Millions of people die every year from heart disease, cancers, respiratory diseases, stroke, Alzheimer’s, and diabetes, while millions of others suffer long-term symptoms from these conditions. Unfortunately, traditional drug discovery has failed in identifying solutions to these diseases.
That’s why Fauna Bio is taking a comparative genomics approach to drug discovery by using data from “extreme mammals”—those capable of surviving conditions or physiological events that would be lethal to humans—in order to identify drug targets to treat human disease.
For example, whereas a single heart attack can kill a person, certain animals not only survive 25 heart attacks a year but also go on to thrive, living 2 times longer than others their size. By identifying and understanding the protective physiological mechanisms that enable this survival, Fauna Bio is seeking to rapidly develop novel treatments for a plethora of diseases.
Editor-in-Chief Michelle Taylor recently interviewed Fauna Bio CEO Ashley Zehnder, DVM, Ph.D., about her company’s unique, broad-based approach to genomics, disease and the development of effective drugs.
Q: Tissue samples from how many different mammals reside in Fauna Bio's biobank?
A: Fauna Bio’s drug discovery platform, Convergence, leverages genomic analyses across 452 mammal species (65 hibernators). Fauna’s primary discovery biobank data includes over 22 distinct tissue types collected at 13 unique and highly precise physiological time-points from the 13-lined ground squirrel, as well as tissue samples from tenrecs and spiny mice. In total, we have thousands of transcriptomes, proteomes, and epigenomes and over 22 billion sequence reads.
Q: How are the included animals chosen?
A: Fauna Bio chooses species that have evolved in a variety of ways to heal multiple tissues from damage, enhance regenerative processes, reverse tau phosphorylation in the brain, reverse insulin independence, and other processes that contribute to disease in people. We focus on species that naturally repair damage or are uniquely resistant to damage. Out of 300 species reviewed thus far, over 50 demonstrate evolved resistance toward one or more human disease states.
Q: Could you give a few examples of unique species and their "abilities" that are captured in your biobank?
A: Yes. Take 13-lined ground squirrels for example. As they enter hibernation, their neurons retract and lose connectivity, becoming effectively braindead. Then, as they leave hibernation, their neurons regrow and emerge unharmed. The 13-lined ground squirrel has the physiological equivalent of at least 25 heart attacks every winter. Such an experience would cause irreversible inflammation and fibrosis in humans, but these species entirely avoid these consequences. 13-lined ground squirrel and tenrecs naturally resist strokes and heart attacks when they drastically reduce the oxygen supply in their brain and heart during hibernation-like states, called torpor.
From the non-hibernator world, the spiny mouse (Acomys cahirinus) seemingly regenerates skin and multiple organs—including the kidney and spinal cord—without fibrosis or scarring after injury.
Q: Why is it important to analyze non-human species when looking at genetics and drug discovery?
A: Roughly 75% of drugs are designed against well-known biology, meaning only an estimated 25% are designed against truly novel targets (based on reviewing new FDA approvals from 2020, 2021 and 2022). Clearly, large areas of drug development have run stagnant. We urgently need to look to untapped and otherwise ignored sources of data. There are so many interesting similarities and patterns we can draw between animal genes and human genes that help us deepen our understanding of human disease, and how and why certain animals are able to both resist and reverse potential pathologic states and return to health. By looking beyond well-trodden genes and pathways, we can attempt to unlock protective mechanisms that have evolved with other animals (but still using human genes).
Looking outside our species is like building a stronger magnet to help us find that elusive needle in the haystack. Taking a comparative genomics approach allows us to look at how other species have adapted the same genes humans have, but in very different ways for resistance to extreme environments and also to resist disease.
Genes with a high level of conservation are more likely to be important for disease. Genes that haven’t changed in hundreds of millions of years are likely to be doing something important. Viewing genes from this broader evolutionary context allows us to find the functional genes in human disease more rapidly and precisely.
Q: What information/data are you looking to leverage from non-human species?
A: The difficulty in identifying highly effective drug targets stems from separating genes that cause disease from those that are just “along for the ride” or are secondary changes. Using human data alone is often not enough. Fauna’s platform enables us to highlight genetic networks that are different between the protected state of certain species (e.g., hibernators) and the disease state of humans. For example, we can examine what genes are changing in the hearts of hibernators at timepoints when they are protected from physiological conditions resembling human heart attacks.
Q: Can you explain Fauna Bio's overall approach?
A: Because the biology we interrogate is so extreme, it often takes us 100-fold less data to find novel therapeutic targets than it would require if we were using human data alone. Our approach and process is as follows:
- As a first step, we identify timepoints where animals are protected from damage and use RNA-seq to examine how gene expression changes at these specific timepoints in the organ of interest.
- Next, we compare gene expression changes to what we see in human disease and cross-examine humans with mutations in those same genes to see if there are links to specific diseases.
- Once we enrich for genetic networks that demonstrate this opposing regulation, we can look at the hubs of these networks for clues to what is driving the repair or regeneration. Alternatively, we can directly map these gene expression signatures to small molecules to jumpstart our therapeutics programs.
- Finally, we validate our gene and compound predictions in human cell assays in our own labs before moving into in-vivo experiments to examine their role in disease models.
Q: How does your previous work as a veterinarian influence your current research at Fauna Bio?
A: My experience treating patients—rabbits with thymomas, birds with colon cancer and snakes with skin tumors—made me realize that I wanted to understand cancer at a basic level, including its common drivers and pathways. This interest influenced me to enter the Cancer Biology Ph.D. program at Stanford University. At the time, my purpose was clear—I saw an opportunity to close the chasm between veterinary and human medicine with the understanding that they are very often the same. I pursued this idea, completing both a Ph.D. and a postdoctoral fellowship, and establishing the Exotic Species Cancer Research Alliance (ESCRA), which is still active. The work with ESCRA helped me realize the many advances in human cancer research that can be made by studying mechanisms across species.
My clinical background drives me to focus on how our work can rapidly translate into therapies that will help patients. At Stanford, I met two exceptional scientists, Katie Grabek, Ph.D., and Linda Goodman, Ph.D., who shared this realization. By coming at it from very different, yet complementary perspectives, we co-founded Fauna Bio.