Devoted to development
By Noga Martin
Dr. Alejandro Aguilera Castrejón expected to turn his love of animals into a career studying wildlife in the jungle. But a single course on developmental biology, during his BSc studies at Universidad Nacional Autónoma de México (UNAM), redirected his interest from creatures of the wild to molecular biology and embryo development.
When searching for a lab in which to work on his undergraduate thesis, Dr. Aguilera Castrejón found a group at UNAM’s Instituto de Fisiología Celular that was working with stem cells, reprogramming bone marrow cells into neurons. “From there, my whole career has been devoted to development. I really enjoy it,” he says.
He knew little about the Weizmann Institute or Israel when he was accepted to the Weizmann School of Science. He spent the next eight years pursuing his MSc (2019) and PhD (2024) in the lab of Prof. Jacob Hanna in the Department of Molecular Genetics, where he was a fundamental part of the group’s pioneering discoveries in mammalian development, which attracted international attention in scientific circles and the mainstream media.
As a member of the Hanna lab, Dr. Aguilera Castrejón and his colleagues engineered a system that makes it possible to grow mouse embryos outside the uterus from Day 5 after implantation to Day 11—the period of embryo development at which all the mouse’s organs form. Then they took the research a step further and successfully created an embryo from stem cells, which they were able to grow until Day 8, at which point the embryos had the precursors of a brain, a spinal cord, a heart, and other organs.
“This is the only stem cell model thus far that is capable of growing organs, of recapitulating the development of the mouse from Day 5 to Day 8,” he explains.
Engineering growth
The team’s astonishing success is the result not only of creativity and ambition, but also engineering. As Dr. Aguilera Castrejón explains, the group spent “a lot of time” working with an engineer to construct a system that allowed “precise control of gas flow, concentration, and pressure”—all vital to embryo development. In addition, they spent years developing a viable growth medium, composed of serum (blood spun down to remove the cells but retain the metabolites) and supplements used for cell cultures.
The embryos are placed in a bottle, which sits in a metal drum, constantly spinning, allowing oxygen to mix with the growth medium and deliver nutrients to the body of the embryo—an artificially induced flow that compensates for the lack of the maternal circulatory system that nourishes embryos in utero.
Apart from achieving what had until then been impossible—growing mouse embryos ex utero and creating embryos without sperm or eggs—the system has enormous potential for human biomedical research.
“It allows you to do experiments in a critical period of mammalian development, when the organs are established,” Dr. Aguilera Castrejón says. “Right now, it’s almost impossible to do experiments in mammals at this very early stage. This will give us a greater understanding of development and help scientists recapitulate the differentiation of tissues to create tissues for cell replacement.”
“In the distant future, I can envision it becoming possible to detect a genetic defect in utero, remove the embryos for gene therapy or cell therapy, and continue growing the embryo ex utero until it’s born. This would be a way to treat congenital diseases,” he explains.
Dr. Aguilera Castrejón also points out that some scientists use embryo models to create better organs for transplants—not to mention cultivating blood from stem cells.
“Embryos can generate blood, so we could try to generate stem cell embryos that will grow to a more advanced stage, then take some blood progenitors, which are much better for transfusion than cells created in vitro.”
Collaborative culture
Since March 2024, Dr. Aguilera Castrejón has been building on his training at the Weizmann Institute as head of his own lab at the Howard Hughes Medical Institute’s Janelia Research Campus in Virginia. Discussing his decision to open a lab at a research institution rather than an academic one, he notes that at HHMI, he is not required to teach, so he can devote 100% of his time to research. He also appreciates the instrumentation experts at HHMI and hopes to combine his ex utero setup with the microscopes they are designing, to observe mammalian development in real time.
He also appreciates the Howard Hughes culture. “Groups are small, three to five people, to make sure that PIs have time for students,” he says, adding that—like Weizmann—the culture is highly collaborative.
One of his current goals is to see a mouse develop ex utero and be born alive after a normal gestation of 19 days. “I dream of seeing if it’s possible to grow a mammalian embryo completely independent of the mother. To create a system capable of that, you really need to understand development—metabolism as well as mechanics.”
He and his team are now manipulating mechanics in the embryo—a different approach to the widespread focus on genes and genomics. “In our embryo culture system, the metabolism of the mother and the culture are completely separate, allowing us to understand what the mother gives a natural embryo in utero that allows it to grow, and the differences between our ex utero embryos and natural conditions,” he explains.
He and a colleague in the US are also studying metabolomics in the whole body of the embryo as well as in the growth medium, to understand what the embryo consumes from the medium and what it excretes.
In another project, Dr. Aguilera Castrejón and his team are using light to manipulate the skeletons of embryos, which could make it possible to cause mechanical perturbations in the embryos. These experimental systems will help them better understand development, and in the future build ex utero devices that can mimic in utero development more closely.
Going big
Dr. Aguilera Castrejón grew up in the suburbs of Mexico City. His parents are furniture makers, but he always knew he wanted to study and became the first member of his family to pursue higher education.
“They always encouraged me to follow my interest. They’re very hard-working people, and I think that helped me a lot in science,” he says.
Reflecting on his years at Weizmann, Dr. Aguilera Castrejón says he still considers it “an extremely good place to do science.”
“It was very different from what I was used to… [Weizmann] was my first experience doing top-level science and it basically taught me how to do breakthrough science, how to not be afraid of doing something too difficult. I don’t try to do ‘safe’ projects that I know will work. I learned to take on tough projects that not many people can tackle.”
The Institute, he says, gave him “many tools to understand or learn how to make the big discoveries. I think that’s one of the main things I learned at Weizmann—to focus on big, important questions, not on the small things.”