Wednesday, March 1, 2017

Now That We Can Alter Our Genetic Code, Should We?

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. (...)

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. 

by Siddhartha Mukherjee, Tonic |  Read more:
Image: Kitron Neuschatz