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Limb-regenerating fire-god salamander central to wound repair quest

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By Anthony King

Regenerating lost body parts is impossible for humans, but cracking the cellular code of salamanders could help to treat serious wounds.

Salamanders are remarkable creatures. If one of these amphibians loses a finger, it grows back. Furthermore, if you chop away a piece of heart or spinal cord, it will regenerate. Perhaps most impressively, they can even regrow a leg bitten off by a hungry predator.

One of the most famous salamander species is the axolotl (Ambystoma mexicanum), which is found in lakes near Mexico City.

The axolotl is a veritable Peter Pan of salamanders. Even the 30-centimetre-long reproductive adult retains features of its youthful phase throughout its lifecycle.

The prominent gills protruding from the back of its head are retained from the axolotl’s larval phase. The fact that it never leaves the water throughout its life is unusual for an amphibian.

Fire god

Axolotls were named after the Aztec god of fire Xolotl who, legend has it, disguised himself as a salamander to avoid being sacrificed. Today, scientists study axolotls in their laboratories because of their amazing ability to regrow one or even two limbs.

‘I’m still fascinated by how the limbs regenerate,’ said Professor Elly Tanaka at the Research Institute of Molecular Pathology in Vienna, Austria, who has studied salamanders for almost two decades.

Her lab focuses on the distinctive axolotl species but ‘All salamanders people have studied seem to regenerate limbs,’ she remarks.

As part of the EU-funded RegGeneMems project, Prof Tanaka is trying to unravel the mystery behind how molecules command cells inside the injured axolotl to develop and move, thereby restoring an entire limb in the right proportion and size.

This regeneration is possible as far as the shoulder, and it happens as if the animal was first growing a limb.

While it remains within the realms of science-fiction for a person ever to regrow an arm or a leg, researchers believe that the salamanders can offer insights into how patient injuries might be better treated.

‘When they lose a limb, or even two limbs, they’re still pretty mobile because they can swim around using their tail,’ said Prof Tanaka.

Cellular kit

‘The lesson from the salamanders is that you use very much the same molecular machinery that you do during the development of the limb,’ said Prof Tanaka. With lessons from the axolotl, we could therefore boost our own injury-repair kit.

Once an axolotl limb is lost, a blood clot forms at the site of the wound. Skin cells move to cover the wound within a day. Then the tissues underneath start rearranging, first forming a jumbled mass of cells – a blastema – that seems to lack any organisation. 

A blastema is a mass of undifferentiated cells that has the capacity to turn into an organ or appendage. It is particularly important in the regeneration of severed limbs.

In human wounds, scar tissue is formed by glue-like cells called fibroblasts. In salamanders, something amazing happens as, within weeks, these cells take a step back in time to become less specialized.

They regain enough flexibility to become bone, ligament, tendon, or cartilage. Then, they shoot each other signals that direct the reconstruction of the missing body part from the stump, growing an exact replicate.

Prof Tanaka recently discovered how some crucial signals help with the arrangement of cells and tissues from what looks like a confused jumble.

She discovered that cells in the regenerating tissue that come from the thumb side of the limb start to produce different signals than cells from the pinky-finger side.

Sonic Hedgehog

‘The thumb side produces FGF-8 (fibroblast growth factor), and this tells the pinky-side cells that they need to produce Sonic Hedgehog,’ said Prof Tanaka.

Named in honour of the famous Sonic the Hedgehog videogame character, the Sonic Hedgehog signalling molecule (SHH) is crucial to embryonic development in animals and humans.

Another signal molecule, also found in people, is FGF-8, which also has a role in tissue repair and development.

Together, FGF-8 and SHH stoke pro-growth conditions inside the damaged limb and help direct the jumble of cells in the blastema.

‘You need cells from the pinky and thumb side of the limb to come into this blastema, and so you have all the cell types that you need to rebuild,’ said Prof Tanaka.

Another scientist intrigued by axolotls is cell biologist Dr Sandra Edwards at TU Dresden. She became interested in salamanders after attending a research course in the US during her PhD in Chile, redirecting her career. 

She applied to join the lab of Tatiana Sandoval-Guzmán, an eminent researcher of axolotl limb repair at the Centre for Regenerative Therapies Dresden (CRTD).

‘The more I heard about salamanders, the more I became fascinated,’ recalled Dr Edwards, who hopes her research can one day go to help patients.

Tissue tension

In the ProDistReg project, the Marie Skłodowska-Curie Actions (MSCA) fellow Dr Edwards, studies how differences in tension within tissues may influence the repair and help the animal turn what seems like cellular chaos into a perfectly functioning limb.

She became intrigued with the fact that limb regrowth takes a similar amount of time, regardless of the amount of tissue being replaced. This means limbs must grow faster when more tissue is removed.

