One man’s fascination with fat
Ram Rajasekharan’s two decades of research is converging in ways that offer hope for commercially viable technologies and products
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“This is the world’s tiniest grain”, says Ram Rajasekharan, handing a fistful with a magnifying glass. Under the lens, Teff seeds look oblong and wispy and, like many seeds, harbour a story which is culturally deep and nutritionally wide.
After three years of field and laboratory testing and selecting for Indian conditions, Rajasekharan is ready to introduce this so-called wonder grain to Indian farmers. High on protein, equivalent to the white of an egg, Teff is the most important cereal of Ethiopia and Injera, made by fermenting the batter in controlled temperature for days, has been their cultural food for centuries. In the last two decades as the oversize disc-like bread—a gigantic Indian dosa as it were—gained popularity outside Ethiopia, a global “Teff-tiff” ensued. Allegations of bio-piracy flew furiously between countries which eventually led the US Department of Agriculture to begin sharing seeds with other countries.
Rajasekharan brought 18 varieties into India, through the Indian Council of Agricultural Research, and to his lab at the Central Food Technological Research Institute (CFTRI) in Mysuru. Only two varieties, brown and ivory in colour, survived. As a wholegrain cereal, Teff is drought-tolerant, high in resistant starch which makes it a slow-releasing food good for diabetics, and, above all, it is free of gluten, a protein that causes allergy and celiac disease, an autoimmune disorder.
“I am from a village which has no water,” he says. Rajasekharan grew up on a farm in a village in Manamadurai taluk of Tamil Nadu where he not only witnessed acute shortage of water but also a blatant caste divide between the two resident colonies which lived just 50 metres apart—Pallars, the land labourers, and Thevars, the warrior caste. Those scars and experiences shaped his science, forever.
As a first graduate from his village, he came to the Indian Institute of Science (IISc) for PhD and fell for lipids—fats which form the outer layer of a cell and provide structures for containing water. In his subsequent years in the US, first as a post-doctoral student at the University of Illinois, then as a scientist at DuPont, and later again as an academic at New Mexico State University, he continued to study lipids and their role in human diet.
After nearly 10 years in the US, when he was returning to the biochemistry department at IISc as a professor in 1995, he and his wife, also an academic, learnt they were entitled to import a car each. And they did, two Mercedes, one of which was sold right at the port, the second one a little later. “For quite some time his Mercedes would be parked in IISc and we used to look at it in wonder. Ram’s business sense was strong even then,” recalls Samir Brahmachari, then a scientist at IISc and retired as director general of the Council of Scientific and Industrial Research (CSIR) in 2013. Rajasekharan used that money, and his savings to buy 175 acres of land near his village and rehabilitated the Pallars on the bank of the Vaigai river.
He may have paid emotional debts but his adventure had just begun.
The first five years at IISc were bewilderingly harsh. “I had no grants, I worked by myself,” he says. When he began publishing in reputed journals, grants trickled in but, mysteriously, some were withdrawn before the projects could be completed. “The government was benevolent, it gave research grants to all; nobody’s was pulled out but mine was, on some unfathomable (and unsubstantiated) ground like ‘no progress’,” he recalls, a mix of rue and anger still noticeable in his voice. Gradually, he found his footing in the science of fat. He and his team were the first to decode and describe a new pathway for synthesizing fat in plants. “Until then there was only one pathway. We found the alternative pathway that showed monoglyceride is part of the biosynthesis of triglyceride. The prevailing dogma said monoglyceride was the terminal step,” he says.
Monoglycerides are used as binding additives in processed foods. He went on to prove the same pathway worked in yeast, and showed when that pathway becomes “major” and when it becomes “minor”.
Over time, Rajasekharan and his students showed that under nutrition deficiency, like that of phosphorous, zinc and other micronutrients, the plant system is forced to produce more fat. He licensed two technologies from this research to Dow Chemicals. Another on “gelling of oil”, converting liquid form of oil into solid or semi-solid form, was licensed to the Nagarjuna group.
Now his two decades of research is converging in ways that offer hope for commercially viable technologies and products. He likens this to the laws of chemical equilibrium: every forward reaction has a backward reaction. “Once we know how oil is stored and produced, we can work at both ends. At one end I want to increase the amount of oil production in plants, at the other end I find a reverse mechanism to control this in humans, say, in my own body,” he says. “I am learning that I can use food to do that.”
