In a cavernous room inside a low-slung glass building in south Delhi, the lights turn on and off automatically in tune with the biological rhythms of fish. About 10,000 zebrafish—each half the length of a human finger when fully grown—swim daintily in 2,000 small tanks stacked up on shelves, all kept at a controlled 28 degrees Celsius. The lights come on at 9 am, and go off at 11 pm—an ideal light-dark cycle for the fish, creating an indoor night and day. Zebrafish like to breed in the morning, and getting them to breed is the point. At the room’s double-door entrance, a sign says visitors are not allowed beyond 7 pm. Otherwise, “the fishes get agitated,” Adita Joshi, a genetic researcher, told me.
I visited the fish, at the labs of the Institute of Genomics and Integrative Biology, on a morning in early September. Parents are kept in smaller tanks at the top, I was told, while their progeny proliferate below. The IGIB houses numerous strains of zebrafish, some of which occur naturally, while others are produced through gene manipulation. Next door to the tank room, zebrafish embryos are kept refrigerated on Petri dishes, with tens or even hundreds on each one. Researchers tweak the embryos’ genetics through various processes, including “gene knockdown,” which inhibit the expression of particular genes through the use of chemical substances.
Sridhar Sivasubbu, who heads the lab, likened the zebrafish to a sandbox for genetic experimentation. In scientific parlance, zebrafish are model organisms—species fast to breed and easy to keep in laboratory conditions, and whose characteristics allow certain kinds of experimentation. Famous examples include mice and fruitflies. The seemingly unremarkable zebrafish, native to the Indian subcontinent and widely available in pet stores, is particularly interesting since a large portion of the genes that code for protein are conserved in it, despite its genome being half the size of that of humans. Its embryos are also transparent, meaning that “right from one cell to a functional, free-swimming organism,” Sivasubbu said, its development can be observed in detail under a microscope. This allows researchers to test the physiological effects of manipulations of the zebrafish genome, and so to correlate particular genes to particular physical traits and defects efficiently—within three days the researchers are done with the embryos. Widespread research on zebrafish across the world in the last decades has advanced the understanding of basic genetics, vertebrate development and human disease.
Sivasubbu, in his early forties, is a functional geneticist, who holds a PhD in zoology. He is a short and taut man, and speaks in abbreviated but perfectly clear sentences. He said that understanding the human genome—a massive sequence of four recurring chemical compounds that incode genetic information, strung together in “base pairs” in our DNA—was like trying to read “three billion alphabets without punctuation.” In other words, though we now know the full sequence of the human genome, the functions of many genes—sections of base pairs responsible for particular traits—are still largely a mystery. “What you do in functional genomics is take the genetic material of an organism—in this case humans or vertebrates—and see, ok, from point 0 to 10,000 is one gene,” Sivasubbu said. Then you test if that sequence is responsible, say, for the rhythmic beating of the heart, or the development of the eyes.
The first taxonomical description of the zebrafish, or Danio rerio, dates back to 1822. It appeared in An Account of the Fishes Found in the River Ganges and its Branches, a book by Francis Hamilton, a British surgeon. Hamilton did not think highly of the fish. “In an economical view,” he wrote, they are insipid, small, and of little value, “nor does their number anywhere compensate for these defects.”
About 150 years later, George Streisinger, a pioneering molecular biologist, cloned zebrafish at an American university. In doing so, he achieved the first ever cloning of a vertebrate species, and laid the groundwork for the zebrafish’s use as a genetic model organism. Streisinger used a strain of zebrafish called AB, which he bought from a pet store. Today, after years of collaborative international work on the species, the number of strains has multipied, and their names reflect the zebrafish’s current cosmopolitanism: AB/Tubingen, Cologne, Ekkwill, Darjeeling, Hong Kong, Singapore SJA.
An international effort to map the zebrafish genome began in the early 2000s, using a strain drawn from laboratory specimens. IGIB, a government funded organisation, was founded in 1977, and took up research on zebrafish, under Sivasubbu, in 2006. In 2009, Sivasubbu and his colleagues mapped the genome of the Assam Wild Type strain, in an exercise to improve gene sequencing techniques in India, and to document genetic variations within the zebrafish population.
In recent years, the IGIB—one of around half a dozen zebrafish labs across the country—has conducted research on human genetic disorders. Vinod Scaria, who analyses genomic data for the institute, told me that “in the past year or so” IGIB has “set up a large collaborative network, with about 55 clinicians and 16 or 17 centres” involved in research in this field. One case referred to Scaria and Sivasubbu involved two siblings suffering from lamellar ichthyosis, a genetic condition causing the formation of scales all over the skin. The researchers are experimenting with zebrafish to better understand the workings of such diseases.
Sivasubbu told me that the IGIB’s first zebrafish specimens, like Streisinger’s, were bought at a pet store, and he praised the species as “a very good hobby fish.” But no one is allowed to take home any fish from the lab. This, Adita Joshi explained, is because many of them have altered genes, and the researchers don’t want them to contaminate the natural zebrafish gene pool by escaping the institution’s premises—beyond the cavernous room, the glass exterior and the automated lights.