We developed tools to study cancer in Tasmanian devils. They could help fight disease in humans


Andrew S. Flies, University of Tasmania; Amanda L. Patchett, University of Tasmania; Bruce Lyons, University of Tasmania, and Greg Woods, University of Tasmania

Emerging infectious diseases, including COVID-19, usually come from non-human animals. However our understanding of most animals’ immune systems is sadly lacking as there’s a shortfall in research tools for species other than humans and mice.

Our research published today in Science Advances details cutting edge immunology tools we developed to understand cancer in Tasmanian devils. Importantly, these tools can be rapidly modified for use on any animal species.

Our work will help future wildlife conservation efforts, as well as preparedness against potential new diseases in humans.

The fall of the devil

Tasmanian devil populations have undergone a steep decline in recent decades, due to a lethal cancer called devil facial tumour disease (DFTD) first detected in 1996.

A decade after it was discovered, genetic analysis revealed DFT cells are transmitted between devils, usually when they bite each other during mating. A second type of transmissible devil facial tumour (DFT2) was detected in 2014, suggesting devils are prone to developing contagious cancers.

A Tasmanian devil with devil facial tumour disease.
Save the Tasmanian Devil Program

In 2016, researchers reported some wild devils had natural immune responses against DFT1 cancers. A year later an experimental vaccine for the original devil facial tumour (DFT1) was tested in devils artificially inoculated with cancer cells.

While the vaccine didn’t protect them, in some cases subsequent treatments were able to induce tumour regression.

But despite the promising results, and other good news from the field, DFT1 continues to suppress devil populations across most of Tasmania. And DFT2 poses an additional threat.

Read more:
Deadly disease can ‘hide’ from a Tasmanian devil’s immune system

Following a blueprint requires tools

In humans, there has been incredible progress in treatments targeting protein that regulate our immune system. These treatments work by stimulating the immune system to kill cancer cells.

Our team’s analyses of devil DNA showed these immune genes are also present in devils, meaning we may be able to develop similar treatments to stimulate the devil immune system.

But studying the DNA blueprint for devils takes us only so far. To build a strong house, you need to understand the blueprint and have the right tools. Proteins are the building blocks of life. So to build effective treatments and vaccines for devils we have to study the proteins in their immune system.

Until recently, there were few research tools available for this. And this problem was all too familiar to researchers studying immunology and disease in species other than humans, mice or rats.

Into the FAST lane

You could build a house with just a saw, hammer and nails – but a better and faster build requires a larger, more versatile toolbox.

In our new research, we’ve added more than a dozen tools to the toolbox for understanding tumours in Tasmanian devils. These are Fluorescent Adaptable Simple Theranostic proteins – or simply, FAST proteins.

The term “theranostic” merges therapeutic and diagnostic. FAST proteins can be used as a therapeutic drug to treat a disease, or as a diagnostic tool to determine its cause and better understand it.

A key feature of FAST proteins is they can be tagged with a fluorescent protein marker, and can be released from the cells that we engineered in the lab to make them.

This way, we can collect and observe how the proteins attach and interact with other proteins without needing to add a tag later in the process.

To understand this, imagine trying to use a tiny key in a tiny lock in the dark. It would be difficult, but much easier if both were tagged with a coloured light. In the context of the immune system, it’s easier to understand what we need to turn on or off if we can see where the proteins are.

By mapping how proteins within the devil’s immune system interact, we can find better ways to stimulate the immune system.

An overview of the FAST protein system. Fluorescent proteins and immune system proteins from different species can be rapidly swapped to make new FAST proteins.
Andrew S. Flies/WildImmunity

The FAST system is also adaptable, meaning new targets can be cut-and-pasted into the system as they’re identified, like changing the bits on a drill. Therefore, it’s useful for studying the immune systems of other animals too, including humans.

Also, the system is simple enough that most people with basic cell culture and molecular biology experience could use it.

Read more:
A virus is attacking koalas’ genes. But their DNA is fighting back

Needle in a haystack

Cancer cells in humans and animals can travel via the bloodstream to spread, or “metastasise”, throughout the body. Identifying single tumour cells in blood can shed light on how cancer invades devils’ organs and kills them.

Using FAST tools, we discovered CD200 – a protein that inhibits anti-cancer responses in humans – is highly expressed in devils. With FAST tools, we were able to mix DFT2 cancer cells into devil blood and pick them out, despite there being about one cancer cell for every 1,000 blood cells.

CD200 is a powerful “off switch” for the immune system, so identifying this off switch allows us it can help us produce a vaccine that disables the switch.

A devil facial tumour 2 (DFT2) cell, with the cell nucleus shown in blue.
Andrew S. Flies/WildImmunity

By rapidly sifting out the best ways to stimulate the devil’s immune system, FAST tools are accelerating our research into developing a preventative vaccine to protect devils from DFT.

Why study animal immune systems?

COVID-19 has once again brought emerging infectious diseases onto the global stage. The ability to rapidly develop immunology tools for new species means we can jump into action when a new virus jumps into humans.

Additionally, species are going extinct at an alarming rate, and wildlife disease is increasingly threatening conservation efforts.

