ASIA-PACIFIC
BI TECH
NEWS
BIOTECHNOLOGY IN INDIA
AN INTRODUCTION
D. Balasubramanian*
activities in India can broadly be classified under two
B iotechnological
categories — classical and modern. Classical biotechnology mainly refers
to areas of biotechnology where tissues and organs, whole plants, organisms
and animals are used, while modern biotechnology is largely based on molecular
and cellular techniques. Classical biotechnology was already in practice
effectively by a few universities and national agricultural research institutes in
India around the 1950s. Scholars trained in the classical disciplines of botany,
zoology and agriculture were leading the research activities and indeed some
trail-blazing discoveries and developments were made in these universities. It
is not commonly known that the areas of protoplast fusion, anther culture and
callus culture, as well as micro-propagation using tissue culture of plants got
its earliest start in India, notably in the department of botany at the University
of Delhi. The pioneers in these techniques are Professors Indra Vasil (protoplast
fusion), S. Maheshwari and his student Sipra Guha (callus culture and anther
culture), B M Johri and H Y Mohan Ram (micropropagation, promiscuous
flowering of plants). Even as early as the late 1950s, micro-propagation of a
variety of plants was successfully achieved in their laboratories. (It is thus
notable, but not surprising, that much of the biotechnological activities in
India at present is still pretty much plant-based and is focused on micropropagation in green houses.) It was around that time that plant geneticists
realized the importance of hybrid seeds, cross varieties, selection breeding and
other biotechnological inputs. The Indian Council of Agricultural Research
(ICAR), which predates independent India, had established excellent field
stations and research outlets at various places such as Pusa, New Delhi, and
Coimbatore.
“
It is not commonly
known that the areas
of protoplast fusion,
anther culture and
callus culture, as well
as micro-propagation
using tissue culture of
plants got its earliest
start in India.
”
*Professor D. Balasubramanian is Director of Research, Hyderabad Eye Research Foundation, L.V. Prasad Eye Institute, Hyderabad, India.
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“
The fact that a nation that was forced
to import food two generations ago
now produces more than its needs and
is able to export food grains is testimony
to the successful use of biotechnology
in agriculture.
Classical Biotechnology
When the Mexican grass variety of wheat was introduced
to the world by Norman Borlaug, one of the earliest
countries to take advantage of this was India. Based on a
systems approach, involving hybrid seed selection and
breeding, irrigation, use of appropriate fertilizers, postharvest technologies and distribution of the produce, led
to what is now recognized as the Green Revolution. From
a mere 50 million tons output of food grains in the late
1940s, India now produces 200 million tons — in just a
matter of slightly more than 50 years. The fact that a nation
that was forced to import food two generations ago now
produces more than its needs and is able to export food
grains is testimony to the successful use of biotechnology
in agriculture. Amongst the active promoters of this form
of biotechnology are the scientists M S Swaminathan,
Gurdev Khush, and M V Rao.
Classical biotechnology has also been used in India to
improve the livestock industry. Selective breeding of chosen
breeds of milch cattle, sheep, horses and other animals has
been successful. The White Revolution in dairy has closely
followed the Green Revolution in food production.
Cooperative dairy management involving thousands of
dairies, proper choice of livestock and milch cattle, an
efficient people-friendly, and people-participatory
distribution system led to this revolution. Varghese Kurien
is highly regarded in this matter. It is interesting to note
that while M S Swaminathan, Gurdev Khush and M V
Rao are trained scientists, Kurien is a generalist and a
systems manager. This underscores another facet of
biotechnology, namely the close and necessary interaction
between the researcher and the manager.
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”
Concurrent with these national efforts in food production
and livestock improvement, vaccination and other
intervention methods have also been in practice on a large
scale in order to eliminate debilitating and death-causing
diseases such as cholera, smallpox, measles, and goiter,
among others. Delivery of the vaccines and immunization
of several hundred million people across a nation of
3000 km x 2000 km is an exercise of continental
proportions, which has been carried out successfully
more than once. The most recent instance has been the
immunization of over 150 million Indian children against
polio using the oral polio vaccine in a ‘pulsed’ fashion
twice within 60 days. Similarly, the large-scale elimination
of goiter from focal areas through the use of iodized salt
and the administration of vitamin A doses to school children
to counter night blindness have also been a story of
success in India’s march towards better health. Drs. V
Ramalingaswami and C Gopalan, two former chiefs of
the Indian Council of Medical Research, have played key
roles in promoting and coordinating these efforts on a
national scale.
