Now That We Can Alter Our Genetic Code, Should We?
Facing a breast-cancer survivor, a doctor grapples with the implications of new gene-editing recommendations.
A few days ago, I had just stepped off a podium at a cancer conference when a 50-year-old woman with a family history of breast cancer approached me. I had been discussing how my laboratory, among hundreds of other labs, was trying to understand how mutations in genes unleash the malignant behavior of cancer cells. She told me that she carried a mutation in the BRCA-1 gene—a mutation that she had likely inherited from her father.
Diagnosed with cancer in one of her breasts when she was 30, she had undergone surgery, chemo, radiation and hormonal therapy. But that grim sequence of diagnosis and treatment, she told me, was hardly the main source of her torment. Now, she worried about the development of cancer in her remaining breast, or in her ovaries. She was considering a double mastectomy and the surgical removal of her ovaries. A woman carrying a BRCA-1 mutation has nearly a 60-70 percent chance of developing cancer in her breasts or ovaries during her lifetime, and yet it's difficult to predict when or where that cancer might occur. For such women, the future is often fundamentally changed by that knowledge, and yet it remains just as fundamentally uncertain; their lives and energies might be spent anticipating cancer and imagining survivorship—from an illness that they have not yet developed. A disturbing new word, with a distinctly Orwellian ring, has been coined to describe these women: previvors—pre-survivors.
The uncertainty and anxiety had cast such a pall over this woman's adult life that she did not want her grandchildren to suffer through this ordeal (her children had not been tested yet, but would likely be tested in the future). What if she wanted to eliminate that genetic heritage from her family? Could she ensure that her children, or her grandchildren, would never have to live with the fear of future breast cancer, or other cancers associated with the BRCA-1 gene? Rather than waiting to excise organs, could her children, or their children, choose to excise the cancer-linked gene?
That same morning, a National Academies of Sciences panel issued a report on the future prospects of "gene editing" in human embryos. Gene "editing" (more on this below) refers to a set of techniques that enables the deliberate alteration of the genetic code of a cell. In principle, if the BRCA-1 mutation could be altered in egg cells or in sperm cells bearing that genetic mutation, the gene would be "fixed" (or restored to its non-mutant form) forever.
To understand what the report proposes, we need to understand how genes function, and how we might be able to manipulate genes in the future. First, though, a quick primer: A gene, crudely put, is a unit of hereditary information. It carries information to specify a biological function (although a single gene might specify more than one function). To simplify somewhat: You might imagine genes as a set of master-instructions carried between cells, and between organisms, that inform a cell or an organism how to build, maintain, repair and reproduce itself.
The BRCA-1 gene specifies a protein that allows cells to repair other damaged genes. For a cell, a damaged gene is a catastrophe in the making. It signals the loss of information—a crisis. Soon after genetic damage, the BRCA1 protein is recruited to the damaged gene. In patients with the normal gene, the protein launches a chain reaction, recruiting dozens of proteins to the knife-edge of the broken gene to swiftly repair the breach. In patients with the mutated gene, however, the mutant BRCA1 is not appropriately recruited, and the breaks are not repaired. The mutation thus enables more mutations—like fire fueling fire—until the growth-regulatory and metabolic controls on the cell are snapped, ultimately leading to breast cancer. Breast cancer, even in BRCA1-mutated patients, requires multiple triggers. The environment clearly plays a role: Add X-rays, or a DNA-damaging agent, and the mutation rate and cancer risk climbs even higher. And other gene variants can change the risk: If a BRCA-1 mutation is present with other gene-variants that increase cancer risk, then the chance of developing cancer multiplies.
Until recently, a woman carrying a mutation in the BRCA-1 gene had the means to alter her personal genetic destiny, but no means to alter the transmission of that destiny in her children. She could choose to undergo intensive screening for early breast cancer, and intervene only if and when cancer is detected. She could choose to take hormonal medicines to reduce her risk. Or she could choose to remove her breast and ovaries, thereby drastically reducing the future chance of developing breast and ovarian cancer (although the mutations also increase the risk of other cancers, such as pancreatic cancer, or prostate cancer in men). But notably, until the 1990s, she could not prevent the transmission of the mutated gene to her children.