Understanding how the immune systems of other animals fight diseases could provide a blueprint for developing vaccines and therapeutics to help them.The Conversation

Andrew S. Flies, Senior Research Fellow in Immunology, University of Tasmania; Amanda L. Patchett, , University of Tasmania; Bruce Lyons, , University of Tasmania, and Greg Woods, Professional Research Fellow, University of Tasmania

This article is republished from The Conversation under a Creative Commons license. Read the original article.

Tasmanian devils are evolving rapidly to fight their deadly cancer

Menna Elizabeth Jones, University of Tasmania; Andrew Storfer, Washington State University; Hamish McCallum, Griffith University; Paul Hohenlohe, University of Idaho, and Rodrigo Hamede, University of Tasmania

For the past 20 years, an infectious cancer has been killing wild Tasmanian devils, creating a massive challenge for conservationists. But new research, published today in Nature Communications, suggests that devils are evolving rapidly in response to their highly lethal transmissible cancer and that they could ultimately save themselves.

Cancer is usually a disease that arises and dies with its host. In vertebrates, only two known types – Canine Transmissible Venereal Cancer in dogs and Devil Facial Tumour Disease (DFTD) – have taken the extraordinary evolutionary step of becoming transmissible. These cancers can grow not just within their host but can spread to other individuals. Because the cancer cells are all descendants of one mutant cell, the cancer is effectively immortal.

To grow in the new host, the tumour cell must evade detection and rejection by the immune system. Both the devil and dog transmissible cancers have sophisticated mechanisms for hiding from the host’s immune system. Our research suggests that the devil is nevertheless evolving resistance to the disease.

Ecological disaster

The Tasmanian devil is too important to lose – and this would seem careless following the extinction of the thylacine, the world’s largest marsupial predator, in the 1930s. Since the thylacine’s extinction, devils have stepped up to the role of top marsupial predator, keeping numbers of destructive feral cats at bay in Tasmania. With the decline of the devils, invasive species have become more active.

Since it was first detected in northeastern Tasmania in the mid-1990s, DFTD has spread slowly southward and westward. It will reach all parts of Tasmania within a few years; only the far northwest coast and parts of the southwest are still disease-free.

Devil Facial Tumour Disease has spread across the island over two decades.
Menna Jones

Devil populations have declined by at least 80%, and by more than 90% in some areas within six years of local disease outbreak.

DFTD kills most devils at sexual maturity. Before the disease arrived, most devils produced three litters over their lifetime. Most now raise only one.

The cascading effects of the loss of Tasmania’s top predator on the rest of the ecosystem could lead to loss of further species. Already, feral cats have increased activity and small mammals on which cats prey have declined.

Cats may also be preventing recovery of the eastern quoll. Brushtail possums behave as if devils were already extinct, grazing freely on pasture in the open.

Evolution in action

Our research has been a truly international effort. We used data collected by Menna Jones at the University of Tasmania since 1999. This archive of tissue samples now represents one of the best resources globally for studying evolution of an emerging infectious disease in wildlife.

Andrew Storfer at Washington State University and Paul Hohenlohe at the University of Idaho compared the frequency of genes in devils in regions before DFTD arrived to devils 8-16 years after DFTD arrived.

We identified significant changes in two small regions in the DNA samples of devils from regions with DFTD. Five of seven genes in the two regions were related to cancer or immune function in other mammals, suggesting that Tasmanian devils are indeed evolving resistance to DFTD. Evolution is often thought of as a slow process, but these changes have occurred in as few as 4–8 generations of devils since disease outbreak.

Devils are surviving at our long-term sites, despite models that predicted extinction. Previously, studies have shown that devils with lower rates of DFTD showed specific changes in their immune response. Our genetic results might explain why.

New infectious diseases put strong pressure on their hosts to evolve, leading to rapid changes in resistance or tolerance. Rapid evolution requires pre-existing genetic variation. Our results are surprising because Tasmanian devils have low levels of genetic diversity.

Evolution doesn’t just act on the devils; it also also acts on the disease. The disease evolves to not kill the host before it can spread to another host, but also to overcome the host’s defences. Over the long term, pathogen (the cause of the disease) and host usually evolve to live together as rabbits and Myxoma virus have evolved together.

Our results suggest that devils in the wild may save themselves through evolution. However, it is essential for managers to develop strategies that help the devils do so. For example, releasing fully susceptible devils that have had no exposure to the disease into populations where resistance is developing is likely to be counterproductive.

DFTD presents a unique opportunity to study the early stages of the evolution of a new disease and transmissible cancer with its animal host. Ultimately, through future research, we may understand how cancers can become transmissible and how their hosts respond.

The Conversation

Menna Elizabeth Jones, Associate professor, University of Tasmania; Andrew Storfer, Professor & Associate Director, School of Biological Sciences, Washington State University; Hamish McCallum, Professor, Griffith School of Environment and Acting Dean of Research, Griffith Sciences, Griffith University; Paul Hohenlohe, , University of Idaho, and Rodrigo Hamede, Post Doctoral Research Fellow, Conservation Biology and Wildlife Management, University of Tasmania

This article was originally published on The Conversation. Read the original article.