakthrough.7 Sperm and eggs had been generated from skin cells and used to give birth to healthy mice.
Two years later, in 2014, scientists in England and Israel figured out a way to replicate the same finding, but they made human egg and sperm cells out of adult skin cells in a dish.8 The efficiency of this process was again extremely low. Then, in September 2018, Saitou and his collaborators announced they had induced egg precursor cells from human blood cells, which were then incubated in tiny ovaries developed from mouse embryonic cells. Even though these induced human egg precursor cells were not mature enough for human fertilization, reaching that point was tantalizingly near. Although the large number of unknowns still makes this procedure not at all safe for humans in the near term, the science is improving fast, and the implications are massive for the future of human reproduction (and your experience in the 2045 clinic).9
The average woman who has her eggs extracted yields about fifteen eggs for potential fertilization. Because some of the eggs often prove unfit for fertilization, or because the embryos have one problem or another, a large attrition rate is normal for IVF. The number of early-stage embryos actually available for selection is, therefore, significantly lower than fifteen. But induced stem-cell technology could multiply that number in a very big way.
That one hundred milliliters of blood your assistant took during your meeting contains around three hundred million peripheral blood mononuclear cells, or PBMCs—blood cells with a cel
l nucleus. Each of these PBMCs (or any other type of adult cell, for that matter) can be transformed by Yamanaka factors into induced stem cells. Then, using the process Hayashi and Saitou developed, each of these millions of stem cells could be turned into egg precursor cells and, ultimately, into eggs.
Now you have hundreds or thousands or even millions of eggs. The father’s sperm cells already number in the hundreds of millions. But even if the father’s sperm is not at first available or he is infertile, the same process could be used to generate sperm from iPS cells. Put the sperms and eggs together in a dish at the right temperature, or inject the sperm cells into the eggs, and now instead of around fifteen fertilized eggs you have hundreds or thousands. Then the lab can use advanced AI tools to machine-sort the fertilized eggs to identify those with optimal shapes and biologies, the technological version of what embryologists do manually in fertility clinics today. The next step would be to grow these fertilized eggs for five to seven days, until each is about one hundred cells, and then extract five or so cells from each blastocyst and sequence them.
Because the cost of sequencing a genome will soon be largely negligible, sequencing these early-stage embryos will be cheap, easy, and quick. And because low-cost, universal sequencing—paired with electronic medical and life records and big-data analytics—will by then have unlocked far more secrets of the human genome, the information these hundred embryos each provide will be astonishing by today’s standards. It will likely be a normal component of the baby-making process then, as you experience in 2045.
In the weeks since the drone messenger picked up your blood sample, you’ve been living your normal life, but your blood sample has been experiencing a metamorphosis. At the clinic, Yamanaka factors are used to turn your blood cells into induced pluripotent stem cells. These stem cells are induced into egg precursor cells, just like the ones you produced inside your body when you went through IVF a decade ago—only this time many more eggs are being created outside your body than you ever could have produced within.
You’ve been feeling a growing sense of excitement. You’ve been talking about the possibilities of a third child for years, but your big day is finally here.
This is a hypothetical, so we can experiment with who we slot into this story in the role of your partner. It could be your husband, but also potentially anybody else. We could imagine a version where two men could have their own 100 percent biologically related babies, using the sperm of one father and eggs induced from an adult cell taken from the other father. Or both the egg and sperm might conceivably be generated from the same man who would become the father and the mother of his child, a scenario seeming more feasible than ever before.
American scientists have already produced viable offspring from two male mice. In November 2018, Chinese scientists announced they had successfully and efficiently harvested stem cells from a mouse egg that they induced into sperm cells used to fertilize the eggs of another female mouse, resulting in healthy mouse pups with half their genetics coming from the first mother and the other half from the second mother. Recent research has pointed to the distinct possibility of generating eggs from 3-D printed ovaries that could be filled with follicles and implanted into a man or transgender woman.
Don’t start purchasing your male maternity clothes just yet, but biology is certainly not what it used to be!
On the big day, you wait expectantly in the clinic to be called.
The waiting room has been redecorated since your last visit a decade ago. Settling in to the lush sofa under the soft lights with gentle, spa-style music playing, you feel secure with the choice you’ve made to stick with this clinic, now part of a larger brand competing in this $50 billion assisted reproduction technologies U.S. business sector.
The door opens, and the doctor comes in to greet you. The office walls are now made up of large screens. She has chosen a beach motif, and as you sit it feels like you are relaxing at a table on the waterfront. The sound of gentle waves soothes you.