‘My hypothesis is that tension or stiffness is higher in tissues that grow slower,’ she said.

It may seem surprising, but the mechanics and rigidity of tissues can influence their development and regeneration as well as pathologies like cancer.

There is a web-like network called the cytoskeleton inside cells. This can sense external pressures when compressed, which opens entry points (akin to postal boxes) to the nucleus of a cell, allowing molecular messages to flow in and turn genes on and off.

‘In our system, we have observed that during limb generation in the axolotl, tissues that are closer to the body are softer and grows faster than tissues that are further away from the body on the end of a limb, for example, which are stiffer.’

Cell matrix

Knowledge about tissue stiffness could help injured patients. While conceivably such patients might be treated with stem cells delivered in a matrix, the pressures within the patient’s tissues may prove important.

‘It may be that the tissues and their cells on different parts of the body behave differently, even within the same structure such as the arm, such as upper and lower arm, said Dr Edwards. Therefore, in regenerative medicine, where cell-containing matrixes are transplanted into large wounds, such scaffolds may need to be different, depending on where in the body they will be placed.

Though Prof Tanaka spends most days studying the molecular mechanics of axolotl repair, she too foresees future benefits to injured patients. But salamanders and mammals develop differently.

In mammals, like ourselves, when we first develop an arm, this happens at a tiny scale in an embryo. The salamander is different. It seems to contain a bud capable of developing into a large adult arm.

Stem cells

‘We are not going to be able to ask a human cell to do this, because it’s wired to work at tiny scales,’ said Prof Tanaka. ‘But we might be able to produce a group of human stem cells that regenerate like an axolotl.’

This could be extremely beneficial, for example, to people who suffer extensive burn wounds. Repair of this skin currently does not give a person sweat glands, hair follicles and other cell types, but lessons from the salamander could make this possible.

‘Resetting these fibroblasts – which the axolotl does – could be quite relevant to better healing in very large wounds, such as from burns,’ Prof Tanaka said.

Research in this article was funded via the EU’s European Research Council and the Marie Skłodowska-Curie Actions (MSCA). This article was originally published in Horizon, the EU Research and Innovation Magazine. 

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Health & Wellness

Noncommunicable diseases now ‘top killers globally’

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From heart disease to cancer and diabetes, noncommunicable diseases (NCDs) now outnumber infectious diseases as the “top killers globally,” the UN health agency said in a new report, released on Wednesday, with one person under 70 dying every two seconds from an NCD.

The report and new data portal, was launched on the sidelines of the 77th session of the General Assembly, at an event co-organized by the World Health Organization (WHO) together with Bloomberg Philanthropies.

Report assets

NCDs constitute one of the greatest health and development challenges of this century, according to WHO.

Chief among them are cardiovascular diseases, such as heart disease and stroke; cancer; and diabetes and chronic respiratory diseases – as well as mental health illnesses.

Together they account for nearly three-quarters of deaths in the world, taking 41 million lives every year. 

The report, Invisible numbers: The true extent of noncommunicable diseases and what to do about them, highlights NCDs statistics to illustrate the true scale of the threats and risk factors they pose. 

It also shows cost-effective and globally applicable interventions that can lower those numbers and save lives and money.

“This report is a reminder of the true scale of the threat posed by NCDs and their risk factors,” said WHO chief Adhanom Ghebreyesus.

Country-specific portal

Sharing the latest country-specific data, risk factors and policy implementation for 194 countries, the NCD data portal brings the numbers in the report to life. 

Moreover, it allows data exploration on cardiovascular diseases, cancer, diabetes and chronic respiratory diseases along with their main drivers and risk factors, which include tobacco, unhealthy diet, harmful use of alcohol and lack of physical activity. 

The portal spotlights patterns and trends throughout countries and allows comparison across nations and/or within geographical regions.

Important timing

To date, only a handful of countries are on track to meet the 2030 Sustainable Development Goal (SDG) target of reducing early deaths from NCDs by a third.  

And yet, NCDs are at the heart of sustainable development and their prevention and treatment is a prime opportunity for investment that would have myriad impacts on economic growth, far outweighing the money spent.

“It is a misconception” that they are “diseases of high-income countries”, said Bente Mikkelsen, WHO’s Director of Noncommunicable Diseased, adding that a full 85 per cent of all premature deaths happen in low and middle-income countries.

At a critical juncture for public health, WHO said that the new information offers a chance to address the issue and recommends spending more on prevention.

Investing $18 billion a year across all low and middle-income countries could generate net economic benefits of $2.7 trillion by 2030.

At the event, the WHO chief called on global leaders to take urgent action on NCDs and renewed the two-year appointment of Michael R. Bloomberg as WHO Global Ambassador for Noncommunicable Diseases and Injuries – his  third reappointment since 2016.

