By Mark Couch
Sometimes a scientific collaboration happens by coincidence, a happy accident that pairs experts who wouldn’t have otherwise met.
And so it goes with a package of zebrafish embryos intended for Christian Mosimann’s group that ended up in Catherine Musselman’s lab during the pandemic lockdown of buildings on the Anschutz Medical Campus.
That misdelivered package has now led to a scientific partnership awarded with a $1.3 million National Science Foundation grant to support the scientists’ efforts over the next four years to better understand mechanisms of genome regulation.
“I moved to CU with my lab in the summer of 2019, and I hadn’t had a chance to get to know a lot of people before the lockdown happened,” says Mosimann, PhD, associate professor and Johnson Endowed Chair in Heart Developmental Research in the Department of Pediatrics Section of Developmental Biology. His lab uses zebrafish, an increasingly popular research organism to study the mechanisms of organ development and causes of congenital disease.
“Then, one day I get this email that says, ‘We have your fish!’”
Despite the potentially ominous tone, the Musselman crew wasn’t holding the Mosimann’s zebrafish embryos for ransom. They just wanted to help them find their rightful home.
“One of my lab members emailed me because we were not allowed to be in the lab at the same time at this point,” recalls Musselman, PhD, an associate professor in the Department of Biochemistry and Molecular Genetics. “So, it’s one person at a time there, and this person says, ‘We have these fish embryos,’ and I was like, ‘Oh, those are not ours!’”
While the Musselman-Mosimann alliance begins like a game of hide-and-seek, it has turned into a rewarding relay race to better understand genome organization and gene regulation.
After receiving that email, Musselman set up a Zoom call to chat with Mosimann and to work out the details of getting his package to him.
“I didn’t know many people here, so this was a serendipitous networking opportunity,” says Mosimann, who surfed over to the Musselman lab’s website. “What I discovered was that Catherine’s lab works on molecular mechanisms that are associated with what I grew up with scientifically, which is how genes get regulated in the genome.”
Musselman’s lab focuses on how the proteins that package the DNA in cells function to control access to the information encoded in our genomes. The group is especially interested in proteins that have been neglected due to their so-called “intrinsically disorganized regions” – protein parts that the Musselman lab can now resolve.
Both labs work at different ends of the gene regulation spectrum, so a combination of their efforts is regarded as potentially fruitful for new scientific discoveries. Their NSF grant combines state-of-the-art structural analysis and biophysics in the Musselman lab with first-ever direct testing of developmental and physiological functions of these disordered regions using zebrafish in the Mosimann lab.
“If we both wrote a sentence about the goal of what we want to understand, it would actually be quite similar,” says Musselman. “But we look at very different length scales. I’m looking at hundreds of atoms at a time and Christian is looking at a whole organism.”
Combining their areas of expertise, Mosimann and Musselman plan to study large proteins that control the packaging of DNA and harbor what are called “intrinsically disordered regions.” These regions are disorganized protein elements and they have been challenging to study compared to the usually well-organized and folded proteins that cells generate.
Musselman’s lab discovered that the role of some proteins was more complicated than previously understood. Those proteins not only switched genes on and off to affect how DNA is packaged, but some of those proteins were binding to the DNA itself. They now think that the intrinsically disordered regions play a critical role in regulating this DNA binding.
Observing that activity itself is technically challenging. It becomes even more complicated to determine how those processes and interactions are involved with each particular cell type in a developing heart, retina, hair follicle, or any other part of the body.
“That’s where this overlap with my lab comes in,” says Mosimann. “The proteins that Catherine is studying float around in all our cells, but they do interact with other factors in the heart or in blood in highly specialized ways. These interactions also go wrong in several congenital diseases. Yet, we don’t yet understand how things can happen just in the heart, or just in the blood, and how they can only go wrong in heart disease.”
Working together, the Musselman and Mosimann labs will design experiments that are intended to observe the ripple effects of breaking those protein interactions from the beginning of development. If those interactions do not occur as usual, what happens in the developing heart or blood of the zebrafish?
“Once we know how they work, we know how to break them,” Musselman says.
“And my lab is very good at breaking things in cells,” jokes Mosimann, whose lab specializes in the study of how those broken protein interactions manifest later in development. He and his team are working to understand how cells acquire their fates by applying the latest genetic and microscope techniques.
Their work together has the potential to reveal new insights into how our genome is organized and its information retrieved during development and disease. Notably, the factors involved in their study have been found mutated in congenital anomalies, such as of the heart and in an increasing number of pediatric cancers.
For all the effort that academic medical centers put into fostering collaborations among researchers – inviting guest speakers, hosting grand rounds lectures, creating study groups and mentorship programs, and many more activities – a lost package has led to a coincidental collaboration and a productive new partnership.
“If only there were more misdelivered packages,” quips Mosimann, “that might trigger even more research collaborations!”