Birth of Modern Biotechnology
Modern biotechnology was introduced in India around
the 1970s when a significant number of Indian researchers
trained in the US and Europe in various aspects of modern
biotechnology returned to India. In fact, some of them
were front ranking players in the development of numerous
methods and significant discoveries in enzymology,
biopolymer structure and conformation, reverse transcription, molecular virology, ribosome structure, transcription
and translation, cell culture techniques, biomolecular
spectroscopy, computer methods and so on. Indeed in the
field of biopolymer conformation, the pioneering work of
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The DBT operates with an overseas scientific advisory
committee, as well as an internal scientific advisory
committee comprising of experts from within the country.
The DBT not only funds extramural research projects but
has also started institutions and centers of excellence in
areas of modern biotechnology such as the National
Institute of Immunology, National Centre for Cell Sciences,
Centre for DNA Fingerprinting and Diagnostics, and the
National Centre for Brain Research. It also supports
university centers of excellence. The DBT has also prepared
guidelines on the use of recombinant DNA techniques,
transgenics, and other issues.
An important fillip to capacity building in biotechnology
in the country has been provided by the DBT through
their MSc programs in biotechnology, for which students
are chosen on the basis of a national examination, and the
DBT postdoctoral research program which supports about
a hundred postdoctoral research fellows in four or five
centers across the nation. Sponsored projects and grant-inaid projects also employ postdoctoral researchers.
International cooperation in the area of biotechnology has
also been possible through the DBT Visiting Associateships
and Visiting Fellowships offered to both Indian and
overseas scholars.
G N Ramachandran had already established him as a world
leader. His school in Madras and later in Bangalore,
comprising researchers such as V Sasisekaran (nucleic
acid conformations), V S R Rao (polysaccharides),
C Ramakrishnan (protein structure), M Vijayan (X-ray
crystallography), and their students and associates continues
to lead in the field of conformational predicts and analysis.
It was about the same time that the Department of Science
and Technology (DST) of the Indian Government initiated
the National Biotechnology Board or NBTB. This board,
through its two pioneering researchers — the bio-organic
chemist S Varadarajan (then secretary of the DST) and the
biologist S Ramachandran (then head of the NBTB), played
a proactive role in promoting specific methods and
technologies, curricular programs, research laboratories and
funding research projects to individual scientists. Within a
short time, NBTB matured into a full-fledged department
of the government, called the Department of Biotechnology
(DBT). During the 15 years of its existence, it has been
led by prominent scientists such as S Ramachandran, C R
Bhatia and currently, Manju Sharma, who have started
and sustained programs of education, training, research
and development in various areas of biotechnology in the
country.
In addition to the DBT, other governmental agencies
such as the Indian Council of Medical Research (ICMR),
Indian Council of Agricultural Research (ICAR),
Department of Science and Technology, Council of
Scientific and Industrial Research (CSIR), and the Bureau
of Research in Nuclear Sciences (BRNS), as well as the
Universities Grants Commission are other sources of
research funding in biotechnology in the country. It has
been estimated that close to 60% of all grants-in-aid offered
by these national agencies goes into areas of modern
biology. Professional associations in the area of modern
biology have also been active for over two decades now.
Notable amongst these are the Society of Biological
Chemists of India, Indian Cell Biology Association, Indian
Immunological Society, Association of Indian Microbiologists, Indian Biophysics Society, and the informal and
yet very effective annual meeting called the Guha Research
Conference. These have led to camaraderie and cooperation
between investigators within the country so that exchange
of scholars, exchange of materials and sharing of equipment
has become far more common in the areas of biotechnology
and modern biology than in other branches of science in
India.
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Biotech products through basic research — Launch of leprosy vaccine (Leprovac); The vaccine was developed at the
National lnstitute of Immunology and transferred for commercial production to Cadila Pharmaceuticals.
Contemporary Centers of Biotechnological Activity
Amongst the internationally known players in biotechnology are the Indian Institute of Science in Bangalore
(a postgraduate institution of 80 years standing, with close
to 85 faculty members in all areas of biology), the Tata
Institute of Fundamental Research in Mumbai, and its
offspring the National Centre for Biological Sciences in
Bangalore, the Jawaharlal Nehru University in New Delhi,
the Madurai Kamaraj University in Madurai, the Pune
University in Pune, the University of Hyderabad in
Hyderabad, the M S University in Baroda, the Banaras
Hindu University in Varanasi, and the Bose Institute in
Calcutta. Equally important are the national laboratories
such as the Centre for Cellular and Molecular Biology and
the Centre for DNA Fingerprinting and Diagnostics, both
in Hyderabad, the Indian Institute of Chemical Biology in
Calcutta, the National Institute of Immunology in New
Delhi, the Centre for Biochemical Technology in Delhi,
the Central Drug Research Institute in Lucknow, the
Institute of Microbial Technology in Chandigarh, and the
UNDP — aided International Centre for Genetic
Engineering and Biotechnology in New Delhi (which has
its twin in Trieste, Italy). Significant agri-biotech research
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goes on in the ICAR laboratories and provincial agricultural
universities such as the ones in Hyderabad, Coimbatore
and Pantnagar.