In April 1990, Nature magazine announced the birth of a new technology that raised the stakes of human genetic diagnosis. The technique relies on a peculiar idiosyncrasy of human embryology. When an embryo is produced by in vitro fertilization (IVF), it is typically grown for several days in an incubator before being implanted into a woman's womb. Bathed in a nutrient-rich broth in a moist incubator, the single-cell embryo divides to form a glistening ball of cells. At the end of three days, there are eight and then sixteen cells. Astonishingly, if you remove a few cells from that embryo, the remaining cells divide and fill in the gap of missing cells, and the embryo continues to grow normally as if nothing had happened. For a moment in our history, we are actually quite like salamanders or, rather, like salamanders' tails—capable of complete regeneration even after being cut by a fourth.
A human embryo can thus be "biopsied" at this early stage, the few cells extracted used for genetic tests. Once the tests have been completed, cherry-picked embryos possessing the correct genes can be implanted. With some modifications, even oocytes—a woman's eggs—can be genetically tested before fertilization. These techniques together are called "preimplantation genetic diagnosis," or PGD.
Preimplantation genetic diagnosis was first used to select embryos by two English couples in the winter of 1989, one with a family history of a severe X-linked mental retardation, and another with a history of an X-linked immunological syndrome—both incurable genetic diseases only manifest in male children. The embryos were selected to be female. Female twins were born to both couples; as predicted, both sets of twins were disease-free.
For a woman carrying a BRCA-1 mutation, preimplantation genetic diagnosis offers a new way to think about genetic selection in the future. An embryo (or even an egg) might be biopsied and diagnosed as a carrier for the BRCA-1 mutation, and the woman might choose not to implant that embryo. Some mathematics might put the choices into perspective: If a woman carrying the BRCA-1 mutation conceives a child with a man carrying no mutation, then the chance of having a child with the mutation is one in two. If the father also happens to carry the BRCA-1 mutation, then the chance increases to three in four (actually, for complicated reasons, the figure is closer to two in three). But with gene sequencing and PGD, a woman might be able to reduce the risk to zero—essentially erasing the BRCA-1 mutation from her future lineage.
In the spring of 2011, Jennifer Doudna, a biochemist, and a bacteriologist, Emmanuelle Charpentier, discovered yet another powerful mechanism to manipulate the human genome. Doudna and Charpentier were working on a mechanism by which bacteria defend themselves against invading viruses—"the most obscure thing I ever worked on," as Doudna would later put it. Building on earlier work by microbiologists, Doudna and Charpentier began to dissect the way bacteria could inactivate viral genes. Some microbes, they found, encode genes that can specifically recognize viral DNA and deliver a targeted cut to it.
In 2012, Doudna and Charpentier realized that the system was "programmable." Bacteria, of course, only seek and destroy viruses; they have no reason to recognize or cut other genomes. But Doudna and Charpentier learned enough about the self-defense system to trick it: They could force the system to make intentional cuts in other genes and genomes. The same bacterial defense system might, in principle, be "reprogrammed" to deliver a cut to the BRCA-1 gene, or to any gene of choice. Scientists working at Harvard, MIT and other institutions refined the system further, enabling its use in human cells.
The system could be manipulated even further. By tweaking a cell's own repair mechanism in conjunction with cutting a desired genetic sequence, researchers found, they could introduce a genetic sequence to a gene. A defined, predetermined genetic change could thus be written into a genome: The mutant BRCA-1 gene can be reverted to normal gene. The technique has been termed genome editing.
The method still has some fundamental constraints. At times, the cuts are delivered to the wrong genes. Occasionally, the repair is not efficient, making it difficult to "rewrite" information into particular sites in the genome. But it works more easily, more powerfully, and more efficiently than virtually any other genome-altering method to date. Only a handful of such instances of scientific serendipity have occurred in the history of biology. An arcane microbial defense system has created a trapdoor to the transformative technology that geneticists had sought so longingly for decades, a method to achieve directed, efficient, and sequence-specific modification of the human genome.
