The Jackson Laboratory's Dan Cortes. Photo credit: Tiffany Laufer.
Dan Cortes, M.D., Ph.D., has embarked on a multifaceted journey powered by an innate curiosity about the human body. His path has led him to pioneering stem cell research within the Pera lab, where he explores the intricate genetic landscape underlying neurological diseases and disorders.
The winding trail
Musician. Cyclist. Doctor. Researcher. Dan Cortes has worn many hats. Growing up, Cortes loved playing the guitar. Writing and producing original music, he always thought he would have a career as a musician. That was until he discovered sports. Taking up first running and then cycling, Cortes developed his athletic abilities enough to be a sponsored cyclist on a local team in Mexico. While he enjoyed racing, though, Cortes still felt something was missing. After rediscovering his fascination with human biology, he decided to attend medical school.
“If you silence your brain for a second and pay attention to who you are, you will find who you have been all along,” says Cortes. “There will be signs of who you have always been. You just have to follow them. When it was time for me to make a career decision, I had to pay attention to myself. When I was a kid, one thing that always remained consistent was my love for science. I always loved watching documentaries about how the body works.”
Nearing the finish line?
Around the time Cortes graduated from medical school, human-induced pluripotent stem cells (IPSCs) emerged as a new tool for studying disease.
“Stem cells were being identified as something really important,” says Cortes. “I became interested in cell therapy and how we can use stem cells to understand diseases. This concept reignited my passion for basic biology and drove me to the stem cell field.”
Cortes decided to go back to school. After graduating with his Ph.D., Cortes searched for a postdoctoral program where he could perform cutting-edge stem cell research. He found that opportunity with Professor Martin Pera, Ph.D., at The Jackson Laboratory (JAX). Now an associate research scientist, Cortes studies how differences in genetic composition play a role in neurological diseases. Recently, he and Pera developed a novel platform to differentiate mouse embryonic stem cells into neurons, laying the foundation for further research into a wide range of neurological conditions.
“We used pluripotent stem cells to generate a platform to study genetic background interaction These stem cells are capable of regenerating indefinitely. They also give rise to all the tissues of an adult organism. Using this platform, you can study whatever neurodegenerative disease you are interested in. If you want to study Parkinson’s, Alzheimer’s, stroke or autism, you can differentiate these cells to mature and then study their development in the context of the disease. As a proof of concept, we started with DYRK1A, a gene that is associated with neural differentiation and development,” says Cortes.
Bridge the gap
Why choose DYRK1A? When DYRK1A or the protein it generates is inhibited, neural development can be severely disrupted, which may lead to a range of symptoms, depending on genetic context. This disruption can lead to microcephaly — a condition affecting newborns where the brain is underdeveloped, causing the head to be smaller than expected — or it can go unnoticed with barely any visible traits. In stem cells, DYRK1A inhibition keeps the cells in a pluripotent state. Pluripotent cells can be turned into various cell or tissue types in the body. Cortes and Pera utilized this capability to prompt stem cells to become neurons. This allows researchers like Cortes, who are interested in neurological diseases or disorders, to have an endless supply of the specific cells they need for their studies, as well as the ability to easily start and stop experiments at different stages of development for more complete analysis.
Linked to autism and haploinsufficiency syndrome (a neurodevelopmental disorder leading to developmental delay and intellectual disability), DYRK1A is important for understanding how neurons form. Involved in every step of neural development in the embryo, the gene takes on different, stage-dependent roles associated with changes at the protein level and in other proteins it interacts with. Based on previous findings where DYRK1A inhibition was tested in the 129 mouse strain, Pera found this disruption was also present in human stem cells. The team then developed protocols for neuronal differentiation in seven other strains and found that some were more susceptible to changes in DYRK1A while the rest were not affected. When Cortes began looking into the genetic background of these susceptible models using the new neuronal differentiation platform, he discovered downstream gene regulators were significantly contributing to susceptibility.
“Genetic background is important,” says Cortes. “You cannot just inhibit this gene and call it a day. If you do not take the genetic background into account, then you are going to have a misinterpretation of the disease’s biology. With this platform, researchers can study neuron development by itself or within a disease implication.”
Hitting the open road
Cortes is also using the mouse stem cell platform to identify stroke-susceptible or -resilient genes. Generating cerebral organoids (three-dimensional tissue cultures grown from stem cells) from genetically diverse mouse strains, he analyzes cells after a stroke to classify how they responded to the neurological event. Were the cells affected or not? Once this is determined, he investigates what gene(s) contributed to this result. Cortes is testing these findings in human organoids to harness these genetic findings into better therapeutical approaches.
“Performing these types of experiments solely in live mice is expensive, labor-intensive and time-consuming. The beauty of the stem cell platform is that it is high throughput. You can gather more data in a shorter period. At JAX, we have access to mouse facilities, but that is not the case for everyone. If someone has a gene candidate for a therapeutic, it is going to be hard to prove in the mouse alone. But they can do their first experiments in cells. Of course, they still need to validate their findings, but once they have a clear idea of what the most important genes are, then they can go back into the mice,” says Cortes.
Throughout the twists and turns, Cortes believes he is headed down the right path. He has found a mentor in Pera and appreciates being surrounded by problem-solvers.
“The beauty of our lab is we all have certain areas of expertise,” says Cortes. “That is something that I appreciate. I am happy with where I am right now. I have learned that there is not one correct path. It is not only our genetic backgrounds that make us different. We are shaped by the decisions we make throughout our entire lives.”