From IVF to Gene Surgery

In July 1978, Louise Brown became the first IVF-conceived embryo to be born. “What I couldn’t possibly know as I was screaming away,” Brown wrote in her 2015 autobiography, “. . . was that the mere fact that I had been born was one of the most important moments in world history.”

That was over 40 years ago. Since then, becoming masters of IVF has done more than help individuals and infertile couples begin families; it has made real what were once only imagined possibilities. Today, as we combine IVF procedures with an expanding knowledge of not only the human genome but also gene-editing tools, new and previously unimaginable options have opened: before an IVF embryo is implanted in a womb, we can now alter it genetically.

Jennifer Doudna, the Berkeley biochemist who codiscovered the CRISPR-Cas9 gene-editing technology, told Vision in 2016: “We are not going to do anything overnight. But the big-picture view is that we have the tools to change our DNA and change the things that we are passing on to future generations. And now we can make those decisions. That is a profound thought.”

And so it is. How did we arrive where we are today?

IVF: Under the Microscope

IVF, the mixing of egg and sperm outside the body to generate a fertilized egg, or zygote, was first attempted in the late 19^th century with small mammals such as mice, rabbits and guinea pigs. All organisms that reproduce sexually—that is, where two parents contribute genes to create a new individual—must bring egg and sperm together.

When this happens in a dish, all the important changes, from cell division and differentiation to the growth of tissues and organs, can be monitored. For a frog, the entire developmental sequence can be observed. For a mammal such as a mouse, monkey or human, the early embryo must be properly implanted into a womb to complete its gestation.

Long before IVF and embryo transfer succeeded, however, novelist Aldous Huxley took the manufacturing of humans one step further. In the dystopian future pictured in Brave New World (1932), reproduction itself had been removed entirely to the lab and reduced to a set of procedures, recipes, equipment and growth media. Racks of aquarium-like artificial wombs nurtured castes of embryos programmed not only to take their predestined place in the social order but to find happiness there: “All conditioning aims at that: making people like their unescapable social destiny.”

“The faint hum and rattle of machinery still stirred the crimson air in the Embryo Store. . . . Majestically and for ever the conveyors crept forward with their load of future men and women.”

Anxiety about that sort of manipulated destiny hangs over reproductive science today, especially in relation to genetic engineering. Huxley’s imagined technologies don’t exist (yet), but our understanding and study of the embryo and its mysteries have made stunning advances. Moving from simple observation and dissection to microscopy and genomics, the curious have opened new windows to understanding.

For example, we know today that once egg and sperm meet, an intricate chemical choreography begins. Genes are turned on and off, and that first cell divides: two, four, eight, and so forth. About five days after conception, the dividing cells form a sphere called a blastocyst. The outer layer will form the placenta, connecting the developing baby to the lining of the mother’s uterus. The inner mass, made of embryonic stem cells, will grow and differentiate to form the fetus.

Embryologists of the 1950s and ’60s began to learn these things through the study of animals, but by the end of the 1960s, British physiologist Robert Edwards had moved on to creating in vitro human embryos. The response was predictably mixed: Was it a miraculous scientific leap forward or the epitome of amoral behavior—the treating of a human life as an object?

In his 1979 essay “‘Making Babies’ Revisited,” bioethicist Leon Kass described the procedure in stark terms: “With in vitro fertilization, the human embryo emerges for the first time from the natural darkness and privacy of its own mother’s womb, where it is hidden away in mystery, into the bright light and utter publicity of the scientist’s laboratory, where it will be treated with unswerving rationality, before the clever and shameless eye of the mind and beneath the obedient and equally clever touch of the hand.”

Ethical Questions

How should we think of these first cells? In a 2006 interview with Vision, Stanford bioethicist William Hurlbut described them as part of the continuum of human life: “My perspective is that once you have a living human being, even in its earliest phases of development, you have the initiation of the organism that begins with fertilization and ends with natural death.”

It is biologically clear that life begins at conception; for each of us, physical being started at that singular point, a personal singularity. Does creating that moment through science make it different than when it happens naturally?

When is a human not a human? Answers to that question have likely always been sectarian, social—a matter of whom and when you ask. It may seem that today we can answer it scientifically, objectively; yet we still tend to hedge.

The question of when the embryo becomes human is also open to religious argument. Is there a point where cells go from being just cells to being human?

One Jewish interpretation, writes fertility expert Sherman J. Silber, is that “we all have an obligation to have offspring and to ‘be fruitful and multiply.’” According to this view, “IVF is absolutely obligatory when it is medically indicated in order for a couple to have children. It is not just allowable, but it is obligatory.”

Human embryo-making and embryo use for research purposes are also allowed. Silber notes that “according to the Talmud, the soul does not enter the embryo until 40 days after conception.” By this reasoning, all manner of embryo manipulation is allowable. Even killing and discarding them would be ethically sound. The IVF embryo is a step toward fruitfulness, Silber writes, “but it would not be considered murder to utilize an early embryo for research that might eventually save lives.”

