Growing up in Brazil, Marcos Simões-Costa frequently visited his grandparents’ farm in the Amazon. That immersion in nature, squawking toucans and all, sparked his fascination with science and evolution. But a video of a developing embryo, shown in his high school science class, cemented his desire to become a developmental biologist.
“It’s such a beautiful process,” he says. “I was always interested in drawing and art, and it was very visual: the shapes of the embryo change, the fact that you start with a cell and the complexity increases. I got lost in that video.”
Today, Simões-Costa, of Harvard Medical School and Boston Children’s Hospital, honors his younger self by demystifying how the embryo develops. He studies embryos and stem cells from birds and mice to learn how networks of genes and the elements that control them influence the identity of cells. The work could lead to new treatments for various diseases, including cancer.
“The embryo is our best teacher,” he says.
Simões-Costa focuses on the neural crest cells of the embryo, a population of stem cells that form in the developing central nervous system. The cells migrate to other parts of the embryo and give rise to many different cell types, from bone cells in the face to muscle cells to brain and nerve cells.
Scientists have wondered for years why, despite being so similar, neural crest cells in the cranial region of the embryo can form bone and cartilage, while those in the trunk region cannot. While doing a postdoc at Caltech, Simões-Costa studied the cascade of molecules that govern how genes are expressed in each type of cell. With his adviser, developmental biologist Marianne Bronner, he identified transcription factors (proteins that can turn genes on and off) that were present only in cranial cells. Transplanting the genes for these proteins into stem cells gave the cells the ability to create cartilage and bone.
Now, in his own laboratory, he continues to unravel how this vast regulatory network influences the specialization of cells. His team reconstructed how the neural crest cell’s complete set of genetic instructions, or the genome, folds up into a compact three-dimensional shape. The researchers identified short DNA sequences, called enhancers, that are located in distant regions of the genome, but end up near key genes when the genome folds. These enhancers work with transcription factors and other regulatory elements to control gene activity.
Simões-Costa is also using neural crest cells to elucidate a strange behavior shared by cancer cells and some embryonic cells. These cells produce energy anaerobically, without oxygen, even when oxygen is present. Called the Warburg effect, this metabolic process has been extensively studied in cancer cells, but its function remains unclear.
Through experiments manipulating the metabolism of neural crest cells, Simões-Costa’s team discovered that the Warburg effect is necessary for cells to move during early development. The mechanism, which should remain deactivated in non-embryonic cells, is somehow “reactivated in adult cells in the context of cancer, which makes these cells more migratory and more invasive”, says Simões-Costa.
“He is one of the few people who has really looked [this process in neural crest cells] at the molecular level and delved into the underlying mechanisms,” says Bronner.
The clever combination of classical embryological methods with the latest genomic technologies to address fundamental questions in developmental biology is what makes Simões-Costa special, says Kelly Liu, a developmental biologist at Cornell University. He wants to understand not only what individual genes do, but also how they work at the systems level, she says.
How does the genetic blueprint tell cells where they are in the embryo and what they should be doing? How do cancer cells hijack the Warburg effect, and understanding that process could lead to new treatments? These are some of the issues that Simões-Costa wants to address next.
“It’s been 20 years since the Human Genome Project came to an end,” he says, referring to the massive effort to read human genetics instruction book. “But there is still a lot of mystery in the genetic code.”
Those mysteries, plus a deep passion for laboratory work, fuel Simões-Costa’s research. “Being at the bank is when I’m happiest,” he says. He likens the delicate craft of performing precise surgeries on tissues and cells to meditation. “Does not get old”.
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