You appreciate the effort but have bigger things on your mind. You’ve now been exposed to scientifically assisted reproduction for two decades and have two wonderful kids—your healthy and robust twenty-year-old, now at college, and your brilliant, artistic, and optimistic ten-year-old at home. This time you don’t need any convincing. “Well?” you ask expectantly.
“Okay,” she says, “let’s get down to it. Your blood sample arrived safely a week ago. We spun your blood in a centrifuge to extract the cells we needed, then reprogrammed them into the stem cells we used to create the egg precursor cells and then your eggs. We decided to fertilize a thousand of your eggs, but then machine sorted those thousand down to the hundred we grew into six-day-old embryos. We then extracted five cells from each of these blastocysts for sequencing and the result is—”
This is the moment you’ve been waiting for. You hold your breath.
Suddenly, the beach scene goes away and the walls become a massive grid filled with numbers between zero and a hundred. Your eyes scan the room in awe as you stand and look around.
“This may seem a bit confusing,” the doctor says, “but the chart shows the probabilities for each of your hundred embryos having the listed outcomes. The Y-axis lists your early-stage embryos from one to a hundred. The X-axis lists the estimated percentage chance each embryo will have a specific condition or trait should that embryo become a person.”
There are so many different traits the chart wraps around the entire room. “This is incredible. The science is advancing so fast.”
“Welcome to the future of human reproduction,” she says.
You walk over and point to the column under the heading Alzheimer’s. “So, the 90 in this column means that these embryos would have a 90 percent chance of getting Alzheimer’s during their lifetimes?”
“Actually no,” she replies. “All of the numbers are relative to what’s considered the more positive outcome. That 90 percent means that embryo would have a 90 percent chance of not getting Alzheimer’s if it were selected. The higher numbers are generally what you would likely want for a given trait.”
“I see,” you say. “And this one would be a great sprinter?”
“He—that embryo’s male—would have a genetic proclivity for fast-twitch muscles. And, of course, to be a great sprinter he’d need to have a high score for determination, as well as train, eat well, be exposed to positive role models, et cetera, whatever the genes say.”
You scan the walls in awe. And then it hits you. “My mother always used to tell me that I was perfect just as I was.”
“I just need to reiterate,” the doctor says, “that these are all your natural children, just the same as if you had conceived through sex, just the same as when you went through IVF and embryo selection last time, when the number of eggs was limited by your natural ability to produce them. We’ve only increased the number of options. All of these qualities, the good ones and the dangerous ones, are all your genetic inheritance. They all reflect the genetics of you and your partner’s ancestors going back billions of years. Change is hard for all of us, but the ultimate question people are asking is whether they feel better off with all these choices or better off the old way, where so much was left to chance.”
“Am I really just shooting for a high composite score?” you ask, still struggling with the idea that the magic of life can be reduced to a series of percentages on a graph.
“Nature is no fool,” the doctor replies thoughtfully. “Evolution isn’t random. It just made some trade-offs for us over the years that today don’t always seem that great. We have to approach all of this with a great deal of humility.”
You look around the room at the cascade of numbers and don’t see humility. There’s a 10 percent chance some of your embryos won’t get Type 1 diabetes, a 20 percent chance some won’t get Alzheimer’s. Something still doesn’t feel right. You’ve always known that people with genetic disorders were just different. Some of them, like some people with a
utism, even have superpowers far beyond their so-called normal peers. What does it mean to select these conditions out with a simple nod of the head?
But you also realize these aren’t just numbers on a wall. You close your eyes and imagine your future grandchildren holding your third child’s hand as her mind deteriorates from Alzheimer’s or weeping at the cemetery after her premature death. Would you play Russian roulette with your next child’s fate by not affirmatively selecting health? Would you even consider not giving your child the best genetic possibilities that your and your partner’s genes make possible? If this is hubris, you realize, sign me up. “What’s the next step?”
The doctor leans in. “First, we should eliminate all the embryos with high likelihoods of having major diseases. That means the ones with 0 to 50 in the disease-state columns. With so many possible choices, why select embryos so likely to suffer?”
There goes Kafka and Van Gogh, you think to yourself. “And then?”
“There are so many traits influenced in one way or another by genes. The algorithm in this chart weighs each trait by our level of confidence in how important genetic factors are for the trait. For hair and eye color, for example, there’s an almost 100 percent certainty that your genes determine the outcome. For some of the other traits, take musical ability for example, we only have a 50 percent confidence the genes we’ve identified are impactful.”
“So where does that leave us?”
“You need to make hard choices in ranking your priorities,” the doctor continues. “Picking everything is kind of like picking nothing. If empathy is really important to you, put that in your highest category. If being a good marathon runner with slow-twitch muscles is nice but not that important to you, put that lower so you don’t skew the results. Do you follow?”