Can gene editing be used to change the genetic information of a human embryo in a permanent, heritable manner? In other words: Could we envision using it to revert the dysfunctional BRCA-1 gene, say, to functional version? The quick answer is yes, but only if we can overcome some strong technical hurdles.
There's one strategy of many that may be the most approachable. A genetic change could be introduced into human sperm and eggs—or, conceivably, into cells that make sperm and eggs. Now consider a thought experiment: If a human embryo can be created by IVF using such gene-modified sperm or eggs, then the resultant embryo will necessarily carry these genetic changes in all its cells—including its sperm and egg cells. The preliminary steps of this process can be tested without changing or manipulating an actual human embryo—and can thus safely skirt the moral boundaries of human embryo manipulation. Most critically, the process mimics the well-established protocols of IVF, in which a sperm and an egg are fertilized in vitro, and an early embryo is implanted into a woman's body—a procedure that raises few qualms.
This final challenge of altering cells that make sperm and egg was largely on its way to being solved exactly as Doudna, Charpentier, and other scientists were perfecting the systems to alter genomes. In the winter of 2014, a team of embryologists in Cambridge, England, and at the Weizmann Institute in Israel developed a system to make primordial germ cells—the precursors of sperm and eggs—out of human embryonic stem cells. The technique is still cumbersome and inefficient. Obviously, due to stringent restrictions in the creation of artificial human embryos, whether these spermlike and egglike cells can give rise to human embryos capable of normal development is yet unknown. But the basic derivation of cells capable of transmitting heredity has been achieved.
It is one thing to manipulate individual genes. It is quite another thing to manipulate entire genomes, which comprise the complete sets of any given creature's genetic material. In the 1980s and 1990s, DNA-sequencing and gene-cloning technology allowed scientists to understand and manipulate genes and thereby control the biology of cells with extraordinary dexterity. But the manipulation of genomes in their native context, particularly in embryonic cells or germ cells, opens the door to a vastly more powerful technology. What is at stake is no longer a cell, but an organism—ourselves.
Under what circumstances can we alter genes in human egg cells, sperm or embryonic cells? Would the woman with the BRCA-1 gene mutation be justified in seeking to edit that gene in her egg cells, say? The report, authored by an international panel of scientists, ethicists and advocates and published last week, sets out to answer these questions. The report thoughtfully divides the arena of human genome editing into four categories.
The first involves the use of gene editing as a tool to study biological problems. This, of course, is the most permissible application: A cancer biologist could choose to edit the BRCA-1 gene in cells in her lab to study how and why this mutation functions to increase cancer risk. Although concerns about the biosafety of such applications have to be continuously addressed—there is a fear that a gene-edited microorganism or plant might contaminate the biosphere—the report proposes no severe restrictions to the use of gene editing in laboratory settings.
The second application involves the use of gene editing in human cells other than sperm or egg cells, i.e., genetic manipulations that cannot be transmitted from one human to another. The report urges caution here; such genetic manipulations could have unintended consequences, such as increasing the risks of cancer in the gene-manipulated cells. Despite these risks, human trials with gene editing cells, such as blood cells or muscle cells, are already in progress or being planned, especially for genetic diseases where few medical options are available (think of the boy born with a genetic illness that caused such severe immune deficiency that he was forced to spend his life in a medical bubble, or men and women with blood clotting disorders who experience recalcitrant bleeding episodes). Genetic interventions in blood stem cells might allow such patients to be relieved of their illnesses.
It's the third potential application of gene editing that raises tricky conundrums. Should gene editing be used to change genes in eggs, sperm or embryonic cells—that is, in tissues where such changes would become permanently and heritably changed? Here, the stakes are obviously higher:
Because germline genome edits would be heritable, their effects could be multigenerational. As a result, both the potential benefits and the potential harms could be multiplied. In addition, the notion of intentional germline genetic alteration has occasioned significant debate about the wisdom and appropriateness of this form of human intervention, and speculation about possible cultural effects of the technology ... these include concerns about diminishing the dignity of humans and respect for their variety; failing to appreciate the importance of the natural world; and a lack of humility about our wisdom and powers of control when altering that world or the people within it.
