The Gene: An Intimate History

Gene therapy may have repeatedly run into the roadblocks of ethics and feasibility, but the field of genetic diagnosis seems safer. However, Mukherjee questions the notion that genetic diagnosis is always ethical and useful. The applications of genetic diagnosis become particularly murky when it comes to diseases of a polygenic (influenced by many genes) nature. A case in point is the BRCA1 gene associated with breast and ovarian cancer. Geneticist Mary-Claire King identified the gene during the 1980s while studying women with a family history of the cancers. King found the cancers recurring across generations, with 30 women affected in one family of 150 members.

Over the next decade, it was obvious that the BRCA1 mutation led to an 80% lifetime risk of breast cancer. The gene could be detected by taking a swab of cells from a woman at risk, and cloning the genetic material through PCR technology (polymerase chain reaction, the same technology used in Covid tests). The millions of copies made it easy to detect the gene. However, the conundrum with BRCA1 testing is that despite the diagnosis of risk, it is impossible to say which woman will develop breast cancer. It is also yet impossible to predict the age at which the disease will develop, or its severity. This makes the preventive treatment for breast cancer—typically a double mastectomy and possible removal of ovaries—a fraught choice. For women who adopt a wait-and-see approach to cancer, the constant testing and worrying becomes all-consuming. The term for people who know of their risks for serious disease is previvors or pre-survivors.

Questions around genetic diagnosis have intensified with the widespread use of preimplantation genetic diagnosis (PGD) in IVF, where cells can be removed from early-stage embryos and tested for chromosomal normalcy. Only embryos which are chromosomally normal are then implanted in the uterus. PGD is a very useful tool when it comes to conditions like Huntington’s Disease or Trisomy 18, but also enters grey areas. In India, for instance, PGD was used to detect sex in embryos to choose only males for implantation, till the government banned PGD for gender selection. The dangers of PGD are that it can potentially be used to select embryos for traits like eye color, leading to Gattaca-like scenarios.

Despite hiccups, the field of gene therapy had been growing since the 2000s, the tools used in Jesse Gelsinger’s trial replaced by next-gen technologies. In 2014, scientists successfully used gene therapy to treat hemophilia. Similar therapies may also be developed for diseases caused by single gene mutation, such as cystic fibrosis.

Around the same time, a major discovery changed the field of human genetics forever. The discovery was the continuation of Paul Berg’s idea of using a bacteria’s mechanism for “cutting” a virus to insert genes in viral DNA. In the mid-2000s, French scientists Phillipe Horvath and Rodolphe Brangou isolated the cutting function to the bacterial enzyme Cas9. Biochemist Jennifer Doudna and bacteriologist Emmanuelle Charpentier seized on the Cas9 protein as a method to make an “intentional cut” in gene therapy. If a synthetic RNA (designed to match a specific DNA sequence) could be attached to a Cas9 protein and injected in cells, the Cas9 would cut the DNA sequence. As the cell’s natural repair and cloning mechanism kicked in place, it would also unwittingly copy the DNA sequence carried in the infusion, effectively replacing the old sequence with the new. Essentially, Cas9 gene therapy, called CRISPR, can be used to edit a mutated gene to its normal version, by cutting out the wild-type base in a sequence and replacing it with the regular type.

Mukherjee deems the Cas9/CRISP system the most powerful and efficient gene-altering method to date (in 2020, four years after The Gene was first published, Doudna and Charpentier won the Nobel Prize for their discovery). Nevertheless, in 2015, Doudna herself was part of a group that called for a moratorium on gene-editing technology, following fears it could be used to permanently introduce mutations in embryos. Such projects are ongoing in China at the time Mukherjee writes the book, leading him to believe that soon the “first successful targeted genomic modification of a human embryo” would be achieved in a lab.

To ensure the ethical use of gene-editing in germline cells, what is required is a “manifesto—or […] a hitchhiker’s guide—for a post-genomic world” (479). Mukherjee provides 13 suggested guidelines, the most important of which is that genetic selection should only be practiced in cases where an organism’s genetic make-up is exceptionally mismatched with their environment, as in the case of chromosomal disorders linked with very poor quality of life.

If abhed, the term Mukherjee’s father used for genes, means indivisible, bhed, its antonym, means to divide, pierce, and cure. Mukherjee depicts the relationship between genes and scientists as strung along the bhed-abhed axis: Scientists try to pierce what is deemed impenetrable. In this search, they must be guided by three enormous projects that are the remit of human genetics. The first is the complete understanding of the human genome, as even though the genome has been sequenced, very few genes have been understood completely. A deep understanding of the genome will enable scientists and doctors to better unpack the mechanism behind diseases with polygenic roots.

The second is using the knowledge of genes to create a computational map of possible phenotypes, thus heightening the predictive power of the human genome. The third is the ethical use of gene-editing technologies in germ cells and embryos. In all these pursuits, science must be guided by the contradictory nature of genetics: Genes are meant to replicate, yet it is their ability to mutate that drives evolution. Genetics must aim to alleviate suffering while preserving the variable traits that make people human.