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A big step toward producing rhino gametes

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To save the northern white rhinoceros from extinction, the BioRescue team is racing to create lab-grown egg and sperm cells of the critically endangered subspecies. The team has now reported a milestone in Science Advances: they have generated primordial germ cells from stem cells – a world’s first.

Thirty-three-year-old Najin and her daughter Fatu are the last surviving northern white rhinos on the planet. They live together in a wildlife conservancy in Kenya. With just two females left, this white rhino subspecies is no longer capable of reproduction – at least not on its own. But all hope is not lost: according to a paper published in the journal Science Advances, an international team of researchers has successfully cultivated primordial germ cells (PGCs) – the precursors of rhino eggs and sperm – from embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs).

The last two surviving females live in the Ol Pejeta Conservancy in Kenya./CREDIT:Jan Stejskal, Safari Park Dvůr Králové


The last two surviving females live in the Ol Pejeta Conservancy in Kenya./CREDIT:Jan Stejskal, Safari Park Dvůr Králové

This represents a major milestone in an ambitious plan. The BioRescue project, which is coordinated by the Leibniz Institute for Zoo and Wildlife Research (Leibniz-IZW) and has been funded by the German Federal Ministry of Education and Research (BMBF) since 2019, wants to save the northern white rhino from extinction. To this end, the scientists are pursuing two strategies – one of them trying to generate viable sperm and eggs from the skin cells of deceased rhinos. The idea is to implant the resulting embryos into closely related southern white rhino females, who will then carry the surrogate offspring to term. And so the northern white rhino subspecies, which humans have already effectively wiped out through poaching, may yet be saved thanks to state-of-the-art stem cell and reproductive technologies.

First success with an endangered species

To get from a piece of skin to a living rhinoceros may be a true feat of cellular engineering, but the process itself is not unprecedented: the study’s co-last author Professor Katsuhiko Hayashi leads research labs at the Japanese universities of Osaka and Kyushu in Fukuoka, where his teams have already accomplished this feat using mice. But for each new species, the individual steps are uncharted territory. In the case of the northern white rhinoceros, Hayashi is working in close cooperation with Dr. Sebastian Diecke’s Pluripotent Stem Cells Technology Platform at the Max Delbrück Center and with reproduction expert Professor Thomas Hildebrandt from Leibniz-IZW. The two Berlin-based scientists are also co-last authors of the current study.

“This is the first time that primordial germ cells of a large, endangered mammalian species have been successfully generated from stem cells,” explains the study’s first author, Masafumi Hayashi of Osaka University. Previously, it has only been achieved in rodents and primates. Unlike in rodents, the researchers have identified the SOX17 gene as a key player in rhinoceros PGC induction. SOX17 also plays an essential role in the development of human germ cells – and thus possibly in those of many mammalian species.

The southern white rhino embryonic stem cells being used in Japan come from the Avantea laboratory in Cremona, Italy, where they were grown by Professor Cesare Galli’s team. The newly derived northern white rhino PGCs, meanwhile, originated from the skin cells of Fatu’s aunt, Nabire, who died in 2015 at Safari Park Dvůr Králové in the Czech Republic. Diecke’s team at the Max Delbrück Center was responsible for converting them into induced pluripotent stem cells.

Next step: cell maturation

Masafumi Hayashi says that they are hoping to use the cutting-edge stem cell technology from Katsuhiko Hayashi’s lab to save other endangered rhino species: “There are five species of rhino, and almost all of them are classified as threatened on the IUCN Red List.” The international team also used stem cells to grow PGCs of the southern white rhino, which has a global population of around 20,000 individuals. In addition, the researchers were able to identify two specific markers, CD9 and ITGA6, that were expressed on the surface of the progenitor cells of both white rhino subspecies. “Going forward, these markers will help us detect and isolate PGCs that have already emerged in a group of pluripotent stem cells,” Hayashi explains.

The BioRescue scientists must now move on to the next difficult task: maturing the PGCs in the laboratory to turn them into functional egg and sperm cells. “The primordial cells are relatively small compared to matured germ cells and, most importantly, still have a double set of chromosomes,” explains Dr. Vera Zywitza from Diecke’s research group, who was also involved in the study. “We therefore have to find suitable conditions under which the cells will grow and divide their chromosome set in half.”

Genetic variation is key for conservation

Leibniz-IZW researcher Hildebrandt is also pursuing a complementary strategy. He wants to obtain egg cells from 22-year-old Fatu and fertilize them in Galli’s lab in Italy using frozen sperm collected from four now deceased northern white rhino bulls. This sperm is thawed and injected into the egg in a process known as intracytoplasmic sperm injection (ICSI). However, Hildebrandt explains that Fatu is not able to bear her own offspring, as she has problems with her Achilles tendons and cannot carry any additional weight. Her mother Najin, meanwhile, is past child-bearing age and also suffers from ovarian tumors. “And in any case, since we only have one donor of natural eggs left, the genetic variation of any resulting offspring would be too small to create a viable population,” he adds.

