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INDIA he classic image of India that most people can conjure has cows, beggars, small children and sari-clad women all jostling Tfor space on crowded streets. That image still reflects reality — but with palpable differences. Along some of those streets now are gleaming, modern buildings where men and women churn out medicines for poor countries. Many children are being immunized with affordable vaccines produced by India’s own biotechnology industry. And if the country continues to prosper as it has for the past REUTERS/CORBIS decade, there soon may not be many beggars left. Since 1991, when India discarded its socialist past and instituted broad reforms, its economy has been p496 Editor, Nature growing rapidly. By 2032, India’s economy could be Philip Campbell larger than those of all but the United States and Supplement Editor China, according to an estimate by the investment features Apoorva Mandavilli banking firm Goldman Sachs. Supplement Publisher In the following pages, we look at what effect these 478 Then and now Sarah Greaves Inder Verma Production Editor changes have had on India’s life sciences. Indian Maria Hodges biotechnology companies have been remarkably 480 Biotech boom Senior Art Editor successful, but they have made most of their money K. S. Jayaraman Martin Harrison copying patented drugs. To sustain growth, they will 484 Vaccines on trial Diagrams have to become more innovative. The same is true of Nik Spencer Paroma Basu Layouts basic-research institutes, which have only recently Jane Walker begun to be globally competitive. 485 India’s drug tests Picture Researcher While developed nations are seeing their T. V. Padma Barbara Izdebska populations shrink, half of India’s growing 486 Ayurveda Production population is under the age of 25. The government Susan Gray T. V. Padma must improve India’s ailing universities to educate Marketing 487 Breathing life into biology and train these young people and stem the Claire Aspinall Mriganka Sur haemorrhage of its brightest students to the United States and Europe. It must also untangle the still- 488 Coming home rampant red tape that stifles creativity and set up Satyajit Mayor ethics panels to monitor clinical research. 490 Rivalry and red tape Most important, it must find a way to protect its T. V. Padma people from grave health crises. India has among 492 Among the best the highest rates of HIV/AIDS, diabetes and K. S. Jayaraman tuberculosis, which threaten to sap the country’s resources and derail its progress. 496 The coming epidemic This is a critical juncture for India. The Apoorva Mandavilli opportunities, whether in partnership with multinational pharmaceutical companies or as an outsourcing centre for clinical trials, are many. Seized judiciously, they can allow India to build a scientific and technological future to be proud of. We are pleased to acknowledge financial support from the Centre for Cellular and Molecular Biology, Metahelix, Avesthagen and the Tata Institute of Fundamental Research in producing this Outlook. As always, Nature carries sole responsibility for all editorial content. Apoorva Mandavilli, Senior News Editor, Nature Medicine. p488

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Then and now Inder Verma celebrates the recent success of India’s biotechnology industry, applauds the increased investment and looks to the future.

our job is to collect urine in with a plant researcher in another lab. At no Inder Verma believes that young scientists the men’s bathroom and point was I consulted during these arrange- must be able to challenge the status quo. As bring it to the laboratory at ments. I was merely a graduate student a graduate student (inset), Verma felt that he “Ythe end of the day.” These expected to do as my supervisor commanded. had to obey all his thesis adviser’s commands. were the instructions my thesis adviser gave In the years since, the situation has improved, me when I began my graduate career in 1966. and the overbearing attitude of many advisers the world. Funding agencies such as the Coun- Others would then purify factors from the is becoming a thing of the past. Young scien- cil of Scientific and Industrial Research have urine that might function as a male contracep- tists in India are more independent and always emphasized translational research but, tive in monkeys. He pointed to a 20-litre glass increasingly resentful of the autocratic system. because the success of such programmes rests bottle with a broken rim and a small glass fun- For many decades, Indian universities have on a strong foundation of basic science, the nel. I was expected to obey his orders — and I churned out biologists, many of whom move results were often dismal. Indian medical did. (My only intellectual contribution was to to the United States or Europe. Those that schools, lacking resources for research, have switch to a larger funnel, which made it easier remain in India are usually destined to publish failed to train scientists in translational for both the donors and for me.) in local or low-impact scientific journals. Life- research. Not surprisingly, India has not pro- A few months later I was told that monkeys science research in India has been constrained duced a single original drug sold in the world were no longer available and the study was by insufficient funds and equipment coupled market. All this, I hope, is about to change. being shelved. From now on I would work with a lack of will to compete with the rest of I’ve been to India every year for the past 35 years, have visited many institutions, met many colleagues, students and young investigators and participated in countless meetings. In that time, I’ve witnessed the growth

of Indian biosciences with concern and pride. BETTMAN/CORBIS Recently, I’ve been delighted by a run of excellent papers published in top-tier journals P. PARANJPE/REUTERS/CORBIS by scientists in India. And I’ve been impressed by the desire of the biotech and pharmaceutical industry to undertake novel challenges. The first prime minister of India, Jawahar- lal Nehru, believed that science is the way out of poverty. The scientific opportunities in India may well prove him to be a true vision- ary, but there is much work to be done first. Novel ideas Biotechnology companies are among the most profitable in the country. Today, Indian companies provide 22% of the world’s generic drugs — copies of brand-name drugs. India Science has always been important to the Indian government. It’s first prime minister, Jawaharlal also manufactures a significant proportion of Nehru, greatly admired Albert Einstein. Current leader Manmohan Singh has made science a priority. vaccines made for the developing world. 478 © 2005 Nature Publishing Group

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Within India, vaccines against hepatitis if they can learn from the success of the INDIAN GOVERNMENT BUDGET, 2005–06 B are manufactured by Indian compa- IT sector. Total: US$118 billion nies and sold for less than 30 cents per India’s position in the global IT indus- dose. True, most of India’s biotech and Agriculture and allied try is a source of pride and confidence. Social services, activities, 3% pharmaceutical industry is based on 26% Rural development, Graduates of the Indian Institutes of duplicating existing products, but that General economic 7% Technology (IIT) have started numer- still requires considerable sophistication services, 2% Energy, ous companies worldwide, and their and know-how. But with the passage of 27% innovative spirit should inspire biolo- FINANCE OF MINISTRY SOURCE: a new law on 23 March this year forbid- gists to be more adventurous. ding companies from making copycat Last year, 60 Minutes, a popular inves- drugs (see page 480), Indian companies tigative television programme in the will be forced to be more innovative. United States, featured the IITs. When But how do we encourage such inno- Science, technology, Industry and minerals, the interviewer asked N. R. Naryana vation? In the mid-1980s, the Indian environment, 3% 6% Murthy, founder and chairman of the government established the Department Transport, 20% multibillion-dollar company Infosys, of Biotechnology (DBT) and invited Communication, 7% what his son would do if he did not pass several researchers —including me — to the arduous entrance examination for serve on its overseas advisory committee. We problem is compounded by the lack of lateral the IITs, Murthy replied, without skipping a encouraged the DBT to furnish state-of-the- mobility in India. Most scientists who train beat: “Well, we have back-ups like Cornell, art laboratories, provide increased funds for abroad return to India for family reasons and MIT and Stanford.” research, reduce the bureaucracy required for are loath to live away from their home town. I don’t usually support starting new institu- importing research materials such as restric- They would sooner go back abroad than swap tions, but an Indian Institute of Integrative tion enzymes, initiate projects that promote cities or states within India. Biology, much like the successful IITs, is the sharing of expensive equipment, offer But science thrives when there is a nucleus worth considering. Alternatively, the IITs visiting fellowships and build manpower to of scientists striving for excellence. The Indian could broaden their curriculum to include support the biotech industry. Institute of Science in Bangalore and the degrees in biology and biotechnology. Since the DBT’s inception, its budget has National Institute of Immunology in New grown from a meagre US$15 million to more Delhi have achieved this. Scientists at these Promoting science than US$125 million a year. That may not be institutes, which are independent of universi- The time is ripe for life sciences to blossom in much compared with the US$27 billion bud- ties, are publishing in international journals India. Every day, newspapers carry headlines get of the US National Institutes of Health, but and are being invited to prestigious national reporting Indian successes in information it’s a good start. and international meetings. To be competitive technology, tales of rich Indian biotech on a global scale, India needs to nurture such tycoons and highlighting the enormous pur- Increased investment centres rather than worry about equitable dis- chasing power of the growing middle class. In addition to the DBT, there are at least three tribution of the country’s resources. In my experience, the Indian government, major funding sources for life scientists within These centres can also encourage collabora- regardless of which party was in power, has India, so finding funds for a good project is no tions across cities and disciplines. Modern always been highly supportive of science. But longer a hurdle. Indian scientists have been biology requires the expertise of scientists the current left-leaning administration is par- able to win significant funding from interna- from many different fields. Unfortunately, ticularly so (see graphic, above). For example, tional sources such as the US National Insti- scientific departments at Indian institutions the government recently gave the Indian Insti- tutes of Health, the Bill & Melinda Gates and universities have traditionally operated as tute of Science a one-off grant of about Foundation, the European Union and the islands. Experts in microbiology, biophysics US$25.3 million. Prime minister Manmohan Wellcome Trust (see page 489). and biochemistry might all work within a few Singh has also endorsed the creation of a Despite this, India will not succeed unless it feet of each other and yet hardly interact, much US$250-million independent agency to sup- encourages innovation and rewards excel- less collaborate. The government should pro- port basic research. lence. Most Indian universities still operate vide incentives for interdisciplinary research. India is not a poor country — indeed, it is under a feudal system, which stifles creativity. It should also encourage academics to forge rich in natural and intellectual resources — but Science is best carried out in an irreverent alliances with industry, market their inven- it has many poor people. More than 700 mil- environment, where the status quo is chal- tions and set up technology-transfer offices. lion people, nearly 70% of the population, live lenged, often at the risk of offending superi- Government officials are always coming up in rural areas but contribute only 20% of the ors. But the Indian scientific enterprise frowns with catchy slogans, such as ‘IT today, BT GDP. Until this disparity changes, vast sectors on questioning authority and rewards obedi- tomorrow’, but often they do not follow of the Indian population will never see the ben- ence. Senior scientists are too often selected through on those ambitious plans. India is still efits of biotechnology or modern medicine. It’s by seniority and rank, rather than their ability far behind the United States, Europe and very clear what India needs to do to become a and achievements. Japan. Although India has the advantage that world player in the life sciences, but unless the In common with many scientists at insti- its citizens know English, it still lags behind government, researchers and the industry tutes in neighbouring China, Indian other Asian countries such as China and work together to put the solutions into practice, researchers once hired are there to stay. I do South Korea. all their best laid plans will not succeed. I not know of any case in which someone was India sometimes gives the impression that Inder Verma is American Cancer Society denied tenure or did not have their contract it will never compete properly in the global Professor of Molecular Biology at the Salk renewed because of low productivity. This arena. But life scientists will be able to Institute, La Jolla, San Diego 479 © 2005 Nature Publishing Group

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Biotech boom India’s thriving biotechnology industry is threatened by a change in the law. Will the current high levels of investment be enough to secure its future? K. S. Jayaraman finds out.

