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When Cells Rebel: the dark side of evolution

I love dystopian horror. I love to relish in the thrill of disgust from the comfort of safety – a comfort bolstered by the knowledge that such grotesquerie could never actually happen in real life. Zombies don’t exist. Monsters aren’t trying to escape from the underworld. Cancer isn’t contagious. Actually, maybe scratch that last one. . .

You see, nature may not have the imagination of Stephen King, but it does have something even more powerful in its arsenal: mutations. Mutations are to evolution what creativity is to horror writers – the raw material that allows them to conjure up new and wondrous forms. From the most beautiful (buttercups, butterflies, butter yellow bumblebees) to the most horrific (flesh eating bacteria, pandemic inducing viruses, cancer cells).

Evolution favours the fittest individuals, be they butterflies or bacteria. In this case, “the fittest” just means the ones that are most successful at reproducing. If we are talking about koalas, reproduction means making cute little baby koalas. Everyone likes those. But when we’re talking about cancer cells, reproduction means growing and spreading and killing one’s host. Nobody likes that. Even the cancer cells probably wouldn’t like it – because killing their host also means killing themselves in the process. Kind of like a suicide bomber without the political motivation. But evolution is blind to morality and selects for the cute little baby koalas and murderous cancer cells equally – whatever is most efficient at making more copies of itself. Survival of the fittest.

Mutations are constantly arising in nature. Sometimes these make more successful versions of things, sometimes less successful. It’s a bit of a trial-and-error process. And somewhere in that trial-and-error process, a handful of cells have stumbled across the secret to become the most successful cancer cells ever. Super-cancers! How? By finding a sneaky way around that whole unfortunate dying-when-your-host-dies bit.

They do this by taking a leaf out of the life history book of parasites. Like cancer cells, many parasites are reliant on a host to survive. But unlike cancer cells, many parasites have the power to survive the death of their host by simply finding a new host – a power that evolution has also bestowed upon these super-cancers.

Yes, nature has managed to take one of the most awful diseases known to humanity and done perhaps the only thing that could make it worse. It has made it contagious.

Thankfully, such contagious super-cancers are mercifully rare and none of them affect humans (yet). But the rest of the animal kingdom has not fared quite so well. Leukaemia cells drift through the sea like hidden assassins, spreading from one unsuspecting clam to the next. Dogs can get mushroom shaped tumours on their penises from sex with a poorly chosen partner. And one of our most iconic Australian animals, the Tasmanian devil, is at risk of extinction from not only one but two contagious cancers (creatively named Devil Facial Tumour Disease 1 and Devil Facial Tumour Disease 2). Sometimes lightning really does strike twice.

The good news is, this is where we come in. By researching Devil Facial Tumour Disease – one of the most uniquely horrifying and bizarre diseases to ever arise – we aim to understand how it works, how it spreads, how it evolves and, hopefully one day, how we can stop it.

Follow me for more fun and uplifting facts about the animal world!

Patra Petrohilos (PhD Student) is researching the evolution of devil facial tumour disease (DFTD). By investigating anticancer properties of naturally occurring peptides, she is aiming to identify novel agents with therapeutic potential against DFTD. Patra Petrohilos is a PhD student with the Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science (CIPPS). Follow their exciting research at https://cipps.org.au.

Translating genomic advances into biodiversity conservation

Type: Journal Article

Reference: Hogg, C.J. Translating genomic advances into biodiversity conservation. Nat Rev Genet (2023). https://doi.org/10.1038/s41576-023-00671-0

Abstract

A key action of the new Global Biodiversity Framework is the maintenance of genetic diversity in all species to safeguard their adaptive potential. To achieve this goal, a translational mindset, which aims to convert results of basic research into direct practical benefits, needs to be applied to biodiversity conservation. Despite much discussion on the value of genomics to conservation, a disconnect between those generating genomic resources and those applying it to biodiversity management remains. As global efforts to generate reference genomes for non-model species increase, investment into practical biodiversity applications is critically important. Applications such as understanding population and multispecies diversity and longitudinal monitoring need support alongside education for policymakers on integrating the data into evidence-based decisions. Without such investment, the opportunity to revolutionize global biodiversity conservation using genomics will not be fully realized.

