When humans began selectively breeding plants and animals thousands of years ago, they effectively blurred the lines between natural and artificial selection, and took the first steps into the world of genetic modification.
Technology has brought us a long way since those primitive days. A great leap was made in the 1950s with the discovery of the double-helix structure of DNA and the first attempts at gene editing to alter traits.
The next monumental breakthrough was in 2012, when scientists stumbled upon a new way to influence evolution. Called CRISPR, or “clustered regularly interspaced short palindromic repeats”, the technology is a powerful tool for editing genomes. It allows scientists to fix DNA segments, as easily as correcting an error in an article.
It is a tool that bacteria have been using for aeons. To protect itself from an invading virus, a bacteria will use what’s called a “Cas protein” to cut a part of the virus’ DNA and stitch it into the bacteria’s CRISPR region (a set of repeating patterns). This scissor and glue mechanism creates a memory of the infection, which is used to hunt around if the infection tries to sneak in again.
The CRISPR breakthrough won its discoverers the Nobel Prize in 2020. But in the wider community, it has set off anxieties about the unscripted rules of the technology. In the minds of many, it conjures images of test tube babies and eugenics – a coming to life of Brave New World and Gattaca.
One of the few researchers in India working on the human applications of CRISPR is Debojyoti Chakraborty. A senior scientist at the CSIR-Institute of Genomics and Integrative Biology in Delhi, he and his colleagues created a CRISPR-based Covid-19 diagnostic test called FELUDA in 2020.
Chakraborty spoke at length about his research, a potential “gene gap” determined by wealth, and DNA being the next silicon. Edited excerpts from the interview:
Can you describe your research?
We are trying to improve CRISPR [in partnership with Souvik Maiti’s lab at the CSIR Institute of Genomics and Integrative Biology] so that it becomes therapeutically relevant.
We are working towards getting one of the first gene-editing therapeutic applications in India for treatment of diseases, such as sickle cell anaemia. That’s the long-term goal [and] we have made quite significant strides in that direction... We are currently moving towards preclinical studies and [after that] we should be able to recruit the first clinical trial patients in the next couple of years.
There’s currently a safety concern with CRISPR in therapy. When we target a specific place in the DNA, we could end up hitting other parts of the DNA. There are a lot of people around the world working on this problem, apart from us. Our approach is to use a different type of protein that we found had particular properties to make it even more specific in targeting.
During our research, one of the things we found is that, because of its specificity, we can use CRISPR for diagnostics as well, which is where the FELUDA CRISPR diagnostics test for Covid-19 came from.
What do you see as the biggest potential of CRISPR? What are some other fields we will see it in?
We once thought that we are a product of our genes and there is no way to change it. We thought what we are born with, we will have to live with. But in the next 20 to 30 years, we are going to see a lot of diseases cured completely – things that were unthinkable. That’s the power of genetic engineering.
The applications [of genetic engineering] are quite diverse and heterogeneous. It is used in terms of modelling disease in cells and tissues and organ systems on a plate. Earlier, we were not able to study the disease outside the body of an individual.
You can also make decision trees inside living systems using CRISPR. You could, say, make a cell know that it has a cancer-causing mutation and then take a decision that might eliminate it. This would potentially auto-regulate things inside the body. We have started some work on this. We will see how it goes.
One of the major fields [where genetic engineering is being used] is food products and crops – [for instance, in] increasing certain beneficial vitamins in them. We can fortify bananas with Vitamin A or improve livestock. Some scientists are working to create sterile mosquitoes.
Another big field in the next four to five years will be to edit not just the DNA but also the RNA. A lot of diseases are caused by faulty RNA. Across the world, there are a lot of crazy applications too. [Harvard geneticist] George Church is trying to bring a woolly mammoth back to life, for example.
But the actual question is – of course, we will be able to do it – but who will be able to afford it and to what extent does this impact the stability and power structures across the globe. These are the deeper moral, ethical questions that we have to ask.
On that subject, what sort of “gene gap” will be created by the wealth gap?
CRISPR is very promising, but it can be very expensive and get limited to those who can afford it. For India and those parts of the world that are not lucky to have good healthcare, we must strive for more frugal innovations that don’t compromise on safety or efficacy. This needs to be emphasised at the level of policy-making and funding as well.
Could this potentially affect the diversity of the human genome overall?
At this point, we are talking about a single gene or a small set of genes that make the difference between a healthy individual and one with a disease. A change in the gene in an organism would get passed on to the offspring. So, if we are trying to eliminate a disease in the population, this would be beneficial.
But, yes, I do agree that the unintended changes happening in the genome need more and more studies with analyses of genetic data to create a clear picture. Unfortunately, that can only be done on a long-term scale – only then do you realise some of the unintended changes.
Right now, when a parent asks for a few more years for their child, they don’t want a line to be drawn. The benefits far outweigh the risks at this moment.
Speaking of ethical questions, a Chinese scientist was reprimanded a few years ago for making edits to a human embryo. Do you think there should be a global pause on this use of the technology?
There is strong consensus among scientists around the world regarding embryo research.
One, we do not know the full extent of the safety and efficacy of CRISPR editing. We are only scratching the surface. When we send a protein inside a cell and say it should break a DNA or change it, we assume that it is doing its job perfectly. But there is more and more evidence that, just like every drug has an off-target, every CRISPR intervention too has off-targets.
