Revolutionary new gene editing methods are transforming the world of biotechnology. India must not allow regulatory confusions and Luddite activism to deny itself the benefits
A group of modern gene-splicing techniques that are making headlines around the world are “gene editing” methods that have the unique ability to delete undesirable genes in a highly precise manner. Simply put, bad genes can be removed. Scientists can snip off unwanted sequences of DNA from the genome, the total gene pool of an organism, just like a film editor or a copy editor can erase erroneous or unwanted scenes or lines.
As much as this has excited scientists about all sorts of possibilities to cure human, plant and animal ailments, the Luddites are as usual clamouring to raise hell. The German Biotech Risk Assessment agency (BVL) has already declared the first genome-edited herbicide-resistant canola (rapeseed) developed by a biotech company CIBUS, to be a non-genetically modified organism (GMO) for the purposes of providing regulatory oversight within the meaning of its Genetic Engineering Act. It has allowed the company to go ahead with field testing without any permission needed from the authorities. It is highly likely that other biotech regulatory agencies will follow the German decision.
The technology used by CIBUS to develop the canola is called Rapid Trait Development System (RTDS). The company’s scientists introduced “gene repair oligonucleotides” (GRONs) to knock out genes or alter existing sequences (equivalent to gene mutations), and then quickly dissolved the GRONs, so no new DNA sequence was added.
This means the product of the gene editing technology cannot be classified as transgenic or genetically modified as per most legal definitions of genetic engineering used by regulatory agencies.
This is a fine example of how regulations cannot keep pace with the rapidly advancing field of modern biotechnology and genetic engineering. Currently, most countries define GMOs or transgenics based on the introduction of an alien sequence of DNA. For example, the Bt gene in Bt cotton. But the new advanced method of plant breeding does not lead to a conventionally defined GMO, and therefore, does not trigger any regulatory oversight.
What has been happening with biotech regulations all these years is that the process or the method by which the GMO was derived was used as a regulatory criterion, irrespective of the nature of the resulting organism. The classical debate about process vs product comes to the fore again. All right-minded scientists have argued that it is the nature of the GMO and its impact on the environment that one should worry about, and not the method by which it was produced. But, politically-minded environmental activists have ganged up all over the world to force governments to regulate the process, and have even forced a regulatory definition of what a GMO is, not realizing how the technology will develop in the future.
Scientists knew better, and kept warning governments to not overreach on regulations, but it all fell on deaf years. Scientists are dismayed and activists are celebrating. Take for example, the CIBUS herbicide-tolerant canola. It could have been developed by many other methods and, indeed, one of the most common methods by which such plants could be obtained in the pre-genetic engineering era (less than 30 years ago) was by tissue culture.
Many tissue culture or mutagenized herbicide-resistant varieties of crop plants and vegetables are already around without any regulations, but if you get the same plant using gene splicing technology, it becomes regulated. That is how all sorts of woolly-headed questions about the socio-economic benefits of herbicide -resistant crops have come to the fore without any end in sight.
Not that socio-economic questions are not important. They are important for a category of plants depending on the nature of the problems associated with weeding. Right now, finding agricultural labour is becoming very difficult in India. So the manual labour used to handle weed fields is not possible. Today’s Indian farmer needs modern technology to restrain weeds in an integrated management process. Weeds are causing almost 40 per cent of yield loss in Indian agriculture and herbicide-resistant crops are urgently needed. But, the anti-GM lobby would have none of it.
All right-minded plant breeders routinely ask questions about the risks and benefits of their newly-bred varieties and hybrids. No one is so foolhardy as to release new varieties willy-nilly. Here, the whole idea of the Luddites is to strangulate modern biotechnology with regulations, whether or not it is beneficial to the farmer. They just want to sock it to biotech scientists for having built an industry based on modified living organisms. How dare they mess with nature, is the opprobrium. But, that is what both farmers and scientists have been doing for over 10,000 years in the name of improving agriculture.
The modern GMO (transgenic organism that expresses genes from another totally unrelated organism) has already become a classical technique like classical breeding with the advent of genome editing in 2006. This is nothing but targeted genome engineering. Zinc finger nucleases (ZFNs) are like molecular scissors that can cut DNA at specific sites (loci), and so do TAL effector nucleases (TALENs). Nucleases are enzymes that catalyze a chemical reaction in living cells. These techniques are complicated and involve laborious laboratory protocols due to the association of DNA binding proteins. However, now there is a new technique known as CRISPR/Cas9 (Clustered Regularly Interspaced
Short Palindromic Repeats/ CRISPR-associated) immune system.
Palindromic sequences are sequences of nucleotides denoted by the letters ATGC, which remain the same whether you read it from right to left or left to right. For example, the word “Malayalam”, the language of the state of Kerala, reads the same, forwards or backwards. With the CRISPR/Cas9 method of gene editing, the Cas9 nuclease and an engineered single-stranded guide RNA (sgRNA) specify a targeted DNA sequence, which is accomplished with relative ease compared with other methods of targeted gene editing.. The important staple crop rice’s genome has been altered using TALENs and CRISPR/Cas9, specifically deleting large chromosomal segments to derive desired characteristics in the plant. Other major cereals are also being tackled with the same gene editing techniques.
Already, the CRISPR-based biotech industry has a market capitalization of $100 billion and growing swiftly.
In case of animals, genome editing is applied for improving genomes adapted to local environment conditions that produce food more efficiently; improving animal models for studying human diseases which can provide reliable pre-clinical information to assess the safety of test drugs; and design to harbour patient-specific organs, tissues and cells for transplantation that will not induce adverse immune responses, like the immune rejection of transplantations.
