Lokman Hakim Mondal, the overweight ‘wonder baby’, made regular headlines until he died on May 22 at the SSKM Hospital. Even bloggers in the Internet had been exchanging the health updates of the 11-month-old kid who weighed 24 kilos. But, surprisingly, his life, or death, did not affect the country’s scientists who just let a tremendous research opportunity slip by them. This, probably, speaks volumes for Indians’ love of things scientific.

Babies like Lokman, who suffer from gross obesity, are extremely rare. However, a few such cases were identified by the scientists at the University of Cambridge in the early 1990s. Intensive study of these overweight babies helped to crack the mystery of obesity? one of the most complex medical problems.

Before speculating what might have gone wrong with Lokman’s physiology, let us take a look at obesity and its usual causes. A person is called obese when his or her body weight exceeds by 30 per cent of the ideal weight ? as marked in a height-weight chart available with any general physician. A commonly used measure of obesity is body mass index (BMI), which is calculated by dividing a person’s weight (in kilograms) by his or her height (in metres) squared. Those with a BMI above 25 are considered obese, and people who possess a BMI below 19 are underweight. Ideally, an Indian adult man (assuming an average height of 5 feet 3 inches), whose BMI is 25, should weigh around 64 kgs. However, such values, framed by US scientists, cannot be taken as the final yardstick, because they don’t take into account ethnic, cultural or climatic variables.

Common obesity is a complex disease caused by several factors ? genetic, environmental, behavioural and socio-cultural. The nature of these interactions are not understood completely as yet. Studies on twins and adopted children have shown that genetic factors contribute 60 to 80 per cent of body mass. And obesity is determined by a group of genes each incrementally contributing to body weight influencing food intake (the supply of energy) and metabolism (the expenditure of energy). Besides, genes affect physiological activities which determine whether a person is lethargic or athletic. Genes also decide a person’s choice of food, eating habits, working of hormones etc. Subtle changes in a single or a handful of genes may upset the whole genetic balance, ushering in obesity to the extent of a disease. The worst part of the story is that some people are predisposed to obesity at multiple sites (or loci) in the gene. This helps them put on weight easily, but it’s difficult to lose that extra flab.

It’s not easy to pin down the genetic causes of obesity. Nowadays, variability in a single gene, or single nucleotide polymorphism (SNP), is possible to be detect through expensive techniques called fluorescent in situ hybridisation (FISH) or polymerase chain reaction (PCR). And for detection of the suspected mutated gene region, its sequencing and finding out the absence of the protein which the gene codes for (genes hold the instructions for making proteins) is also possible. All these techniques have to be handled by seasoned experts in genetics.

It’s a pity that Lokman’s case was handled in Calcutta by physicians who are not experts in genetics. It’s even more unfortunate that there are several institutes in India which are not only fully equipped but have scientists who could have identified the genetic anomalies in the kid. The Centre for Cellular and Molecular Biology (CCMB) and the Centre for DNA Fingerprinting or Diagnostics (CDFD) in Hyderabad, the Institute of Genomics and Integrative Biology (IGIB) in Delhi, and the Central Forensic Science Laboratory (CFSL) in Calcutta would have been the ideal institutes to carry out studies on Lokman’s genetic makeup.

What are the probable genetic anomalies he might have been suffering from? According to newspaper reports, he was a case of Prader-Willi syndrome ? a kind of obesity occurring in one out of 15,000 children in the US. This genetic abnormality is caused by one of these two types of mutations: a partial deletion or loss in the long arm of the chromosome 15 inherited by a child from its father, or the so-called ‘disomy’ of the chromosome 15 (both members of this pair coming from the mother, instead of each from both the parents).

In the Prader-Willi syndrome, the baby has initial feeding difficulty, underdeveloped sex organs (hypogonadism), cognitive impairment, mental retardation and hyperphagia ? characterised by constant hunger, continual demand of food, disruptive behaviour when food is denied and morbid obesity. These symptoms ? except for feeding difficulty and hypogonadism ? appear when the baby grows up into an infant. Lokman doesn’t seem to be a case of the Prader-Willi syndrome.

However, he might have been a case of congenital anomaly. His symptoms seem more appropriate for ‘monogenic congenital’ obesity ? caused by a defect in a particular gene. A plethora of possible genes have been implicated in different types of chronic and morbid obesity. The major genes are those which are responsible for the production of a protein called leptin (leptos means ‘thin’ in Greek) and neuropeptide Y, a substance that is a potent stimulator of appetite. Leptin is considered to be an important bloodborne signal from adipose, or fat cells, to the weight-regulating hypothalamus region in the brain.

Simply put, leptin is supposed to tell the brain how much fat is there, but in obese people the message may not get through. One of leptin’s main effects also may be to inhibit synthesis and release of neuropeptide Y from the brain, controlling continual pangs of hunger.

Leptin is produced by the ‘ob’ gene (named after obesity), first discovered in mice. The identification and sequencing of the mouse obese (ob) gene in 1994 opened new avenues in obesity research. The defective gene produces inefficient or limited amount of leptin, causing a mouse put on thrice the normal weight. When mice were administered with artificial leptin they shed excess weight quite dramatically.

Comparable genes have been found in the human genome too, but their role in human life is unclear. Only a small per centage of cases have been linked to a low level of leptin. Most cases are due to a defect in the leptin receptor (a specialised cell that translates a stimulus from the environment, or from within the organism, into nerve impulses).

Only in extremely rare cases have low levels of leptin been linked to the sort of obesity seen in Lokman. In 1997, biochemists at the University of Cambridge described two children of Pakistani origin in Nature suffering from obesity comparable to Lokman. The first child (a girl) weighed 86 kilos when she was eight and her two-year-old cousin (a boy) weighed 29 kilos. The girl had normal weight at birth but began gaining weight excessively about four months of age. She had hyperphagia, was constantly hungry and became agitated when food was denied. As a result of her severe obesity, deformities had developed in her legs. According to a report by biochemists Stephen ’Rahilly and C.T. Montague at Cambridge, doctors had to perform liposuction to remove fat from her legs when she was 6. Quite remarkably, both these children came from a highly consanguineous family (in which close relatives marry one another). Both the kids had a defective leptin gene caused by a mutation.

Later, a pair of Iranian children was discovered with a similar gene defect. The Cambridge team also came across more such children of Turkish and Pakistani origin. All these children have very low or undetected levels of leptin. Their family members too were found to have partial leptin deficiency. When the Cambridge scientists treated these overweight kids with artificial leptin (produced by recombinant DNA techniques) they showed a sustained loss of weight coupled with a suppression of hunger. Such a positive response to leptin in the regulation of body weight in humans establishes an important role of the hormone in the regulation of appetite. The babies highlighted by Cambridge scientists show a remarkable similarity with Lokman. So it can be surmised that he too had been suffering from congenital leptin deficiency due to a mutation in his ob (leptin) gene.

If scientists in India had been a little more enthusiastic, a study of Lokman’s genetic makeup would not only have saved the kid from untimely death, but would have opened up an avenue in obesity research here too. It was shocking that no expert from any of the premier genetic laboratories came forward to grab this research opportunity. Just a little bit of tissue from the hapless child’s body would have helped any of the big laboratories find out the nature of Lokman’s genetic anomaly by matching his DNA with that of the Human Genome Database available free on the Internet.

It would neither have been a difficult, nor an expensive, experiment. We simply lacked the initiative. When will research come of age in India?

(Dr R.K. Mandal is a former professor of biochemistry, Bose Institute)