“As we continue to respond to this pandemic and prepare for the next, we have seen the critical importance of addressing a major risk factor in COVID-19 hospitalizations and deaths – noncommunicable diseases,” said Mr. Bloomberg.

He maintained that they can often be prevented with investment in “proven, cost-effective interventions” and looked forward to continuing to make “life-saving investments in NCD and injury prevention” alongside WHO.

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Health & Wellness

Rare Ebola outbreak declared in Uganda

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An outbreak of Ebola virus has been declared in Uganda after a case was confirmed in Mubende district, in the centre of the country.

The UN World Health Organization (WHO) said on Tuesday that a sample taken from a 24-year-old man was identified as the relatively rare Sudan strain.

It is the first time in more than a decade that the Sudan strain has been found in Uganda, which also saw an outbreak of the Zaire strain of Ebola virus in 2019.

Suspicious deaths

The latest outbreak follows six suspicious deaths in Mubende district so far this month. There are also eight suspected cases who are receiving care in a health facility.

Dr Matshidiso Moeti, World Health Organization Regional Director for Africa, said that the UN agency was working closely with Ugandan authorities to investigate the source, and support efforts to control it.

“Uganda is no stranger to effective Ebola control”, she said. “Thanks to its expertise, action has been taken to quickly to detect the virus and we can bank on this knowledge to halt the spread of infections.”

No effective vaccine

Existing vaccines against Ebola have proved effective against the Zaire strain but it is not clear if they will be as successful against the Sudan strain, WHO said in a statement.

Ebola is a severe, often fatal illness affecting humans and other primates. It has six different strains, three of which – Bundibugyo, Sudan and Zaire – have previously caused large outbreaks.

Case fatality rates of the Sudan strain have varied from 41 per cent to 100 per cent in past outbreaks. Early roll-out of supportive treatment has been shown to significantly reduce deaths from Ebola, WHO said.

Sending supplies

The agency has dispatched supplies to support the care of patients and is sending a specialized tent that will be used to isolate patients.

While ring vaccination of high-risk people with Ervebo (rVSV-ZEBOV) vaccine has been highly effective in controlling the spread of Ebola in recent outbreaks in DRC and elsewhere, said WHO, this vaccine has only been approved to protect against the Zaire strain.

Another vaccine produced by pharmaceutical company Johnson and Johnson may be effective but has yet to be specifically tested against the Sudan strain.

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Health & Wellness

The end of the COVID-19 pandemic is in sight

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As the number of weekly reported deaths from COVID-19 plunged to its lowest since March 2020, the head of the World Health Organization (WHO) said on Wednesday that the end of the pandemic is now in sight.

“We have never been in a better position to end the pandemic”, Tedros Adhanom Ghebreyesus told journalists during his regular weekly press conference.

The UN health agency’s Director-General explained however, that the world is “not there yet”.

Finish line in sight

“A marathon runner does not stop when the finish line comes into view. She runs harder, with all the energy she has left. So must we. We can see the finish line. We’re in a winning position. But now is the worst time to stop running”, he underscored.

He also warned that if the world does not take the opportunity now, there is still a risk of more variants, deaths, disruption, and uncertainty.

“So, let’s seize this opportunity”, he urged, announcing that WHO is releasing six short policy briefs that outline the key actions that all governments must take now to “finish the race”.

Urgent call

The policy briefs are a summary, based on the evidence and experience of the last 32 months, outlining what works best to save lives, protect health systems, and avoid social and economic disruption.

“[They] are an urgent call for governments to take a hard look at their policies and strengthen them for COVID-19 and future pathogens with pandemic potential”, Tedros explained.

The documents, which are available online, include recommendations regarding vaccination of most at-risk groups, continued testing and sequencing of the SARS-CoV-2 virus, and integrating effective treatment for COVID-19 into primary healthcare systems.

They also urge authorities to have plans for future surges, including the securing of supplies, equipment, and extra health workers.

The briefs also contain communications advice, including training health workers to identify and address misinformation, as well as creating high-quality informative materials.

Committed to the future

Tedros underscored that WHO has been working since New Year’s Eve 2019 to fight against the spread of COVID and will continue to do so until the pandemic is “truly over”.

“We can end this pandemic together, but only if all countries, manufacturers, communities and individuals step up and seize this opportunity”, he said.

Possible scenarios

Dr. Maria Van Kerkhove, WHO’s technical lead on COVID-19, highlighted that the virus is still “ intensely circulating” around the world and that the agency believes that case numbers being reported are an underestimate.

“We expect that there are going to be future waves of infection, potentially at different time points throughout the world caused by different subvariants of Omicron or even different variants of concern”, she said, reiterating her previous warning that the more the virus circulates, the more opportunities it has to mutate.

However, she said, these future waves do not need to translate into “waves or death” because there are now effective tools such as vaccines and antivirals specifically for COVID-19.

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