very year, on the presumed birthday Institute for Molecular Science in Japan. once a small manufacturer of tetanus toxin, of Krishna, the blue-skinned Hindu TCGA is the youngest of several biotechnol- now makes 80% of the world’s measles and god, New Delhi’s Mathura Road is ogy laboratories that have sprung up in India in DTP (diphtheria, tetanus and pertussis) vac- E choked with traffic. Buses, cars and recent years. It is a shared venture between the cines (see ‘A shot of success’, opposite). bullock carts packed with devotees advance Chatterjee Group, a Kolkata-based industrial Other companies that have made a global toward Vrindavan, where Krishna is believed house, and two government agencies — the impact include the Mumbai-based company to have been born 5,000 years ago. Council of Scientific and Industrial Research Cipla, which rewrote the rules of the interna- This August, pilgrims to Krishna’s leg- (CSIR) and the Department of Science and tional AIDS drug market when, in 2001, it endary birthplace will pass an imposing Technology — which shared the US$ 5.7-mil- introduced inexpensive generic antiretroviral BANGALORE BIOINFORMATICS, INST. three-story structure of sandstone and glass. lion cost of construction. drugs. Strand Genomics in Bangalore has Inside, at The Centre for Genomic Applica- The centre, which aims to provide world- formed a partnership with Japan’s MediBIC to tions (appropriately shortened to TCGA, the class facilities for genomics and proteomics, is develop informatics solutions for pharmaceu- letters of the genetic alphabet), white-coated the first to be built by a public–private part- tical companies in Japan. And Avesthagen, also scientists are devoted to a god of a different nership. It also symbolizes the current revolu- based in Bangalore, has joined up with France’s kind. On the centre’s first birthday in May tion in India’s biotechnology industry. bioMérieux to develop diagnostic instruments 2005, scientists acquired a new Hewlett- With fewer than 300 registered companies, for medical and industrial applications. Packard supercomputer, the fastest in India, the biotechnology sector is small but is gaining worth a whopping US$2.2 million. Capable of in global stature. According to the World Profits soar four trillion operations a second, the com- Health Organization, India is the fourth largest In 2003–04, Indian biotechnology companies puter places the centre among the ranks of producer of pharmaceuticals, and 66.7% of its together had a revenue of more than US$700 international institutions such as the Well- exports go to developing countries. For exam- million (see graphic, below). This year, they come Trust Sanger Institute in Britain and the ple, the Pune-based Serum Institute of India, have surpassed US$1 billion. “The biotech-

INDIA’S TOP 20 BIOTECHNOLOGY COMPANIES

LOCATION OF TOP 20 BIOTECHNOLOGY COMPANIES Company name Revenue 2003–04 Revenue 2004–05 Growth (US$million) (US$million) (percentage) 1. Biocon 115 148 29 1 company 2 companies 2. Serum Institute of India 126 130 3 (17) (3, 15) 3. Panacea Biotec 34 50 46 4. Venkateshwara Hatcheries 20 43 114 New Delhi 5. Mahyco Monsanto 12 38 208 7 companies Bulandshahr 6. Novo Nordisk 25 31 23 (5, 8, 9, 10, 11, 16, 19) 7. Rasi Seeds — 20 — 8. Aventis Pharma 17 19 15 Calcutta 9. Bharat Serums & Vaccines 18 19 2 10. Chiron Behring Vaccines 15 18 16 11. GlaxoSmithKline 14 18 28 Mumbai 12. Indian Immunologicals 13 17 28 Pune Hyderabad 13. Shantha Biotechnics 9 16 75 4 companies 14. Novozymes 12 16 30 Attur (12, 13, 18, 20) 15. Eli Lilly & Company 15 16 1 2 companies (2, 4) 16. Wockhardt 9 15 68 Bangalore 17. Bharat Immunologicals 5 12 147 & Biological 18. Bharat Biotech 8 9 14 1 company (7) 19. Advanced Biochemicals 7 9 31 3 companies 20. Biological E 9 8 –6 (1, 6, 14) Data from the ABLE–Spectrum Industry survey

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A SHOT OF SUCCESS

On a sunny Friday morning in BIOTECHNICS SHANTHA January, the students of the Shiva Shivani School in Hyderabad were ushered, one by one, into a room where a doctor and nurse stood with syringes. The school’s 470 students, ranging in age from 5 to 12 years, all received a shot of Shanvac-B, a hepatitis B vaccine produced by a local vaccine. As a result, GSK’s says Krishna Ella, managing company, Shantha share of the vaccine in the director of Bharat Biotech. Biotechnics. At just Rs18 per Indian market has plummeted To encourage innovation the dose (equivalent to US 40 to 10% from a virtual Department of Biotechnology cents), the vaccine is so monopoly (see graph, below). is supporting the World class: researchers from the Institute of affordable that scenes like The Serum Institute, based in development of 11 original Bioinformatics in Bangalore managed to this are commonplace. Pune, is the world’s largest vaccines. Four of these, for characterize the human X chromosome. Such widespread manufacturer of the diphtheria, rotavirus, cholera, Japanese vaccinations were unthinkable tetanus and pertussis vaccine, encephalitis and malaria, will nology sector is witnessing an impressive 40% early in 1997 when which now protects three out enter clinical trials this year. annual growth,” says Kiran Mazumdar Shaw, GlaxoSmithKline (GSK) sold of ten of the world’s children, Outside of India, the number according to figures released of companies producing chief executive of Biocon, Bangalore. “The its product at Rs500 per dose. But later that year, Shantha’s by UNICEF. The Mumbai- vaccines has dwindled to 4 profile of Indian biotech companies is under- based Haffkine Institute in 2005 from 26 in 1967. This going a change and they are becoming inter- hepatitis B vaccine became India’s first recombinant supplies 75% of India’s oral reduction presents an national.” Biocon, the most profitable product to be made polio vaccine, and Indian opportunity for India and biotechnology company in India, this year indigenously in the healthcare Immunologicals in Hyderabad, other developing countries, posted revenues of US$150 million, a 30% sector. Today this vaccine is already the world’s largest says Ganguly. increase over the previous year. available in 52 countries and manufacturer of vaccines for The Global Alliance for Shaw, sometimes called India’s ‘biotech makes up 40% of UNICEF’s foot-and-mouth disease, plans Vaccine and Immunization, queen’, and several other company chiefs are supply. to make human vaccines launched by the Bill & quickly becoming household names in Varaprasad Reddy says he against rabies, hepatitis B and Melinda Gates Foundation in India. Five of them won this year’s Padma launched the company, named measles. 2000 is purchasing vaccines awards, the nation’s highest honour for civil- after his mother Shantha, after “Not many people are aware from Indian companies at low ians. “Never in the history of these coveted he heard multinational that the United States is one prices. In return, these awards has a small section of the industry companies disparage India’s of the largest importers of companies are assured a grabbed the entire limelight,” says N. Suresh, dependence on them for its measles vaccine from India,” long-term contract to editor of BioSpectrum magazine, published vaccine needs. “India can says Nirmal Kumar Ganguly, guarantee revenue. The in Bangalore. position itself as an affordable director-general of the Indian alliance has awarded The biggest boost to the biotechnology base for producing vaccines Council of Medical Research. contracts to the Serum industry has come from the government itself. for the entire developing But Indian companies are Institute, Shantha “Biotech is the government’s priority area,” world,” he says. only beginning to venture into Biotechnics and Panacea original territory. Biotec to make and test says science minister Kapil Sibal. Less than a Shantha’s success inspired four other Indian companies to “It is true we have not made heat-stable vaccines. year after Sibal took office, the Department of any new vaccine on our own,” K. S. Jayaraman Biotechnology (DBT) released an ambitious bring out their own hepatitis B plan to create a biotechnology industry that would generate US$5 billion in revenues per

year and create one million jobs by 2010. NATIVE COMPANIES DOMINATE INDIA’S PHARMACEUTICALS MARKET 2005 , As part of its strategy, the DBT is planning Multinational companies to make it easier for foreign-owned compa- 100 nies to set up in India. Foreign investors have Indian companies in the past had to knock on the doors of several different government agencies. But the DBT’s new plan is to set up a single independent authority to replace the committees at different ministries. 50 The DBT has also subsidized the construction of three biotechnology parks, including % share, Market Genome Valley (see ‘Land for rent’, overleaf) and aims to help finance at least ten such INDUSTRY PHARMACEUTICAL INDIA’S AND WTO THE 0 parks by 2010. Together with the Ministry of 1970 1971 1978 1980 1991 1996 1998 2002 2003 2004 SOURCE: SOURCE: Information Technology, the DBT plans to Year build the country’s first biotech/IT park. This 481 © 2005 Nature Publishing Group

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LAND FOR RENT K. S. JAYARAMAN S. K.

Beyond the gateway of the Biotech Park near Hyderabad the land lies empty. Companies are reluctant to build there until the infrastructure is complete.

“Welcome to Genome Valley”. Biotech Association. “They did place. The water pipe was laid it manufactures itself. Instead it’s The giant green-and-white sign not listen to me.” only a few months ago. the anti-snake venom stocked in stretches across the road on the In reality, Genome Valley is the To make matters worse, the first-aid kit. “The place is way from the Hyderabad airport Knowledge Park, 40 km from the builders are selling the land at crawling with snakes,” says the to this bustling south Indian city. city on 80 hectares of about US$112,000 per hectare, company’s communication But don’t blame the taxi driver if government land and set up by nearly ten times the government’s manager U. V. L. Ananda. he meets your queries with a ICICI, a premier financial original price. To help employees with the three- blank look — almost no one institution. There is no public “I had no choice,” says hour daily commute, Bharat Biotech knows where the valley is. transport to the area and, at one S. P. Vasireddi, chairman and operates shuttle buses to the city. In Not too long ago, Hyderabad point, cars have to snake through managing director of Vimta Labs, the meantime, there is no hospital, was dubbed ‘Cyberabad’, muddy roads, occasionally who is building a US$10-million bank or police station nearby. ICICI reflecting its strength in interrupted by cows and hens. facility in a 4.5-hectare plot. bank is noted for its cash machines, information technology. These The park offers modern modular “Land of this size is not available but it has yet to set one up in its own days, it’s aiming for pastures laboratory units of approximately inside the city.” Knowledge Park. new: the biotechnology sector. 300 square metres to rent. In the For the moment, the valley has Bharat Biotech buys water from For now though, the ‘genome past six years, 13 companies have one undisputed king: Bharat private tankers and generates its valley’ exists only in the minds rented spaces, and an additional Biotech, built by US-educated own electricity to operate its of those who conceived it eight 7 have booked space. microbiologist Krishna Ella and vaccine unit because the unit in years ago. A second area of the valley his wife Suchitra. “Whenever a nearby Turkapally village crashes The name refers to a 600- is the Biotech Park, which is government guest wants to visit at the slightest environmental square-km area bound by an intended for companies to use the genome valley, he or she is disturbance, such as rain or imaginary line that links nearly for manufacturing units. This brought to our company,” says lightning. The company has every institution in the city that park, which opened in 2001, has Seema Kumar, general manager gleaming state-of-the-art has anything even remotely to an impressive arched entrance to of public relations for the technology, but no broadband do with science. its 126 hectares — but it is company. Internet connectivity and, until “I actually suggested that the almost empty. Officials say 19 Bharat Biotech, which earned recently, workers there could not whole of Hyderabad should be companies have purchased plots US$10 million in 2004, produces use their mobile phones. Says one declared Genome Valley,” says and 7 have begun construction, vaccines, but the most used employee: “We do cutting edge Bhim Sen Bajaj, chairman of the but the promised infrastructure product at the company’s science in such a primitive setting.” southern chapter of the All India for these companies is not yet in headquarters may not be one that K. S. Jayaraman