“I brought this plant from Kashmir. After some hard work, we’ve selected it for growing in hot, dry conditions,” says Prasanna Anjaneya Reddy, a field scientist at CFTRI. In a 15ft X 10ft patch of land, Buglossoides arvensis plants look like a green ground cover, just about eight inches in height, en route its normal height of about 20 inches. Seeds of this plant produce oil that is a rich (20%) source of stearidonic acid, a precursor to omega-3 fatty acids found in fish oils and other plants like flax and are among the most important essential nutrients for humans.
Being resistant to germination, Buglossoides was a difficult plant to tame. It required cold treatment to break the dormancy. “Initially, the germination rate was 0 in 100 seeds, now we’ve come to 50 in 100,” says Rajasekharan. The UK is cultivating and studying this plant at a massive scale, keeping in mind its ageing population whose fish consumption levels are dropping. “Monsanto has a genetically modified variety of this plant but we have got the same composition in the seeds by conventional breeding,” he adds.
In the next patch, cheek by jowl to Buglossoides, is Portulaca oleracea, followed by Talinum fruticosum (also known as Philippine spinach). These two desert plants can grow without water, adding more flavour to Rajasekharan’s repertoire of Omega-3 sources. “I went back to the old culture and screened the entire leaf system in the food chain and asked a simple question: What are the best plants for Omega-3.”
For him, the science is specific: Bioavailability of Omega-3 in the body from leafy sources is five times more than that from marine sources like fish oil. So people need to consume less. Once he introduces this to farmers, the awareness will increase that Portulaca is a better leafy vegetable than, say, amaranth. He did the same with Chia seeds two years ago. Business-wise, once you dry the leaves, they become microbiologically safe, stay longer and can be consumed in different ways, such as seasoning. “It tastes good, I can assure you” he says sincerely.
A South American plant, Chia not only has the highest amount of Omega-3 but substantive amounts of protein, dietary fibre, antioxidants, other vitamins and minerals. To popularize it, in August 2015, for the first time CFTRI engaged with farmers from across the country and organized a workshop in Mysuru where it gave all 150 farmers Chia seeds.
Kurubur Shanthakumar, president of the Karnataka Rajya Kabbu Belegarara Sangha, who attended the workshop, says the farmers are very excited by this crop: “It’s a gift for us”. He has grown two crops so far in his 15 acres land, giving up millet, the dry land crop which he had cultivated earlier. The reason is higher value, lesser hassle and protection from the grazing cattle because unlike millet, animals don’t like chomping on Chia plants. Through classical breeding, these white Chia seeds have been selected for higher yield and erect growing.
Shanthakumar has floated a company, “not a cooperative” he insists, to capitalize on the opportunity. As chairman of Raithamitra Farmers Producer Co. Ltd, he has a contract farming arrangement with Nutriplanet, a newly formed company to commercialize Chia-based products. In the first year, nearly 80 farmers have grown 20 tonnes of Chia, but Shanthakumar says some 300 more farmers are willing to join hands with RaithaMitra this year. Already a handful of companies, including Jindal Naturecure Institute in Bengaluru, are trying out the seed samples.
Raja Nayak, who owns Mumbai-based MCS Logistics and has businesses in packaging and bottled water, has co-founded Nutriplanet to sell the seeds, oil and other nutritional products like Chia-coated energy bars and Chia-laced honey. He has licensed the technology from CFTRI to process seeds as well as to make oil because he found customers in food, pharma and cosmetics industry to be very interested. “This was a rich man’s food so far. It retails in grams, not kilos (whose price ranges from Rs.2,000 to Rs.3,000 per kg). We’ll break into that market. Within a year we hope to bring down the price by 30-35%,” says Nayak.
Rajasekharan is more ambitious, though. “I can bring down Chia seed price to one-tenth, globally,” he claims. Unlike flax seeds, Chia can be eaten straight from the farm. Sure enough, farmers in Karnataka are consuming it, and relishing it too. “We’ve noticed (the gastric reflux is better controlled), blood sugar management is better and there is an overall sense of wellness,” says Shanthakumar.
For new users, Chia can be consumed like fennel, though it’s a far cry from being a mouth freshener because the seeds emulsify, almost tastelessly, on chewing.
On 4 January, CFTRI organized a CEO meeting in Mysuru where nearly 40 business executives participated. One common complaint during that meeting was that Rajasekharan is “possessive” about his technologies and they are “expensive” to licence.
“My technology is like my daughter. I don’t spend time, money and energy to keep it at home. It has to go out but if I have to give it to somebody I will make sure I give it to somebody who will take care of it. I can’t give it to a street vendor, nor can I give it to someone very rich who will not value her,” he says. He has licensed nine of his 11 patents under this philosophy.
