Give the fruit fly a chance in brain research

The brain is made up of hundreds of thousands of neurons. The stem cells divide to give rise to this staggering number of neurons. How do these neurons organize themselves, connect in a way that makes sense and ultimately lead to a brain that can receive input, process information and influence behaviour of an organism?

These are questions intriguing developmental and neurobiologists alike. Concrete answers have eluded us thus far though scattered research results have helped construct a somewhat rudimentary picture. The use of a model system to best answer these questions has also been a debatable and open ended issue. What experimental feats are possible in a given model organism depends on historical, economic and biological factors.

Drosophila melanogaster, or the fruit fly, is one such widely used model system. Drosophila is arguably one of the most powerful genetic tools in the world. An easy, cost-effective animal to grow in the lab, its use in understanding genetics dates back to 1910 when Thomas Morgan isolated the first fly mutant. Since then, thousands of fly lines have been generated and made publicly available (Flybase, for instance). It was no surprise when the fly genome was sequenced in March 2000 by the Berkeley Drosophila genome project in collaboration with Celera Genomics. As a model system, sophisticated genetic calisthenics are possible in Drosophila with reproducible and stable results, something that is unparalleled in other model systems, such as the mouse.

The fruit fly is thus, a highly amenable organism to study complex and fundamental questions about brain development and the issues surrounding it. Even though differences between insects and mammals appear overtly to be huge, research over the past decade has shown that the underlying molecular framework of the developing brain is pretty similar. Meaning, the molecules that build the vertebrate and invertebrate brains are conserved even though a lot of fine tuning happens later to make both brains anatomically different¹.

Indian scientists have done pioneering work on many aspects of brain development in the fly. The Siddiqi lab, first based at the Tata Institute of Fundamental Research (TIFR) at Mumbai and currently at the National Centre for Biological Sciences (NCBS) in Bangalore, is a much recognized and respected team the world over. Their long standing research about how flies smell and how they distinguish odors has contributed to understanding behaviours innate to living beings, such as recognizing good versus bad smells. Veronica Rodrigues and her team of researchers at TIFR and NCBS have made a serious attempt at answering questions about the cell and developmental biology of brain development in Drosophila. Their work on molecular processes that occur during development of sense organs such as the antennae has been highly acknowledged by peers all over the world². In addition, their work has shed light on how different cell types organize to function within the olfactory system or the smell system of the fly³. The present fly brain research scenario in India is thus, a bright faced one, given the increasing number of acclaimed works coming from Indian labs.

That said, there is still a gaping void where a bridge between basic research and pharmaceutical industry should have been. Our western contemporaries, on the other hand, are slowly but surely progressing in this direction. Neurodegenerative diseases are increasingly been studied using the fly as a model system. There are now fly models for Parkinson's and Alzheimer's disease in particular and the pharmaceutical giants are raking in the results, regarding them as a long term investment⁴. Their heightened interest and investment in University based research encourages researchers and vice versa.

Indian researchers suffer from a lack of interest of the pharmaceutical industry in their research. Industries are more interested in generics and their research and development has very little to do with long term investments. Fundamental research, in their opinion, is best left to Universities. Although this might be a sound strategy to keep the money mill going for the next five years, it is certainly a myopic one.

The short summary that follows highlights one such area where Drosophila brain research and industry could mix. An increasing importance is being attached to brain stem cells these days. Not just because stem cell is the buzzword but because stem cells have the potential to be the probable new generation of therapeutics.

One such fundamental question of high significance to the above is that of the properties of neural stem cells. Brain stem cells or neural progenitors start dividing and continue till they have cues to stop, making up the brain's definitive size. So what are these cues that tell stem cells when to stop dividing?

Neural stem cells are easily recognizable in the fly nervous system at certain stages wherein complex markers are generally needed to spot them in a more complex mouse brain. Therefore, questions about their division properties and how and when neural progenitors stop to divide are comfortably addressed in Drosophila.

A recent work⁵ from the Gould lab in London, published this year in the journal Cell, has pinned down a handful of molecules that schedule the end of this dividing process, also called neural proliferation. Using Drosophila larval and adult central nervous systems, they have identified the molecular cues that signify the end of an aging progenitor.

The authors conclude that neural progenitors stop dividing by either exiting the cell cycle or by undergoing a form of programmed cell death. However, even though the strategies used to end proliferation are different, the "molecular timer" used is the same by both types of progenitors.

This molecular timer is actually a carefully orchestrated series of molecules expressed in relation to time, or in technical jargon, in a temporal series. The temporal series generated within a neural stem cell thus specifies a combinatorial code, which then acts on its respective targets, ultimately stopping the stem cell from dividing after it has reached a certain age; meaning acquired its "old age" signature of molecules.

In fact, when lineages were mutated for one or several of these factors, the stem cell could no longer stop dividing. It continued to proliferate into adulthood, something that normally never happens. This probable immortalization of the stem cell without disrupting its intrinsic division properties could in the future prove to be a useful tool in stem cell therapy and regeneration.

The idea may not be as far fetched as it first sounds. Although it is a fundamental study in Drosophila, some of the molecules required in making stem cells stop dividing may have functional equivalents in mammals. It is also probable that even though the "molecular timer" in itself may be different, the downstream targets may be functionally conserved.

Research studies such as these, besides improving the picture about fundamental processes like neurogenesis in the fly, is also in itself a stepping stone for similar research in mammals such as humans. Why? Because if scientists already have a clue about possible suspects, it narrows down the search for key control molecules, with vital therapeutic implications.

The author is a graduate student at the fag end of her PhD at the Biozentrum, University of Basel, Switzerland. Her work involves investigation of mechanisms that lead to lineage differentiation in the developing Drosophila brain.