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is expected to attract bioinformatics When the Bangalore-based Insti- contracts from around the world GROWTH IN DRUG PRODUCTION IN INDIA tute of Bioinformatics (IOB) needs 2005 , and foster innovative companies. 7 someone who knows the computer “We not only want to build on the 6 programming language Oracle, it existing platform but expand the 5 can find a good candidate within a base to create global leadership in week. That’s because there are so biotechnology,” says Maharaj K. 4 many good programmers in the Bhan, secretary of the DBT. “This 3 Industrial Technology Park, where will require larger investments.” the institute is based. The science ministry has already US$ billion Revenue, 2 Akhilesh Pandey, a professor at announced a 50% increase in its 1 the Johns Hopkins University, budget over the past year for drug- 19741981 1988 1996 2003 founded the IOB in 2002. In three

discovery research and called for years, it has published more than 40 INDUSTRY PHARMACEUTICAL INDIA’S AND WTO THE proposals from the industry. Bangalore. And Wockhardt, a large pharma- papers, including several in high-impact jour- To encourage small businesses, the DBT ceutical company, last year built a US$50- nals. In April 2005, the IOB published its SOURCE: SOURCE: gives out grants of Rs5 million (US$115,000) million complex — India’s largest — in annotation of the X chromosome (H. C. Har- for proof-of-concept research and low-inter- Aurangabad. Nicholas Piramal India, which sha et al. Nature Genet. 37, 331–332; 2005). est loans for subsequent product development opened its US$25-million research facility in The study, carried out in direct competition and commercialization. Any money that September 2004, says it already has eight orig- with Britain’s Wellcome Sanger Institute, companies spend on maintaining patents is inal products, including potential treatments marks the first time that any institute other also exempt from income tax. for cancer and diabetes, in preclinical tests. than a genome-sequencing centre has charac- Other generic producers such as Dr Reddy’s terized an entire human chromosome. Patent crackdown Laboratories in Hyderabad and Delhi-based One reason for this increased investment is that Ranbaxy Laboratories are moving along Training biotechnologists from 1 January 2005, a new patent law, which this innovation route even as they continue With a booming biotechnology business and brings India in line with World Trade Organi- to scout for patent-expired generics in the a demonstrated prowess in information tech- zation (WTO) rules, came into effect. Indian US market. nology, there should be a dozen such bioin- companies will have to honour international Still, “the odds are not in India’s favour in formatics success stories in India. But even the patents and stop producing unlicensed generic the innovation driven global drug markets”, big Indian pharmaceutical companies have drugs, a major source of their revenue over the says Prasanta Ghosh, a consultant to Cadila been slow to adopt bioinformatics. past 30 years (see graphic, above). Pharmaceuticals in Ahmedabad and former Although the country grants nearly 300,000 The pharmaceutical industry’s research and adviser to the DBT. “We are nowhere com- degrees and diplomas in biotechnology, bioin- development spending has shot up from pared with China, South Korea, Cuba or formatics and the biological sciences each Rs2 billion in 2000 to Rs8 billion in 2004, Brazil,” he says. “Our research has not gone year, companies struggle to find skilled staff. says D. G. Shah, secretary-general of the into product development.” “Most of them get their degrees without see- Indian Pharmaceutical Alliance. Chennai- Local companies will also have to compete ing a biotech lab,” says Krishna Ella, managing based Orchid, which earned US$82 million on Indian soil with powerful multinational director of Bharat Biotech International in in 2004, is building a US$15-million plant. companies, others warn. Companies such as Hyderabad. Most of those qualified also leave Biocon is adding a US$170-million research Merck and Bristol-Myers Squibb left India for greener pastures: up to 90% of those who lab and manufacturing plant to its assets in years ago because cheap copycat drugs cut into finish their PhDs at the Indian Institute of Sci- their profits. But with the WTO rules enforced ence go abroad. India needs to find ways to to protect their patents, those companies will stem that massive brain drain, says Ella. return, says Yusuf Hamied, Cipla’s chairman. In the meantime, companies are wooing “Multinationals will invade India in force and scientists to India from around the globe.

A. MANDAVILLI A. wipe us out in five years,” he warns. According to estimates from the Indian Companies face other obstacles too. “Biol- Pharmaceutical Alliance, 10% of the new ogy is extremely technology-driven and yet recruits at senior levels are expatriate Indians we do not make any instruments in this coun- or foreigners. try,” says Syed Hasnain, director of the Centre Geetha Vani Rayasam, an IISc graduate, for DNA Fingerprinting and Diagnostics in joined the Ranbaxy Research Labs in Novem- Hyderabad. “Except for flasks and syringes, ber 2004 after spending several years in every instrument is imported. We do not trust Europe and the United States. Rayasam says the local centrifuges, so we import even many more like her would return to India if a these.” Most institutes also have limited access few essential things were fixed. “There are to good animal-research facilities. several things that need to be improved, like a Another problem is the shortage of people more professional approach, less bureaucracy trained in the latest techniques. India’s role in and providing better salaries,” she says. “But information technology is supported by the the day is not far off when India might be massive number of software experts in cities leading the way in drug discovery.” I Science minister Kabil Sibal is backing a plan to such as Bangalore, but such a pool of biotech- K. S. Jayaraman is Nature’s India create a thriving biotechnology sector. nologists is not available. correspondent. 483 © 2005 Nature Publishing Group

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Vaccines on trial

One of the largest ever INSTITUTE VACCINE INTERNATIONAL vaccine studies is under way in Kolkata. Paroma Basu uncovers the benefits, and difficulties, of inoculating 60,000 people against cholera and typhoid fever.

A rhyming couplet written in Bengali invites Kolkata’s residents to receive free vaccinations.

amed for its poets and filmmakers, November, researchers injected the same pop- and human rights groups, Hindu priests, Mus- disgruntled Marxists and sleepy gov- ulation with a vaccine against typhoid fever. lim imams and community thugs. ernment clerks, Kolkata, a city of The typhoid fever vaccine was developed at But the clearances were easy compared with F about 14 million people in northeast- the US National Institutes of Health, and was gaining the confidence of the study partici- ern India, may seem an unlikely setting for donated by GlaxoSmithKline. The cholera pants. During the typhoid vaccine trials, for one of the largest clinical trials in the world. vaccine is modelled on a widely available oral instance, rumours spread that scientists were In the poorest areas of this city, residents vaccine, Dukoral, which was developed in injecting cancer cells into people. Others live in homes jammed together along winding Sweden during the 1970s. believed they were being sterilized. “There sewage-littered pathways and rely on shared But at several dollars a dose, Dukoral is too was mass panic,” Sur recalls. toilets and drinking water. Typhoid fever and expensive for most developing countries. About 65% of the targeted study group even- cholera are endemic in India, and are chronic Vietnamese scientists licensed the technology tually gave their informed consent and received problems in Kolkata. Cholera, in particular, in the early 1990s and formulated a cheaper the typhoid jab. Sur thinks a big reason for this has a tenacious grip on the state of West Ben- version at about 20 cents per dose. level of success was her tactic of employing 250 gal, often called the ‘homeland of cholera’. With the IVI and Kolkata-based National slum-dwellers to serve as the ‘face’ of the study, The vaccine industry has been reluctant to Institute of Cholera and Enteric Diseases working as community health workers, field commit resources to the development of vac- (NICED), Shantha Biotechnics, an Indian supervisors and sample collectors. cines for some of the world’s poorest people. biotechnology company, is developing a local The strategy paid off largely because of But a grant of US$40 million from the Bill & version of the Vietnamese vaccine and has staggeringly high unemployment levels in the Melinda Gates Foundation is helping to intro- procured regulatory clearances for the Kolkata slums. Montu Chandra Das, who was previ- duce affordable vaccines to cities such as trials. It has also secured the right to market ously unemployed, now earns roughly US$60 Kolkata. The money has funded the five-year the vaccine if it is approved, says Raman Rao, per month as a health worker. “It feels good to Diseases of the Most Impoverished (DOMI) head of clinical research for Shantha. help others,” he says. Program, an initiative of the South Korea- Meanwhile, the roadblocks encountered Das goes door-to-door sending patients based International Vaccine Institute (IVI). during these trials in Kolkata are an example with persistent symptoms of diarrhoea or DOMI is studying the social, economic and of the difficulties of carrying out such a pro- fever to one of seven ‘health outposts’, where clinical effects of introducing vaccines into six gramme, from political and religious tensions patients receive free blood tests and medicines other countries: Pakistan, Bangladesh, China, and bureaucratic delays to mistruths spread- if diagnosed with cholera or typhoid. Indonesia, Vietnam and Thailand. Since 2000, ing like wildfire among the largely illiterate “I like the way that the health workers it has launched two cholera studies, six pro- trial participants. come to check on us all the time,” says jects investigating typhoid fever and another The project got off to a smooth start in 2002, Kamala Das, a 35-year old domestic helper six exploring shigellosis, a common bacterial with Kolkata epidemiologists performing a who is taking part in the study. “Now we can disease. The work is unprecedented, says John year-long surveillance study before identifying see a doctor and be treated right away,” adds Clemens, the IVI’s director, not only because two slums that were particularly hard-hit by another study member, Gopal Balmiki, a car of the project’s size but also because it focuses cholera and typhoid fever. But the next step was driver who shares a room with 11 family on a demographic long ignored by drug com- a bureaucratic nightmare, says Dipika Sur, members. “We know now that it’s really panies, lawmakers and public-health officials. deputy director of epidemiology at the NICED. important to keep the bathroom clean and In a unique research effort, 60,000 Kolkata The institute had to get an endless list of clear- drink unpolluted water.” I slum-dwellers will participate this summer in ances from, among others, the national health Paroma Basu is a freelance writer based in phase III trials of an oral cholera vaccine. Last ministry committee, local councillors, ethics Madison, Wisconsin. 484 © 2005 Nature Publishing Group

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oral cancer patients from 1999 to 2000 (see Nature 412, 466; 2001). But the researchers India’s drug tests tested the drugs without the required federal or university approvals and without adequate Drug companies are converging on India to conduct low-cost preliminary tests in animals (see Nature 414, 835; 2001). clinical trials. But is it ready to become the outsourcing centre Following this incident, the Indian govern- for the world? T. V. Padma investigates. ment ordered a full review of the ethics and safety of all trials. In 2000, the Indian Council of Medical Research (ICMR), the country’s he average cost of a clinical trial in all the trials currently under way, despite each premier agency for biomedical research, the United States is US$180 million. one having to be cleared by the Drug Con- issued guidelines for research on humans. The The average cost in India is US$100 troller General of India. following year, the health ministry released its T million. No surprise, then, that In addition, contract research organizations policy on good clinical practice. multinational companies are flocking to India (CROs) are struggling to recruit enough par- But scandals continued to surface. In 2003, to launch their trials. “It’s a lot cheaper to do ticipants to its trials, despite India’s enormous private clinics across India used a generic ver- things in India,” says Sameer Deb, general population. An even greater obstacle is the sion of the anticancer drug letrozole to treat manager of government affairs at Glaxo- lack of trained staff. Trials of this size will need more than 435 women with fertility prob- SmithKline’s office in Mumbai. an estimated 3,000 investigators, 600 medical lems. This trial did not have clearance from Multinational companies are not the only institutions and 9,000 other professionals — the health ministry, and the women involved ones to benefit financially from these studies — numbers India cannot produce at present. did not know that the drug was not approved India does too. The consultancy firm McKinsey Some CROs, in partnership with educational for this use. The manufacturer, Mumbai- estimates that US and European pharmaceuti- institutes and trial sponsors, are addressing based Sun Pharmaceuticals, denies ordering cal companies will spend US$1.5 billion per this by setting up specialized institutes and this trial. year on clinical trials in India by 2010. centres of clinical excellence. Government agencies concede that the reg- India has several advantages as a host for The bureaucracy-ridden Indian system is ulations need to be tightened. “We are looking such trials. Its biggest asset is probably the size no small barrier, either. Officially, the gov- into strengthening institutional ethics com- of its population at more than 1 billion. In addi- ernment has limited the time it takes to mittees and are conducting training work- tion, Indians are increasingly suffering from accredit trials to 90 days for phase I, 45 days shops for them,” says Vasantha Muthuswamy, the same illnesses as Americans and Europeans for phase II and 45 days for phase III trials. deputy director-general of the ICMR. — diseases for which companies are desperate But “we are yet to see such speedy approvals Tightening the regulations will protect the to find cures. For instance, at least 70 million in reality”, notes Dhananjay Bakhle, director trial participants, but it may be possible to go Indians suffer from heart disease and 35 mil- of regulatory affairs at Aventis Pharma, based further. “Participants should benefit from any lion have diabetes. It also has the edge over in Mumbai. drugs that result from the trials,” says Prasanta most developing countries because of its The thorniest issue by far may be the ethics Ghosh, president of the biotechnology divi- sophisticated hospitals and because many of its of conducting these trials. In one instance, sion of Cadila Pharmaceuticals, based in medical personnel speak English. scientists at Johns Hopkins University in Bal- Ahmedabad. In which case, expansion of clin- But India does not have the robust infra- timore, Maryland, and the Regional Cancer ical trials in India could benefit everyone. I structure needed to sustain this expansion. It Centre in Thiruvananthapuram, India, tested T. V. Padma is a freelance writer based in does not even have a central database listing two experimental anticancer molecules on 27 New Delhi. C. STOWERS/PANOS C.

