The Future of Comparative Genomics?

Dr. Ashley Zehnder is the co-founder and CEO of Fauna Bio, a San Francisco, Bay Area-based company founded in 2018. Fauna Bio has adopted a fascinating strategy for drug development, studying animal genomics to cure human diseases. They use unique and varied proprietary data sources to identify novel drug targets across a range of clinical applications, beginning with cardiovascular protection. Dr. Zehnder is a veterinarian-scientist at the intersection of animal biology and human health. Today she joins the show to discuss her background in Cancer Biology, her specialty training in exotic/non-traditional species, and the experience of launching Fauna Bio with co-founders, Dr. Linda Goodman and Dr. Katie Grabek in 2018.

Dr. Zehnder explains how genomes from non-model systems and animals can inform our thinking about human disease, why her background in veterinary medicine gives her an advantage in studying comparative physiology, and what her team has learned about neurodegeneration from the hibernation process of the thirteen-lined ground squirrel. She talks about studying highly conserved disease traits across species and whether we can reactivate certain genetic pathways to reverse those diseases. You’ll hear about Fauna Bio’s work with RNA Seq. data, their focus on cardiovascular research and other indications they are now expanding into, as well as the company’s relationship with Novo Nordisk as they explore the connection between hibernation, metabolic changes, and obesity. Dr. Zehnder offers her perspective on the University of Washington’s Dog Aging Project, and talks about the current drug discovery pipeline at Fauna Bio. She addresses how Fauna Bio fits in with other aging research and concludes with her thoughts on how the field of comparative genomics will evolve over the next five to ten years.

Episode Highlights:

• Dr. Ashley Zehnder is a veterinarian with a background in companion exotics (birds, mammals, reptiles)
• She completed a Ph.D. in Oncology and Cancer Biology at Stanford University
• Co-founded Fauna Bio with Dr. Linda Goodman and Dr. Katie Grabek in 2018
• Her background in studying the molecular basis that drives cancer across all different species
• Studying human genetics alone became difficult and frustrating in trying to determine what drives human disease
• Turning to comparative genetics was a way to solve that problem
• Origins of Fauna Bio as a company - decided academia was not the way to take full advantage of new, richer data sets; wanted to make them usable for drug discovery and drug development as quickly as possible
• Traditional model systems organisms versus non-model systems and animals
• Model organisms do not fit the bill in trying to do therapeutics discovery for more complex disorders
• Instead of trying to mimic human diseases in model organisms, Dr. Zehnder focuses on finding similar situations that already exist and have been solved in nature, and learning from those solutions directly
• Her medical training as a veterinarian gives her an incomparable advantage in studying comparative physiology
• Scientists who focus only on humans have a blind spot to the fact that the same disease syndromes can be seen across the animal world
• Research on the thirteen-lined ground squirrel and neurodegeneration
• Certain adaptations that help animals end up causing diseases in humans; animals have a way of reversing these while humans do not
• 200 Mammals Project looks at which animals, including humans, can go into torpor
• Largely study mammalian species due to the similarities with humans
• They work with RNA-Seq data
• Studies on traumatic cardiovascular events (heart attacks) for hibernating species show that they may be resistant to damage caused by reperfusion injury 
• Fauna Bio initially focused on cardiovascular health, and is now expanding into other organs of the body, such as the brain hypothalamus, liver, kidney, muscle and skeletal tissue
• Their relationship with pharmaceutical company Novo Nordisk and studying how certain animals change their metabolism
• Brown fat versus white fat
• University of Washington’s Dog Aging Project
• Fauna Bio’s current drug discovery pipeline
• Branching out into more chronic diseases such as fibrosis
• 30 to 50% increase in life expansion for species that are able to hibernate as compared to similarly sized counterparts who do not hibernate
• What they’re learning from animals is how to repair damage in a way that reduces disease
• How the field of comparative genetics will evolve over the next five to ten years

Quotes:

“I'm a veterinarian. My background is in companion exotics. So I was clinically trained to treat birds, mammals, reptiles, all sorts of strange species. I ended up doing a Cancer Biology Ph.D. at Stanford, focused on the intersection of animal and human health.”

“Looking at cancer traits across different species, why some species get cancers, why some species don't, and understanding the molecular basis that drives all those cancers, which turns out to be the same across all these species.”

“We really have spent a lot of time trying to understand what drives human disease from a genetic level, and really became quite frustrated with the difficulty of trying to figure it out just by studying human genetics.”

“We realized that there was this huge untapped opportunity in the emerging genomic data sets for hundreds of different species that are - the genomes are coming out in higher quality RNA Seq, and Proteomics has become exponentially cheaper. So there's much richer data sets available out there for animals that have naturally evolved disease resistance.”

“It was very much aThree musketeers sort of moment, because we really needed all three of our skill sets to make what Fauna does work.”

“That's really one of the key failure points in biological development and drug development, is that transition back from animal models into humans.”

“Model organisms have a role. And if you need to knock out a gene and know what it does, I think that that's helpful. But in terms of trying to do therapeutics discovery for more complex disorders, they just don't fit the bill.”

“We do use a significant amount of human genetic data on our platform to help enrich the gene sets that we work with.”

“Let's stop trying to make these animal models mimic a human disease. And let's instead look for the reverse. Let's look for situations in nature, where there's been a solution to this problem already. And let's learn from that directly.”

“There's a complete blind spot to the fact that we see all these same disease syndromes across the animal world.”

“We're looking at disease traits and traits across species that are highly conserved. And I think that's why we've seen such success in the compounds in the genes that we've been looking at.”

“Thirteen-lined ground squirrels - they increase their metabolism by 235-fold over a matter of one or two hours. And there's just not many other models in the world that can do that repeatedly, week after week for months at a time.”

“Dogs are not necessarily a species with disease resistance, which is where we tend to focus, but a species that in many ways can age very similarly to humans - they get that same kind of cognitive disorders, they get some of the same metabolic syndromes, they can get some of the same types of muscle wasting and whatnot. But on a shorter timescale - they don't live as long. So you can do aging studies in a shorter timescale.”

“We now have seven genetic targets that we validated in human cardiac fibroblasts that can reduce collagen formation up to 60%.”

“If you look at similarly sized species - ones that hibernate and ones that don't, there is around a 30 to sometimes up to 50% lifespan extension for species that are able to hibernate.”

“That's really what we're learning from these animals is how do you repair damage in a way that reduces disease.”

“How do animals repair damage? How does that relate to lifespan extension? And how do they keep their tissues healthy even as they age? And I think that's something that we can learn from, from hibernators, and other species as well.”

“I want to be able to show that we can create drugs or help others create drugs that are going to work better than drugs that are found by traditional means.”

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