Some of the more notable contributions in the area of
modern biotechnology in India would be macromolecular
conformation (theory and experiment), glycobiology and
lectin structure, procaryotic transcription and the mode of
action of drugs such as rifampicin, choloroquine and so
on, enzymological approaches to malaria control and
drug design, molecular biology of cytochrome P450,
peptide design, molecular mimicry, epitope-based vaccine
design, expression vectors for protein production, structural
basis of chaperone action, drug delivery systems, DNA
typing and lineage analysis, and so on.
Biotech Products through Basic Research
A few notable biotech products have come through active
industry-academic collaboration in the last few years. For
example, two medium range companies have been able to
produce and market effective hepatitis B vaccine, through
collaborations with academic institutions. The mode of
collaboration here is of interest. One of these companies
was actually housed at a national laboratory, with its
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scientists working as guest researchers, when the products
were developed and validated. Once this was done, clinical
trials, up-scaling and production followed. The company
scientists enjoyed all the privileges of scientists from the
academic institution — used the facilities of the host
research laboratory and learnt the grammar of basic
research, while the scientists from the institution had
the feel for what it is like to meet deadlines, business
demands on research products and so on. It was what is
called a win-win situation for both parties. The research
laboratory profited in terms of revenue while the company
had a host of talented scientists working as surrogates.
Other products hitting the market through such
collaborations are streptokinase, interferon, and a generalpurpose salt inducible expression vector system, which is
of great use for both academic and large-scale production
of proteins from recombinant
DNA technology. This vector
has been patented in the US
and licensed to a company
there for global marketing.
In addition, there is a whole
range of serum diagnostic
kits that have been developed
in academic institutions
and handed to the industry
for marketing and sales.
Amongst the more notable of
these is a diagnostic kit that
exploits an agglutination
method using whole blood to
detect the presence of the AIDS virus. Laboratories in
academic institutions are developing cholera vaccine,
leprosy vaccine, and vaccine against the Japanese
encephalitis virus. While the leprosy vaccine has already
been licensed to a firm, the other two are expected to be
licensed shortly.
Turning to the industry, perhaps the most prevalent
biotechnology industry in India in almost every major city
is that of tissue culture and micro-propagation of plants,
shrubs and flowers. There are several major players such
as SPIC, A V Thomas, Godrej, but there are also many
small scale micro-propagators. It is interesting to note
that during the severe winter of 1994–95 in Europe, tulips,
the favorite of the Dutch people, were exported in cargo
loads by air from Hyderabad to Amsterdam — a
biotechnological twist to the phrase ‘carrying coal to
Newcastle’! Hybrid seed production and sales is another
flourishing area where the major players are Mahyco, IndoAmerican Hybrid Seeds, SPIC, EID Parry, and lately
Monsanto.
Among the major Indian drug firms are Ranbaxy,
Dr. Reddy’s Laboratories, Cadila, Unichem, and Cipla,
among others. The notable point about these companies
is that they are completely home grown and at present
have full fledged R&D laboratories associated with them.
Apart from classical methods of drug discovery, some of
them have dived right into the quest for new molecules.
Three new molecules have already appeared on the drug
scene and are being licensed to firms abroad. The firm
Biocon, located near Bangalore, is a success story in the
custom-production of enzymes and biochemicals for
specific clients. Astra Zeneca has its research and
development center in Bangalore, where it concentrates on
the development of drugs for infective diseases, and high
throughput screening of candidate molecules. Traditional
Indian medicine and natural products is also an active area
of research. Companies such as Dabur, Arya Vaidyasala
Kottakal, among others, are focusing their attention on
looking for validation, promotion and marketing of drugs
“
Traditional Indian medicine and natural products
is also an active area of research.
A noteworthy national effort is the inter-laboratory
program of the CSIR to test and validate a large
number of bioactive natural products through the
use of chemical, biochemical and pharmacological
methods of screening.