India’s enormous population makes it an attractive destination for clinical drug trials.

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Ayurveda Science and business are racing to tap the 3,000-year- old system of medicine for

new drugs, says T. V. Padma. SPL GOUNOT, CORBIS/BSIP, HEBBERD, L.

n November 1987, ethnobotanist Palpu Ayurvedic herbs Pushpangadan was trekking through the (left) — numbered tropical forests in the southern Indian at more than 10,000 Istate of Kerala. Pushpangadan and his by one source — colleague were struggling to keep up, but their are made into guides, men from the local Kani tribe, kept remedies that are sold popping brownish-black fruit about the size across India (above). of a cardamom pod into their mouths, and walking briskly ahead. Curious, the scientists 3,000 years old and prescribes remedies for a Because plants, in adapting to local condi- ate the fruit and felt a surge of energy. range of problems, from diarrhoea to contra- tions, produce the substances at different stages Locally known as arogyapacha, meaning ception. The Sanskrit classics Atharvaveda, of growth, the herbs must be cultivated and ‘evergreen health’, the fruit, Trichopus zeylani- Charak Samhita and Sushrut Samhita collected in a certain way. The original texts cus, is noted in ancient Indian texts as a source together describe more than 700 medicinal described the specific location, time of year of health and vigour. With the tribe’s help, herbs, cataloguing everything from their taste, and developmental phase of the plant, and this Pushpangadan and his colleagues studied the appearance and digestive effects to safety, effi- knowledge was passed down orally. “The best plant extracts, isolated the active ingredients cacy, dosage and benefits. collection practices have eroded with the pas- and developed an energy-boosting drug, For example, the texts refer to neem sage of time,” says Pushpangadan. Jeevani, combining T. zeylanicus with two (Azadirachta indica) as an antidiabetic, With- With the herbs in hand, scientists must cor- other herbs mentioned in the texts. ania somnifera or the Indian ginseng as an rectly identify the active ingredient, standard- The team patented the drug and granted a antitumour agent, and curcumin — the active ize the manufacturing process, and conduct manufacturing licence to the Indian company ingredient in the spice turmeric — as an anti- clinical trials to test their effectiveness. Arya Vaidya Pharmacy. Sales now garner infective, anti-inflammatory and antidiabetic. nearly US$230,000 a year. Under an agreement Scientists are following intriguing leads that Data mountain signed in 1995, the Kani got a 50% share of the curcumin might have antimalarial activity and There is no centralized database of the herbs US$50,000 licence fee, and have earned nearly inhibit the replication of some viruses. under investigation, but one database of tribal US$5,000 a year in royalties. “The Ayurvedic database in classical texts traditional knowledge at the National Botani- The Jeevani story is one often told in India can be used for bioprospecting and new drug cal Research Institute in Lucknow catalogues as a success both in scientifically validating discovery,” says Bhushan Patwardhan, coordi- more than 10,000 plant species. Of these, traditional knowledge and in setting up a nator of the CSIR’s arthritis Ayurveda project. fewer than 200 have so far been investigated. model that benefits the local population. But that task is easier said than done. Some Ayurveda-based drug discovery uses species have become extinct. Time and envi- ‘reverse pharmacology’, in which drug candi- Updating traditional remedies ronmental factors, as well as pesticide and dates are first identified based on large-scale Today, several laboratories and private compa- heavy-metal contamination of soils and use in the population, then validated in clinical nies are racing to tap the ancient Indian system waters, may also have wrought subtle, but trials. Experts say this approach can cut the of medicine, Ayurveda, for new drugs. The important, alterations in the plant products. time for drug discovery from 12 years to 5 government’s Council of Scientific and Indus- In some cases, there is simply not enough years or less, and for a fraction of the usual cost. trial Research (CSIR) and the health ministry raw material to meet market demand. For Unlike Jeevani, most herb-derived drugs are jointly digitizing Ayurvedic knowledge and example, the Central Drug Research Institute are widely used across India and cannot be translating the information into English, Span- in Lucknow developed an anticholesterol drug, traced back to a particular community. In ish, German, French and Japanese to forestall guggul, from the resin of the tree Commiphora general, there are few guidelines to ensure that contentious patent applications. mukul. The institute patented the drug in the local population benefits from these “India can benefit enormously if it can build Europe and the United States, and in 1987 drugs, notes Darshan Shankar, president of a golden triangle between traditional medi- licensed it to a Mumbai-based company. The the Foundation for Revitalisation of Local cine, modern medicine and modern science,” drug brought in about US$80,000 in sales per Health Traditions in Bangalore. says Raghunath Mashelkar, CSIR director- year, but in 1999, the company was forced to At the moment, even the Kani agreement general. The CSIR has funded three Ayurveda- stop making it because the slow-growing tree has problems. The licence agreement expired based projects seeking drug candidates for failed to produce fast enough. The institute has last year and has not yet been renewed. I arthritis, type-2 diabetes and liver disease. since developed a synthetic version of the drug, T. V. Padma is a freelance writer based in The Ayurvedic system of medicine is nearly which is set for phase III clinical trials in June. New Delhi. 486 © 2005 Nature Publishing Group

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Perhaps federal research grants can include infrastructure costs. Breathing life There are signs that the government is responding to these concerns. In March 2005, the Science Advisory Council recommended into biology setting up a National Science and Engineering Research Foundation, on the lines of the US National Science Foundation, to support Mriganka Sur says that life sciences will prosper in India research in various disciplines. Universities once research and teaching reconnect. are expected to be important beneficiaries. As funding for these universities increases, there should be accompanying changes in hen I was a teenager, I thought and instruments. At some biology depart- culture. Research and teaching should be I had only two choices — to be ments, even introductory procedures such as valued as mandatory components of faculty a doctor or an engineer. Grow- DNA extraction are merely described. appointments and promotions. Universities Wing up in Allahabad in the This unfortunate division between research should also institute periodic review of the northern state of Uttar Pradesh, students and teaching runs deep. The Indian govern- faculty members; this approach is also begin- like me were so frequently asked to choose ment decided more than 50 years ago to create ning to find favour in China, a country beset between these two careers that most of us focused research institutes. The scheme set up by similar problems. never considered any other options. Becoming distinct priorities: universities would focus on The particular structure of Indian science a biology researcher did not figure on the list. teaching, and the institutes would concentrate also suggests solutions. For instance, funding There is no question that to capitalize on on research. That policy led to a handful of agencies might consider establishing long- the life-sciences and biotechnology revolu- excellent scientific institutes but also impov- term research faculty positions within univer- tion, India must build excellence in life-sci- erished university-based research. There is no sities. New research centres could be closely ence training. In most countries, this is the shortage of funds for university research or allied with or even located on university cam- task of universities. Unfortunately, the Indian teaching laboratories, but a heavy teaching puses. The researchers would be required to university system is in serious decline — load, an overly bureaucratic system of teach in the university, and university students acknowledged to be so both within India and appointments and promotions, and the lack of would have access to research labs. elsewhere — and unequal to this task. infrastructure have all made it difficult to One model for effectively integrating As it turns out, I eventually became a recruit capable researchers. research and teaching already exists within the neuroscientist, driven mainly by my interest The institutes, meanwhile, have good IITs. These institutes continue to attract the in understanding how the brain works. I research projects, but little teaching. Yet good best Indian undergraduates in engineering and never had a university-level course in biology researchers are also often the better teachers. the physical sciences, and give them a world- — there were simply none to be taken at the Still, many institutes have begun training class education. Their success has positioned Indian Institute of Technology (IIT) in Kan- students by evolving grad- India as a key player in the pur, where I studied electrical engineering as uate-level courses for IT industry. One small step an undergraduate in the early 1970s. But in a small classes. Unfortu- towards boosting the life E. QUINN E. sign of the increasing importance of the life nately, the top students sciences may be to encour- sciences, the IITs are beginning to embrace who train at these insti- age the IITs to expand their biology. When I went back to give a lecture at tutes often choose to leave biological sciences cur- the IIT Kanpur a few years ago, I was asked to India and complete their riculum. But that cannot advise the institute on its newly created PhDs abroad — at least in be the only solution, if only Department of Biological Sciences and Bio- part because few of the because a wider transfor- engineering and a new programme in cogni- centres can match the mation is needed. tive sciences. breadth of education at a Innovation in universi- At the IIT Kanpur, I attended classes taught first-rate university in the ties is part of a broader by excellent teachers and had a few hands-on United States or Europe. theme in how a society projects. But the IITs are largely an exception. What might be done? educates not only its élite Most Indian universities are ill-equipped to There is little question but all of its citizens. A tackle the complex, interdisciplinary nature of that the government hard look at education in modern biology. Faculty members at both should actively support the life sciences is particu- undergraduate teaching colleges and univer- university-based research. larly urgent for a country sities offering advanced degrees are largely Universities need help in such as India, which has concerned with teaching, and tend to focus upgrading their research both a strong need for more on theory than on experimental science. infrastructure and labora- development and the But as most scientists can attest, research and tories, and in recruiting ambition to match it. I teaching are inseparable components of a scientists with dedicated Mriganka Sur is head of the modern science education. research space and Department of Brain and Many Indian universities don’t have the healthy start-up packages. Cognitive Sciences at the equipment or the faculty members and staff to The government could Indian universities focus on theory rather Massachusetts Institute give students a solid grounding in techniques contribute to these costs. than experiments, says Mriganka Sur. of Technology.

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Coming home M. SUDHAKARAN M. Reagents may be slow to arrive, but the freedom to explore his own research interests more than compensates. Satyajit Mayor is thriving in India.

t can never be the same as doing and they’re leading produc- science in America.” This was the tive lives at the many small- near-unanimous response from sized institutions that are “I my peers when, in late 1995, I committed to competing in announced my decision to move back to India the international arena. from the United States. By then, I had spent The National Centre for nearly 11 years in America, first as a graduate Biological Sciences (NCBS) student at Rockefeller University and then as in Bangalore recruited me a postdoctoral fellow at Columbia University. in 1995, and I have Like most expatriates who long to return remained here ever since. home, I had planned for many years to return The centre was set up in Happy times: Satyajit Mayor enjoys his membrane-biology research to India — but I kept putting it off. I worried 1992 as an arm of the at the National Centre for Biological Sciences in Bangalore. that my career in India would become marked Mumbai-based Tata Insti- by obscurantist science, an ossified research tute of Fundamental Research. The founding was the adjustment to life in an Indian city set-up and cash-strapped institutes; that I director, noted Drosophila geneticist Obaid after living in New York. I was also not look- would be surrounded by mediocre science and Siddiqi, wanted to establish an institute where ing forward to confronting the depressing scientists; and that I would have to wait for a diverse group of people with distinct political reality in India at the time. (Happily, weeks for supplies that can be in summoned in approaches to biology could do world-class things have changed for the better, thanks to New York within a day. research. I knew from the beginning that this India’s democratic tradition.) But exciting Happily, I was wrong on most counts. would be a good place. scientific interactions at the NCBS and else- And I’m not the only one. Like me, many Since its launch, the institute has moved where in India have been more than adequate other researchers are choosing to return home, into a much bigger campus and hopes to grow compensation for these travails. from its current 15 research groups to a full Beating bureaucracy PUBLICATION RECORD OF THE NATIONAL capacity of around 40 teams. Together, NCBS CENTRE FOR BIOLOGICAL SCIENCES researchers published 60 papers in 2004, When I joined the NCBS, my area of research,

