Rats are a nuisance to most people, but neuroscientists at the National Centre for Biological Sciences (NCBS) in Bengaluru buy rats with specific dispositions and look after them with great care. Some of the rats are healthy, others have a disorder similar to autism in human beings. You can’t put electrodes into a living human brain, but scientists can do that to a rat. By looking into a rat’s brain, scientists hope to understand something about a living human brain. Especially, how it goes haywire.
Neurological disorders affect a large proportion of Indians. Epidemiology studies have put its prevalence at about 2.3% of the country’s population. Children are also vulnerable to neurological diseases. For example, autism affects roughly one child in 500 in India, and its rate of incidence seems to be increasing. Although scientists have found genes that can sometimes cause autism, they do not know the precise mechanisms in the brain that make a child autistic. Rat brains are a good substitute for understanding human brains, but scientists in Bengaluru have another trick up their sleeve: a living human brain in a dish.
By studying the brain in a dish and rat brains together, scientists at NCBS hope to understand autism and, by extension, other disorders of the brain. It is hard for an institution to do this all by itself. NCBS is holding hands with two other institutions: the Institute of Stem Cell Biology and Regenerative Medicine (InStem) in Bengaluru, and the University of Edinburgh in the United Kingdom (UK).
NCBS professor Sumantra Chattarji(In Pic)
Together, these three institutions – through a joint entity called the Centre for Brain Development and Repair – have launched a multipronged attack on autism. “We have never had a joint project like this with another institution,” says University of Edinburgh vice-chancellor Timothy O’Shea. The project, started three years ago with Rs 70 crore from the Department of Biotechnology and further funding from the Wadhwani Foundation, has moved surprisingly quickly. Scientists moved to an empty room in mid-2014, and set up the lab in a year and a half. Experiments began more than a year ago. The laboratory in Bengaluru has been mirrored in Edinburgh, and supplemented with equipment for sophisticated imaging. The three techniques together provide an approach that is as powerful as any other method that has been used to study the brain.
To biologists, rats are great animals to study. They have sophisticated brains, and a physiology that closely matches that of human beings. And yet they are low enough in the animal hierarchy to not raise too many concerns among animal rights activists. For a long time, the mouse was the favourite animal of researchers. “We often say that the human being is a bad model for the mouse,” says Sumantra Chattarji, professor at NCBS. What you see in the mouse may not ring true in a human being.
Several labs around the world research autism deeply, for which funding has risen sharply over the last decade. The prevalence of autism has risen in parallel, and equally sharply. About 10 million children are affected by the disease in India. Despite all these efforts, autism remains a mystery but most neuroscientists think that it is a developmental disorder. If this is true, scientists have to study the brain as it develops, both in healthy and autistic people. It is hard to look into the brain at any stage of its life, let alone while it is developing. Modern technology has begun to provide some answers to this question.
NCBS is a small but extremely well-funded institution, originally spun off from the Tata Institute of Fundamental Research under the department of Atomic Energy. InStem is India’s premier institute for stem cell research, and is under the Department of Biotechnology. Both are present in the same campus, with scientists in them working closely together.
“One of my goals here,” says Sidharthan Chandran, who leads the project at the University of Edinburgh, “was to establish a human stem cell laboratory that could model human neurological diseases. Now we have a top-class laboratory that can not only stand on its own but that also mirrors my own lab at Edinburgh.”
This neurological model has been provided by stem cells. In the last decade, scientists have learned to take skin cells of an animal, turn them into a kind of stem cells, which can then be grown in special environments into any type of cell that you want to study. For example, you could take skin cells from a human being, induce them into stem cells, and then coax them into becoming neurons. You could take the cells of an autistic adult and create their brain in a dish and let it develop a bit. You then have autism in a dish.
You could create a similar brain in a dish from a healthy person as well. Comparing the electrical activity of the two dishbrains might provide clues about how autism develops. “We have to infer function through what we think are sophisticated methods, but they are still very crude in terms of resolution,” says Chandran. “If the brain is the map of India, you have functional MRI images showing Bengaluru lighting up. But I want to see that I have just moved my phone.”
Stem cells provide that opportunity at high resolution. Scientists can look at individual neurons and their connection in the dish, as the brain develops. It is complemented by studies on rat brains as the rodents are challenged with tasks involving understanding, social recognition, complex emotional processing, and so on.
Through such a multi-pronged approach, neuroscientists hope to understand how autism develops. Even in a dish, a developing brain can show differences depending on where the cells came from. A few research papers have started coming out of the programme now. “The initial focus is some of the genetic forms of autism,” says Chandran, who is a neurologist by training.
“But the principles of the disease and the platforms have applicability beyond that.” Understanding autism is the first step. The next would be to treat the disease.
Drugs for neurological disorders have been slow to come by. The risks and costs of developing a central nervous system drug are higher when compared to cardiovascular drugs. It is hard enough to look into the brain. It is even harder to find out how drugs affect the brain precisely. The autism model in a dish can be used here as well.
Big companies like Astra Zeneca, Novartis and Glaxo Smithkline Beecham have given up the task of developing brain drugs in the last decade. “Drugs do well in animal models,” says Chattarji. “But they crash on human beings.”
Rats are closer to human beings than mice. The brain in a dish could be a model later for drug development as well, by providing a platform for initial testing. If a drug or treatment option emerges out of the project at some stage, India can be a great resource for providing a clinical platform as well.