july 15, 2019
Think marathon runners have amazing metabolism?
Try being an elephant seal!
(Part 1 in a series of interviews with researchers investigating novel species
for insight into human diseases)
By Ashley Zehnder,DVM, PhD, ABVP(Avian)
Featuring: Jane Khudyakov - Assistant Professor of Biological Sciences at University of the Pacific
I met Jane when I attended my first meeting of the American Physiological Society with Katie Grabek. Katie was there to present on her study of genomic drivers of hibernation. I was there to network and learn about interesting work was going on in the world of non-model organisms. Since I had recently met and heard talks by the hibernation researchers (we held a conference in SF a few months prior on that very topic), I took the opportunity to check out other sessions. I ended up in a session focused on metabolic disease models and was amazed to hear Jane discuss Northern Elephant Seals (NES’s to their friends) and their extreme metabolic shifts and adaptation to obesity and prolonged fasting, not to mention diving-related hypoxia. She was also pioneering new studies in lipidomics, metabolomics and proteomics in these animals to better understand their biology. I followed up with her after the conference, visiting her lab at UofP and chatting about the overlap in our model systems. I invited her to help us kick off a series of interviews with non-model organism researchers as I think elephant seals make an interesting counterpoint to the research we’re doing at Fauna with 13-lined ground squirrels and other hibernators. Research into these diverse species are providing new insights into potential therapeutic pathways for diseases like obesity, diabetes and other metabolic conditions.
What is unique/special about NES that makes them a key resource for biomedical research?
NES routinely fast from food completely for several months while maintaining extremely high metabolic rates and participating in energetically demanding activities such as reproduction. In contrast, most other animals reduce metabolic costs during fasting via hibernation or torpor. Elephant seals undergo dramatic fattening and fasting without any of the pathologies associated with obesity and rapid weight fluctuations in humans. In addition, fasting seals are hyperglycemic, hyperlipidemic, and insulin-resistant, resembling humans with metabolic syndrome. Their fasting metabolism is almost entirely fat-based but they do not undergo ketoacidosis. Last but not least, elephant seals are elite divers that undergo routine bouts of hypoxia during diving and sleep apneas on land. They appear to have enhanced antioxidant responses and other mechanisms of hypoxia protection that are not yet fully elucidated. Therefore, elephant seal physiology may hold insights into metabolic disease and tissue protection from hypoxia in humans.
What inspired you to start working with marine mammals in general?
As a comparative physiologist, I am especially fascinated by animals that can tolerate extreme environmental and physiological challenges which are lethal to many other species. Marine mammals exhibit some of the most dramatic morphological and physiological adaptations among mammals and offer unparalleled insights into mechanisms that drive convergent evolution on a relatively short time scale (20-50 million years). Some adaptations of marine mammals, such as extreme tolerance to hypoxia and prolonged food deprivation, are uncommon among mammals and challenge established principles of matching metabolic supply and demand. I wanted to use my cell and molecular biology background to examine the molecular basis of marine mammals’ incredible physiological feats.
What is holding the field back?
We are currently unable to conduct many types of functional experiments or any genetic manipulations in elephant seals. However, since elephant seals come ashore on California beaches at predictable times throughout the year and remain on the beach, fasting for up to 4 months, we are able to collect biological samples and conduct metabolic and physiological manipulation experiments (e.g. metabolic tracer studies, hormone infusions). The combination of such organism-level experiments with functional manipulations of seal cells in culture may address these challenges.
How have you seen the research in marine mammals change over the last 5 or 10 years and where is the field going?
The field has been revolutionized by “omics,” especially genome and transcriptome sequencing. We now have a better understanding of the genomic basis of several physiological adaptations in marine mammals. In addition, a better understanding of molecular pathways involved in hypoxia tolerance, fat metabolism, and endocrine regulation of energy homeostasis in laboratory mammals has facilitated comparative studies of these mechanisms in marine mammals.
Where do you see parallels between your work and other "non-model" organism researchers?
I think we struggle with similar challenges, such as the lack of molecular manipulation tools and having to convince funding agencies that research on non-model organisms has scientific and societal value. We also share curiosity about biological diversity and excitement to learn how diverse animals function, especially those that are not well-studied.
What do you wish people understood about the animals you work with?
Marine mammals are protected by federal law and we need permits to do research with them. The experiments that we conduct with wild seals are very challenging, but they would be impossible in many other marine mammal species. We are often limited by the types of tissues we can collect from wild seals and by small sample sizes, which is something that researchers working with traditional model systems don’t always understand.