Year Total no. of Publications in high- including 18 in high-impact journals such as cell biology, was not yet the focus of much publications impact journals Nature and Cell (see table, left). study there: protein structure and develop- The institute’s current director, K. Vijay- mental neurobiology were more in vogue. I 1997 24 Nature Struct. Biol. (1) Raghavan, is generous to a fault, and accom- had trained almost entirely outside India so I 1998 23 Nature (1) modates the most outrageous of whims of his had very different expectations when I 1999 26 colleagues in the interest of furthering sci- arrived, but I was able to shape my environ- 2000 28 Nature (1), Development (1), ence. Most laboratories at the institute are ment as much as it shaped me. For example, J. Mol. Biol. (3), Curr. Biol. (1) engaged in research on different biological my colleagues and I have helped to create an 2001 28 Nature Struct. Biol. (1), Dev. Cell (1), Virology (1), scales — from understanding the structure of administrative structure that is both efficient EMBO J. (2), J. Mol. Biol. (2) molecules to the evolution of behaviour. My and responsive to our needs. This is some- 2002 35 Science (1), J. Mol. Biol. (1), own lab aims to unravel the molecular mech- thing most scientists in developed countries Development (1), Dev. Cell (1), anisms of endocytosis, the process by which might take for granted, but revising the old J. Neurosci. (2), Cell (1), cells internalize viruses or molecules, using a bureaucracy-ridden model is an important 2003 45 Virology (1), EMBO J. (1), multidisciplinary approach that combines step forward for Indian science. J. Neurosci. (1), J. Cell Biol. (1), biology, physics and chemistry. Upon arrival, my priority was to set up my Immunology (1), J. Cell Sci. (1) Being a researcher in India is not as diffi- laboratory, and the NCBS seemed to share this 2004 60 Science (1), Mol. Cell. Biol. (2), cult as I had expected. In some ways, my tran- emphasis, something that is rare at most Indian Virology (2), J. Neurosci. (2), J. Cell Sci. (1), Development (2), sition from being a privileged graduate institutes. Still, some of my fears were legiti- J. Mol. Biol. (2), Cell (1), student at Rockefeller University to a post- mate. When I was at Columbia University, for Neuron (2), Immunology (2) doctoral fellow at Columbia University was instance, I could simply pick up the phone and 2005 20 (up to June 2005) more of a culture shock than my move to the have reagents instantly delivered to my bench. Nature Struct. Mol. Biol. (1), NCBS, where the scope of my research is lim- Here, it can take up to four weeks depending J. Virology (1) ited only by my imagination. More difficult on where the manufacturer is located. 488 © 2005 Nature Publishing Group

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Another formidable challenge is convincing (see ‘Wellcome funding’, below). Such inter- scientific base. Institutions such as the NCBS customs officials that my high-resolution cam- national agencies have helped bridge the can help accomplish this goal. Another ten eras need not be exposed to the elements while gap between the salaries in India and more similar institutions could completely trans- numerous public holidays pass by. Things have developed countries. form the nature and quality of biological changed for the better as suppliers have set up Wellcome Trust fellows are required to pro- sciences in India. If these institutes then form shop in or near Bangalore, but there is much vide frequent research reports and attend productive alliances with universities, they room for improvement. meetings to evaluate progress, which ensures could tap into India’s vast student pool. At the For the majority of Indian researchers, pub- that they stay focused. A major flaw in India’s very least, this could boost the woefully under- lication in prestigious international journals is system is that the funding agencies seem to funded and often stifling university depart- as much a marker of success as it is elsewhere. expect little intellectual return on their investments. The much touted biotech revolution in But scientists here have not been able to fully ment, which can breed complacency. India may even acquire well-trained scientific meet this goal.Most of my colleagues in India One of the biggest attractions as a scientist personnel and a semblance of reality. believe that this is, partly, the result of a bias, in India today is the freedom to take on In an encouraging development, the gov- conscious or unconscious, against Indian sci- unusual and innovative projects without ernment in February this year announced a ence. The critical mass of biologists — except much interference. Because the pool of active US$250-million National Science and Engi- perhaps in protein chemistry (see page 494) researchers is small, it fosters truly multidisci- neering Research Fund to fund basic research — in India is too small to have any visibility in plinary collaborative links. I have been able to in India. The goal is to establish two inte- international publishing. The lack of name forge meaningful collaborations with a con- grated universities to teach and train a new recognition may make it easier to dismiss densed-matter physicist, a fruitfly geneticist breed of basic scientist, the most important exceptional and controversial work from interested in neuronal conduction and a resource for a productive scientific future. I unfamiliar institutions. physiologist of the immune system. Satyajit (Jitu) Mayor is an associate India’s biological research enterprise professor at the National Centre for Manual work requires a broad and visibly multidisciplinary Biological Sciences, Bangalore. At many of the biology-based institutions in India, almost all the work is done by graduate students, and they can take up to four years to WELLCOME become productive. This is the result of an educational system that prevents students FUNDING P. ANIL KUMAR from getting their hands wet, partly because the system does not value experimental train- Many of Indian biology’s ing and partly because of a genuine lack of rising stars, such as Satyajit resources. One reason for this is a bias against Mayor (see main text), are manual work among the élite classes who recipients of the Wellcome populate the universities. Fortunately, this Trust International Senior seems to be changing (see page 487). Research scheme. Although the graduate-student pool gener- These fellowships, awarded ates a group of committed researchers, the for five years and renewable for another five, are highly lack of a vibrant postdoctoral research culture coveted because of their size is the sign of an unsophisticated research — bigger than the budget of Rajan Sankarnarayanan’s fellowship money helped to pay for community. Some institutions in India are the science departments in his state-of-the-art structural biology laboratory. beginning to recruit postdocs from around some Indian universities — the world, albeit slowly. But even among and because they can be used Harbor Laboratory Press. to return after postdoctoral Indian students, going abroad to train is still flexibly. In 2004, 14 scientists Sanjeev Galande, a fellow training abroad and establish the most attractive option. The handsome from India were interviewed at the National Centre for their own laboratories in the salaries offered by research positions in for the grants; all won. Cell Sciences, has also home country,” says Europe and the United States are no small Unencumbered by the published six papers in Sankarnarayanan. factor in their decision. More attractive pressure to raise their own prestigious journals in the Altogether, 37 Indian salaries would go a long way to retaining money, many of the fellows past four years. biomedical researchers researchers in India. are doing very well. Utpal Rajan Sankarnarayanan, have benefited from the At 1.1% of the gross domestic product, Bhadra, a fellow at the Centre another fellow at the CCMB, grant. The trust has also India’s budget for science is woefully inade- for Cell and Molecular used his Rs33 million supported researchers in quate. But the government has pledged to Biology (CCMB) in (US$800,000) award South Africa since 1992 and increase this to 2% by 2007. Already, funding Hyderabad, has co-authored to set up a world-class in Central Europe since opportunities for biological sciences in India six papers in high-impact crystallography lab to study 2002. These countries are at an all-time high. Several agencies fund journals, including Science, protein structure with shared 15% of the funding; projects and any well-structured proposal has Nature Genetics and Molecular equipment that would the rest was earmarked for otherwise have been out scientists from Britain. But a high chance of getting funded. Cell, since his return to India in 2002. His book on RNA of his reach. from 2005, all applicants In addition, researchers have access to interference, written with his “This kind of fellowship has will have to compete with international agencies. The arrival of the Well- wife, a 2005 fellow, is to be helped many young UK scientists. come Trust in India six years ago wooed many published by the Cold Spring scientists, including myself, K. S. Jayaraman young talented researchers back to India 489 © 2005 Nature Publishing Group

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Rivalry and red tape Researchers are suffering as a result of the conflicts between funding agencies. T. V. Padma uncovers plans to heal the rift.

radeep Seth has given up. For nearly back to square one,” says Seth. A new commit- Awaiting approval: Pradeep Seth waited for two years, Seth, a microbiologist at tee then recommended in November 2004 more than two years for the go-ahead from the the prestigious All India Institute of that trials on the vaccine should proceed with- government for phase I trials of his HIV vaccine. P Medical Sciences (AIIMS) in New out further delay. Then the health secretary, Delhi, has been awaiting word on his HIV who had to okay the licence agreement, ICMR funds projects in epidemiology and vaccine candidate from the health ministry. retired. “Again back to square one,” says Seth. clinical research. Seth’s vaccine research was funded by the Finally, a third committee reviewed the vac- In theory, the health and science ministries Department of Biotechnology (DBT), part of cine in February 2005. This committee, led by would coordinate research. “In practice, how- the science ministry. He published his work in Nirmal Kumar Ganguly, director-general of ever, overlaps do take place,” says Martanda peer-reviewed journals and received positive the Indian Council of Medical Research Sankaran Valiathan, former president of the feedback from several evaluation committees. (ICMR) — the research arm of the health min- Indian National Science Academy. In March 2003, the DBT gave him the green istry — recommended on 29 March 2005 that These glitches occur despite representatives light to form a partnership with an Indian the trials should proceed. By then Seth had from funding agencies sitting on each other’s company and manufacture the vaccine for almost retired. committees and asking applicants to note phase I human trials. whether they receive funds from elsewhere. Everything went according to plan. A com- Lack of coordination Some projects can be neatly classified as mittee at the AIIMS helped Seth select an Seth’s story is well-known in Indian academic basic or clinical, but increasingly there are industrial partner and write a licence agree- circles. Some say the story is a tragicomic case many projects that are ‘applied’. Stem-cell ment. The institute’s legal and financial depart- of classic Indian bureaucracy. But others say research falls squarely into this hazy overlap. ments approved the agreement. Then, in the events are no accident. Seth’s vaccine did No single government agency in India has December 2003, an over-cautious AIIMS not fare well because of a deep-seated rivalry been assigned responsibility to licence or director sought additional approval for the between the DBT, which funded his research, monitor stem-cell work. As a result, the DBT agreement from the health ministry. Seth has and the ICMR, they say. “Most DBT-funded and the ICMR each issued guidelines — the been waiting for that approval ever since. projects in the AIIMS have met a similar fate,” DBT in 2001 and the ICMR in 2002 — with- The quality of the potential vaccine does not says Seth. out consulting each other. The result was a seem to be the problem. The healthy ministry There are several branches of government plethora of public- and private-funded insti- formed a committee to review the vaccine in that fund biomedical research, but money tutes that joined the stem-cell bandwagon. December 2003. But before it made a decision, comes primarily from the health ministry, Researchers at Nutech Mediworld, a private India headed for national polls, and a new which finances research through the ICMR, clinic in Delhi, say they have used stem cells to government took charge in May 2004. “It was and the science ministry, which oversees the successfully treat paralysis in 24 patients since DBT, the Department of May 2003; their work is as yet unpublished. OVERALL BUDGETS OF KEY FUNDING AGENCIES Science and Technology P. Venugopal, a surgeon at the All India Insti- and the Council of Sci- tute of Medical Sciences in Delhi has used 350 Council of Scientific entific and Industrial bone-marrow derived stem cells to repair dam- and Industrial Research (see graph). aged heart muscles (see Nature 434, 259; 2005). 300 Research Each agency has — or And the L. V. Prasad Eye Institute in Hyder- 250 is at least supposed to abad has since 2001 used limbal stem cells to 200 have — a well defined repair damaged corneas in 260 patients (V. S. 150 Department of role. For example, the Sangwan et al. Biosci. Rep. 23, 169–174; 2005). Department of Science The competition between the DBT and the

US$ million Biotechnology 100 and Technology looks ICMR in particular has been the focus of 50 Indian Council of after basic research; the much discussion among researchers. “Greater Medical Research 0 DBT focuses on the collaboration between agencies is a critical

01 –04 development of biotech- issue,” says secretary of the DBT Maharaj nology products and Kishan Bhan. “Our research efforts are getting 2001–02 2002–03 2003 2004–05 2005–06 2000– processes; and the fragmented because of this lack of coordina- 490 © 2005 Nature Publishing Group

