Facilitating everything from space travel to resistance to cancer radiation therapy, it may soon be possible for humans to use tardigrade genetics to better resist radiation, suggests new work published in the journal Nature Biomedical Engineering.
With their small size – less than a millimeter – and their strange appearance reminiscent of a faceless pillow, tardigrades are known as the hardiest animals on Earth. In a state of dormancy, or cryptobiosis, they withstand extreme temperatures ranging from -273°C to +273°C, pressure of up to 7500 bars (75 times the pressure felt at a depth of 1,000 meters) and radiation doses 1,000 times higher than the lethal dose for humans. Tardigrade-inspired biotechnology could improve human resistance to extreme conditions", enthuses Professor James Byrne, radiation oncologist at the IOWA Health Care Medical Center (United States) who co-directed this new work.
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Dsup, DNA shield against radiation
The scientists' choice is called Dsup (for "damage suppressor"). This protein was identified in previous work in the tardigrade species. Ramazzottius varieornatus, which has extreme tolerance to radiation. Human cells expressing Dsup showed a 1.5-fold higher survival rate after exposure to high doses of radiation", reports Professor Giovanni Traverso, gastroenterologist at Brigham and Women's Hospital and who co-led the study.
In the nucleus of cells, Dsup binds to DNA and protects it from radiation-induced breaks. Other highly efficient DNA repair systems and resistance to oxidative stress also play a role in tardigrades' resistance to radiation, but Dsup is one of the key factors", explains James Byrne. For a transient and safer effect, it is not the Dsup gene itself that was introduced into human and animal cells, but its mRNA from which the cell itself manufactures the protein.
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35% less cell destruction in mice and miniature pigs
In mice and miniature pigs, the level of protection was even greater than expected, reports James Byrne, with 40 to 60 TP3T less radiation-induced DNA damage! These DNA breaks make radiotherapy toxic by causing massive suicide of the affected cells. The resulting breaks then fuel inflammation in the mucosa, causing patients treated in the mouth or gastrointestinal tract to experience painful swallowing or rectal bleeding, respectively. But local delivery of Dsup mRNA reduced this radiation-induced cell suicide by about 35 TP3T in the targeted tissues, the researchers rejoice.
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If this administration must be local, it is of course to avoid extending the protection of Dsup to the tumor cells that we wish to eliminate by radiation. To ensure this, the Dsup mRNA was encapsulated in lipid nanoparticles combined with biodegradable polymers. ensuring local absorption in targeted tissues such as oral and rectal mucosa", explains Giovanni Traverso. In addition, the injections were made only in the target tissues. Equally important, " tumor control was preserved", adds the gastroenterologist, " which means that Dsup did not interfere with the effectiveness of radiotherapy against tumors, which is particularly promising!“.
Patients, astronauts, military personnel, many potential uses in humans
These results could likely be improved by optimizing the delivery method, or by modifying Dsup to increase its DNA-binding properties and thus its protective capacity. We could also combine Dsup with DNA repair-promoting factors to create a dual protection system", imagines James Byrne. Further studies will also need to be conducted to assess its safety and efficacy in humans before considering its administration to patients.
But for doctors, the game is worth the candle. Radiotherapy is one of the main treatments for cancer. Using methods to prevent its side effects will improve the quality of life of our patients during treatment and, potentially, months and years later." hopes Giovanni Traverso. Ultimately, Dsup could even be used to protect astronauts, military personnel or anyone else likely to be exposed to high doses of radiation.
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