"The study of genetics took off with a lot of hype, but soon tapered down. But now the technology is maturing and good things are emerging from it" - Dr Rajesh Gokhale, director, Institute of Genomics and Integrated Biology, Delhi
Recent studies have suggested mitochondrial variations and mitochondrial dysfunction to be associated with a number of disease conditions, including neurological disorders such as Alzheimer’s disease.
For scientists who have been working in genomics in India, the biggest challenge, apart from shortage of resources and political will, is gathering data on disease.
"Currently, when one has symptoms, we measure its biochemical parameter. We work on symptoms. We eliminate the symptom, and in the process we may eliminate the disease as well" - Dr Samir Brahmachari, geneticist
Vinod Prajapati's eight-year-old son suffers from deafness and muscle weakness, a disorder that runs in his wife, Kanchan’s family. Kanchan does not suffer from the disorder, but her sister’s son and a few cousins do. Last year, the Prajapatis decided to have a second child, but were worried the child, too, would have the disorder. Prenatal genetic tests, in the fourth month of pregnancy, helped rule out the possibility of the gene mutation responsible for the disease.
Genes are fast becoming a key to understanding disease and dealing with them. While it takes nearly four-and-a-half-years to decode a person's entire genetic makeup, doctors are changing the way diseases are managed, controlled and cured by reading a part of the gene sequence. Genomics is revolutionising health care by helping doctors understand, to a large extent, how a disease manifests and by empowering pharmacologists, who can now alter the drug dynamics to suit a patient’s genome.
Researchers say the next five years will see far-reaching changes in the health care delivery system. “Genomics is all set to revolutionise medical care like never before,” says Dr Rajesh Gokhale, director, Institute of Genomics and Integrated Biology, Delhi. “The study of genetics took off with a lot of hype, but soon tapered down. But now the technology is maturing and good things are emerging from it.”
Genome testing also predicts one’s susceptibility to various diseases. Dr Annie Hasan, a Hyderabad-based senior geneticist, once got a breast cancer patient, in her 50s, who was carrying a mutation in the BRCA1 gene. Hasan counselled the family and advised her sisters, brothers and daughters to undergo the genetic test. Shockingly, seven of eight women from the family were found to be carrying the mutation. “These women may not develop breast cancer but are at a heightened risk of developing either breast or ovarian cancers,” says Hasan. “Male members carrying the same mutation may develop breast, pancreatic, colon or prostate cancer later in life. These people can go for regular screening to detect it in its early stage, when it is curable.” Not all breast cancers are hereditary; only 10 per cent are. But women who are prone to hereditary cancers can prevent an early onset by avoiding oral contraceptives and hormone replacement therapy. Besides, they can do routine self-examination and screening. Researchers are also beginning to understand how two cancers are different from each other. The manifestation of a disease is not uni-directional; rather it is like a river's tributaries.
In India, researchers are also working on a complex skin pigmentation disease called leucoderma or vitiligo, where melanocytes—cells responsible for the pigmentation—disappear from a part of the skin and result in a white patch. The occurrence of the patch signifies the full impact of the disease. “Generally, people go to a doctor after they already have a patch. Now with genomics, we can catch the disease at the stage when these cells start dying and find out why they are dying—[whether it is] because of some mutation in mitochondria or because of a problem with the immunity of that cell,” says Gokhale. “We have data to show how these cells go away initially. We have also found out that to manage the skin without its pigment, the tissue changes itself to protect the skin in the absence of melanocytes. We have done similar studies in liver disease. With liver damage, too, the tissue undergoes change.”
With such details, doctors feel diseases can be treated at an early stage and holistically. Study of genes help these researchers in tracking the trajectory of the disease. “Currently, when one has symptoms, we measure its biochemical parameter. We work on symptoms. We eliminate the phenotype—the symptom—and in the process we may eliminate the disease as well. Genomic medicine may allow you to holistically eliminate the disease from the beginning,” explains Dr Samir Brahmachari, a geneticist and former director general of Council of Scientific and Industrial Research, who has been working on the Human Genome Project in India since its inception some 30 years ago.
Citing an example of diabetes, Gokhale says: “It occurs when a person loses a beta-pancreatic cell that produces insulin in the body. Currently, we manage the disease by controlling the blood glucose level by supplementing the insulin from outside. We will be able to cure a person of diabetes the day we crack the reason why one loses beta-pancreatic cell.”
Genomics is quite helpful in cases where two diseases may have the same symptoms but need different treatment. For instance, a child who has a degree of albinism, bleeding problems and who suffers from recurrent gingival (gum) or ear infections may have two possible diseases—Chédiak-Higashi syndrome or Hermansky Pudlak syndrome—which need different treatments. While the first has a cure in bone marrow transplant, the latter can be managed by taking an injectable medicine once a month. Both the diseases represent themselves as a mutation in a panel of genes. By studying these two panels, doctors can give an accurate treatment instead of going for a hit and trial approach. Similarly, genetic study helps in detecting many rare disorders including chromosomal defects, metabolic syndrome, cardiac myopathy, neurological disorders such as depression, schizophrenia, ataxia and epilepsy.