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tion.” If the different departments worked year while their application is processed, and petence,” says Sandip Basu, director of together, they could avoid duplication and months more to get the money after approval. National Institute of Immunology in Delhi. “It save enormous resources, Bhan says. “Right The funds go to the institution and not to the is not easy to take severe disciplinary action, now all agencies work subcritically.” investigator, so additional delays occur during and all jobs are until retirement,” he says. Bhan, who has led the DBT since 2004, and the transfer of money to the researcher. Some delays are entirely avoidable, Basu Ganguly both say they are taking steps to put Researchers have to submit nearly 30 adds. These are the ones agency chiefs are an end to the famous rivalry.After much dis- copies of their proposal to funding agencies committed to cutting down. Some researchers cussion, the two agencies have agreed to meet such as the ICMR. So cumbersome is the red are reporting that recently submitted proposals in June 2005 to combine the two sets of guide- tape that in January 2005, at the opening of to the Department of Science and Technology lines. They are also jointly drafting a national the science congress in Ahmedabad, prime and the Council of Scientific and Industrial stem-cell initiative and plan to work together minister Manmohan Singh lamented the Research cleared in six months. What’s more, on HIV vaccines and microbicides. “tyranny of bureaucracy” in Indian agencies. the process required only two hard copies: the He went on to ask whether India has “allowed rest was handled through e-mail. A waiting game bureaucratic systems and patron–client rela- But this may have all come too late for Seth Another area of researchers’ lives that could tionships to stifle creativity” and “scare away” whose last working day was 30 April. “I am be improved is that of paperwork. For exam- young researchers. through with it,” Seth says. I ple, to get a grant approved, Indian scientists “Most of the red tape is due to the fact that T. V. Padma is a freelance writer based in have to be prepared to wait for more than a there are no serious consequences for incom- New Delhi. A TOUGH JOURNEY To outsiders, Vijaylakshmi R. PATHANIA/LINKINDIA PATHANIA/LINKINDIA R. Ravindranath’s story might seem a resounding success. In 2000, she was appointed director of the nascent National Brain Research Centre in Manesar, on the outskirts of New Delhi. But her achievement did not come easily. When Ravindranath was a postdoc at the US National Institutes of Health, her husband, also a scientist, remained in India. She initially took her two-year-old Vijaylakshmi Ravindranath is one of the very few high-achieving women scientists in India. She is the son with her, but, unable to arrange director of the National Brain Research Centre, near New Delhi, but she could not have reached this position for his care when she was in the without the support of her husband and son. lab, she sent him to be looked after by her parents. “I had to be away nine of 398 Shanti Swarup and co-chair of an international The government is beginning during two critical years of my Bhatnagar awards, India’s highest advisory panel on women to take action. In 2003, the son’s childhood,” she recalls. honour for science, went to scientists. Department of Science and Twenty years later, she was once women.Within the INSA, women Apart from the usual factors, Technology initiated a scheme to again faced with a difficult choice. have won only 14 of the such as marriage and lack of offer fellowships to women whose The offer to head the new centre academy’s 502 awards and adequate childcare, Indian women careers were interrupted by their was a rare opportunity, but it medals, and no woman has ever also have to endure the country’s husbands’ geographical moves. meant a five-year separation from led the academy. staunch patriarchal culture. Many More than half of the 2,000 her husband and son. “Had my Like their counterparts complain that male colleagues applicants were from life sciences. husband and son not cooperated, worldwide, Indian women do not treat them as peers and Women scientists particularly it would have been impossible,” scientists fare better in biology often assign them to reception need assistance when they are she says. than in engineering or physics. In committees or to choosing menus struggling to balance their early Ravindranath is one of the 2000, women accounted for 32% for conferences. career with a growing family, says lucky few. Unable to juggle of medical students, compared Women also face considerable Ravindranath. “If the woman can professional and domestic with 16% in engineering. But, as bias in the interview process, says tide over the period of marriage demands, and sometimes coping elsewhere, there is a steep drop-off Sharma, who has served on the and child rearing, a critical mass of with nepotism and sexual in women at graduate level. Many interview committees of several women scientists can develop in harassment, most Indian women of those who continue opt for a national institutes. “I have noticed biology,” she says. “Today, my scientists give up early in their career in medicine or teaching, a tendency to ignore the excellent son and husband are among the careers. According to a 2004 rather than research, says Manju career records of women proudest and happiest about report of the Indian National Sharma, former secretary of the scientists when it comes to my success.” Science Academy (INSA), only Department of Biotechnology selecting top positions,” she says. T. V. Padma

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Among the best India’s life-sciences institutes are rewriting the rule books for research. K. S. Jayaraman finds that they are focusing on higher standards and enterprise.

ust two years ago, the tree-lined roads The Indian Department of Biotechnology is on the campus of the Indian Institute of encouraging this trend by allowing faculty Science (IISc) in Bangalore were a jog- members to hold positions in industry and J gers’ paradise. The only sounds were academia simultaneously. It has earmarked those of rustling leaves and chirping birds. 30% of its US$105-million budget for 2005–06 These days, blaring horns and speeding to such partnerships. Toyotas are more the scene, occasionally forc- A similar scene is being played out all over ing terrified pedestrians into the wedge- the country. With nearly 450 faculty members shaped drains on the sides of the roads. in disciplines ranging from biochemistry to “Everyone here is in hurry,” says S. Vijaya, a metallurgy, the IISc is the largest and the most professor of microbiology at the institute. established Indian institute. But a handful of This flurry of activity is a result of a radical smaller life-sciences institutes that have culture change at the IISc, widely considered sprung up in the past decade are also rewriting India’s premier scientific institute. Fourteen the rules of Indian research. “We have suc- companies — including Belgium’s Janssen ceeded in setting higher standards for our- Pharmaceutica and New Jersey-based selves and achieving them,” says G. C. Mishra, Novozymes Biologicals — now rent labora- director of the National Centre for Cell tory space on campus. Researchers at the IISc Sciences (NCCS) in Pune. have acted as consultants for 161 companies Not everyone is happy with this change. For and completed more than 100 projects in the many Indian researchers, making money from past ten years. And in the past three, five pro- science is an uncomfortable concept. Hindu fessors have launched their own companies. mythology even holds that Lakshmi, the

The massive size of India's STRENGTH IN NUMBERS population has always been seen as its biggest weakness, but geneticists are turning this burden into a boon. India could be the ideal place to study complex diseases. “Given the enormous genetic

M. HENLEY/PANOS M. diversity, India has a strategic advantage,” says Samir Brahmachari, director of the Institute of Genomics and Integrative Biology in Delhi. With roughly one-sixth of the world’s population, India is home to 4,693 communities, 532 tribes, 325 functional languages (representing four major linguistic groups) and 25 distinct scripts. Because members of many of these communities tend to marry within their group, they have evolved over time into distinctive gene pools. To map genes for complex diseases, researchers have often turned to geographically isolated groups such as those in Iceland or Estonia. But Indian ethnic India’s huge and diverse population is an asset to researchers studying complex genetic diseases. groups are genetically more

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Leading the way: the Indian Institute of Science in Bangalore is the most productive of India’s life-science institutes.

goddess of wealth, and Saraswati, the goddess of learning, cannot coexist.

“Half of us would be happy teaching and SHARMA S. publishing papers,” says P. N. Rangarajan, associate professor of biochemistry at the IISc. But the other half are making the most of this new opportunity. Rangarajan is firmly in the latter group: this year he won an award for transferring the DNA vaccine he developed against rabies into a commercial setting. His vaccine can be stored at room temperature and so is ideal for tropical countries. The IISc licensed the technology to Hyderabad-based company Indian Immunologicals. But this achievement came at a price for Rangarajan. His promotion was delayed by two years because the number of papers he published declined during the time he spent with his industrial partner. Measuring success This attitude is slowly changing, but many administrators still insist that academic pur- suit should be the faculty’s first priority. “Our basic objectives continue to be research and teaching,” says G. Mehta, director of the IISc. “If the faculty finds time to hold hands with industry, that is welcome.” Some researchers feel that this attitude is a little short-sighted. “We should have a different yardstick for assessment,” says Govindarajan

homogeneous than the Icelandic find genes associated with human note repeats of nucleotides and based CCMB are also studying population, says Partha Majumdar, disease and response to compare their frequency across disease susceptibility in various head of the human genetics unit at pharmaceuticals, asked Majumdar different groups. Brahmachari's castes and tribes. In collaboration the Indian Statistical Institute (ISI) for samples from some Indian team has already collected with the Anthropological Survey in Kolkata, who compared ethnic groups. But the ISI does not samples from more than 40 of India and 15 universities, the published genetic data of Icelandic have the technology to be a proper populations, but because the researchers have collected more populations with those of ethnic partner in this project, and report is unpublished, he declined than 9,000 DNA samples from Indian groups. Majumdar says he declined to reveal further details. 130 groups. In India, it is possible to study because he did not want only Other genomics projects are From these samples, scientists genetic variation both within to supply samples. also under way in increasingly have already identified genetic and between communities, The Indian project’s goal is to well-equipped labs at the diseases that are particularly Brahmachari adds. He is collect blood samples from Institute of Genomics and prevalent among certain groups, coordinating a five-year 15,000 individuals drawn from Integrative Biology, the Centre for says Kumarasamy Thangaraj, a US$5.8-million project that different communities across the Cellular and Molecular Biology researcher at the CCMB. includes researchers from his country, select about 1,000 genes (CCMB), the Centre for DNA For example, the Onges tribe has institute and five others under relevant to complex diseases Fingerprinting and Diagnostics in dwindled to only 98 people from the Council of Scientific and common in India and assess any Hyderabad, the Indian Institute of 700 in 1858. Genetic analysis of 46 Industrial Research. Launched differences in drug response. The Science in Bangalore and the members of the tribe has revealed in 2003, the Indian Genome scientists plan to study candidate University of Delhi. 23 mutations in the mitochondrial Variation consortium aims to map genes reported by other groups as In November 2004, India genome and deletions of some genetic markers for diseases such well as any new ones that crop up. agreed to take part in a pan-Asian Y-chromosome genes needed for as diabetes, cancer and heart The team plans to record DNA initiative to study genetic sperm production. disease. The ISI will analyse the sequence variations that occur diversity and similarities in Asia. “It is astonishing that in several data from the project and help when a single nucleotide in the The ten-nation study, an initiative populations, the load due to choose sample populations for genome sequence is altered. of the Pacific chapter of the genetic diseases is so high it is the studies. These are known as single Human Genome Organisation, is leading to their extinction,” says In 2003, the International nucleotide polymorphisms or slated to begin later this year. Thangaraj. HapMap Project, which aims to SNPs. The group also hopes to Researchers at the Hyderabad- T. V. Padma

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STRONG

BONDS SUBRAMANIAN E. Basic research in the life sciences has not been India’s strong suit. But in one field — protein science — Indian researchers have made their mark. India’s love affair with proteins began more than 50 years ago, when G. N. Ramachandran, a physics professor at the University of Madras, and his colleague, G. Kartha, used X-ray data analysis to unveil the triple-helical structure of collagen, one of the most abundant proteins in mammals. Highly respected: Indian scientist G. N. Ramachandran (first row, centre) made a significant contribution to The X-ray machine was the field of protein science. Here, he is shown sitting next to his wife (first row, second from left). primitive, and Ramachandran Ramachandran is talking animatedly with S. Ramasesham (first row, fourth from left), another eminent performed painstaking manual crystallographer. G. Kartha, the co-discoverer with Ramachandran of the triple-helical structure calculations to work out of collagen, is seated in the fourth row (far left). collagen’s structure. He also came up with a formula, later produce groups of people and prefer projects that rely more on among Indian scientists. dubbed the Ramachandran enough institutional expertise to individual creativity and Countries around the world may plot, to predict the conformation work on both protein physics and competence because they fear be able to benefit from India’s of proteins. During his career, protein chemistry, which proved large groups will detract from expertise. “With rising costs and he trained several biophysicists to be an advantage,” says individual recognition, says the closure of some chemistry who worked with him first in Padmanabhan Balaram, a Govindarajan Padmanaban, departments in the United States Madras, now called Chennai, protein physicist and chairman scientist emeritus at the and Europe,” Balaram says, “India and then at the Indian Institute of biological sciences at the department of biochemistry at could become a destination for of Science (IISc) in Bangalore. IISc. In the 1980s, the field the IISc. “Indian scientists on the outsourced chemistry research Around the same time, received a further boost when whole do not integrate in large and development, including teaching and research in government agencies began groups,” he says. theoretical work such as the study biochemistry gained ground providing funds to buy equipment Because protein research of protein dynamics and in India, and scientists from for selected centres. rarely requires large computer modelling for drug both disciplines began to Work on proteins also suits the interdisciplinary collaborations, design.” collaborate. “India could thus research culture. Indian scientists it has remained a popular choice T. V. Padma