It was this farm-to-fork approach that got him the directorship of the Central Institute of Medicinal and Aromatic Plants in Lucknow in 2009 when he wanted to get out of IISc. “The Lucknow centre was just breeding aromatic plants and marketing oil, it did not have much science going there. Ram brought the culture of research, connected with farmers and gave them new plants and best farm practices,” says Brahmachari. “What surprised me most was that he could not communicate with the farmers in Hindi but when we went out in the field, nearly 100 of them came and touched his feet. They were so positively impacted with his extension programmes.”
Under one such programme, he taught the villagers to make incense sticks using dried temple flowers, which were earlier dumped in the river. Dozens of women were able to earn a living—Rs.3,000 a month. “He ensured that all women sent their daughters to school and none brought them to incense-making. In one of my presentations to the Prime Minister (Manmohan Singh) I had presented this technology suggesting this could be propagated in all temples,” says Brahmachari.
In 2012, when the CFTRI director retired, Rajasekharan took a transfer back to south India. His mandate from Brahmachari was the same: seed high quality science in a place which was more a kitchen-and-sink operation. In three years, says the new director general Girish Sahni, “Ram has transformed the place, in infrastructure and in spirits. He is a doer; he’s set new ambitious directions for the Centre.”
That, however, has made him fall out of favour with some in the establishment. While streamlining the administrative affairs, he “suspended four-five people who had different activities going on in their name outside CFTRI”. Soon after, some activists roughed him up and threw black ink on his face accusing him “of being anti-Kannada”, just one of the many such charges heaped on him in recent times, which even got the local Lok Sabha member Pratap Simha to issue statements against Rajasekharan.
Sahni, who has looked into the investigation (and found nothing), is sympathetic: “Administration is an art, and sometimes it requires a soft touch.”
(A retired CSIR director says CFTRI has always been a “very political place”. “In the mid-nineties, an overseas scientist, S.R. Bhowmik, was appointed as the director but he couldn’t manage and went back to the US.”)
For a while Rajasekharan gets sombre: “The system sometimes tries to make me feel small because I am of a backward caste”. But soon he perks up. He is a survivor.
At IISc, he and his colleague, another innovation-driven academic in the late nineties, P.N. Rangarajan, were into serious industry collaboration. Rangarajan spent two years developing a novel DNA vaccine for rabies, which would have been the first such vaccine in the world and which Hyderabad’s Indian Immunologicals Ltd was supposed to manufacture. However, after a commercial rethink, the company dropped the ball. It cost Rangarajan his promotion—he neither had a product, not any significant publication in those years. Watching that, Rajasekharan forced himself to sideline innovation at his lab to publish papers.
In the following years, he experimented with different roles and places—at the biotech park in Chennai, at the Monash University campus in Malaysia and eventually at CSIR. However, for much of his prolific tech licensing, some critics say a scientist of his calibre has yet to claim a big scientific discovery that eventually reached the market and made a mark.
Rajasekharan is quick in his defence. “It’s coming, in one year both the patent and the paper will be ready. And this time I’ll make sure to create a company around it,” he says. (He doesn’t take equity in the start-ups he helps to incubate.) During his years in Lucknow, as he watched people switch diets for keeping themselves warm in winter, the idea of thermogenic food for reducing fat dawned on him. He is more than three-fourths his way towards proving that a food-derived active compound (which he wouldn’t disclose yet) that can bring weight loss, not through consumption but by a slight increase in body temperature. “In science we call it Diet Induced Thermogenesis,” he says with a chirp, which makes him look a decade younger than his 56 years. He is his own muse, perhaps like Feynman.
Talking about his act of doing science, physicist Richard Feynman once said, “I always consider it something like Africans when they were going out to battle, to beat drums and get themselves excited. I talk to myself and convince myself that this problem is tractable by my methods and the other guys are not doing it right. The reason they haven’t gotten it is that they aren’t doing it right. And I’m going to do it a different way. I talk myself into this and I get myself enthusiastic.”
Students, peers, seniors—all are struck by how Rajasekharan sustains his enthusiasm. “He is as passionate as he was 25 years ago. When I get depressed I visit him or talk to him. He always has a few new ideas to discuss, ideas backed by solid science,” says Rangarajan.
Rajasekharan himself is driven by just one dream: “To build an Omega farm before I die, a farm that feeds people and does research to improve products.”