The team’s top priority, therefore, is turning the PGCs they now have at their disposal into egg cells. “In mice, we found that the presence of ovarian tissue was important in this crucial step,” Zywitza explains. “Since we cannot simply extract this tissue from the two female rhinos, we will probably have to grow this from stem cells as well.” The scientist is hopeful, however, that ovarian tissue from horses could come in useful, as horses are among the rhinos’ closest living relatives from an evolutionary standpoint. If only humans had taken as good care of the wild rhino as they had of the domesticated horse, the immense challenge now facing the BioRescue scientists could perhaps have been avoided altogether.

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Boosting physical activity/curbing sitting time likely to lower breast cancer risk:Mendelian randomisation study reveals

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Boosting physical activity levels and curbing sitting time are highly likely to lower breast cancer risk, finds research designed to strengthen proof of causation and published online in the British Journal of Sports Medicine.

The findings were generally consistent across all types and stages of the disease, reveals the Mendelian randomisation study, prompting the researchers to recommend a stronger focus on exercise as a way of warding off breast cancer.

Mendelian randomisation is a technique that uses genetic variants as proxies for a particular risk factor—in this case lifelong physical activity levels/sedentary behaviour—to obtain genetic evidence in support of a causal relationship.

Exercise/Photo:en.wikipedia.org

Observational studies show that physical inactivity and sedentary behaviour are linked to higher breast cancer risk, but proving they cause breast cancer is another matter.

The researchers therefore used Mendelian randomisation to assess whether lifelong physical activity and sitting time might be causally related to breast cancer risk in general, and specifically to different types of tumour.

They included data from 130,957 women of European ancestry: 69, 838 of them had tumours that had spread locally (invasive); 6667 had tumours that hadn’t yet done so (in situ); and a comparison group of 54,452 women who didn’t have breast cancer.

Exercise-Yoga/Photo:en.wikipedia.org

The researchers then drew on previously published studies that had used the vast repository of UK Biobank data on potential genetic explanations for overall predisposition to physical activity, vigorous physical activity, or sitting time—as measured by wrist-worn activity trackers—to genetically predict how physically active or inactive their own study participants were.

Next, the researchers estimated overall breast cancer risk, according to whether the women had or hadn’t gone through the menopause; and by cancer type,stage (size and extent of tumour spread), and grade (degree of tumour cell abnormality).

Analysis of the data showed that a higher overall level of genetically predicted physical activity was associated with a 41% lower risk of invasive breast cancer, and this was largely irrespective of menopausal status, tumour type, stage, or grade.

Similarly, genetically predicted vigorous physical activity on 3 or more days of the week was associated with a 38% lower risk of breast cancer, compared with no self-reported vigorous activity. These findings were consistent across most of the case groups.

cancer cells/photo:en.wikipedia.org

Finally, a greater level of genetically predicted sitting time was associated with a 104% higher risk of triple negative breast cancer. These findings were consistent across hormone-negative tumour types.

The findings were unchanged after factoring in the production by a single gene of two or more apparently unrelated effects (pleiotropy), such as smoking and overweight, for example.

There are plausible biological explanations for their findings, say the researchers, who point to a reasonable body of evidence indicating numerous causal pathways between physical activity and breast cancer risk, such as overweight/obesity, disordered metabolism, sex hormones, and inflammation.

“Mechanisms linking sedentary time and cancer are likely to at least partially overlap with those underpinning the physical activity relationship,” suggest the researchers.

Their findings provide “strong evidence” that more overall physical activity and less sitting time are likely to reduce breast cancer risk, they say.

And they conclude: “Increasing physical activity and reducing sedentary time are already recommended for cancer prevention. Our study adds further evidence that such behavioural changes are likely to lower the incidence of future breast cancer rates.

“A stronger cancer-control focus on physical activity and sedentary time as modifiable cancer risk factors is warranted, given the heavy burden of disease attributed to the most common cancer in women.”

JOURNAL

DNA screen: World-first preventative saliva test for cancer and heart disease risk

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Young Australians can now access a free DNA saliva test to learn whether they face increased risk of some cancers and heart disease, which can be prevented or treated early if detected, in a world-first DNA screening study.

The nationally collaborative project, led by Monash University and supported by researchers and clinicians across Australia, will screen at least 10,000 people aged 18-40 for genes that increase risk of certain types of cancers and heart disease that often go undetected.

Those found to be at high risk after DNA testing – about one in 75 or 1.3 per cent – will have their situation explained by experts and be offered genetic counselling and prevention measures, such as regular scans and check-ups.

cancer/photo:en.wikipedia.org

Until now, genetic testing for the DNA changes that increase disease risk has only been available on a small scale for those with a known family history or prior disease diagnosis. Population testing, open to everyone, has the potential to drastically improve access and maximize the preventive benefits of DNA testing.

Monash University’s Associate Professor Paul Lacaze said the project enabled a more efficient and equitable approach to genetic testing, identifying far more people at high risk than current testing methods.

“We hope to identify those at risk while they are young and healthy, not after the fact, and empower them to make more informed decisions about their health,” he said. “For some people, this could save their lives through early detection and prevention of cancer and heart disease. This will also save considerable health system costs in Australia through prevention.