Sydney Science in Instagram: Meet PhD Student Holly Nelson

Meet PhD student Holly Nelson. Her research with the USYD Australian Wildlife Genomics group and NSW Department of Planning and Environment focuses on using genomic data to help provide tools for the management of threatened species, especially the critically endangered Bellinger River snapping turtle.

Watch the full video here: https://www.instagram.com/sydney_science/reel/Cw1FG6-hhD8/

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How to catch a Tasmanian devil

by Dr Elspeth McLennan (Post-doc)

Tasmanian devils are nocturnal. We set traps during the day and overnight curious devils will come to investigate. The traps we use are made of strong PVC plastic fashioned into a cylinder with a spring trap door (see cover picture). The traps are baited with a devil’s favourite treat, a piece of fresh lamb or wallaby. The meat is tied onto the end of a string, fed through the trap, and tied to a pin which holds the door open.

When a devil comes investigating the smell of the meat, they walk to the end of the trap and take the bait. When the meat is pulled and eaten, the pin holding the door open is pulled free and the door swings shut. A second pin slides forward as the door closes and locks it. Devils spend the night in a cosy enclosed space with a full belly. The field biologists begin checking the traps as soon as the sun is up. As its daylight, we often find devils snoozing in their traps.

To perform a health check on the devil, we place a hessian sack over the opening of the trap, gently tilt the trap and the devil slides forward into the sack. The sack is used to keep the devil’s eyes covered to keep them calm making them easier to handle while we check them over. We take their weight, check their body condition, look for wounds and record pouch young in females. For populations suffering from devil facial tumour disease (DFTD), the disease status of each animal is also recorded. Once the devil has been processed, they are released. On a single trapping trip, we will often see the same devils a few times. The free food and somewhere to crash is clearly a good draw.

Author

Dr Elspeth McLennan

Dr Elspeth McLennan (Post-doc) is working the on the Koala Genome Survey, investigating both neutral and functional diversity across the koala’s range to better understand the impacts of a changing climate. Elspeth has expertise in conservation genetics and using translocation and assisted colonisations as a conservation management tool.

DNA methylation networks underlying mammalian traits

Type: Journal article

Reference: Haghani, A., et al. (2023). DNA methylation networks underlying mammalian traits. Science, 381(6658), eabq5693. https://doi.org/doi:10.1126/science.abq5693

Abstract

Using DNA methylation profiles (n = 15,456) from 348 mammalian species, we constructed phyloepigenetic trees that bear marked similarities to traditional phylogenetic ones. Using unsupervised clustering across all samples, we identified 55 distinct cytosine modules, of which 30 are related to traits such as maximum life span, adult weight, age, sex, and human mortality risk. Maximum life span is associated with methylation levels in HOXL subclass homeobox genes and developmental processes and is potentially regulated by pluripotency transcription factors. The methylation state of some modules responds to perturbations such as caloric restriction, ablation of growth hormone receptors, consumption of high-fat diets, and expression of Yamanaka factors. This study reveals an intertwined evolution of the genome and epigenome that mediates the biological characteristics and traits of different mammalian species.

Universal DNA methylation age across mammalian tissues

Type: Journal Article

Reference: Lu, A. T., et al. (2023). Universal DNA methylation age across mammalian tissues. Nature Aging. https://doi.org/10.1038/s43587-023-00462-6

Abstract

Aging, often considered a result of random cellular damage, can be accurately estimated using DNA methylation profiles, the foundation of pan-tissue epigenetic clocks. Here, we demonstrate the development of universal pan-mammalian clocks, using 11,754 methylation arrays from our Mammalian Methylation Consortium, which encompass 59 tissue types across 185 mammalian species. These predictive models estimate mammalian tissue age with high accuracy (r > 0.96). Age deviations correlate with human mortality risk, mouse somatotropic axis mutations and caloric restriction. We identified specific cytosines with methylation levels that change with age across numerous species. These sites, highly enriched in polycomb repressive complex 2-binding locations, are near genes implicated in mammalian development, cancer, obesity and longevity. Our findings offer new evidence suggesting that aging is evolutionarily conserved and intertwined with developmental processes across all mammals.

