The old biological idea that experience modulates inheritance is undergoing a resurgence and CIFAR Azrieli Global Scholar Brian Dias is at the vanguard.
A parent’s stresses, successes and failures may affect the biology and development of future generations. This is an old idea, first proposed by Greek scholars like Hippocrates and Aristotle and popularized in the 1800s, that for the last century had been discredited and considered nearly heretical to the basic tenets of biology. But research into the possibility that a child’s biological inheritance is determined in part by the experiences of their parents has been undergoing a renaissance in the last decade thanks to work by a growing cadre of scientists including CIFAR Azrieli Global Scholar Brian Dias.
With a growing number of examples across the plant and animal kingdoms including nematode worms, pea plants and mice passing on molecular messages of the stress they experience, it’s becoming clear that the Greeks might have been on to something. Even in humans, there is mounting, if still controversial, evidence that a parent’s adversity can have effects later on.
So we sat down with Dias to understand more about what a parent passes on to their child and when stress can transcend generations.
In a seminal 2014 study, Dias taught mice to associate a particular smell with a mild foot shock. When those mice had pups, they were raised by a surrogate parent and monitored. Dias showed that the pups, who had never been shocked themselves, would develop sensitivity to the smell their parents had learned to associate with electricity. This was surprising because it suggested that parents pass down more than just the genes they were born with to their children. They were somehow transmitting the effects of life experience as well.
Summarizing the findings of that study, Dias emphasizes that the effects were deeper than behavioural: “their brains devote more real estate towards processing the smell, and their sperm bears imprints of that stress at genes that encode the receptors that detect that very smell”. Dias stresses that, despite what often gets reported, his work is not evidence for Lamarckian inheritance. “Unlike their fathers that become fearful of the smell that was paired with the mild foot shock, to our knowledge the next generation doesn’t inherit a fear of the smell, they inherit a sensitivity. They are more aware of it, but if there is no valence associated with the smell, we do not know.”
More recent work, published by Dias’ team this summer in Biological Psychiatry, shows that, as Dias puts it, “the die is not cast. There is malleability to this process.” Just as you can train a mouse to fear a smell by always pairing it with a mild foot shock, you can eliminate the association by presenting the smell on its own, without a shock. Dias and his team found that this extinction training, which is similar to human cognitive behavioural therapy treatment, stopped the mice from being afraid of the smell. It also stopped their sperm from carrying the molecular markers and stopped their children from having altered brains or developing a sensitivity to the smell. This finding provides hope that breaking the cycle of intergenerational stress is possible.
Dias and others in this field have shown convincing evidence that, in mice at least, life experience can affect future generations. But how that happens is still an open question. “We want to understand the nuts and bolts of how information is being transmitted across generations”, he says.
One oft-cited mechanism is DNA methylation, a series of molecular tags on the genome that act as switches. Dias and others have shown that life experience can alter methylation patterns in sperm. But there’s a catch. Every sperm cell undergoes major epigenetic reprogramming that resets these switches at least twice – once at fertilization and once as an embryo.
But perhaps the reprogramming isn’t as complete as commonly thought. Citing work published in the journal Cell in 2015, Dias says that “there were genetic loci associated with obesity and schizophrenia that escaped epigenetic reprogramming.”
It’s also possible that DNA methylation is not what carries the signal across generations at all. Non-coding RNA – bits of genetic material long thought to be irrelevant – have become the topic of intense study as potential messengers of parental trauma. Non-coding RNA is an attractive mechanism because the RNA can pass into sperm cells without being reprogrammed. But their role in development is still mysterious and the research is just beginning.
Dias sees two major hurdles for his field: one is cracking the mystery of mechanism, and the other is figuring out what all this means for human health.
Dias is reticent to draw sweeping conclusions about humans from his work in other mammals. He admits, “disentangling biological inheritance from the contribution of social factors to the human condition is incredibly difficult.” In other words, in humans it’s hard to know if people get traumatized by the way their parents raised them, or by what molecular tags were passed on to them via sperm and egg. One promising line of evidence comes from Michael Kobor, another member of the CIFAR Child & Brain Development program. He has recently published work that suggests marks of early childhood abuse show up in the sperm of adult men. What remains unclear, however, is the extent to which epigenetic messages survive reshuffling before being expressed in their children.
Understanding the balance of nature and nurture in human development is one of the key goals of the Child & Brain Development program, and research conducted by Dias’ team shows that the story may be even yet more complicated than previously thought.