“Providing genetic testing based on family history alone is not enough. Up to 90 per cent of those at high risk in the general population are not identified by current family history-based testing. Most people don’t find out about their genetic risk until it’s too late, like after an incurable cancer or heart attack is diagnosed. We want to change that.”

DNA Screen will identify people with DNA variants in the BRCA1 and BRCA2 genes that lead to an increased risk of hereditary breast and ovarian cancer in women. These genes are also linked to breast and prostate cancer in men, although not as strongly. Men and women who carry DNA variants in the BRCA1 and BRCA2 genes can also pass them onto their children.

The DNA Screen test will also focus on Lynch Syndrome – another condition that increases risk for colorectal, endometrial, and other gastrointestinal cancers. Both cancer-related conditions have effective, proven interventions available to reduce risk if identified early.

This includes attending annual check-ups and screens from age 30, and the option of risk-reducing surgery for some people. Early detection and prevention are often life-saving for cancer.

The DNA test also encompasses heart disease risk, focusing on familial hypercholesterolemia (FH) or ‘genetic high cholesterol’, which results in high risk of heart disease from a young age. Despite effective medications such as statins being available to reduce risk, an estimated 95 per cent of FH carriers are currently undiagnosed.

Associate Professor Lacaze, from the Monash University School of Public Health and Preventive Medicine, is leading a team of national collaborators who were awarded a $2.97 million Medical Research Future Fund (MRFF) grant for the project. The project is supported by the Precision Medicine laboratory at Monash University and the state-of-the-art Biobanking Victoria facility.

The eventual goal is to develop a new population-based DNA screening program that could be offered through the Australian public healthcare system, available to everyone but targeted on certain medically-actionable conditions where early detection is key.

“We expect to identify about 1 in 75 people at high risk of these diseases. Those found to be high risk won’t necessarily get the disease, but pinpointing risk before symptoms appear enables prevention through regular check-ups, medication, or risk-reducing surgery. It could save their life.

DNA Screen, which is recruiting young people via social media, is expected to save lives and could lead to a wide scale preventive DNA testing program for cancer and heart disease risk, where early detection and prevention can be life-saving.

DNA Screen is the world’s first preventive DNA screening study designed specifically to assess population DNA screening through a national healthcare system. The test is free and involves placing a saliva sample into a small tube received by mail, and sending it back in a postage paid envelope. People can sign up online at dnascreen.monash.edu

 

What makes dog man’s best friend?

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From pugs to labradoodles to huskies, dogs are our faithful companions. They live with us, play with us and even sleep with us. But how did a once nocturnal, fearsome wolf-like animal evolve over tens of thousands of years to become beloved members of our family? And what can dogs tell us about human health? Through the power of genomics, scientists have been comparing dog and wolf DNA to try and identify the genes involved in domestication.

Amanda Pendleton, a postdoctoral research fellow in the Michigan Medicine Department of Human Genetics, has been reviewing current domestication research and noticed something peculiar about the DNA of modern dogs: at some places it didn’t appear to match DNA from ancient dogs. Pendleton and her colleagues in assistant professor Jeffrey Kidd, Ph.D.’s laboratory are working to understand the dog genome to answer questions in genome biology, evolution and disease.

Breed dogs, which mostly arose around 300 years ago, are not fully reflective of the genetic diversity in dogs around the world, she explains. Three-quarters of the world’s dogs are so-called village dogs, who roam, scavenge for food near human populations and are able to mate freely. In order to get a fuller picture of the genetic changes at play in dog evolution, the team looked at 43 village dogs from places such as India, Portugal and Vietnam.

Armed with DNA from village dogs, ancient dogs found at burial sites from around 5,000 years ago, and wolves, they used statistical methods to tease out genetic changes that resulted from humans’ first efforts at domestication from those associated with the development of specific breeds. This new genetic review revealed 246 candidate domestication sites, most of them identified for the first time by their lab.

Now that they’d identified the candidate genes the question remained: What do those genes do?

‘A good entry point’

Upon closer inspection, the researchers noticed that these genes influenced brain function, development and behavior. Moreover, the genes they found appeared to support what is known as the neural crest hypothesis of domestication. “The neural crest hypothesis posits that the phenotypes we see in domesticated animals over and over again — floppy ears, changes to the jaw, coloration, tame behavior — can be explained by genetic changes that act in a certain type of cell during development called neural crest cells, which are incredibly important and contribute to all kinds of adult tissues,” explains Pendleton. Many of the genetic sites they identified contained genes that are active in the development and migration of neural crest cells.

One gene in particular stuck out, called RAI1, which was the study’s highest ranked gene. In a different lab within the Department of Human Genetics, Michigan Medicine assistant professor of human genetics Shigeki Iwase, has been studying this gene’s function and role in neurodevelopmental disorders. He notes that in humans, changes to the RAI1 gene result in one of two syndromes — Smith-Magensis syndrome if RAI1 is missing or Potocki-Lupski syndrome if RAI1 is duplicated.

Kidd said that they are using these changes that were selected for by humans for thousands of years as a way to understand the natural function and gene regulatory environment of the neural crest in all vertebrates.