Regulation of emerging gene technologies in India

In India, genetically modified organisms (GMOs) and the products thereof are regulated under the “Rules for the manufacture, use, import, export & storage of hazardous microorganisms, genetically engineered organisms or cells, 1989” (referred to as Rules, 1989) notified under the Environment (Protection) Act, 1986. These Rules are implemented by the Ministry of Environment, Forest and Climate Change, Department of Biotechnology and State Governments though six competent authorities. The Rules, 1989 are supported by series of guidelines on contained research, biologics, confined field trials, food safety assessment, environmental risk assessment etc. The definition of genetic engineering in the Rules, 1989 implies that new genome engineering technologies including gene editing and gene drives. May be covered under the rules. India is a signatory to the Cartagena Protocol on Biosafety (CPB), however, the definition of modern biotechnology, as in CPB is yet to be adopted in the national regulations. The regulatory authorities review and take into account the experience by other countries in dealing with new technologies. However, there is yet no clarity on how the emerging technologies will be dealt with in India, though research has been initiated in several leading institutions.


Background
India has a systematic and structured regulatory framework for biosafety evaluation of genetically modified organisms (GMOs) and products thereof. India was one of the early movers in development of a biosafety regulatory system for GMOs, way back in 1989. The apex rules for regulation of all activities related to GMOs are notified under Environment (Protection) Act, 1986. In addition, there are other acts, rules and policies which are also applicable to these organisms.

Regulation of GMOs in India
An overview of biosafety regulations is presented below:

Rules, 1989
In India, Ministry of Environment, Forest and Climate Change (MoEFCC) introduced the Environment (Protection) Act, 1986 as an umbrella legislation to provide a holistic framework for the protection and improvement to the environment. Thereafter, a series of Rules were notified to address various problems such as hazardous chemicals, hazardous wastes, solid wastes, biomedical wastes, etc.
In connection with the use of micro-organisms and application of gene technology, the MoEFCC notified the "Rules for manufacture, use/import/export & storage of hazardous microorganisms/genetically engineered organisms or cells, 1989" [1] as per powers conferred by Sections "Regulation of Genome Engineering Technologies in India", 8 and 25 of Environment (Protection) Act, 1986. These rules are very broad in scope essentially covering entire spectrum of activities involving GMOs and products thereof. They also apply to any substances, products, and food stuffs, etc., of which such cells, organisms or tissues hereof form part. New gene technologies apart from genetic engineering have also been included. The gene technology and genetic engineering have been defined as follows in the text of the Rules, 1989.
(i) "Gene Technology" means the application of the gene technique called genetic engineering, include self-cloning and deletion as well as cell hybridization.
(ii) "Genetic engineering" means the technique by which heritable material, which does not usually occur or will not occur naturally in the organism or cell concerned, generated outside the organism, or the cell is inserted into said cell or organism. It shall also mean the formation of new combinations of genetic material by incorporation of a cell into a host cell, where they occur naturally (self-cloning) as well as modification of an organism or in a cell by deletion and removal of parts of the heritable material. The interactive mechanisms between committees have also been provided in Rules, 1989. All IBSCs are required to review the applications and submit their recommendations and reports to RCGM. RCGM review and gives its recommendation for large scale activities, field trials and environmental release to GEAC. DLCs are also required to regularly submit its report to the SBCC/GEAC.

Rules
In addition to the above, various sub-committees and expert committees are constituted by RCGM and GEAC on a case by case basis. Such committees comprise of experts from various disciplines drawn from public sector institutions to prepare and review various guidelines and biosafety data. Central Compliance Committees are also set up for monitoring of confined field trials on case by case basis. An example of functioning of regulatory system for confined field trials and environmental release of a GE plant is illustrated in Fig. 1.

Approvals and prohibitions
Rules, 1989 provide for compliance of the biosafety safeguards and any violation and non-compliance in this area attracts punitive actions provided under the EPA, 1986. The approvals and prohibitions under Rules 1989 are summarized below: No person shall import, export, transport, manufacture, process, use or sell any GMOs, substances or cells except with the approval of the GEAC. Use of pathogenic organisms or GMOs or cells for research purpose shall only be allowed in laboratories or inside laboratory areas notified for this purpose under the EPA, 1986. Any person operating or using GMOs for scale up or pilot operations shall have to obtain permission from GEAC. Experiments for the purpose of education involving GMOs can be undertaken with the oversight of IBSCs. Deliberate or unintentional release of GMOs not allowed. Production in which GMOs are generated or used shall not be commenced except with the approval of GEACAll approvals shall be for a period of 4 years at first instance renewable for 2 years at a time. GEAC shall have powers to revoke approvals in case of: i. Any new information on harmful effects of GMOs. ii. GMOs cause such damage to the environment as could not be envisaged when approval was given. iii. Non-compliance of any conditions stipulated by GEAC.

Supervision and penalties
GEAC supervises the implementation of the terms and conditions laid down in connection with the approvals accorded by it. GEAC may carry out supervision through SBCC, DLC or any authorized person. If orders are not complied, SBCC/DLC may take suitable measures at the expenses of the person who is responsible. In case of immediate interventions to prevent any damage, SBCC and DLC can take suitable measures and the expenses incurred will be recovered from the person responsible. Various notifications have also issued under Rules, 1989 from time to time to address issues such as empowering Seed Inspectors/Seed Analyst/Laboratories notified under Seed Act under Environment (Protection) Act, 1986, exempting certain categories of recombinant pharmaceutical products, GM food stuffs, ingredients in food stuffs, and additives from the purview of Rules, 1989.