FOOD FOR RARE DISEASES
Prasanna Shirol’s daughter was two when he noticed an odd change in her walk. By the time doctors could figure out her disease, she was seven and on ventilator. In 2007, she was the first patient in India to be diagnosed with Pompe disease.
It’s a genetic disorder which creates an enzyme deficiency that leads to progressive muscle degradation and other symptoms. Shirol’s daughter needed enzyme replacement therapy (ERT), which Genzyme Corp. was selling in the US but not in India. Through International Pompe Association he managed to get ERT via Genzyme’s charity programme but it unravelled facts about rare diseases that blew his mind. Depending upon the body weight, ERT can cost upwards of Rs.1.5 to Rs.3 crore for a year’s dose. Innovator companies offer free doses, on first-come basis, to a few dozen patients in the country.
Difficult to diagnose, expensive to treat, rare diseases until recently were restricted to the walls of the families that suffer in silence. India does not even have a definition—prevalence per 10,000 persons. A few disease-specific support groups have emerged but it was the founding of the non-profit Organization for Rare Diseases India in 2014 by Shirol, Vijay Chandru, founder and chairman of Strand Life Sciences, Harsha K Rajasimha, a genomics scientist and entrepreneur, and others that the patients now have a collective voice. There are at least 7,000 rare diseases worldwide and nearly 70 million Indians, 1 in 18, are afflicted.
As the Centre for Human Genetics in Bengaluru under professor H. Sharat Chandra began to systematically diagnose and treat rare diseases—80% of these are genetic in nature—it became apparent that along with correct diagnoses, these patients needed a special diet. Hundreds of such diseases, 40 on the Lysosomal Storage Disorders (LSD) spectrum, nearly 50 under Inborn Errors of Metabolism, and several others, need some form of food supplement to survive.
It was during one academic brainstorming in 2015 that G. Padmanaban , former director of Indian Institute of Science, who is on the research council of Central Food Technological Research Institute (CFTRI), connected the dots between the unused technology at one centre and the patients’ plight at another. Ram Rajasekharan had been readying gluten-free grains—Quinoa and Teff—which could be used to make bread and other bakery products for celiac disease patients. He had also developed a proprietary process by which another amino acid, phenylalanine, could be removed from protein foods for the benefit of patients of Phenylketonuria, another rare disorder in which children develop permanent intellectual disability without treatment.
“We went to a few food companies but none was willing to take it up because the target market was small,” says Arun Vijay, a scientist at CFTRI who will supervise tech transfer to Oleome Biosolutions Pvt. Ltd. At an investor meeting in Tamil Nadu in 2015, he met two business executives who had such patients in the family and wanted to help out. Within weeks and with Rs.50 lakh in seed money, Oleome was founded. Its name derives from the intracellular organelle in plants where fatty oils are generally stored. Oleome is incubated at the Bangalore Bioinnovation Centre in Electronics City, close to the Centre for Human Genetics which will conduct all food studies in patients and has strong patient support. Vijay says Oleome would like to be the repository of food technologies for diseases or conditions that are neglected by the food or pharma industry.
Rajasekharan isn’t done yet. He is transferring three other technologies to Oleome, one being lactose-free milk derived from plant sources, including Chia. Apart from serving lactose-intolerant people, the milk’s nutrition level could be customized for diabetics or pregnant women. Then there is a process to keep the Omega-3 oil stable in powder form, which can be stored easily and used in various industries. And finally, he’s found a way to extract Vitamin-D from fungus—mushroom and brewery waste—which could come handy in addressing the increasing Vitamin-D deficiency in Indians, either through food fortification or as seasoning.
It may sound a mouthful, even look like a smorgasbord of technologies parked in one start-up but under a savvy chief executive, it could prove ground-breaking. Rare disease numbers seem small now, but with treatment more patients will survive and turn into lifelong customers. Big pharma companies, led by Genzyme and Novartis , have already showed rare disease route leads to guaranteed profits. Shirol says once LSD patients began to be diagnosed, the number went up from nine to 600 in two years.
“If we create incentives for companies with an Orphan Drug Act (like in other countries), address the reimbursement under health insurance and share the diagnostic protocol with doctors across the country, we could save and improve millions of lives,” says Namitha Kumar, one of the co-authors of the draft framework on Rare Disease Policy, the first-ever to be conceived in India and submitted to the Karnataka government in February.
Seema Singh is a Bangalore-based journalist. Her book, Mythbreaker: Kiran Mazumdar-Shaw and the Story of Indian Biotech is being published by HarperCollins this month.