(Note: the PI, or principal investigator, is the research group leader)
For years, Eduardo Moreno has been unraveling how competition for survival between cells in an organism plays out to make it develop healthily – or, as it ages, give rise to cancer and other diseases.
The social life of cells can be a ruthless affair. As an embryo develops, whenever poor quality cells – “loser” cells – arise in an organ, better quality cells, or “winner” cells, will make the loser cells kill themselves to ensure the body becomes as good as can be. In the same manner, as the organism ages, “healthy” cells kill “damaged” cells in order to maintain tissue quality. But there’s also a dark side to it: when certain cells become “super-winners” and start to kill healthy, normal “winner” cells, cancer arises.
In fact, it has been suspected since the early 2000s that cell competition boils down to a question of Darwinian “survival of the fittest”. No wonder, then, if Eduardo Moreno, who for years has been doing pioneering work on the molecular mechanisms that enable cells to compete (and the fittest to survive) speaks of his work as being the study of “evolution inside the organism”.
Moreno was born in Madrid in 1970, where he lived until 2000. At 6 or 7 years of age, he wanted to be a chemist. He was fascinated by a toy chemistry set he had. “Mixing powders, creating new things fascinated me”, Moreno recalls. “They smelled really bad and sometimes exploded!”
But when he was around 14 years-old, he swapped chemistry for biology after he heard his high school biology teacher explain Darwin’s Theory of Evolution to the class. “It seemed to me that evolution explained everything”, he says.
A number of years later, while doing his PhD on embryonary development genetics in the fruit fly – which he finished in 1999 at the Severo Ochoa Molecular Biology Centre, in Madrid –, Moreno read a paper co-authored in 1981 by Ginés Morata, his thesis adviser and lab chief. It deeply piqued his curiosity – and would in fact shape his future scientific endeavors.
The paper expanded earlier seminal results on cell competition in an organism and showed how certain cells were able to eliminate other cells in their neighborhood. “At the time I read the paper, nobody was working on cell competition, but for me it was just natural selection at work inside the organism”, Moreno explains.
He told Morata that he wanted to look at the phenomenon from the molecular genetics angle but his boss, who didn’t think Moreno could tackle that issue by himself, told him to finish his PhD instead.
Moreno was set on it, though. “Everybody thought this was very complicated”, says Moreno. “So I finished my thesis and then started my post-doc in the same lab – and spent a year looking at the problem by myself in the fruit fly.”
As his work was starting to pay off, he decided to leave Madrid and go to Konrad Basler’s lab in Zurich. “I left for Switzerland in 2000, taking my project with me”, says Moreno, who believed he would be able to understand the genetic and molecular mechanisms of cell competition in the fruit fly thanks to techniques recently developed.
The reward came several years later. “In 2002, Ginés, Konrad and myself published a paper concluding that there were ‘loser’ and ‘winner’ cells, that the loser cells’ death was induced by the winner cells, and that this happened through the activation of a system of apoptosis, or programmed cell death”, recalls Moreno. Simply put, cells decided to commit suicide when in the presence of fitter cells.
But nothing was known about the signal the winners used to communicate with the losers, ordering them to kill themselves. How did this cellular culling happen? It would take Moreno more than ten years to pin down the answer.
Along the way, while doing his post-doc in Zurich, Moreno discovered a potential link between cell competition and cancer. “I found that certain oncogenes [cancer-promoting genes] were able to transform cells into ‘super-winners’ or “super-competitors”, which then killed normal cells” he explains. “Konrad and myself then proposed that this could be very important for the tumoral process, and that tumors used this strategy to invade healthy tissues.”
More than ever, Moreno’s prime interest was, he says, “to discover how cells communicate with each other, what are the ‘marks’ that distinguish the winners from the losers and how they manage to recognize each other’s fitness.”
Flowers and fingerprints
In 2005 he returned to Madrid, where he started his own lab at the Spanish National Cancer Center (CNIO). And in 2010, in collaboration with Christa Rhiner, came the big discovery: cells in the fruit fly had certain proteins on their membrane, which the team would later dub “flower proteins”, that characterized its fitness. Moreover, they found that these cellular “fitness fingerprints” evolved with age. If all the cells are the same age, they display the same fitness fingerprints; there are neither losers nor winners and nothing happens. But as a cell’s fitness decreases with age, it will be deemed less fit by its “sisters”.
But why would this mechanism be useful in a normally functioning organism? Back to Switzerland in 2011, this time at the University of Bern, Moreno and his team finally found the answer to this question in 2015, by showing that this type of cell competition is essential for the health of the body at all stages of life.
“For the first time, we found this was very important to prevent accelerated brain aging”, says Moreno. Indeed, if aging neurons were not culled, they would accumulate, disturbing the normal functioning of neural circuits. “Cell death is in this case a sort of quality control, and it’s good for the brain.”
This could have implications for understanding Alzheimer’s disease. “There is this idea that cell death in Alzheimer’s is something bad”, says Moreno, “but we have found that at least 60% of this cell death is in fact a good thing, because it eliminates neurons that disrupt neural communication”.
At the beginning of life, during embryo development, the same mechanism also allows the growing organism to avoid malformations in its tissues. “This system allows for the recognition and elimination of cells that occupy an incorrect position. In this way, a cell that is not growing in the right place, that is not ‘happy’ with its situation, is eliminated because it displays the wrong fitness proteins like little flags”, telling other cells that it doesn’t belong there, says Moreno. “Cells are social animals, programmed to say when something is wrong.”
At the Champalimaud Centre for the Unknown since late 2016, Moreno’s team has discovered another type of cellular competition: a mechanical rather than chemical phenomenon, where cells “compete for space, push against each other, and some are compressed, while others are crushed and die – once again, by committing suicide. “We don’t know how these mechanical changes induce apoptosis”, says Moreno. “In fact, he adds with a laugh, “we still don’t know much about the chemistry of fitness either…”
Paradoxically, his most memorable scientific achievement is something altogether unrelated to cell competition and fitness. It’s a “synthetic fruit fly” he created in 2012. “I was frustrated by the fact that our work on cell fitness was a never-ending story”, he recalls, “and I was looking for a project that motivated me to fill my free time”, says this sports-loving (he takes jogging and sailing very seriously) father of three boys.
These flies, called Drosophila synthetica, can reproduce, but they are unable to breed with the most used species of fruit fly for research, Drosophila melanogaster. “It was really something, to create, by using genetic tricks, a new species of Drosophila in the lab. “For me, it was like a bomb. The genetics were complicated, and when I succeeded I got back my sense of what it is to want to do science with your own hands. I remember that time with great fondness”, concludes Moreno.
In case you might be wondering, his genetically engineered flies cannot survive outside the lab.
Ana Gerschenfeld works as a Science Writer at the Science Communication Office at the Champalimaud Neuroscience Programme
Edited by: Catarina Ramos(Science Communication office). Photo credit: Tor Stensola(CCU)