Tasmanian devil cathelicidins exhibit anticancer activity against Devil Facial Tumour Disease (DFTD) cells

Type: Journal Article

Reference: Petrohilos, C., Patchett, A., Hogg, C.J. et al. Tasmanian devil cathelicidins exhibit anticancer activity against Devil Facial Tumour Disease (DFTD) cells. Science Report 13, 12698 (2023). doi: 10.1038/s41598-023-39901-0

Abstract

The Tasmanian devil (Sarcophilus harrisii) is endangered due to the spread of Devil Facial Tumour Disease (DFTD), a contagious cancer with no current treatment options. Here we test whether seven recently characterized Tasmanian devil cathelicidins are involved in cancer regulation. We measured DFTD cell viability in vitro following incubation with each of the seven peptides and describe the effect of each on gene expression in treated cells. Four cathelicidins (Saha-CATH3, 4, 5 and 6) were toxic to DFTD cells and caused general signs of cellular stress. The most toxic peptide (Saha-CATH5) also suppressed the ERBB and YAP1/TAZ signaling pathways, both of which have been identified as important drivers of cancer proliferation. Three cathelicidins induced inflammatory pathways in DFTD cells that may potentially recruit immune cells in vivo. This study suggests that devil cathelicidins have some anti-cancer and inflammatory functions and should be explored further to determine whether they have potential as treatment leads.

The genome sequence of the critically endangered Kroombit tinkerfrog

Type: Journal Article

Reference: Farquharson, K., McLennan, E., Belov, K., & Hogg, C. (2023). The genome sequence of the critically endangered Kroombit tinkerfrog (Taudactylus pleione). F1000Research, 12(845). https://doi.org/10.12688/f1000research.138571.1

Abstract

The Kroombit tinkerfrog (Taudactylus pleione) is a stream-dwelling amphibian of the Myobatrachidae family. It is listed as Critically Endangered and is at high risk of extinction due to chytridiomycosis. Here, we provide the first genome assembly of the evolutionarily distinct Taudactylus genus. We sequenced PacBio HiFi reads to assemble a high-quality long-read genome and identified the mitochondrial genome. We also generated a global transcriptome from a tadpole to improve gene annotation. The genome was 5.52 Gb in length and consisted of 4,196 contigs with a contig N50 of 8.853 Mb and an L50 of 153. This study provides the first genomic resources for the Kroombit tinkerfrog to assist in future phylogenetic, environmental DNA, conservation breeding, and disease susceptibility studies.

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Koalas and Chlamydia: How can genomics help?

by Luke Silver (PhD Student) 

The mention of a koala infected with Chlamydia will often be met with rounds of laughter or even concern, “can I get Chlamydia from touching a koala?” For koalas, Chlamydia is no laughing matter with up to 100% of individuals in some populations infected with the bacteria. In many cases infection will lead to blindness, “wet bottom” as a result of bladder infection, infertility and eventually death. Unfortunately, unlike humans, koalas are unable to go to the doctor and receive treatment for the infection. Often koalas are taken to veterinary hospitals after a human interaction (such as vehicle strike or a dog attack) and it is there the infection is noticed and treatment can be administered.

Genomics is the study of the genes and nucleotides contained within an individual’s genome. By studying the genomics of koalas, we have been able to identify important genes which play a vital role in helping a koala clear a Chlamydia infection. One of these genes is a part of the major histocompatibility complex, or MHC, known for its vital role in recognition of pathogens. We are now using the whole genomes of over 400 koalas to investigate how diverse the MHC genes of koalas are across their entire range from northern Queensland to South Australia. A high level of genetic diversity in the MHC results in an individual or population being able to recognise a wider array of pathogens and may be linked to the health of this endangered marsupial. Scientists in other labs are attempting to develop a vaccine which can prevent koalas from contracting the infection in the first place which has shown promising results in early phase testing.

Finally, fortunately you are unable to catch Chlamydia from holding or touching a koala as the species which infects koalas is different from the species which infects humans.

Author

Luke Silver

Luke Silver (PhD Student) is using genomic data to
investigate immune genes in Australian marsupials with a focus on koalas where he is using resequenced genomes to examine patterns of diversity in functional and neutral regions of the genome across the entire east coast of Australia. This work will be used to inform conservation and management decisions in the fight to save our threatened species.