Under what circumstances might we permit germline gene editing? The report proposes the following regulatory guidelines. Gene editing of embryos, sperm and egg cells might be permissible, it argues, if:
1) There are no other "reasonable alternatives"—i.e., the disease or condition cannot be otherwise treated or prevented reasonably.
2) The gene(s) being altered result in "a serious disease or condition";
3) The genes have been "convincingly demonstrated to cause or to strongly predispose to that disease or condition."
The fourth and final category of applications considered by the report involves gene editing not for serious diseases and conditions, but for human enhancement. What about the use of gene editing to enhance height? Or increase muscle mass? How about using gene editing to enhance "intelligence" (whatever that term might mean), or athletic ability?
Enhancement is not an easy term to define or understand. "Enhancements may range from the mundane, such as cosmetic changes in hair color; to the more physically interventionist, such as elective cosmetic surgery; to the more dangerous and problematic, such as the use of some steroids and other drugs among athletes in competitive settings. Enhancement is commonly understood to refer to changes that alter what is 'normal,' whether for humans as a whole or for a particular individual prior to enhancement. The question of what is meant by normal then arises.
Is it average? Is it whatever nature has prescribed? Is it whatever luck has wrought? Given the wide range of capabilities exhibited by humans for any particular trait, there is little basis for deeming any one condition normal or any meaningful value in determining an average. Nonetheless, there have been some attempts to describe the range of conditions that, given the right environment, are consistent with an ability to appreciate life and participate in the world."
The report draws a firm line against the use of gene editing for human enhancement. It argues:
1. "Regulatory agencies should not at this time authorize clinical trials of somatic or germline genome editing for purposes other than treatment or prevention of disease or disability.
2. Government bodies should encourage public discussion and policy debate regarding governance of somatic human genome editing for purposes other than treatment or prevention of disease or disability."
So what of the woman with the BRCA-1 mutation? Under the proposed guidelines, a genetic intervention on her eggs would not be easy to justify.
To justify genetically editing the mutant BRCA-1 gene from her eggs or embryos, she would have to prove (1) that the disease caused by the mutation (breast cancer) involved extraordinary suffering (2) that there were no other medical alternatives available (3) that the link between the gene and the disease was absolute.
In the case of BRCA-1, there can be little doubt about the extraordinary suffering caused by the disease. But the second and third clauses—the absence of a justifiable alternative, and the link between the gene and the disease—are much more nebulous. She could, in principle, use prenatal genetic diagnosis (PGD) to test her eggs or her embryos, and thereby selectively conceive a child lacking the BRCA-1 mutation.
Further, current preventative therapies for breast cancer, such as a dual mastectomy or hormonal treatment, do exist (though they are clearly invasive, disfiguring and toxic). And while the lifetime risk of cancer for a woman carrying a BRCA-1 mutation may reach 60 percent, it is hard to predict which woman will be diagnosed with cancer.
This pattern, I fear, will be representative of many human diseases, and will interpose some of the most difficult questions for the future of gene editing applications. Most human diseases are not influenced or controlled by single gene variants, and yet some gene variants are strongly linked to the disease. The link between the gene mutation and the disease may not be absolute or predictable, yet the presence of the mutation increases risk substantially. And while current therapies exist for some of these diseases, they are toxic, marginally effective and unpredictable. The report attempts to draw strict boundaries against genetically intervening on such illnesses. But future debates on gene editing in embryos, sperm and eggs will inevitably return to these contentious boundaries—and to personal conundrums faced by this woman with the BRCA-1 gene mutation.
Portions of the above were excerpted from THE GENE: An Intimate History (Scribner 2016).
Update 2/26/17: an earlier version of this story misrepresented the risks of inheriting a mutated gene. The figures have since been corrected.