By Cathy Yarbrough
While a graduate student in his native Australia, Stowers Investigator Paul Trainor, PhD, decided to devote his future scientific career to understanding head and facial development. This area of study appealed to him because the human face is inherently interesting from a development, evolution, disease and social perspective. The face has been described as the organ of emotion. It is intimately connected with our identity of self and conveys so much about our social interactions. Oscar Wilde went so far as to say "a man's face is his autobiography".
Trainor's graduate work and ensuing postdoctoral work focused on building the equivalent of a road map of embryonic head and facial development. His goal was to understand and map where neural crest cells come from, where they go, and how they give rise to a wide range of tissues in the body including the bone and cartilage of the face and skull as well as the peripheral nerves that innervate the gut. Many aspects of vertebrate evolution go hand in hand with changes affecting the head and face, and when the mechanisms that drive craniofacial development go awry, the outcome is often a major birth defect.
Birth defects associated with neural crest cells are collectively known as neurocristopathies and include craniofacial anomalies such as Treacher Collins syndrome (TCS) and gastrointestinal tract malformations such as Hirschsprung Disease (HD). In children with TCS, the cheeks, eyes or jaw are often malformed. Hearing loss and respiratory problems also may affect these patients. In HD, neurons are missing from variable regions of the gastrointestinal tract, resulting in intestinal blockage. Children with TCS and HD typically must undergo one or more surgeries to repair these structural abnormalities, but rarely are these procedures fully corrective.
Trainor's lab investigates the development of neural crest cells in laboratory animals, including mouse and zebrafish. Models of TCS were generated by experimentally altering an animal's Tcof1 gene, which is mutated in most children with the syndrome. Subsequently, Trainor and his team discovered that neural stem and progenitor cells that are the precursors of neural crest cells begin to die in the embryonic brain and spinal cord before these cells have a chance to migrate and begin building the face and head.
The team also determined that experimentally blocking the actions of another gene -- named p53 – could prevent the death of the precursor cells in the embryonic mouse models of TCS. By silencing the p53 gene, Trainor and his team enabled the nascent neural crest cells to survive, he explains. As a result, the Tcof1 mutant mouse embryos with inactivated p53 genes did not develop craniofacial defects. They also found that Tcof1 plays a role in the development of HD. In laboratory mouse embryos that expressed about half the normal allotment of Tcof1 and one other gene (Pax3), fewer neural crest cells migrated out of the brain and spinal cord, and many died en route to the gut.
"Approximately one percent of all live births exhibit a minor or major congenital anomaly," says Trainor. "To have any hope of preventing these congenital disorders, you must understand how they originate at a cellular, genetic, and biochemical level. Our findings indicate that intervening to prevent some neurocristopathies during human embryonic development may be possible."
Trainor, who joined the Stowers Institute in 2001 is regarded as a leader in the field of developmental biology by his peers in the international scientific community. He has served as editor for two books on neural crest cells, chaired the 2010 Gordon Conference on Craniofacial Morphogenesis and Tissue Regeneration and was elected to serve as 2015-2016 president of the Society for Craniofacial Genetics and Developmental Biology. In addition, he serves on the board of the American Association of Anatomists and the Society for Developmental Biology.
How much contact do you have with children with TCS or the other neurocristopathies?
I have attended and spoken at the Treacher Collins Connection national conference, which is organized and sponsored by the parents of children with TCS. Meeting the parents of these children is inspiring and motivating. It reminds me that our work has an impact on their understanding of TCS.
Because TCS is a rare birth defect, it's unusual to see many children with the same condition in the same place. However, at the conference, I had the chance to see children with the syndrome having fun and running around, behaving like typical everyday kids.
Attending the meeting also was eye-opening because I learned about some of the non-medical problems that individuals with TCS and their families have to deal with. For example, parents often have difficulty in obtaining coverage for their children's surgery because the insurance companies frequently regard the operations as cosmetic.
What do you envision as the ultimate benefit to your research?
Our ultimate goal is to determine why specific birth defects occur in the first place and to identify the genes and the environmental factors or agents that cause them. If we can understand the origin and development of congenital disorders in enough depth, we may be able to come up with creative ways to prevent them from occurring.
Would prevention involve a targeted genetic change?
No, in most cases that would be too difficult if not impossible, especially given the limitations of current technology. More likely it would involve a dietary or other type of intervention that protects the neural crest cells from being damaged during development. For example, today we know that folate can help protect brain and spinal cord cells during embryonic development. As a result, spina bifida and related open neural tube defects can often be prevented by mothers taking a specific amount of folic acid throughout pregnancy.
Work life balance is important to you. Why do you encourage your team members to take breaks from the lab?
The research that we do in the lab is like a never-ending story. There are highs and lows, but every time we answer one question or hypothesis, we generate another ten. The number of experiments that we want and need to do, therefore, continues to increase exponentially. Just like reading a book, when you get to the end of a chapter, sometimes you need to put it down for a while and do something else. I believe that even individuals who are very passionate about their work need to recharge, to take a break and refresh. It's all about balance.
How do you recharge?
By cycling with my wife and our two children, both of whom were born in Kansas City, and playing water polo with a team in Kansas City. During the summer, I also participate in one or two triathlons.
Do you find that you generate your best ideas when exercising?
When I’m playing water polo, I usually am not thinking about science because I’m too busy thinking about how to beat my opponent or prevent myself from drowning! It’s a remarkable way to relieve stress. Cycling and running, however, are often free-thinking times when I do think about science, but at the same time, I also simply enjoy the fresh air and the sights and sounds around me.
How often do you return to your hometown of Sydney, Australia?
I visit my family in Sydney about every two to three years. It is particularly nice to go home during a Kansas City winter because then it is summertime in the southern hemisphere and I get to enjoy the surf beaches that I don't get in Kansas City. Sydney combines the best parts of San Francisco and San Diego. It's a great city to live in and visit.
What do you and your family enjoy about living in Kansas City?
Kansas City is a very comfortable, easy city to live in with a lively art, music, entertainment and food culture. Basically, anything we want to do, except perhaps go to the beach, is quite accessible. Also, Kansas City does not have the crowd or traffic issues of much larger cities. As a result, I have no idea what a traffic jam is like anymore. Not having to spend a lot of time being stuck in traffic means that I have more time with my family and more time to run, and cycle, and enjoy all that Kansas City has to offer.