Other relevant rules and policies
In addition to Rules, 1989, other Acts and Rules, also refer to specific activities/products involving GMOs [2].  Table 2 summarizes relevant Acts/Rules regulating GMOs in India.

Guidelines for safety assessment of GMOs
A series of guidelines for safety assessment procedures to be followed at various stages of development of GMOs i.e. research, confined field trials, food safety assessment, and environmental risk assessment have been adopted under Rules, 1989 from time to time. Issuance of guidelines by regulatory authorities in India corresponds to the research and development activities. Recombinant DNA Safety Guidelines primarily focussing on research and development activities on GMOs, shipment and importation for laboratory research etc. were adopted in 1990 within a year of notification of Rules, 1989. These guidelines provide guidance on containment measures to be followed for various categories of organisms based on risk category. Appropriate practices, equipment and facilities necessary for safeguards in handling organisms, plants, and animals have been provided [3]. As the active research was initiated in transgenic plants in nineties in India, Guidelines for research in transgenic plants were issued in 1998 by DBT to provide guidance for recombinant DNA research on plants. The guidelines also provide for design of a greenhouse and safeguards to be followed in field trials [4]. Guidelines and Standard Operating Procedures for conduct of confined field trials of regulated GE Plants were issued by DBT and MoEFCC in 2008 [5].
Guidelines for the Safety Assessment of Foods Derived from Genetically Engineered (GE) Plants were prepared by the Indian Council of Medical Research and adopted by RCGM and GEAC in 2008 [6]. These guidelines provide guidance on principles and steps on food safety assessment of GE plants and are based on guidelines and principles of Codex Alimentarius Commission, 2003. A series of accompanying protocols were prepared by DBT [7]. The guidelines include three appendices on dossier preparation checklist, Codex Alimentarius principles for the risk analysis of foods derived from modern biotechnology, safety assessment of foods derived from GE plants modified for nutritional or health benefits and food safety assessment in situations of low level presence of GE plant material in food.
MoEFCC in association with the DBT has recently adopted a set of three documents to strengthen the environmental risk assessment of GE plants in India. These include Guidelines for the Environmental Risk Assessment of Genetically Engineered Plants, 2016; Environmental

Status of research and commercialization of GMOs in India
India has a very rich and innovative R&D pipeline, as evident from the fact that there are more than 500 active IBSCs in the country. Several public and private sector institutions are involved in the research and development of GE plants in India. In one of the surveys conducted by MoEFCC in 2014 under the Phase II Capacity Building Project on Biosafety, over 85 different plant species were identified as currently being used in experimental work, including plants used for food, livestock feed, fiber fuel and dietary or medicinal purposes [9]. A comprehensive list of all of the crop species identified by respondents in the survey is placed in Table 3. Out of the above, more than 20 plants with varying traits such as hybrid seed production, insect resistance, herbicide tolerance, abiotic stress tolerance, nutritional enhancement, etc. are under various stages of field trials [10]. A list of GE plants for which confined field trials have been approved in the past 4 years is placed below Table 4.
To date, Bt cotton is the only GE plant approved for commercial cultivation in India.
In addition to the above, research involving GM microorganisms for healthcare and industrial application under contained conditions is underway in several organizations. Indian companies are actively involved in products of similar biologics (also referred as biosimilars).
Regarding research in GE insects, limited efforts have been made by an Indian company for taking forward from technology from male sterile mosquitoes developed by Oxitec. The company has completed mating compatibility experiments with Indian strains and set up facilities for contained trials.
Development of GE silkworms is being actively pursued and field trials have been undertaken. All these applications are being dealt with on a case by case basis and no separate guidelines have been issued so far by the regulators.

Regulation of genome engineering Technologies in India
Recognising the global advances in the area of genome engineering technologies and huge potential for practical applications in healthcare and agriculture, initiatives have been taken in India by leading research institutions. In 2014, DBT has constituted a dedicated Task Force on "Genome Engineering Technologies and their Applications" with a vision to foster innovation and promote development of Genome-wide Analysis and Engineering Technologies to make them accessible and affordable for wider use in life sciences. It is proposed to strengthen facilities on emerging technologies such as gene editing and support research projects. Efforts are also underway to develop human resource to catch up with the growth in this area and harness the benefits of these technologies for basic or applied use in larger context and drive research for technology development towards basic and applied use.
Regarding regulation of genome engineering technologies, there is still a debate in the country. The definition of GE technology as in Rules, 1989 is very broad based and include "modification, deletion or removal of parts of heritable material". This implies that all new technologies will be subject to regulation under provision of Rules, 1989.

Conclusions
As India is a signatory to Cartagena Protocol on Biosafety, the definition of modern biotechnology as in the Protocol was proposed to be adopted in the Bill for setting up of Biotechnology Regulatory Authority of India in 2013. However, the bill was lapsed and further action on the same is awaited.
In view of the present definition, it is expected that regulatory considerations for new and emerging technologies will be on a case by case basis based on the existing regulatory framework i.e. Rules, 1989 in the near future.