“In orthodox Judaism, which is otherwise a ‘right to life’ and anti-abortion religion, the early embryo does not yet have a soul and so is not yet a person.”

Certainly the Roman Catholic view is opposed to this interpretation. The US Conference of Catholic Bishops summarized the church’s official stance as laid out in a 1987 document known as Donum Vitae (“The Gift of Life”): “If a given medical intervention helps or assists the marriage act to achieve pregnancy, it may be considered moral; if the intervention replaces the marriage act in order to engender life, it is not moral.”

Much of the debate centers on when life begins from a theological standpoint. Is a zygote a human life? It’s interesting to note that the Bible itself offers no specific answer to that question, though it does offer a clue in the story of two pregnancies recorded in the first chapter of Luke’s Gospel. A man named Zacharias was told that his wife, Elizabeth, would conceive and bear a son, “and you shall call his name John [the Baptist]. . . . And many will rejoice at his birth.” Likewise Mary was told that she would conceive a son and that “[He] who is to be born will be called the Son of God.” In each case, the prospective embryo was already being referred to as a very real person. This suggests support for the continuum model of human life beginning at conception.

Clearly, however, the sort of caution many called for, whether on a scientific or a theological basis, would have derailed the quest to solve infertility. Without the initial research, Edwards’s work toward successful IVF would have stalled: he had created and discarded hundreds of embryos before treating the Browns’ infertility.

Socially, there is no easy answer here—no clear-cut, black-and-white dictum. Infertility is a terrible thing for couples to grapple with, and IVF has given millions of them children they could not otherwise have had. But opponents point out that it came at the cost of countless human embryos that ultimately were scrapped. “Clearly, when you destroy the single-celled embryo in a dish,” Stanford’s Hurlbut argues, “you are interrupting the process which is on the trajectory to expressing what we recognize socially to be a human person.”

The controversy overshadowed IVF from the outset, resulting at least in part in Edwards’s requests for funding through the British Medical Research Council being denied. The procedure to obtain human eggs seemed too invasive, the health cost too high for the expected research benefit. Edwards continued his research with private funding.

IVF Comes of Age

Working through the 1970s in partnership with gynecologist Patrick Steptoe, Edwards generated and brought to term the first in vitro baby, Louise Brown, in 1978.

In 1982, Louise’s sister Natalie was born, Britain’s 40^th IVF baby. And in 1999, at the age of 17, Natalie became the first IVF baby to bear a naturally conceived child.

“What we are seeing is the second generation of IVF—where children who were conceived by the test tube process are moving on to parenthood. The fears that they may have been left infertile are completely laid to rest by Natalie’s baby.”

Edwards received the 2010 Nobel Prize in Physiology or Medicine (Steptoe had died in 1988). The presenter remarked that “by charting a new territory in medicine, Robert Edwards has given new hope to millions of people who were involuntarily childless. With his scientific vision and his personal courage, he has showed all of us an example of how a medical therapy, though highly controversial at first, can become established over time.”

Edwards died in 2013, but his scientific legacy reaches forward to today and tomorrow, as do the children he helped bring into existence. “It took my parents nine years of heartbreak before they had my sister,” Natalie Brown told the Mirror, “and if it wasn’t for IVF Louise and I wouldn’t be here now—and neither would our children.”

Louise Brown was the proof-of-concept experiment confirming that a human being, conceived outside the body, could be carried successfully to term. But the event of her birth in 1978 not only provided John and Lesley Brown a child, it also provided scientific access to the human embryo from the very outset of its existence.

Today more than 8 million IVF babies have been born, with over a half million more being added each year. More than 2 million treatment cycles are performed annually, according to a 2018 European Society for Human Reproduction and Embryology report.

These numbers reveal the inefficiency of the process, however. While in some instances there truly is only one egg and one embryo, in other cases many eggs are harvested and many embryos are created. Some are implanted. For the leftovers there awaits a deep freeze or a waiver granting use for research. Even after all that, fewer than 30 percent of implanted embryos are carried to birth.

All of this feeds the ongoing controversy, of course; the fate of all the embryos created and lost in the process remains a worry for many. Kass voiced his own concern this way: “The human blastocyst, even the human blastocyst in vitro, is not humanly nothing; it possesses a power to become what everyone will agree is a human being. . . . It deserves our respect not because it has rights or claims or sentience (which it does not have at this stage), but because of what it is, now and prospectively.”

But “moral issues had never been discussed when [my parents] were thinking of having a baby,” writes Louise. “They had never once discussed whether what Patrick Steptoe and Robert Edwards were doing was morally right or wrong. All they were interested in was having a baby and if these medical people could come up with a way to help Mum do that they were happy to take part in the IVF programme.”