Padmanaban, a biochemist and former direc- Biology (IGIB) in Delhi US$460,000 each year commercial applications. The institute also tor of the IISc, who has discovered a potential as a ‘knowledge’ fee. The arrangement allows supports scientists who launch biotechnology drug target for malaria. “Publication is not the company to develop any leads the insti- companies by granting them ‘entrepreneurial everything,” he adds. tute’s researchers find. The alliance has leave’, making it a popular partner for multi- The rules are a bit looser at the government already resulted in two joint patents. A poten- national companies. General Motors has laboratories, such as those under the Council tial drug against tuberculosis that has shown invested US$1.4 million and Boeing of Scientific and Industrial Research (CSIR). promise in animal studies is the outcome of a US$500,000 in research at the IISc. In 2000, the CSIR launched a programme to similar alliance between Mumbai-based The IISc is careful to accept only projects promote partnerships with industry. Lupin Laboratories and four CSIR institutes. that involve innovative research. The Society For instance, since 2001 Mumbai-based To promote technology transfer, the IISc for Innovation and Development, the com- Nicholas Piramal India has been paying the has launched an ‘incubation’ centre, where mercial arm of the institute, has turned down CSIR’s Institute of Genomics and Integrative faculty members help students to develop about US$20 million in projects because they

COMPARISON OF FOUR HIGH-PROFILE INDIAN LIFE-SCIENCE RESEARCH INSTITUTES IN 2004–05

No. of faculty No. of No. of No. of faculty members Percentage of faculty members publications patents educated abroad members trained abroad Indian Institute of Science, Bangalore 450 1,367 25 129 98 National Centre for Cell Sciences, Pune 24 37 6 16 96 Centre for Cellular and Molecular Biology, Hyderabad 88 111 15 20 80 National Centre for Biological Sciences, Bangalore 21 49 Nil 14 100

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lacked research content, says S. Mohan, the PRODUCTIVITY OF NATIONS BASED ON THEIR PUBLICATION RECORD society’s chief executive. “Even then, the Publications Publications demand from companies is so great we cannot Country No. of publications GDP per GDP per GDP per capita cope,” he says. Country classification (1997–2001) per capita per capita per year Some partnerships with industry are provid- India IDC 77,201 487 158.52 31.7 ing much-needed training for young scientists. China IDC 115,339 989 116.62 23.32 For example, Hyderabad-based Bharat Biotech United States G8, OECD 1,265,808 36,006 35.16 7.0 has trained nearly 500 interns in biotechnol- Brazil IDC 43,971 2,593 16.96 3.39 ogy. In addition, 12 students of Jawaharlal Nehru Technological University in Hyderabad Germany G8, OECD 318,286 24,051 13.23 2.64 are doing their graduate work at the company. United Kingdom G8, OECD 342,535 26,445 12.95 2.59 Japan G8, OECD 336,858 31,407 10.73 2.15 Critical mass South Africa IDC 18,123 2,299 7.88 1.58 With more than 1,300 papers published in Canada G8, OECD 166,216 22,777 7.30 1.46 peer-reviewed journals last year, the IISc is the Italy G8, OECD 147,023 20,528 7.16 1.43 most productive of the Indian institutes (see table, left), and continues to enjoy the govern- PRODUCTIVITY OF NATIONS BASED ON THEIR CITATION RECORD ment’s favour. In February 2005, the govern- Citations Citations ment gave the institute a massive grant of Country No. o f citations GDP per GDP per GDP per Country classification (1997–2001) per capita per capita capita per year US$24 million. But in the past ten years, a handful of other India IDC 188,481 487 387.02 77.40 institutes have begun to make their mark. The China IDC 341,519 989 345.32 69.06 National Centre for Biological Sciences in United States G8, OECD 10,850,549 36,006 301.35 67.27 Bangalore, an offshoot of the famous Tata United Kingdom G8, OECD 2,500,035 26,445 94.54 18.91 Institute of Fundamental Research in Mum- Germany G8, OECD 2,199,617 24,051 91.46 18.29 bai, produced India’s first paper to be pub- Brazil IDC 155,357 2,593 59.91 11.98 lished in the high-profile journal Cell just four Japan G8, OECD 1,852,271 31,407 58.98 11.79 years after it moved to its own building in Canada G8, OECD 1,164,450 22,777 51.12 10.22 Bangalore. The institute’s faculty members Italy G8, OECD 964,164 20,528 46.97 9.39 were recruited almost entirely from the United States, and they work under a US-style Australia OECD 623,636 20,822 29.95 5.99 Source: D. A. King Nature 430, 311–316 (2004). IDC, internationally developing country; OECD, Organisation for Economic Co- contract system: scientists are hired for five operation and Development. years and their performance is periodically reviewed by the institute’s research council. One contract has already been terminated — 2005 (see table, opposite); all except one are comes from just three medical institutes. the first time a publicly funded scientist in Indians who trained abroad. In the early years, “We have a fair amount of curiosity- and India has been sacked for underperformance. Mishra says, he had to go to the United States individual-driven research,” says Maharaj Kis- But the model is unlikely to catch on. to recruit scientists, but now he gets about one han Bhan, secretary of the Department of “Indian scientists want secure jobs,” says Ran- overseas application each week. Biotechnology. But without clinical garajan. “If there was a poll, 80% would opt for researchers to translate advances into treat- security in preference to contract jobs at Lost in translation ments, “the bulk of Indian research in basic higher salary.” India’s life-science institutes are improving at science is lost,” he says. “The whole chain does As biotech companies continue to prolifer- a rapid rate (see ‘Strength in numbers’, previ- not function in an orderly fashion.” ate, academic centres will find it difficult to ous page, and ‘Strong bonds’, opposite). Bhan says what’s needed is an institute for hold on to scientists unless they raise salaries Already, Indian scientists are more productive translational research where basic-science by an order of magnitude, warns C. N. R. Rao, per dollar invested in their research than their researchers and physician researchers can col- former IISc director and the prime minister’s counterparts worldwide (see tables, above). laborate on finding solutions to India’s public science adviser. Rao says three of his students But overall, India lacks a critical mass of com- health problems. It would focus on developing joined General Electric’s research labs in Ban- petent scientists in basic and clinical research, simple, low-cost technologies that can be used galore at a salary of US$1,400 per month, twice notes Sandip Basu, director of the National in settings where the resources are poor. “We what a professor at the IISc can expect to earn. Institute of Immunology in New Delhi. As a need to build one or two such new technol- Some institutes offer attractions to compen- result, there is limited collegial interaction and ogy-focused institutes,” he adds. sate for the lower salaries. “What they need is unreliable peer review. “The resulting isola- In the United States, the biotechnology sec- freedom and a conducive atmosphere,” says tionist, nepotistically inclined atmosphere tor accelerated rapidly when scientists moved Lalji Singh, director of the Centre for Cellular does no good to the cause of fostering high- from academia to industry, patenting their and Molecular Biology in Hyderabad. quality research in the country,” he says. discoveries. “The opportunities that are NCCS director Mishra says his institute’s The country’s medical schools lack the unfolding in India are breathtaking,” says high productivity — 35 papers were published infrastructure and the faculty staff to train Ragunath A. Mashelkar, director-general of in high-impact journals in 2004 — helps to researchers. A quarter of India’s 229 medical the CSIR. I attract good scientists. The NCCS has grown colleges have never published research reports K. S. Jayaraman is Nature’s India from 13 faculty members in 1995 to 25 in in indexed journals; most clinical research correspondent. 495 © 2005 Nature Publishing Group

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The coming epidemic A staggering 5.1 million people are estimated to be HIV positive in India. Apoorva Mandavilli finds a country on the brink of a crisis.

ur son was born in June 1998. count of 40; a person is said to have AIDS once point, beyond which the epidemic will escalate He was healthy but after eight their T-cell count drops below 200. Afraid to out of control. It took just seven years for South months, he had diarrhoea and tell anyone they have AIDS — their family Africa’s prevalence to rise from 1% to 20%. Ofever all the time. He was in the believes their son died of tuberculosis — they “Considering that our prevalence has been hospital many times. The sixth time, they travel nine hours from Kancheepuram to kept to less than 1%, that shows that our strat- diagnosed him with AIDS. That was when Chennai to visit YRG Care, a non-profit clinic. egies have been on the right track,” Quraishi we found out that my wife and I have HIV. The clinic enrolled Sumithra first in a clin- says. “It’s not by sleeping that we’re not South Our son died 12 July 2002. I also started to ical trial and then in a Global Fund to Fight Africa. Obviously we did something.” get sick. I didn’t take my medicines regularly; AIDS, Malaria and Tuberculosis programme But the statistics are sobering (see graphic, they didn’t tell me not to do that. Now my that provides antiretroviral drugs. She looks opposite). Six states in India already have a health has become worse. I haven’t worked healthy now, and her T-cell count has shot up prevalence greater than 1%, and in 2004 the in six months.We’ll be paupers. I don’t know to 1,000. But Suresh, who is resistant to the number of high-prevalence districts jumped what we’re going to do. drugs that the programmes provide, is des- from 49 to 116. Even in the low-prevalence or — Suresh, air-conditioning technician perate for newer treatments — and the money ‘highly vulnerable’ states, as they are now Suresh is sitting in a small, dark room at an to buy them. “It’s too late for me,” he says. dubbed, there are pockets where more than 4% AIDS clinic in the southern Indian city of of adults are infected. “The epidemic is pro- Chennai. This city is where the first cases of AIDS is a big problem in India but we have gressing to the tipping point, there’s no doubt HIV in India were discovered in 1986 after a been able to keep it in place so that it doesn’t about that,” says Ashok Alexander, director of police sweep of sex workers. Nearly 20 years become a bigger problem. We are not going Avahan, the Bill & Melinda Gates Foundation’s later, there are an estimated 5.1 million cases the South Africa way. AIDS initiative in India. in India, a number second only to that in — Nirmal Kumar Ganguly, director-general, Some experts say that the new administra- South Africa. The difference is that in India Indian Council of Medical Research tion, which in April 2004 replaced the previous the epidemic has not yet peaked. According to In May this year, the Indian government right-leaning government, could yet turn things the CIA, the number of cases in India could announced that during 2004, there were just around. NACO’s strategy is to reach high-risk top 20 million by 2010. 28,000 new cases of HIV infection, down 95% groups — particularly sex workers and truck The people hit by AIDS in India are not the from the previous year — proof, it said, that its drivers — and scale up programmes that have ones you would expect. About 86% of cases strategies are working. But even in the United proved successful. Over the next five years, it are a result of sexual transmission, most of it States there are an estimated 40,000 new cases plans to expand its 670 voluntary testing sites to heterosexual. Intravenous drug use accounts each year, says Kevin Frost, director of 24,000 and increase the number of people on for only 2.4% of infections, except in Naga- TREAT Asia, a network of HIV/AIDS clinics antiretroviral therapy from an estimated 8,000 land and Manipur, two states where HIV and institutions. “So do you believe that to 188,000 (see ‘Seeking care’, opposite). infection is highly prevalent. The earliest cases Indian number?” he asks. “Of course not, that But in the world’s most populous democracy, appeared in high-risk groups: among the would be ridiculous.” good intentions don’t go very far. Despite doub- country’s 3 million sex workers or the 5 mil- S. Y. Quraishi, director-general of the ling its AIDS budget since 2003–04, India still lion truckers who haul the virus up and down National AIDS Control Organization only spends about 29 US cents per person on the highways. But increasingly, the people (NACO) says that the figures were collected in AIDS. In contrast, Uganda, credited with curb- who are flooding hospitals are men like exactly the same way as the previous year. ing its AIDS crisis, dedicates US$1.85 per per- Suresh, and their wives and children. “Tell me, what can we do? This is the best pos- son. Already, India accounts for more than 13% Like many Indian men, Suresh visited sex sible estimate,” he says. of the world’s AIDS burden but with its preva- workers before he got married. He is in his Compared with South Africa, where the lence so close to the tipping point, the stakes are thirties, but looks at least 20 years older. He is prevalence of HIV is 21.5%, India’s prevalence high. “Overall,” says Frost, “the Indian govern- thin, with large sores on his lips. His wife Sum- is just 0.91%, Quraishi notes. That is less than ment’s response has been pathetic and not what ithra Devi was once near death, with a T-cell the 1% generally considered to be the tipping it needs to be for an epidemic of this size.” 496 © 2005 Nature Publishing Group

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NATURE|Vol 436|28 July 2005 OUTLOOK INDIA

Out in the field: in a bid a quash India’s escalating HIV problem (below) health workers are running outreach programmes to teach people about AIDS. A. MANDAVILLI A.

