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, realised 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” – ie, 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.” In many ways, the proposed scheme of restrictions is reminiscent of the Asilomar moratorium. It seeks to limit the use of technology until the ethical, political, social, and legal implications of the technology can be ascertained. It calls for a public appraisal of the science and its future. It is also a frank acknowledgment of how tantalisingly close we are to making embryos with permanently altered human genomes. “It is very clear that people will try to do gene editing in humans,” Rudolf Jaenisch, the MIT biologist who created the first mouse embryos from ES cells, said. “We need some principled agreement that we want to enhance humans in this way or we don’t.”
The word to watch in that last sentence is “enhance”, for it signals a radical departure from the conventional limits of genomic engineering.
Prior to the invention of genome-editing technologies, techniques such as embryo selection allowed us to cull information away from the human genome: by selecting embryos via preimplantation genetic diagnosis (PGD), the Huntington’s disease mutation, or the cystic fibrosis mutation, could be eliminated from a particular family’s lineage.
CRISPR/Cas9-based genomic engineering, in contrast, allows us to add information to the genome: a gene can be changed in an intentional manner, and new genetic code can be written into the human genome. “This reality means that germline manipulation would largely be justified by attempts to ‘improve ourselves,’” Francis Collins wrote to me. “That means that someone is empowered to decide what an ‘improvement’ is. Anyone contemplating such action should be aware of their hubris.”
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?
Excerpted with permission from The Gene: An Intimate History, Siddhartha Mukherjee, Allen Lane.
