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Cell Biology

Maternal inheritance

The mechanism of the transfer of the mother's bacteria to the offspring of insects is helping stem cell research and the treatment of tropical illnesses

HORACIO FRYDMANAll of the cells of this fly have a fluorescent green protein, which facilitates the identification of the transplanted tissuesHORACIO FRYDMAN

From research into a bacterium that under the microscope looks s like a grain of rice has emerged information that is helping to understand the propagation of infections and to explain, a little better, the development of stem cells, the contemporary medical hope as they give origin to other types of cells. As well as this, some conclusions could be useful for combating tropical illnesses such as dengue fever and elephantiasis. The prospects that now appear so wide sprung from a purely scientific question: how could the bacterium Wolbachia have turned itself into one of the most successful microorganisms on the planet, to the point of disseminating itself among millions of species of arthropods, including insects, spiders and crustaceans, as well as worms such as the roundworm. The spider that falls from the curtain or the fly that enters by the window probably carry thousands of bacteria of the Wolbachia genre.

The Brazilian biologist, Horácio Frydman, had this in mind in 2002 when he knocked at the door of one of the laboratories at Princeton University, United States, coordinated by Eric Wieschaus, one of the Nobel Prize for Medicine winners in 1995 for having discovered the genes and mechanisms that control embryonic development – he worked with the fruit fly, Drosophila melanogaster, but these principles also apply to higher organisms, including human beings. Frydman told him that he had completed his master’s degree at the Chemistry Institute of the University of São Paulo (USP) supervised by professor Roberto Santelli and his doctorate degree at Johns Hopkins University, supervised by professor Allan Spradling, a respected specialist in stem cells, and that he intended to study the Wolbachia in the Drosophila. Wieschaus had never heard of the Wolbachia, but liked the proposal and gave him a year to show results; if he could not get any then Frydman would have had to abandon his own project and begin to work on one of the ongoing research lines at the laboratory.

Frydman worked avidly and made it. Firstly he developed some microscope techniques that allowed him to visualize the bacteria in the interior of the Drosophila and, little by little, he worked out how they install themselves in the host organism and are afterwards transmitted. When injected into the abdomen of a fly, these bacteria take 15 days to pass through membranes and muscle tissue and arrive at the insect’s ovaries, which have the appearance of a bunch of bananas. But why the ovaries, and not the intestines, the heart or the brain, as with other parasites? Because the ovaries – or better, in one of these compartments, the germarium – is where the somatic stem cells are, which give origin to the egg shell and other structures that are going to protect the embryo, and the germinative stem cells, which give rise to the sex or gametes cells. The stem cells, on dividing up, give rise to different types of cells, according to the tissue that they will form.

But the bacteria does not directly infect them. Previously – and this was the most notable discovery -, the Wolbachia accumulated in a micro environment of the germarium called a niche, which provides proteins and stimulates essentials for the maintenance and multiplication of the stem cells. As Frydman demonstrated by producing and analyzing images such as those that follow this story, the Wolbachia also makes use of this space, as if it had arrived at its maternal home after a long journey and could finally settle in, feed itself and multiply. Only then does it leave and infect the somatic and germinative cells. “Eighteen days after the initial infection” he says, “all of the germinative cells are infected with Wolbachia.” From the niche, the bacteria can infiltrate into the cells that form the egg and propagate itself in the following generations.

Frydman demonstrated that the so-called transference or vertical infection ” from mother to offspring ” was highly successful when he collected the fly’s eggs into which bacteria had injected itself and verified that the following generations had also been infected. This was the proof that the Drosophila – a 2 to 3 millimeter insect, to which the majority of people usually give little attention, but is considered one of the best study models for genetics as it multiplies rapidly and presents chromosomes that can be manipulated with relative ease – can also teach us a lot about parasite transmission. Published in Nature on May 25th, this work is the first demonstration of the transmission mechanism of this bacterium from one organism to another and the first report of a bacterium specifically infecting the niche of the stem cell.

Maternal home
But why does the Wolbachia firstly conquer the niche? “It’s an extremely advantageous trick, which explains how this bacterium has turned itself so omnipresent” says the forty-year-old biologist who is currently working as an associate researcher at Princeton University, but wants one day to return to Brazil. “The niche is a permanent structure of insects’ ovary, allowing the bacteria population that occupies it to renew itself, multiply and spread. Curiously enough, it’s the same strategy that stem cells make use of when forming tissue.” Spradling, his doctorate degree supervisor, insisted for at least six years on the importance of the niche, a concept loaned from ecology to designate a region that, although of location and constitution even today imprecise, will define the fundamental characteristics of stem cells. The niche will also control the level of division and the differentiation process in other types of cells. Indeed, the identity that stem cells can assume will depend upon the environment in which they had lived.

At the beginning, these ideas only attracted looks of disbelief. Nevertheless, a series of research studies done over the last few years have demonstrated that diverse types of stem cells, from insects to humans, really depend upon the niche in which they live. An article published last year in Nature showed that professor Spradling’s ideas and of other pioneers, are now accepted – the niche has become the object of intense research. Today it is known that already differentiated cells can regress to the stage of stem cells if replaced back in the niche, as if they were adults who would go back to behaving like children on returning to their maternal home.

“The Wolbachia must find something special in the niche, which as yet we don’t know what it is” explains Frydman. For this reason he believes that this bacterium could become a tool for studying the niche and for gaining a better understanding of the development and potential medical applications of stem cells. It would not be the first time that biologists ally themselves to parasites: much knowledge about the cellular skeleton resulted from the study of Listeria, another bacterium that lives in the inside of cells. This time, however, it will be nothing trivial, since each organ – liver, bones and brain – must house specific niches and distinct populations of stem cells. “In many organs, through lack of specific markers, it’s impossible to differentiate the niche and the stem cells from the other cells” he stated.

Even at that, the knowledge about the strategies of survival of this bacterium can help to combat tropical illnesses transmitted by insects or worms. A team from the University of Queensland, in Australia, will receive US$ 10 million from the Bill and Melinda Gates Foundation in order to deter the propagation of the dengue virus in Africa by interfering in the populations of Wolbachia that install themselves in the transmitting mosquitoes. Research with Wolbachia can also offer new prospects in the treatment of illnesses such as elephantiasis, a malady that hits 120 million people in 80 countries, and blocks the lymphatic veins and by uncommon swelling of the legs or genital organs. As recently discovered, the germinative cells of worms that bring about the illness are full of Wolbachia. Indeed, antibiotics, in association with vermifuges, could be very useful. The first tests show that the worms become sterile and also die when the bacteria are destroyed by antibiotics.