These little mice inherited immunity from their parents, but not through DNA

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The rules of succession are meant to be simple. Daddy’s DNA mixes with mom’s DNA to generate a new combination. Over time, random mutations will give some individuals better adaptability to the environment. Mutations are selected over generations, and the species becomes stronger.

But what if this central dogma is only part of the picture?

A new study in Natural immunology ruffles feathers in that it recontextualizes evolution. Mice infected with a non-lethal dose of bacteria, once recovered, can transmit a turbo-boosted immune system to their children and grandchildren, all without altering DNA sequences. The trick seems to be epigenetic changes – the way genes are turned on or off – in their sperm. In other words, compared to millennia of evolution, there is a faster route for a species to thrive. For any individual, it is possible to gain survival capacity and adaptability in a single lifetime, and these changes can be passed on to the offspring.

“We wanted to test whether we could observe the inheritance of certain traits in subsequent generations, say regardless of natural selection,” said study author Dr Jorge Dominguez-Andres of the Radboud University Nijmegen Center.

“The existence of epigenetic inheritance is of primary biological importance, but the extent to which this occurs in mammals remains largely unknown,” said Drs. Paola de Candia at IRCCS MultiMedica, Milan, and Giuseppe Matarese at Treg Cell Lab, Dipartimento di Medicina Molecolare e Biotecnologie Mediche at Università degli Studi di Napoli in Naples, who did not participate in the study. “Their work is a big conceptual leap. “

Progress on steroids

The article is controversial because it is based on Darwin’s original theory of evolution.

You know this example: Giraffes don’t have long necks because they had to stretch their necks to reach taller leaves. Rather, random mutations in the DNA that code for the long necks were ultimately selected, mainly because these giraffes were the ones that had survived and procreated.

Yet recent studies have thrown a wrench into the long-held dogma about how species adapt. At their root is epigenetics, a mechanism “on top” of DNA to regulate how our genes are expressed. It is useful to think of DNA as low level basic code – ASCII in computers. To run the code, it must be translated into a superior language: proteins.

Similar to a programming language, it is possible to silence DNA with additional pieces of code. This is how our cells develop into very different organs and parts of the body, such as the heart, kidneys and brain, even though they have the same DNA. This level of control is called epigenetics, or “above genetics”. One of the most common ways to silence DNA is to add a chemical group to a gene so that, like a wheel block, the gene “gets stuck” as it tries to make a protein. This silences the genetic code without damaging the gene itself.

These chemical markers are dotted along our genes and represent a powerful way to control our basic biology, from stress to cancer to autoimmune diseases to psychiatric struggles. But unlike DNA, chemical tags are thought to be completely wiped out in the embryo, leaving a blank slate for the next generation to start over.

Not really. A now famous study showed that a famine in the winters of 1944 and 1945 altered the metabolism of children who, at the time, were growing fetuses. The consequence was that these children were more susceptible to obesity and diabetes, even though their genes remained unchanged. Similar studies in mice have shown that fear and trauma in parents can be passed on to puppies – and grandchildren – making them more susceptible, while certain types of addiction have increased puppies’ resilience against addiction.

Long story short? DNA Legacy isn’t the only game in town.

Overpowered immunity

The new study plays on a similar idea: that an individual’s life experiences can change the epigenetic makeup of their offspring. Here, the authors focused on trained immunity – the part of the immune system that we have at birth, but which is able to learn and “remember” previous infections to better fight the next round.

The team first exposed adult mice to infectious elements such as fungi or yeast particles to simulate infection. Once recovered, the mice were mated with healthy mice resulting in normal-looking baby puppies.

But they all had super power. When confronted with potential pathogens, for example, bacteria E. Coli– they showed a much stronger immune response than mice with uninfected parents. Puppies’ bodies were able to better recruit immune cells at sites of infection, and they also elicited a more ferocious immune response against bacterial attackers, even though this was their first encounter with these agents. pathogens.

Even more impressive, this superimmunity continued for the next generation. The grandchildren of the originally infected mice also had lower levels of bacteria in their systems after digging through an environment rich in bacteria. However, protection declined in the third generation – the great-grandchildren – suggesting that anything passed on had an expiration date.

A new epigenetic melody

How can the trained immunity be passed on to the offspring?

The first puzzle was that on the surface, white blood cells and other “attackers” did not look different between disease resistant mice and normal mice. But when the team delved into the source of immune cells – the bone marrow – their epigenetic landscape painted a dramatically altered picture.

Mice born to previously infected parents or grandparents had a more open epigenetic landscape. That is, many of their genes that help immune cells grow and activate were more easily accessible, allowing them to activate quickly when needed. A type of immune soldier has been specially prepared for action in these mice, with enhanced metabolism and responsiveness to threats.

But how can these changes be passed on to the next generation when the parents were never directly infected?

One answer appears to be altered semen. Examining the epigenetic landscape, the team found a “fingerprint” that better enhanced white blood cells to protect puppies from any bacteria. Enriched sperm is not the only answer; mice born to previously infected mothers also had turbo-boosted immunity, but how it works remains a mystery. How changes in immune cell epigenetics are telegraphed to reproductive cells is also an enigma, although drifting biomolecules called small interfering RNAs may be the messenger.

At the end of the line ? “Soft” epigenetic inheritance is more common than previously thought. Although the work is being done on mice, a previous study showed that children of parents who received the BCG vaccine had significantly higher survival in infancy. Like mice, we can also inherit immunity from our parents and pass it on to our children.

But it’s not just unicorns and rainbows. Strong inflammatory responses, while effective in fighting bacterial invaders, can also trigger atherosclerosis, heart and vascular disease, and even accelerated aging. The question the team then seeks to answer is: Does inherited superimmunity have any unexpected drawbacks?

For now, the results build on previous observations that DNA is not the end when it comes to heredity. “I’m really curious to see how the scientific community sees this article. I’m sure there will be criticism, ”Dominguez-Andres said.

Image Credit: Gerd Altmann from Pixabay


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