April 11, 2019
In order to cure disease,
we need to remember we are also animals
By Ashley Zehnder,DVM, PhD, ABVP(Avian)
For the past several decades biomedical drug discovery has been a bit like the joke about a drunk man looking for his keys under the lamppost. This is because, until recently, (within the last 5-10 years or so), we understood the genomes of only 4-5 model species. Therefore, we used genetic modifications to tweak these species to be more like the “human” diseases we wanted to study and then, were disappointed when insights from these wrangled models didn’t translate into human therapies. These failures cost billions of dollars and limited the new therapies developed for patients with a range of diseases including heart disease, diabetes, Alzheimer’s, and others. With the precipitous drop in sequencing costs for DNA and RNA and the availability of new, high quality animal genomes for only a few thousand dollars, there are literally hundreds of species now available to us to explore biological processes and help us understand mechanisms of disease, and resistance to disease, that are core to our biology.
This makes for interesting dinner conversation, but more importantly, it highlights a critical failing underpinning our biomedical research complex. Recent research demonstrates that evolutionary conservation in mammals is the best predictor of function, and highly conserved genetic targets advance further in clinical development than targets that have evolved more recently.[source][source][source]
Even the greenest of biology students quickly learns to turn on those conservation tracks on the UCSC browser in order to check the conservation of their favorite gene from their latest sequencing studies and to prioritize what is important from gene lists. It’s intuitive that genes and pathways conserved over hundreds of millions of years of evolution are probably doing important things.
However, what is missing from this approach is an understanding of how those genes, and subsequently proteins, are changing in animals in conditions that mimic or better model human diseases than the mice, rats, fish, flies and worms we use today. In short, functional genomics.
And this is not at all to suggest that research in mice, rats, fish, flies and worms is not important! To the contrary, much of our understanding of the function of single genes is due to studies in these species where we disable single genes and evaluate the resulting effects on model species. However, there are only 8,000 or single gene (Mendelian) disorders that affect humans and many of these disorders affect perhaps only a few hundred or thousand people in the world.
Most diseases are complex and involve interactions of multiple genes in multiple tissues reacting to a set of external environmental cues or risk factors. Attempting to induce a similar set of conditions in an ill-suited animal model is pretty well doomed to fail in terms of predicting treatment responses in people.
Animals, like 13-lined ground squirrels that survive the human equivalent of 25 heart attacks a year and don't end up needing a heart transplant, animals that live 10x longer than their peers, but almost never get cancer, animals that dive to the deepest depths of the ocean and are protected from severe lack of oxygen, animals whose body temperatures dip below freezing, live to tell the tale and can teach us about organ and tissue preservation in extreme settings.
There are rockstar researchers out there who have spent their entire careers understanding these amazing species, building research colonies, creeping into bear caves in the dead of winter, and chasing seals across the Arctic circle (we know, one of these researchers helped start this company and others are on our advisory board!)
These researchers are now taking advantage of the genomic revolution to use high-throughput sequencing technologies to understand the genes involved in the amazing traits they observe. This data is out there, this data is extremely valuable to help us understand how our genes function in health and disease.
However, this data is scattered and unorganized, in genomics repositories, under-utilized tissue banks, in supplemental tables, on hard drives. In order to realize the potential of this emerging resource, we need to bring it together, examine the consistent trends across organisms, and align that data to existing genomic resources in human and other model organism data. Enter Fauna Bio.
My mother always told me everything happens for a reason. For the three co-founders of Fauna, it was a lot of unexpected twists and turns that led us to end up together at Stanford in the fall of 2017. We come from different corners of biology; veterinary science (Ashley), comparative genomics(Linda), and hibernation biology(Katie). And we combine these skillsets for a unique sense of what is possible with the data revolution beginning now in “non-model” organisms.
We are honored to have raised 4.1M in seed funding from strong and aligned partners to advance our goals. If we succeed in our mission to bring non-model organisms into the mainstream of biological discovery, the idea of a “model organism” will be a construct of history and of a time when we only had the capacity to understand the biology of species where we controlled their genes. Now we know all animals can be models, and nearly every human disease can be modeled in one or more species. It’s a matter of finding the right model. This false separation of “human” and “animal” data is an antiquated notion. It’s time to remember that humans ARE animals and by ignoring many of our relatives, we cannot truly understand ourselves.