When we change the embryo, we are not certain about the entire spectrum of changes happening in it. This is ethically wrong because the embryo didn’t get a chance to voice his or her opinion. It is also medically incorrect to do something whose full extent of therapeutic outcome we do not know. In the case of the Chinese experiment, it was a preventive measure for HIV, but it did not consider other diseases that it could make the embryo susceptible to.
Secondly, there are diseases that can be cured in an individual with CRISPR technology. We talk to parents all the time who want CRISPR to save their child who has a deadly disease. These cases should be prioritised over implementing things we are unsure of. Medical interventions targeting diseases in individuals should take the front seat.
Where does India stand in the field of gene editing and, more specifically, the use of CRISPR? What is some of the most interesting research happening in the country? Is it mostly government-funded?
When it comes to genome editing, we are kind of in the infancy. Although the funding for biology in general has been steadily growing, we have not had a long time with a lot of investment in infrastructure. Research in gene editing is not so abundant and it’s not increasing very fast, but it is growing steadily.
For CRISPR as well, not much has been done in India. The majority of institutions in the field are government-funded. Start-ups have only just started showing interest in CRISPR. I have talked to several people in the last couple of years who have become interested. I think the Covid-19 diagnostics test and the hype surrounding the Nobel Prize for CRISPR got many more people interested. Still, it’s in its infancy here compared to the Bay Area, where the majority of CRISPR companies, funded with venture capital, have sprung up. Of course, our Covid-19 diagnostic test was created in partnership with Tata Medical and Diagnostics Ltd, so there are public-private partnerships like that.
We have also seen plant biotechnology applications and use of CRISPR for basic biology questions in India. At the Institute of Genomics and Integrative Biology, Sivaprakash Ramalingam’s lab does basic biology work and application-driven work on β-thalassemia [a hereditary blood disorder] and hemoglobinopathies [a group of disorders involving abnormal haemoglobin production]. Scientists at Christian Medical College are working on similar diseases.
What do you think of India’s draft gene-editing rules that were made public last year? Has there been enough engagement between scientists and policymakers?
It is an instance of forward-thinking policy-making that engaged with multiple stakeholders. Most of the committees [on the subject] have several scientists. We are one of the few countries to have proactively started discussing and implementing policies.
But because the field moves so fast, the legislation and guidelines also need to move fast. We are living in an era where information is getting processed and improved at a rapid pace. The legislation must keep up with this progress.
Until we put CRISPR in the public domain, we won’t really be able to see where the legislation comes in conflict. We need to ensure that people can benefit from CRISPR.
You mentioned specificity. What else needs to be improved in CRISPR?
The major improvement would be in terms of specificity. That said, another major roadblock is the actual delivery of CRISPR into the human cell and body. A lot of work is going on here. We know we can do it in a lab, but how do we put it into a human? You don’t just put DNA in a human – you have to package it into a vehicle sent in a targeted manner to the damaged organ and tissue. Improvement on this front will be the major research over the next four-five years. Another improvement would be to have CRISPR do more diverse things to modify the genome – so single-based changes or a few alphabets of the DNA changed and so on…
Are there any efforts to make an at-home version of FELUDA? What is the current use of the test?
We had shown a prototype that could potentially do the test at home, but very few would be able to take it beyond the major cities. We haven’t been able to come up with an absolutely simple solution that anyone with no prior training can use at home and so it’s not going to be adaptable in India.
TataMD CHECK, the commercial FELUDA kit, is available at diagnostic centres and now there are mobile vans with robotic platform that can take it to the difficult-to-reach places where RT-PCR test is inaccessible. Recently, it was made available in Manipur.
A scientist made the prediction that what silicon was to the last era, DNA will be to the next. He was working to encode data into DNA as a potential storage mechanism to replace our power-guzzling data centres. Interestingly, genetic sequencing is getter cheaper at a faster rate than that computing. What do you think about DNA being at the centre of a new age?
Yes, I do think it has a lot of applications in terms of data coding and storage retrieval. There is no doubt about it. If you can encode any data into the letters of DNA (A, T, G and C) and find a way to read it back from a genome, then it is a powerful method. The pioneers of encoding data into DNA, like George Church, have shown that you can code data into small organisms like bacteria, which can be frozen and then made to grow in multiple rounds of fast replication. So you copy and paste and propagate data very fast.
Anything you would like to add?
It’s true that what silicon was to the IT industry, CRISPR is to the medical field. It has opened a plethora of applications. But with science moving fast, dialogue with people is essential. The common man should be made more aware.
The controversy surrounding genetically-modified organisms has not been good for the field. [That is because] in the past, there wasn’t always an open discussion or dialogue based on evidence and research. This should not happen in the case of gene editing. Of course, a genetically-modified organism is not the same as a gene-edited organism. [The former involves introducing new DNA into an organism, while the latter involves removing a mutation.] These differences, the safety of gene editing and what it can do should be discussed in light of evidence and science. Otherwise, we will fall behind other countries that have a more forward-thinking approach.
Karishma Mehrotra is an independent journalist. She is a Kalpalata Fellow for Technology Writings for 2021.