”
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based on traditional natural product. A noteworthy national
effort is the inter-laboratory program of the CSIR to test
and validate a large number of bioactive natural products
through the use of chemical, biochemical and pharmacological methods of screening. The CSIR has entered into
a joint venture with Kottakal for certification of the
Ayurvedic pharmacopia. Proteins, sugars, gums and resins,
and enzymes from natural and selectively bred microbial
sources are other aspects of the Indian biotechnology
industry that have done well. Today there are a couple
of local suppliers, such as Bangalore Genei (started by
Dr. P Babu, a former academic), which supply their
molecular biologicals to academic institutions, while
competing with companies such as Sigma, Gibco-BRL,
and Amhersham. Most of these local companies supply
enzymes, oligos and probes, offer synthesis and sequencing
services for both peptides and nucleic acids, and also loan
small laboratory equipment to the academic institutions.
Hyderabad – the Biotech Capital of India
The city of Hyderabad in South Central India has fast
turned out to be the hub of biotechnological activity. It is
here that the drug company, Dr. Reddy’s Laboratories
(DRL), has its research lab and drug production center,
from where two new molecules have recently emerged –
one of them licensed to Novo Nordisk. This demonstrates
the fact that the process of inventing a drug, testing it and
putting it out in the market can be done more costeffectively from India and South Asia. It is in Hyderabad
that another notable pharmaceutical firm — Biological
E Limited is located; and it is from here that two
small firms — Shanta Biotechics and Bharat Biotech —
developed vaccines against hepatitis B and marketed them
competitively and successfully. (These efforts also illustrate
the effective and mutually enhancing collaboration between
industry and basic research laboratories — Shanta
Biotechics with the University of Missouri and with the
Centre for Cellular and Molecular Biology (CCMB) in
Hyderabad, and Bharat Biotech with the Indian Institute
of Science in Bangalore.) There are about half a dozen
companies around the city, drug formulating franchisees
that work with global companies such as Glaxo, Procter
and Gamble, and Astra Zeneca, and public sector
(government-owned) drug companies such as the Indian
Drugs and Pharmaceuticals Limited and the Indian
Immunologicals, which specializes in veterinary products.
Hyderabad has some of the more notable research
institutions such as the CCMB (basic and in part applied
research in biology), Centre for DNA Fingerprinting and
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Diagnostics (CDFD), National Institute of Nutrition (NIN),
Dr. Reddy Research Foundation (DRF), Hyderabad Eye
Research Foundation (HERF), International Centre for
Research in Semiarid Tropics (ICRISAT, largely devoted
to five coarse grain cereals), and the Ranga Agricultural
University, Directorate of Rice Research (under Prof. E A
Siddiq who has developed successful rice hybrids),
University of Hyderabad (which collaborates with the
ICRISAT and DRF), Osmania University (with strength in
medical and cytogenetics), Indian Institute of Chemical
Technology (focused on bio-organic chemistry, bioactive
compounds screening) and the Deccan and Gandhi Medical
Colleges. State-of-the-art medical centers and hospitals not
only provide medical services but also interact with research
laboratories in the city.
In addition, support from the state government of Andhra
Pradesh (of which Hyderabad is the capital city) in business
development, particularly in the emerging areas of
information technology and biotechnology, has been full
and proactive. A state-sponsored Biotechnology Park along
the lines of those already established in Singapore and
Hong Kong, is coming up, next to the already established
‘Knowledge Park’ in the suburbs of the city. The park
provides all infrastructures — water, power, building and
lab space, communication facilities, conference and seminar
halls, customs and license clearance and other ‘housekeeping’ facilities. A few biotech firms have already
negotiated for occupation in the Biotech Park, which is
situated right next to the firm Bharat Biotech.
Until about a decade ago India’s economic policy was
pretty much governed and restricted by the government.
In 1991, when globalization of the Indian economy was
initiated, various restrictive practices and procedures were
abandoned, and more and more private enterprise and joint
venture enterprises have been encouraged. This has led to
a significant number of pharmaceuticals, agricultural,
cosmetic and biological firms from abroad entering the
Indian scene. Some of these function as regional offices,
while others work in collaboration as joint ventures with
Indian entrepreneurs. The most recent entrant has been
Monsanto, which has also established its R&D center in
Bangalore. While the rate of growth of the national
economy has been a healthy 5% to 7% per annum, growth
in biotechnology and medical sectors has been even higher.
With pro-active policies, one can expect this figure to keep
growing and India will emerge as one of the major players
in both classical and modern biotechnology. The All India
Biotechnology Association has been attempting to liaise
with its international partners elsewhere towards this goal.
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