The politics about gene editing techniques turned shrill when a group of Chinese scientists published a paper in April, showing how they tinkered (edited) the genome of an embryo. This sparked off a huge ethical debate that will rage on for decades to come. The overwhelming scientific consensus is that such modified embryos should not be allowed to come to term. There are still big critical questions about its efficacy, and the abundant caution is calling for an Asilomar-like conference on bioethics. The first meet at Asilomar (a conference centre in a state park in California) on gene splicing was held in 1975 and resulted in a voluntary code of conduct by the scientists, which eventually became the world famous recombinant DNA guidelines of the US National Institute of Health (NIH).
Today, there is no laboratory in the world employing gene-splicing techniques that does not follow these guidelines. The scientists met for a second time at Asilomar to take stock of the technologies in 2000. They were satisfied that by and large, the voluntary guidelines had been very effective and that a scientist can proceed with further research without too much of regulatory hindrance. This is an example to disprove the constant cry of the anti-technology activists that scientists don’t care, and do whatever they want by playing God.
In fact, it has always been scientists who have raised tough questions about what they are doing and trying to resolve the situation to keep it under control. It is the ignoramus activists who jump into the midst of the technology debate, completely politicize it, stoke anxiety among the public and force governments to regulate it.
This kind of activism will create nothing but technological haves and have-nots of the world. That means developing countries will always be struggling to play catch-up. These are nothing but anti-development and anti-national activities by some NGOs. Prime Minister Narendra Modi’s government’s cracking the whip on this mischief-making is really welcome. It is high time someone holds these NGOs accountable.
The US House Committee on Space, Science and Technology held a hearing on June 16 this year on human gene editing with Dr Jennifer Doudna of the University of California, Berkeley, inventor of CRISPR, and Victor Dzau, president of the Institute of Medicine. The major point of discussion was the “three-parent embryo” in which an egg cell’s diseased mitochondria was replaced by a second woman’s genetic material. The question was whether to allow such a procedure in the US. The regulator US-FDA has said that it has commissioned a report from the Institute of Medicine. It will make up its mind after reviewing that report, and certainly after more public discussions.
A House Appropriations Committee has not given any budget to FDA, so it cannot authorize any experiments with altered human embryos. No money, no game. Congress wants FDA to appoint an independent panel consisting of faith-based institutions and faith-based medical associations to deliberate over the use of experimental human embryos. Meanwhile, Francis Collins, director of NIH, has said that embryo research falls under a 1996 law called Dicky-Wicker Amended Rule, and clinical application of any such technology is out of bounds.
At a meeting of the National Agricultural Biotechnology Council (NABC) in 2014, leading agricultural scientists discussed the pros and cons of applying genome editing techniques like ZFNs, meganucleases, TALENS and CRISPRs/Cas9 to crop plants and farm animals.
All these are highly efficient at targeted gene deletions and replacement of defective genes to yield plants and livestock that should not be classified as GMOs as defined in the current regulatory sense. These genome-editing techniques are remarkably simple to use and cost-effective and have a limitless number of applications to control plant and animal diseases. They are already finding a wide array of applications in agriculture, and it will be just a few years before we will see products derived from these technologies knocking on the doors of commercialization.
The regulatory purgatory for the gene-edited animals will be quite different. Not a single genetically engineered animal has been approved for commercial use in the United States. If there is no way of gaining regulatory approval, activity in these areas will decline rapidly. This is exactly the kind of situation in India with no scientific or technological advancement in agricultural biotechnology due to the so called “temporary” ban on the Bt brinjal. It has been more than 10 years that transgenic salmon was not cleared in the US, and the Obama White House has had a role in delaying it.
Regulations and regulatory policies are strange beasts, fully amenable to political twisting. Anti-technology activists have realized this, and use it to the hilt to confuse lawmakers. And scientists have learnt nothing of the art of public persuasion and lobbying in developing countries.
If you agree to regulate GMOs, then you must start regulating all sorts of fruits, vegetables, crops and animals. If you say “genetically engineered”, then it becomes a catch-all phrase to trap all forms of gene-altered forms. If you stick to the present-day definition of GMO, only transgenic organisms will come under regulatory oversight, and no other form of gene alterations will be covered. This is the reason that a regulatory policy must find a middle ground where the technique and the product are regulated differentially depending on the risk(s) they present. The regulatory conundrum is simply this. Till the terms used in regulations are not properly defined legally, based on the state-of-the-art knowledge of the field, regulatory confusion will cause inordinate delays or in fact, could never end.
These gene-editing technologies are not even 10 years old, but have already changed several times, and that should inform any intelligent regulatory body what is in store for the future of biotechnology. Making regulatory policy and formulating regulations can be extremely tricky, which is why only knowledgeable and smart scientists who understand the technology and are aware of the future must be allowed to be involved in rule making. Others can submit their concerns and issues to the rule makers, but not all, especially the anti-technology activists, must be given a seat at the decision-making table.
Since the NITI Aayog has been tasked by the PMO to develop a forward-looking biotechnology regulatory policy, it should not succumb to pressures of the anti-tech lobby. The Aayog must develop a policy that is dynamic and flexible to accommodate rapid advances in technology and facilitate commercialization of safe and appropriate technologies for the nation’s economic progress. Regulations must be facilitators of safe technology transfer for the benefit of society.
The author is a Visiting Professor at the Seed Science Center and the Biosafety Institute for the Genetically Modified Agricultural Products (BIGMAP), Iowa State University, Ames, and a graduate teaching faculty with the Department of Plant Pathology and Microbiology. A former biotechnology regulator with the United States Department of Agriculture, Dr Shantharam has served as consultant to UN-FAO, UNIDO, World Bank, and Asian Development Bank. He was responsible for initiating the development of India’s biotech regulations in the early 1990s.
This article was published in the August 2015 issue of Swarajya.
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