The gene-editing tool CRISPR Cas9 became a talking point among biologists after He Jiankui, a Chinese researcher, announced he had edited the genomes of two babies in November. In a YouTube video, Jiankui explained he had cut the CCR5 gene out to make them resistant to HIV. The episode set off a furore in the international biologists community.
The genetic editing of human embryos is banned in most of the world. This is partly because scientists are still learning how to use CRISPR to do this.
“CRISPR has certainly made gene-editing easier, but the strategy is not entirely foolproof and may sometimes introduce mistakes at unintended positions” of the genome, Debojyoti Chakraborty, a scientist at the Institute of Genomics and Integrative Biology, New Delhi, told The Wire. What these off-target changes could cause remains uncharted territory.
Sonam Mehrotra, a scientist at the Advanced Centre for Treatment, Research and Education in Cancer, Mumbai, said, “From practical experience, I can tell you that the outcome of CRISPR varies between cases.” Mehrotra uses CRISPR to deliberately introduce mutations in fruit flies (Drosophila melanogaster). Given the vagaries of working with flies, whose genomes are much smaller, she thinks it’s way too early to edit human embryos.
However, both Mehrotra and Chakraborty agree CRISPR has a lot of potential to treat genetic disorders.
The human genome is a long sentence composed of four alphabets: A, T, G and C. Sometimes, when a wrong alphabet appears in a given position in the sentence, it could cause a genetic disease. Armed with CRISPR, scientists are learning how they can correct these mistakes by editing the faulty part.
This is the opposite of what Jiankui did. The embryos he edited didn’t have any genetic errors that made them susceptible to HIV. Instead, Jiankui modified the sequence of letters such that the newborn twins were “ resistant to HIV,” Chakraborty explained. ‘This kind of preventive medicine is not what scientists are aiming for, especially now, while we are still trying to understand CRISPR biology.”
This rather questionable use of CRISPR has since sparked a dialogue on human gene-editing regulations.
Tinkering with genetic material is a sensitive issue because it impinges on one’s identity. At present, there is an international moratorium on the genetic editing of human embryos for reproductive purposes. The practice has even denounced by China’s medical board; it only permits the editing of human embryos less than 14 days old.
In India, the ethical guidelines of the Indian Council of Medical Research (ICMR) disallow any research related to germline genetic engineering or reproductive cloning. But editing the genomes of adult human cells is permissible subject to approval by an ethics committee.
In administrative terms, “we have three levels of regulation,” S.R Rao, senior advisor to the Department of Biotechnology, said at a talk at the second International Summit on Human Genome Editing. It was held in Hong Kong in the last week of November 2018, and counted Jiankui among its participants.
At the first level, an institutional ethical committee screens all proposed projects. The approved ones are then assessed by a risk evaluation body of the Department of Biotechnology. In cases where there could be risks to the environment, the project may require an ‘okay’ from the environment ministry as well.
All clinical trials involving genetic engineering products come under the Drugs and Cosmetics Act, 1940.
Thus far, this labyrinthine process has not deterred scientists from exploring CRISPR as a treatment option for genetic disorders. Many Indian scientists edit the human genome in cells obtained from their patients. Their biggest focus area is developing a therapy for blood disorders due to defects in single genes.
This form of genetic editing is distinct from embryonic editing because it involves adult patient cells, not germ cells. The problem with editing the DNA of embryos is that both somatic and germ cells will carry the mutation, and the edited DNA will be passed on hereditarily.
But when working with adult cells – such as blood cells from patients – CRISPR can be used to correct mutations in the lab. And since the technique is patient-specific, any alterations made in the genome remain confined to one individual and won’t affect the next generation.
In that sense, CRISPR presents a lot of opportunities. China realised this early and eased regulations. And so far, Chinese scientists have used CRISPR to edit the genes of monkeys, human embryos less than 14 days old and are currently testing CRISPR-based therapies in cancer patients.
Things are moving in the US as well. American scientists having embarked on CRISPR-related clinical trials, with the country’s Food and Drug Administration keeping a close watch.
India is yet to start.
At the moment, scientists like Chakraborty are testing proof-of-concept studies in the lab, where he and his colleagues attempt to correct mutations in human blood cells. The next step is to test the technique in animal models, and then begin human trials. The timeline hasn’t been finalised, however.
“Technically, genome editing is not a challenge,” Chakraborty said. But one of CRISPR’s bigger caveats is that one size doesn’t fit all. “The outcome of CRISPR-based therapies will differ from one cell to another, from one gene to another and even from one delivery agent to another,” Chakraborty said. So each clinical trial will have to seek approval on a case-by-case basis. This does suggest officials will pay each proposal the attention it deserves – but it still also falls short.
What India really needs, and lacks at the moment, is a proper framework to regulate CRISPR-based clinical trials. There has been a lot of talk about the need for new policies “but India is unlikely to go the China way in hurrying things up,” Deepti Trivedi, a scientific officer at the National Centre for Biological Sciences, Bengaluru, told The Wire.
Mehrotra is particularly worried about how Jiankui’s brazen foot forward may affect the future of CRISPR Cas9. “If a handful of researchers continue these reckless acts, governments may impose stringent regulations on the use of CRISPR.” This has already happened with stem cells: fearing rampant malpractice, the ICMR banned the use of stem cell technology in 2017 and limited access to them.
Jiankui’s actions prompted a sharp response from the Chinese government. It launched an investigation into his work, his university suspended him and he might be under house arrest. At the same time, scientists rallied to plan a gene-editing meeting in Massachusetts this year, where social scientists and geneticists will discuss the technology’s central issues.
Notwithstanding whether Indian scientists are going to be part of this conversation, Chakraborty believes something similar – “a dialogue between scientists and policymakers” – needs to happen in India. If it doesn’t, this path-breaking tech might never leave the pharmaceutical fringes it currently occupies.