The Gene: An Intimate History
Penguin Books India
IT IS one thing to manipulate genes. It is quite another thing to manipulate genomes. 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.
In the spring of 1939, Albert Einstein, mulling over recent advances in nuclear physics in his study at Princeton University, realized that every step required to achieve the creation of an unfathomably powerful weapon had been individually completed. The isolation of uranium, nuclear fission, the chain reaction, the buffering of the reaction, and its controlled release in a chamber had all fallen into place. All that was required was sequence: if you strung these reactions together in order, you obtained an atomic bomb. In 1972, at Stanford, Paul Berg stared at bands of DNA on a gel and found himself at a similar juncture. The cutting and pasting of genes, the creation of chimeras, and the introduction of these gene chimeras into bacterial and mammalian cells allowed scientists to engineer genetic hybrids between humans and viruses. All that was needed was the threading of these reactions into a sequence.
We are at a similar moment—a quickening—for human genome engineering. Consider the following steps in sequence: (a) the derivation of a true human embryonic stem cell (capable of forming sperm and eggs); (b) a method to create reliable, intentional genetic modifications in that cell line; (c) the directed conversion of that gene-modified stem cell into human sperm and eggs; (d) the production of human embryos from these modified sperm and eggs by IVF . . . and you arrive, rather effortlessly, at genetically modified humans.
There is no sleight of hand here; each of the steps lies within the reach of current technology. Of course, much remains unexplored: Can every gene be efficiently altered? What are the collateral effects of such alterations? Will the sperm and egg cells formed from ES cells truly generate functional human embryos? Many, many minor technical hurdles remain. But the pivotal pieces of the jigsaw puzzle have fallen into place.
Predictably, each of these steps is currently barricaded by strict regulations and bans. In 2009, after a prolonged ban on federally funded research on ES cells, the Obama administration lifted the injunction on the derivation of new ES cells in the United States. But even with the new regulations, the NIH categorically prohibits two kinds of research on human ES cells. First, scientists are not permitted to introduce these cells into humans or animals to enable their development into live embryos. And second, genome modifications on ES cells cannot be performed in circumstances that “might be transmitted into the germline”—i.e., into sperm or egg cells.
In the spring of 2015, as I completed this book, a group of scientists, including Jennifer Doudna and David Baltimore, issued a joint statement seeking a moratorium on the use of gene-editing and gene-altering technologies in the clinical setting, and particularly in human ES cells. “The possibility of human germline engineering has long been a source of excitement and unease among the general public, especially in light of concerns about initiating a ‘slippery slope’ from disease-curing applications toward uses with less compelling or even troubling implications,” the moratorium reads. “A key point of discussion is whether the treatment or cure of severe diseases in humans would be a responsible use of genome engineering, and if so, under what circumstances. For example, would it be appropriate to use the technology to change a disease-causing genetic mutation to a sequence more typical among healthy people? Even this seemingly straightforward scenario raises serious concerns . . . because there are limits to our knowledge of human genetics, gene-environment interactions, and the pathways of disease.”
Many scientists find the call for a moratorium understandable, even necessary. “Gene editing,” the stem cell biologist George Daley noted, “raises the most fundamental of issues about how we are going to view our humanity in the future and whether we are going to take the dramatic step of modifying our own germ line and in a sense take control of our genetic destiny, which raises enormous peril for humanity.”
The crux, then, is not genetic emancipation (freedom from the bounds of hereditary illnesses), but genetic enhancement (freedom from the current boundaries of form and fate encoded by the human genome). The distinction between the two is the fragile pivot on which the future of genome editing whirls. If one man’s illness is another man’s normalcy, as this history teaches us, then one person’s understanding of enhancement may be another’s conception of emancipation (“why not make ourselves a little better?” as Watson asks).
But can humans responsibly “enhance” our own genomes? What are the consequences of augmenting the natural information encoded by our genes? Can we make our genomes a “little better” without risking the possibility of making ourselves substantially worse?
In the spring of 2015, a laboratory in China announced that it had casually crossed the barricade. At the Sun Yat-sen University in Guangzhou, a team led by Junjiu Huang obtained eighty-six human embryos from an IVF clinic and tried to use the CRISPR/Cas9 system to correct a gene responsible for a common blood disorder (only embryos that were non-viable in the long term were chosen). Seventy-one embryos survived. Of the fifty-four embryos tested, only four were found to have the corrected gene inserted. More portentously, the system was found to have inaccuracies: in one-third of all the embryos tested, unintentional mutations in other genes were also introduced, including mutations in genes essential for normal development and survival. The experiment was stopped.
It was a daring, if slapdash, experiment, meant to provoke a response—and it did. Around the world, scientists reacted to the attempted modification of a human embryo with extreme anguish and concern. The highest-ranking scientific journals, including Nature, Cell, and Science, refused to publish the results, citing broad violations of safety and ethical concerns (the results were eventually published in a scarcely read online journal, Protein + Cell). Yet, even as they read the study with apprehension and horror, biologists already knew that this was just the first step past the breach point. The Chinese researchers had taken the shortest route to permanent human genome engineering, and predictably, the embryos had been littered with unforeseen mutations. But the technique could be modified with multiple variations to make it potentially more efficient and accurate. If embryonic stem cells, and stem-cell-derived sperm and eggs, had been used, for instance, these cells could have been screened up front to cull away any deleterious mutations, and the efficiency of gene targeting might have been greatly increased.
Junjiu Huang told a journalist that he was “planning to decrease the number of off-target mutations [using] different strategies—tweaking the enzymes to guide them more precisely to the desired spot, introducing the enzymes in a different format that could help to regulate their lifespans and thus allow them to be shut down before mutations accumulate.” In a few months, he hoped to attempt another variation of the experiment—this time, he expected, with much higher efficiency and fidelity. He was not exaggerating: the technology to modify the genome of a human embryo may be complex, inefficient, and inaccurate—but it does not lie out of scientific reach.
While scientists in the West continue to watch Junjiu Huang’s experiments on human embryos with justified apprehension, Chinese scientists are far more sanguine about such experiments. “I don’t think China wants to take a moratorium,” one scientist reported in the New York Times in late June 2015. A Chinese bioethicist clarified, “Confucian thinking says someone becomes a person after they are born. That is different from the United States and other countries with a Christian influence, where because of religion they may feel research on embryos is not okay. Our ‘red line’ here is that you can only experiment on embryos that are younger than fourteen days old.”
Another scientist wrote of the Chinese approach, “Do first, think later.” Several public commentators seemed to agree with this strategy; in the comments section of the New York Times, readers advocated lifting the bans on human genomic engineering and urged a ramp-up in experimentation in the West, in part to remain competitive with the efforts in Asia. The Chinese experiments had evidently raised the stakes throughout the world. As one writer put it, “If we don’t do this work, China will.” The drive to change the genome of a human embryo has turned into an intercontinental arms race.
As of this writing, four other groups in China are reportedly working on introducing permanent mutations in human embryos. By the time this book is published, I would not be surprised if the first successful targeted genome modification of a human embryo had been achieved in a laboratory. The first “post-genomic” human might be on his or her way to being born.
Excerpted with permission from
Penguin Books India