HIV: A GROWING EPIDEMIC ESTIMATED NUMBER OF HIV INFECTIONS IN INDIA 6

5 2004 NACO, SOURCE: 4 3 2 Millions of cases 1 Less than 5% HIV prevalence 0 in high-risk groups 1999 1998 2001 2003 2002 2004 More than 5% HIV prevalence 2000 in high-risk groups More than 1% HIV prevalence in antenatal women (general population)

I saw people with AIDS die. That’s when I Instead, sex workers — many of whom are reach these unconventional sex workers is started getting scared. I have been teaching married women — work out of their homes, through their peers. At the Community other sex workers about AIDS, telling them hotels or on the highways, earning themselves Health Education Society, an NGO in Chen- to use condoms. Now clients also want to put the nickname ‘highway queens’. Some towns, nai, ‘peer educators’ such as Padma explain to on condoms. They are available at medical such as Peddapuram and Amalapuram in the the women how to use a condom, the differ- shops. But I know where to get them for free. state of Andhra Pradesh, are “like one big red- ence between HIV and AIDS, and why they — Padma, sex worker light district”, says Ashok Babu, a programme are more at risk of getting infected. But the In Mumbai, the bustling metropolis on manager for the AIDS Prevention and Con- message is cleverly delivered through games, India’s west coast, there are nearly 100,000 sex trol Project in the neighbouring state of Tamil songs or as a cost–benefit analysis of, for workers. Volunteers from non-governmental Nadu. “For US$230, you can stay there for one instance, the amount of money squandered on organizations (NGOs) walk through the month and be treated like a mappillai,” h e abortions and treatments for sexually trans- streets of Kamathipura, the red-light district, says, meaning a son-in-law, who is treated like mitted diseases. “When you talk to them just handing out condoms and leaflets. a prince by the girl’s family. In Andhra about AIDS, they get bored,” says Pinagapany But in the southern states, where preva- Pradesh, HIV prevalence jumped from 1.25% Manorama, a physician who runs the NGO. lence is highest, there are no red-light districts in 2003 to 2.25% in 2004. In some ways, sex workers are now to canvass (see ‘The epicentre’, overleaf). Experience has shown that the best way to better informed, and more empowered, than SEEKING CARE When you’re trying to manage an skin. Outside the wards, hairy Rajasekar. “Amazing, right?” the Gere Foundation until March AIDS epidemic and you have black pigs roam beneath drying By June 2005, government 2005, but since then money has limited resources, preventing laundry, accompanied by the centres, including Tambaram come almost entirely from small, infection is the logical priority. But rancid smell of sewage. Hospital, had doled out ARVs to private donations. “Care is where does that leave those who The hospital was one of eight 8,000 people. In the same time, something no traditional donor are already infected? government centres that together since April 2004, small private and wants to fund,” says the centre’s Treating people with AIDS is not were meant to roll out non-profit clinics reached an director, Anjali Gopalan. “They see easy. At the very least, it requires antiretroviral drugs (ARVs) to estimated 30,000 sufferers. But it as a black hole, as one donor told trained medical staff and the 100,000 people over five years. In these clinics are in a constant me. There’s no return on the dollar.” resources to make sure patients the first year, which began April struggle for survival. Scrambling to treat their take the drugs on time. Nobody 2004, it treated fewer than 1,000. One such centre is the Naz patients, doctors at some clinics knows that better than the doctors “From the outside, you may think Foundation’s orphanage in New use medicines that are past their at Tambaram Hospital. it is a low number, but for people Delhi. Of the 24 children there — expiry date; others bring free drugs Built in 1928 as a sanatorium for working here, there are a lot of ranging in age from 19 months to 17 they are given in the United States patients with tuberculosis, the problems,” says S. Rajasekar, the years — 10 are on ARVs. Despite or elsewhere. Staff at the YRG Care government centre is 45 km hospital’s deputy superintendent. one child dying two years ago, only Clinic in Chennai last year began outside Chennai and has more Despite repeated requests, he the oldest one knows that she is asking people to donate just $10 AIDS patients than any other says, the centre has the same HIV positive. To spare the children each. “It’s always beg, borrow, Indian hospital. There are often resources it did in 1993, when it from stigma, their status has also steal, donations, fundraise. That’s more than 900 inpatients for its had just two HIV-positive patients. been kept secret from their how we get funds for care,” says 776 beds, so some have to sleep on In 2004, it saw 14,991 new teachers and neighbours. Suniti Solomon, who runs the the floor. Every hallway is flooded patients and had 140,000 hospital One child’s monthly supply of YRG. “We cannot save the millions with patients who look skeletal, visits from HIV-positive patients. ARVs can cost about Rs900 out there. The government has to with shrunken limbs and sallow “With just 25 doctors,” says (US$20). The home was funded by do that.” A.M.

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THE EPICENTRE In Bangalore, the bustling capital of Maharashtra state. When they the southern state of Karnataka, return home, they bring the people drive shiny new cars, work money they’ve earned — and HIV. in gleaming new buildings and On a map (right), the districts 2004 AVAHAN, SOURCE: carry mobile phones. Just a few along this ‘AIDS corridor’ are hundred kilometres north, the immediately visible. “This is the residents are poorer than many in epicentre of the whole Indian sub-Saharan Africa. In Bangalore, AIDS epidemic,” Alexander says. dubbed India’s Silicon Valley, the He has discussed his theory with land is green, but here it is brown several people in the government. and dry. This is the home of one of “We entirely agree with him India’s two AIDS hotspots. because those pockets are “Someone’s got to wake up to surely high-prevalence,” says the fact that there are two S. Y. Quraishi, director-general Karnatakas,” says Ashok of the National AIDS Control Alexander, director of Avahan, the Organization. earmarks its money for Tamil drug users. It is also backing Bill & Melinda Gates Foundation’s Yet until Avahan — meaning ‘call Nadu and Maharashtra, for research on migration patterns in AIDS programme in India. to action’ in Sanskrit — was instance, and Britain’s the corridor, large-scale surveys to Driven by poverty and launched in April 2003, Karnataka Department for International measure behavioural changes and unemployment, women from was largely ignored by AIDS Development champions states mathematical models that chart northern towns such as Bijapur groups. Most donor agencies such as Andhra Pradesh. the epidemic’s course. “We’re and Belgaum travel across the ‘adopted’ other high-prevalence Avahan has already spent more going to be here as long as it takes border to work as prostitutes in states: the US Agency for than US$17 million working with to make an impact,” says the richer cities in the adjoining International Development sex workers, truck drivers and Alexander. A.M.

housewives. In much of India, arranged mar- no medical care. The best estimates are that the man to visit the makeshift clinic next to riages are still common, notes Rochelle 59% of those infected with HIV live in rural the tent. D’Souza Yepthomi, information officer at areas, but because there is limited surveillance “The word HIV we keep quiet. If you start YRG Care. Half of Indian women marry by there, the real number is likely to be higher. with HIV, they’ll run away,” Selvaraj explains. the age of 18, when most are still virgins, and Compounded by ignorance and illiteracy, “That’s my last chance to talk to him so I the majority remain faithful. “Their only risk myriad myths about AIDS have taken root: should prepare to interact with him in such a is their husband. It’s scary,” she says. that eating chicken and brinjal (aubergine) is way that he remembers.” harmful, for example, or that the virus can be These truckers go home only once every My brother died of AIDS. When he was transmitted by mosquito bites. few months. On the road, they have multiple sick, the doctors kept telling him he had Some largely rural states such as Uttar sexual partners and often abuse drugs and tuberculosis. When they said he had AIDS, Pradesh and Bihar have all the ingredients for alcohol. Many believe that if they don’t have they didn’t explain. They said there was no a massive epidemic — illiteracy, poverty, sex they will build up garmi, a Hindi word treatment, that he would die. We took him migrant labour and sex traffic — but have so meaning heat, and will go blind. back to the village. Nobody there knew far received little attention either from the In recent years, they’ve become accustomed anything about AIDS. I found out about it in government or from donor agencies. The to being chased by volunteers with flipcharts the city. I told him not to sleep with his wife, model of success for those states is perhaps and penis models in their pockets. Selvaraj to not eat from the same plate. I didn’t see Tamil Nadu, where the epidemic spawned works with the HOPE Foundation, which has that anywhere, that you can’t eat from the dozens of NGOs that conduct education pro- counsellors and doctors at several stops along same plate. He died one and half years ago. grammes and provide counselling and sup- a 60-km stretch on the highway. But the mes- There were 1,400 people at the funeral, he port. As a result, it is the only state where sage has not entirely got through. Believing was that kind of man. prevalence has dropped — from 1.13% in that AIDS can only be transmitted by women, — Mohan Singh, tourist-car driver 2001 to 0.63% at the last count. many truckers now have sex with ‘cleaners’, In the past year, two movies from Bollywood, the young boys who travel with them. Homo- India’s prolific film industry, have revolved Before marriage I used to go to those women. sexuality is illegal in India, so the govern- around HIV and AIDS, and the popular tele- Now I don’t. I just drink and go to sleep. ment’s campaigns mostly neglect men who vision show Indian Idol featured an AIDS- I know I shouldn’t go to women, that’s all have sex with men. related song. Film and cricket stars have been I know. My conscience tells me I’m healthy. These truckers have ample access to con- featured in adverts sponsored by the Heroes I can’t have any such thing as AIDS. doms, but many use the condoms to plug Project, an AIDS awareness scheme, launched — Sekar, truck driver pipes in the trucks. According to a report by last year by the actor Richard Gere. Since It’s 10 p.m. on a warm night in February at a India’s comptroller and auditor-general, 75% November 2003, the non-profit organization truck stop on National Highway 45, about 45 of the 1.5 billion condoms made each year are Population Services International has also run kilometres outside Chennai. Every day, more used as sealants for leaky roofs, as lubricants a series of adverts, on television and bill- than 300 trucks stop here on their way south. in weaving gold-embroidered saris, or are boards, featuring the fictitious character Bal- At this hour, there are about 20 trucks parked, mixed with concrete and tar to pave roads. bir Pasha in Mumbai and Pulli Raja in and drivers are eating dinner and preparing to “We’re going for 100% condom promotion,” Chennai. But in a country where more than sleep. At one end of the truck stop is a tent, says health minister Anbumani Ramadoss. 70% of the population lives in villages, the plastered with AIDS posters, where some are “Our job is giving them awareness. After that, reach of the adverts is limited. watching an AIDS-themed show. In front, if they don’t use it, what can we do?” I There are 638,000 villages in India, many of Anthony Selvaraj uses a penis model to show Apoorva Mandavilli is senior news editor of them with bad roads, no running water and a driver how to use a condom, then convinces Nature Medicine. 498 © 2005 Nature Publishing Group