The Future Is Here

Today much more is at stake than simply having a baby. The scientific community’s goals reach beyond overcoming infertility to identifying the best embryos for implantation and editing out disease-related genes. In itself that sounds benign, even laudable. Other possibilities are less so: Was giving couples a child of their own a first step toward the genetic modification of humans? And a darker question: Was this the intent all along?

In 1971 Bentley Glass, retiring president of the American Association for the Advancement of Science, wrote an article titled “Science: Endless Horizons or Golden Age?” He wondered about the future of science: “Are there finite limits to scientific understanding, or are there endless horizons?” His own conclusion was that scientific knowledge must indeed be finite, and that progress would instead be defined “in terms of man’s increasing power.”

“Look where we will along the Time-Scale, we see men eagerly seeking power, patiently fashioning and tenaciously grasping the instruments for exerting it, conferring honor upon those who employ it most effectively.”

But even that kind of progress had boundaries, he wrote: “We have at most a generation or two before progress must cease, whether because the world’s population becomes insufferably dense, or because we exhaust the possible sources of physical energy or deplete some irreplaceable resource, or because, most likely of all, we pollute our environment to toxic, irremediable limits.”

The geneticist went on to show how that might play out in his own field: “In an overpopulated world it can no longer be affirmed that the right of the man and woman to reproduce as they see fit is inviolate. . . . No parents will in that future time have a right to burden society with a malformed or a mentally incompetent child. . . . Unlimited access to state-regulated abortion will combine with the now perfected techniques of determining chromosome abnormalities in the developing fetus to rid us of the several percentages of all births that today represent uncontrollable defects such as mongolism (Down’s syndrome) and sex deviants such as the XYY type. . . . This procedure will be unquestionably most effective if carried out during the early embryonic stages of development, or in the just-fertilized egg itself before it has begun its cleavage into numerous cells. Hence we must look with expectant attention at the startling progress that is being made in the laboratory of R.G. Edwards.”

Seven years before the birth of Louise Brown, Glass anticipated that “in the future age of man it will become possible for every person to procreate with assurance that the child, either one’s own or one prenatally adopted [i.e., from an IVF embryo implanted in a woman other than the one who supplied the egg], has a sound heritage, capable of fully utilizing the opportunities provided by society for optimal development.”

We are now, technologically, in that future. With the discovery of CRISPR-Cas9’s ability to edit genes, a potential mother could, in theory, select an embryo endowed with a preloaded variety of traits “for optimal development.”

Research involving CRISPR moved quickly. By 2015 investigators had created human embryos and then edited their genes. When this first occurred (using embryos that were not actually viable, having been made with genetically flawed cells that terminated their development), the scientists collectively declared: This far and no farther. In a paper titled “A Prudent Path Forward for Genomic Engineering and Germline Gene Modification,” Berkeley’s Doudna was among those recommending that the scientific community “strongly discourage, even in those countries with lax jurisdictions where it might be permitted, any attempts at germline genome modification for clinical application in humans, while societal, environmental, and ethical implications of such activity are discussed among scientific and governmental organizations.”

But not everyone listened.

Boldly Going Where No Man Has Gone Before

In 2018 Chinese scientist He Jiankui created and genetically edited viable human embryos, referring to it as “gene surgery.” Then, like Edwards and Steptoe, He crossed a red line: he implanted the embryos, and several months later two girls were born—not only conceived but genetically edited by human hands. At least one other, according to He, is on the way (or, assuming the pregnancy progressed normally, probably already born).

“When this kind of biochemical sophistication has been attained, when man can write out detailed genetic messages of his own, his powers become truly godlike. . . . Man will presumably be able to write out any set of specifications he might desire for his ideal human being. . . . And who can find fault with creating ideal human beings?”

Just as no one was really sure what might happen to Louise Brown after her birth four decades ago, no one really knows how things will work out for these children. The first IVF baby is a healthy adult today, but no one could be sure about that at the time.

What was done to these babies in China is not fully known either, but it’s done, even though controlling CRISPR’s cutting and splicing is still very much a work in progress. Accuracy is improving, but He’s surgicalchanges can’t be undone; we can only wait to observe their impact. Likewise, we can only wait to see how soon the technology will be taken yet a step further to produce designer babies.

In his 1971 Science article, Bentley Glass wrote: “Human power is advancing with extraordinary rapidity in this realm of control over the genetic characteristics of the unborn. Perhaps . . . our race, far from having any aversion from power, will welcome this power too, will seek it, fashion it, and grasp it tenaciously.”

After wondering whether science would investigate endless horizons or putter off into a golden sunset, Glass summed up: “Man requires a challenge and a quest if he is to avoid boredom. The Golden Age toward which we move will soon look tawdry if we no longer see endless horizons. We must, then, seek a change within man himself. As he acquires more fully the power to control his own genotype and to direct the course of his own evolution, he must produce a Man who can transcend his present nature.”

From IVF to gene surgery to eugenics. Are some windows better left closed?