“In the molecular life sciences, we often say that we study the ‘secrets of life’. While that may sound ambitious, our real goal is more specific: to understand the hidden processes that take place inside our cells, tissues and bodies—processes that are invisible to the naked eye but essential for life. Using genetics, DNA technologies, advanced microscopy and live imaging, and other biological-engineering approaches, we aim to uncover how living cells function at the molecular and mechanistic level. At the heart of this research lies a simple but fundamental question: how do these processes actually work?” said Ylva Engström, of the Department of Molecular Biosciences at the Wenner-Gren Institute, Stockholm University.
In this search for understanding how processes work, Engström and her colleagues are studying the humble – and often extremely annoying − fruit fly Drosophila melanogaster which can teach us a lot about biological processes in health and disease, and could allow us to develop new strategies for treating genetic diseases such as cystic fibrosis, muscular dystrophy and certain types of cancers.
So why is the fruit fly such a good model for such important basic science?
Engström explained that Drosophila melanogaster − also known as the black-bellied dew lover, vinegar fly, pomace fly, vrugtevlieg and bananfluga − is now one of the best-understood animal organisms in the biomedical life sciences. “About 75% of human disease genes (monogenic diseases) are present in flies,” said Engström. “This includes neurogenetic diseases, developmental disorders, muscular dystrophies, cancers, metabolic and cardiovascular diseases, inflammation and infectious diseases as well as alcohol and drug addiction.”
“It has been used as a model organism for over 100 years − starting around 1900 by American geneticist William Ernest Castle. But it was another American geneticist Thomas Hunt Morgan who realised its usefulness for genetic studies – due to its short life, ease of culturing and high fecundity. His work won the Nobel Prize in 1933 and since then work involving Drosophila has won six Nobel Prizes and boasts 11 Laureates.”
Drosophila is characterised by very quick development. It takes 20 to 22 hours to become larvae, and in 10 to 12 days they emerge as flies. Each female can have about 100 offspring in two weeks so there are enormous numbers.
“It also has few chromosomes, a compact genome and giant chromosomes in larvae which are visible using a regular light microscope. The human genome has 23 chromosome pairs while Drosophila has four. Humans have 20 000 genes, Drosophila has about 14 000, but two thirds of which have human counterparts. In 2000 the first whole genetic sequence of a multicell organism was in flies,” explained Engström.
While human cells divide every 24 minutes, nuclear divisions in fly cells occur every eight minutes in the first two hours of development.
“The organisation and function of many organs are equivalent between flies and humans. For almost every organ in humans there is a match in flies, and common genes regulate their development, organisation and function.”
“Although the physiology of flies and humans is obviously different, the intracellular aspects are very similar,” she added.
All of this makes them a good discovery model organism that is cost effective, easy to breed, has a short generation time; and fundamental biological processes, principles and pathways that are evolutionarily conserved between flies and humans. Because of all these advantages more than 3500 laboratories globally use Drosophila.
Engström explained that experimental model organisms are indispensable. “They allow us to observe biological processes as they happen, in real time, within a living organism.”
She gave examples from her laboratory in which advanced microscopy is used to visualise extremely rapidly dividing cells, and to understand how these cells accurately sort and distribute their chromosomes between daughter cells. “Failures in this process are a hallmark of cancer and studying it in detail can inform how we think about cancer cell behaviour.”
She explained specifically that her group has found that cell division fails if the POU/Nub protein is lost in Drosophila cells. Loss or mutation of this protein can mean that chromosomes don’t separate and daughter cells may not be of the correct composition. Similarly, they have found that cell division fails if the human POU/Oct1 protein is lost. POU/Oct1 is associated with cancer in humans, but it’s not known exactly how. It’s possible that this gives cancer cells an advantage allowing them to grow faster and more aggressively. They have concluded that POU/Oct1 factors ensure mitotic spindle assembly and accurate chromosome segregation and that POU/Oct1 in humans and its role in mitosis or cell division could be key in cancer cell proliferation.
Regulation of Programmed Stop Codon Readthrough (SCR)
Engström also explained her group’s work in trying to understand how multicellular organisms—including insects and humans—have evolved alternative ways of reading genetic information.
She explained that in universal genetic code DNA transcribes to messenger RNA which is translated to proteins by ribosomes. However, there can be termination in this translation process. Such translation termination is found to be very accurate – with a mistake rate of only 0.05%. However, all organisms have been found to squeeze the termination process to some extent and allow the ribosomes to produce alternative/larger proteins from some genes. (Viruses also do this in their host cells – they manipulate the ribosomes to produce alternative proteins while bacteria and yeasts have alternative decoding mechanisms that allow then to skip the stop.)
“However, in certain cases, cells can bypass the usual ‘stop’ signal in the genetic code and extend a protein by adding an extra ‘chapter’ to its message, a process called ‘Programmed Stop Codon Readthrough’,” said Engström.
“Very little has been known about SCR in animals and humans until recently,” she continued. “About 400 genes in Drosophila have been predicted to have SCR but few have been experimentally confirmed. Only 15 human genes have been shown to produce different protein isoforms by SCR.”
Their work has concluded that SCR is gene specific and regulated in space and time so it’s not just due to sloppy or leaky termination. They have also found that it’s multifactorial and regulated by a combination of RNA sequence and structures.
Engström also explained that about 11% of human genetic diseases (like cystic fibrosis and muscular dystrophy) and some cancers are caused by mutations that create new SCRs. “Now that we are beginning to understand how programmed stop codon readthrough is regulated, we hope to use the fly model to develop gene-specific correction of such mutations. And we aim to use that knowledge to reprogramme stop-mutations in human genetic diseases. By understanding how genetic decoding can be modulated, we hope to explore new strategies for treating these diseases.”
“Our research can be characterised as ’fundamental or basic research’, but we like to work on something that also can have more direct medical implications,” said Engström. “We ask focused questions but hope they have broader implications.”