In fact, genomics has simplified a lot of complex issues in neurology and psychiatry. In cases of depression or schizophrenia where the patient can neither describe the extent of the problem, nor can a doctor gauge the improvement in a patient's condition post medication, genetic study can help. “By studying their genes, we can see if the prescribed medicines are benefiting them or not,” says Sudha Rao, CEO of Dhiti Omics, a gene diagnostic centre in Bengaluru. “A lot of work has been done at the National Institute of Mental Health and Neurosciences.”
In epilepsy, genetic studies have found that in some women the extent of the attack depends on their monthly hormonal fluctuations. In these women, a fixed dose of medicine may not prove to be as effective as, say, in men, who have relatively stable hormone levels throughout. “We have enough data to identify the problem,” says Gokhale. “We are working on a mechanism to find out how to calibrate the dose of medicine in such women.”
Pharmacogenomics is another branch that has the potential to revolutionise treatment. Hasan explains with the example of her 8-year-old son, who was injured during their visit to the United States. While playing cricket, a ball hit his forehead and he was hospitalised. Doctors performed an oral surgery and put him on medicines. But his condition worsened—he started hallucinating and the pain became unbearable. Doctors thought the injury had caused brain damage. “I decided to put him through gene sequencing,” says Hasan. “We found he had a mutation in gene CYP2D6, which made him react to codeine. In fact, people with these mutations react to many drugs. On returning home, I put my whole family through this gene test. About 30 per cent Indians have this gene mutation that makes medicines react adversely.”
Scientists have also found that 80 per cent of dandruff is caused by a fungus that feeds on long chain fatty acids present on the scalp. “The medicine to treat this fungus generally contains the same long chain fatty acids along with the drug to kill it,” says Gokhale. “How can you kill the fungus when you are giving it its food? By understanding this, we modified the concoction by replacing long chain fatty acids with medium chain fatty acids.”
Then, there is the research in mitochondrial diseases, one of the most common genetic diseases with an incidence of 1 in every 5,000 births. Researchers suggest the next big feat in genetic science will be understanding the genes present in mitochondria, cellular organelles, important for the normal functioning of cells, that are involved in the production of energy. These organelles are aptly termed the powerhouse of the cell. They are composed of double membrane and have a distinct and small circular genome, which encodes for 37 genes.
Mitochondria are peculiar in many ways. Their peculiar pattern of maternal inheritance also has been extensively used to understand human ancestry and migration. A single cell could also have multiple mitochondria, and some may be different from each other in a few genetic variations—a phenomenon known as heteroplasmy. Apart from this, the human mitochondrial genome is also known to have a higher mutation rate compared to the nuclear genome. Mutations in mitochondrial genome are known to cause a range of diseases such as Leber's hereditary optic neuropathy (LHON), Leigh syndrome, neuropathy, ataxia, retinitis pigmentosa and ptosis (NARP) and myoclonic epilepsy with ragged red fibers (MERRF).
Apart from these well-characterised diseases, recent studies have increasingly suggested mitochondrial variations and mitochondrial dysfunction to be associated with a number of disease conditions, including neurological disorders such as Alzheimer’s disease and metabolic disorders such as type 2-diabetes mellitus. The advent of next-generation sequencing technology has offered a unique opportunity to sequence and annotate mitochondrial variations and to identify their association with diseases.
There is also extensive work going on in skin biology, uncommon diseases and asthma. Asthma may have multiple triggers in a person. In some, morning walk may trigger an asthma attack and, in others, a particular smell can. With genomics, one can study what is causing the disease and what medicine will suit the patient.
For scientists who have been working in genomics in India, the biggest challenge, apart from shortage of resources and political will, is gathering data on disease. “Scientists and clinicians work in different spaces here. It makes it difficult for us scientists to correlate our findings with the clinical presence of the disease,” says Gokhale. “What we need the most is a strong collaboration between research labs and medical institutes. It will give us fodder for our research. We will be able to translate our basic research into applied science.”
Studying genomics in India could be challenging and fun at the same time for the varied gene pool. “We have a pool of genes from across the world,” says Gokhale. “The fittest survive in the process of evolution. Without us realising it, many bad genes are getting eliminated on their own. It is different from countries such as Iceland, Denmark or Sweden, which have an ethnic gene pool. There, diseases run in a family generation after generation.” But, mutation in gene-causing diseases in south India may slightly vary from that in north India.
Though genomics allows the selection of the fittest gene, it raises ethical questions such as: Is it okay to sort the fittest? Will it cause imbalance in nature? Is it going to alter the way universe works? Ethical, actionable genomics, says Brahmachari, is what we are doing at a large scale. As long as it is used to improve the quality of life and to bring down the cost of health care, it is ethical. “But mapping genes to find out the diseases one is susceptible to in the later part of life or the qualities of an unborn or newly born child is beyond the ethics of genomics,” he says.
Conceptualised some thirty years ago, the Human Genome Project started in the 1990s. The first human genome graft came in the 2000 and was completed in 2003. At that time it was done at a huge cost, but now diagnostic tests have become quite affordable for families who are desperately looking for an answer to their medical problems. And, there is tremendous hope at the end of the tunnel.