The scientific genius of Caty Casas. In memoriam
The founding member of Clisyne, Caty Casas, a neurobiologist with an inordinate commitment to helping patients with difficult neurological ailments, passed away in June 2020, leaving extraordinary lessons of friendship, mentorship, and originality in scientific discovery. Caty was a world-renowned expert in autophagy, the mechanism whereby cells get rid of junk materials. Autophagy is at the center stage of CNS therapeutics because neurons degenerate in chronic diseases and aging, and do not properly regenerate after acute injuries, in part because they are clogged with clutter. However, the obvious solution of treating CNS diseases by stimulating autophagy has failed in numerous clinical trials. A point in case is the broad autophagy activator rapamycin, enthusiastically embraced as a miracle drug, to no avail. Caty understood that the failure of a drug means incomplete knowledge of the underlying biology. So, with characteristic determination and talent, her team advanced autophagy-targeting therapeutics by developing better models of autophagic dysfunction. First, they unraveled the networks of signaling pathways involved in autophagy using proteomics data from animal models of traumatic peripheral nerve injury. Second, they resorted to artificial intelligence to gain insight into how these networks could be manipulated for therapeutic purposes. They thus pioneered the vision that big data and computerized tools are most valuable tools to cure complex diseases. Third, they created a highly inventive approach to modulating autophagy: simultaneous activation of two pathways with opposite actions on the autophagic flux. The details can be found in their last article1. The key idea is that therapies should restore the complex web of homeostatic feedbacks that regulate autophagy in neurons and is damaged by injury. They explain their strategy with the beautiful analogy that autophagy is to neurons what a shield is to a warrior: ‘A warrior wearing a shield is almost unbeatable. But any damage to the shield would reduce the possibilities of the warrior to avoid accurate blows. Then it is reasonable to think that the repair of the shield will enhance the chances of survival of the warrior. This was the rationale behind our discovery of NeuroHeal2. There are endogenous mechanisms of protection that neurons (and other cells) immediately engage in upon insult or damage. The fact that neurons are long-lived cells is indeed in agreement with the presence of potent endogenous mechanisms of neuroprotection that include the unfolded protein response (UPR), the ubiquitin proteasome system (UPS), anti-apoptotic mechanisms, antioxidant reactions and autophagy, to cite a few. There is, however, a wealth of evidence supporting malfunction of some or several of these processes during aging and neurodegeneration –holes in the warrior’s shield’.1 While fighting a fatal disease like a warrior herself, Caty paved the way for novel avenues that challenged dogma and stagnation in drug discovery and CNS therapeutics. An idealist seeking justice and freedom in all realms of life, she was uniquely generous, honest, and compassionate. Her passion to build, learn and do good was contagious, as was her unforgettable laughter. We will always celebrate the gift of the luminous presence of Caty Casas in our lives.