One of the great mysteries of biology is how one fertilized egg gives rise to a whole life form. An embryo has to generate cellular diversity from a single cell, and not only that, but the cells have to be positioned at precise locations to give rise to the final body plan. “People often equate the body to a machine, but a machine only has to work when you turn it on,” says Marcos Simoes-Costa, Molecular Biology and Genetics. “An organism, though, is alive and physiologically viable as it’s developing. It’s actually constructing itself. How does it do this? That’s the ultimate question in biology.”
Simoes-Costa tackles the puzzle of embryonic development with relish. It’s something he’s been intrigued by since high school when he first watched videos of embryos developing. When he came to Cornell in 2016, from a postdoctoral position at the California Institute of Technology, he set about creating a robust experimental platform to investigate the developmental process. Now, the Simoes-Costa lab looks at the mechanisms that drive the process from a variety of angles.
The Neural Crest
The bulk of the lab’s work focuses on a particular stem cell population, called neural crest cells, that give rise to different components of the body, from the face to skin pigmentation to neurons in the brain. “Neural crest cells are all over the place,” says Simoes-Costa. “They form adjacent to the nervous system, but then they move throughout the body—like a migratory wave that envelopes the whole embryo—and go on to differentiate into different cell types.”
Simoes-Costa has explored how neural crest cells contribute to multiple tissues and organs, but he is also using these cells to study cell behaviors. Together with Debadrita Bhattacharya, PhD ’21 Molecular Biology and Genetics, he is looking at the similarities between cancer cell metastasis and neural crest cell migration. The researchers discovered that, during migration, neural crest cells produce high levels of enzymes related to glycolysis, an anaerobic form of metabolism. This signifies that, unlike most of the cells in our bodies, migrating neural crest cells produce most of their energy without using oxygen.
This is the same metabolic adaptation, known as the Warburg effect, that scientists thought was unique to cancer cells. “It’s not so much an abnormal form of metabolism as it is a developmental form,” Simoes-Costa explains. “For neural crest cells in the embryo, switching to this form of metabolism is important for moving around. We think, for a variety of reasons, the cells need energy very quickly and don’t have time to undergo respiration. So they consume a lot of glucose. This turns on genes that promote migration, and the behavior is linked to the metabolism of the cells.”
The Link between Cancer and Development
By reducing the amount of glucose available to neural crest cells, the researchers are able to affect the cells’ ability to move. This finding has strengthened the link between cancer and development. “The similarity in metabolism is very striking,” Simoes-Costa says. “It supports the view that cancer is actually driven by erroneous activation of developmental mechanisms that should be shut off in adult cells.”
In a follow-up to the earlier study, Simoes-Costa and Bhattacharya are currently researching how neural crest cells transition to an oxygen-based, aerobic metabolism once they stop migrating and begin to differentiate into cell types. “The idea is that maybe we can find out how that transition is regulated in the embryo, and then we can test how those mechanisms would affect cancer cells,” Simoes-Costa says.
“With RNA sequencing analysis, we can see the genes that are turned on in each group of cells. Then we can integrate all the transcriptomes together to generate a 3D map of gene expression in the embryo.”
Spatial Complexity in Early Development
Recently Simoes-Costa began a new project funded by a five-year, $2.3 million Director’s New Innovator Award from the National Institutes of Health, which he received in early 2020. Together with Megan M. Rothstein, PhD ’21 Molecular Biology and Genetics, Austin Hovland, PhD ’22 Molecular Biology and Genetics, and Ana P. Azambuja, postdoctoral researcher, he is building a three-dimensional, single cell–resolution computer model of a chicken embryo to explore how an organism generates spatial complexity in early development.
“One of the first decisions an embryo has to make is what will be the head versus the tail, what will be front versus back, and what will be left versus right,” Simoes-Costa explains. “In the very early embryo made up of thousands of cells, we already see this molecular asymmetry. Some genes are active in the future head of the embryo and some are active in the tail, for instance. There’s already a genetic blueprint of what the adult organism is going to look like.”
Using spatial transcriptomics, a technique to study the sum of an organism’s RNA transcripts, the researchers analyze gene expression in ultrathin sections of very early chicken embryos. “With RNA sequencing analysis, we can see the genes that are turned on in each group of cells,” Simoes-Costa says. “Then we can integrate all the transcriptomes together to generate a 3D map of gene expression in the embryo.”
At the same time, Simoes-Costa and his colleagues are isolating single cells from embryos and mapping which genes they express. They intend to combine the two data sets, positioning the individual cells in the whole-embryo grid, thus creating a computer-generated model. “Once we have that, we can understand where and when all the genes are expressed,” he says. “We plan to do this at different stages of development so that we can see how these expression patterns of different genes change over time.”
How the Genome is Organized within the Cells
Along with the spatial organization of the embryo cells, the researchers are also exploring genome organization within each cell. “Chromosomes in the cells are formed by linear DNA, but they are arranged in well-defined configurations,” Simoes-Costa explains. “The way the DNA is folded and organized will influence whether gene expression is turned on or off. We are testing our hypothesis that this organization of the genome happens very early before the genes are turned on.”
Simoes-Costa calls his first three years at Cornell—during which he wrote multiple grants, set up his lab, and taught for the first time—an adventure. “This is probably the happiest phase of my career so far,” he says. “The scope of my research has become much broader. I wasn’t expecting that. I think it comes from my interaction with other people in my department. Molecular Biology and Genetics is so broad; there’s an array of people working on different things, and when I talk with them, I end up taking from their approaches and their ideas. I came to Cornell with a plan, but my plan changed once I arrived.”