Growing up in Lisbon, Portugal, Miguel Coelho was a curious, contemplative kid, as interested in why things happen as in how they work. It is no surprise, then, that today, as a postdoc in the Murray lab, Coelho studies evolution as a means of predicting the future, and is equally interested in sharing knowledge as in hunting down answers among the unknown.
“A side of me was very religious,” he recalls, “and I was very concerned with problems of life and death and what happens after you die.” These existential quandaries “made me want to know more about how living organisms behave and how they are built and how they propagate themselves and I think that was what lead me towards biology.” As for his parallel interest in chemistry, Coelho kids, that arose “mainly because my mother never gave me a chemistry set.”
At the University of Lisbon, Coelho majored in biochemistry, “a perfect combination of my two favorite disciplines, biology and chemistry,” but craved a more hands-on approach than the theoretical fare offered by his early coursework. So he joined Helena Soares’s lab at the Gulbenkian Institute for Sciences, a private research institute in neighboring Oeiras, Portugal, where he explored cilia biogenesis in Tetrahymena thermophila. After earning his diploma, Coelho stayed on at the institute for two years as a research assistant.
Eager to learn something “different and strange,” Coelho left for graduate school at the Max Planck Institute for Molecular Cell Biology and Genetics in Dresden, Germany, to study the biophysics of aging with Iva Tolic. At first, Coelho struggled with the transition. Leaving his home and family behind was at least as challenging as his research so, in need of a fresh perspective on the latter, he devised a creative if unorthodox solution: Unbeknownst to his P.I., “I decided to put a poster of my work, a small one, in the elevator so people could see it and give me their feedback.” He figured, “If people put posters of ‘I want to give out a kitten,’ or ‘Do you want to buy my car?’ in the elevator, why not have a scientific poster?” The response was ardent if mixed. By the next day, “I had 50 emails in my mailbox about this. Some people really liked it. Some people really hated it.” But the story became legend at the institute and ultimately either the feedback or encouragement ushered him past the temporary slump. He recalls one friend’s equivocal critique: “Miguel, this is the problem: The poster had so much data that you had to go up and down four or five times before you could read the whole poster!”
Coelho’s subsequent work with Tolic lead to a publication in Current Biology which demonstrated that symmetrically dividing cells of the fission yeast S. pombe do not undergo aging as they replicate, challenging the current dogma that all living organisms age. In a recent publication in PLoS Biology, Coelho delved further into the physical and genetic mechanisms that govern the segregation of damaged proteins during cell division. He discovered that Hsp16, a conserved molecular chaperone, promotes fusion of damaged proteins after stress, leading to asymmetric segregation and aging.
His experience at the Max Planck was so intellectually thrilling that, when considering a postdoc, Coelho had a hard time finding anything as novel and exciting at other European institutions. So he looked into postdoctoral positions in the United States, preferably labs conducting research unparalleled in Europe, “so that if I want to return to Europe I can bring something of value back.” Both synthetic biology and experimental evolution peaked his interest and Andrew Murray’s lab offered him the chance to explore both.
Since joining the Murray lab last summer, Coelho has applied his background in biophysics and live cell microscopy (a skill he honed in the Tolic lab) to quantifying cell biological events, while enjoying a field that diverges from his previous studies and learning something new every day. Currently, Coelho uses experimental evolution to understand causation during genetic instability and consequent diseases. He places yeast cells under selective pressure to become genetically unstable, and lets evolution decide the path towards instability. After using whole genome sequencing to hunt down the mutations that correlate with instability, Coelho will re-engineer individual mutations in the ancestral strain, and test whether these mutations drive instability. Genetic instability causing genes that are conserved between yeast and humans may represent important targets for cancer diagnosis or early therapeutic intervention.
Andrew Murray is very enthusiastic about Coelho’s project and believes it “exemplifies the connections between research for research’s sake and the ‘real world.’” “The imperative to evolve or perish,” he elaborates, “is likely to have induced higher mutation rates at various times and places during earth’s history, meaning that [Coelho’s] work could shed light on changes that accelerated evolution. But the same pressure also causes genetic instability in cancer, and new pathways that Miguel finds in yeast could be playing a role in the evolution of cancer in patients.”
In addition to pursuing his own research, this summer Coelho mentored an undergraduate student, David Armenta, through the Systems Biology summer internship program. Over the course of ten weeks, Coelho’s intern tackled a project that mirrors his own, reverse-engineering the genetic instability that Coelho has evolved in order to find compensatory mutations that cause cancer cells to behave like normal cells by decreasing and stabilizing their mutation rates.
Mentoring an intern is a sizable time commitment, Coelho admits, but he finds the task both rewarding and imperative: “The way you educate people and the way you transmit, not only knowledge, but also certain values, certain principles of etiquette and conduct in the lab, may be an even bigger achievement than writing a very nice paper that gets published in a high profile journal” That said, “I still have to find out whether I’m good at teaching,” he demurs, “It’s a big responsibility.” Andrew Murray maintains that Coelho handles this responsibility with brio: Coelho’s “joy in doing science and in teaching it to the undergraduates who work with him is infectious and helps to remind me that keeping science fun is one of the most important parts of my job.”
This spring, Coelho earned the Human Frontier Science Program (HFSP) Long-Term Fellowship, a three year mobile fellowship he hopes will support his transition to a new position two years from now. As an HFSP fellow, Coelho will be eligible for a Career Development Award that could fund his first independent projects, preferably at a European research institute like the Max Planck, located comfortably between his family in Portugal. HFSP grants postdoctoral fellowships to scientists willing to pick up and move to another country, willing to explore subjects they’ve never studied before, maybe even willing to post their data in an elevator for public critique. Coelho’s determined yet flexible curiosity lead him to his postdoctorate at Harvard and will continue to inspire his career.
In 2018 Miguel’s postdoctoral work resulted in the discovery that genetic instability, defined as the heritable increase in mutation rates, starts via single-hit, contrary to the current idea in the field, which for cancer to start two-hits generating a homozygous recessive mutation are required. Genetic instability, starting in a single-hit, accelerates the rate at which tumor suppressor genes and oncogenes are mutated, also contributing to adaptation to drug therapy and hence cancer resistance. His work also revealed new, unconventional targets for genetic instability, not directly associated with DNA metabolism or repair. This discovery, summarized in a manuscript, was recently accepted for publication in the journal “Nature”.
For more on Miguel Coelho and his research visit his personal website
Find out more at PubMed