We honestly don't  remember the exact date, but there was a fairly distinct moment, during one of our regular student-mentor meetings, when we realized something very interesting and unexpected might be afoot. Delaney had switched her Ph.D. project topic, opting to leverage the powerful CCM mouse models that our collaborator Dr. Petr Tvrdik was developing here at UVa.  Given our lab's expertise in MRI-guided focused ultrasound-mediated blood-brain barrier disruption for targeted drug delivery, and knowing that many drug and gene therapy approaches were being considered for CCM, we reasoned that our focused ultrasound approach could potentially facilitate many new therapeutic options for this disease. An early step in this risky project was to ensure safety and verify that focused ultrasound was not exacerbating the lesions. In this particular meeting, Delaney noted that focused ultrasound seemed safe - over a 1 month period after treatment the CCM lesions hadn't grown any bigger.

It was soon thereafter that the lightbulbs went on and we realized the significance of that finding.  That is because, in the particular mouse model of CCM that Delaney was studying, Delaney had already established in a previous paper that CCMs typically grow about 7-fold over this 1 month period. So, in other words, if safety was equated with "normal", we should have seen a 7-fold expansion in CCM volume. Needless to say, when expecting a 7-fold increase, a complete cessation of growth was eye opening. Over the next few months, we examined the data further and Delaney performed more experiments, all of which were remarkably consistent - applying focused ultrasound blood-brain barrier disruption to these lesions caused them to stop growing - completely. Eventually Rich had to ask Delaney - "Are you confident enough to go all in on this"? Answering affirmatively, Delaney pushed ahead with an incredible work ethic for ~2 more years, fortifying the science from every possible critique we could envision. Notably, this era even included yet another fascinating finding, namely that repeat focused ultrasound treatments prevent future CCMs from forming. The timing of this one we remember better- the news of that second finding came to Rich via email on a Sunday evening.

The histology Delaney performed points to a mechanism for CCM control related to cessation of endothelial cell expansion; however, the precise mechanisms(s) remain elusive. Nonetheless, our findings indicate that focused ultrasound could eventually become a safe, minimally-invasive, and effective option for stabilizing CCMs. Every once in a while serendipity offers us a favor, but it takes a really great student to recognize and grab it when they see it.