Treating disease before birth is the next horizon, said William Peranteau, a fetal surgeon at CHOP and co-senior author of the new study in mice, published in Science Advances.

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While he and his colleagues successfully induced the production of proteins in the fetal mice, they did not target a specific disease in this initial proof-of-concept study. Years of research are needed before the approach can be tried on human fetuses.

But the appeal is obvious, Peranteau said. Treating a disease during pregnancy would allow physicians to intervene before it is too late, potentially warding off various developmental delays and other conditions that can be fatal.

“These would be diseases that cause problems before the baby is born – problems that are not easily reversible, and for which there isn’t a great treatment after birth,” he said.

Scientists began to piece together the various roles of RNA not long after they figured out the famous double-stranded helix of its chemical cousin, DNA, in 1953. They soon determined that one type of RNA seemed to act as a courier – carrying the genetic instructions in DNA to the cellular “machinery” that uses those instructions to make proteins: the building blocks of life.

As millions of high-schoolers now learn every year in biology class, that crucial “messenger RNA” is abbreviated as mRNA. Moderna, the maker of one of the RNA vaccines, even uses the abbreviation for its stock ticker symbol.

The idea of using RNA to treat disease took a big leap forward in the early 2000s, when a pair of scientists at the University of Pennsylvania, Katalin Kariko and Drew Weissman, cleared a series of technical hurdles. A key advance: they synthesised RNA so it could be safely administered to the human body without triggering inflammation. (Kariko is now a senior vice-president at BioNTech, the German firm that joined with Pfizer to produce the other RNA vaccine for Covid-19.)

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But another hurdle remained. RNA degrades quickly, so scientists needed a way to protect it for delivery inside human cells. The solution: package the genetic instructions inside tiny spheres made from fatty substances called lipids.

That’s the delivery vehicle that has worked so well with the two RNA vaccines, and it is also the approach that Peranteau and his colleagues used in the fetal mice.

University of Pennsylvania bioengineering professor Michael Mitchell, the other senior author of the mouse study, tested various combinations of lipids to see which would work best.

The appeal of the fatty substances is that they are biocompatible. In the vaccines, for example, two of the four lipids used to make the delivery spheres are identical to lipids found in the membranes of human cells – including plain old cholesterol.

When injected, the spheres, called nanoparticles, are engulfed by the person’s cells and then deposit their cargo, the RNA molecules, inside. The cells respond by making the proteins, just as they make proteins by following the instructions in the person’s own RNA. (Important reminder: the RNA in the vaccines cannot become part of your DNA.)

Among the different lipid combinations that Mitchell and his lab members tested, some were better at delivering their cargo to specific organs, such as the liver and lungs, meaning they could be a good vehicle for treating disease in those tissues.

Mitchell and Peranteau oversaw the mouse research as senior authors. Three first authors were responsible for the bulk of the hands-on work, including Rachel Riley, a former Penn engineer who is now an assistant professor at Rowan University.

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The ability to guide the nanoparticles to specific organs would be crucial in treating fetuses, Riley said.

“We can, to a certain extent, dictate where we want them to go,” she said. “Especially in a fetus, you want to minimise any off-target effects.”

It took a pandemic to prove the point, but now that the lipid particles have been such a success with the vaccines, Riley said friends and family finally understand the importance of what she’s been working on for years.

“Now everyone’s asking me about nanoparticles,” she said.

Training the immune system to fight off infectious disease is fairly straightforward. Training it to fight off cancer is far more challenging.

Yet here, too, scientists hope that RNA can help get the job done. This approach is called a therapeutic vaccine, meaning it is designed to treat someone who already has cancer, as opposed to a vaccine for preventing disease like Covid-19.

But in both cases, the goal is coaxing the recipient’s cells to make custom proteins.

In an RNA cancer vaccine, the genetic molecules carry the recipe for proteins in a patient’s tumour. The recipient’s cells make the proteins, and ideally, the immune system learns to recognise them as foreign, and responds by destroying the tumour itself.

A key challenge in treating cancer is that tumours have evolved a variety of mechanisms for suppressing the immune system. The hope is that RNA vaccines can help overcome this suppression, especially when administered in conjunction with other immune-boosting drugs.