Epigenetics and a Paintbrush

In 1967, Sigi Levine and Victor Denenberg made what seemed like minor observations. They noted that rat pups, when briefly stroked with a paintbrush during the first seven days of their lives, demonstrated less "stress" when they were fully mature than rat pups that had not been stroked with a paintbrush during the first seven days of their lives.

I read this paper when I was a first-year psychiatric resident—that is to say, at a time in my life when I knew almost nothing about medicine, psychiatry, rat pups, and the enduring effects of a paintbrush. Eventually, I grew more competent as a physician, but the rat pups and the paintbrush continued to perplex me. Why would a rat pup have a reaction to a paintbrush that would last for the rest of its life?

In 1942, in the journal, Endeavor, Conrad H. Waddington published a paper called “The Epigenotype.” In it, Waddington struggled with an aspect of genetics that was recognized but poorly understood. It was known that between the genotype (DNA) and the phenotype (physical form), there is an interaction. It was further recognized that the interaction is variable. Thus, monozygotic twins—twins that have identical DNA—develop into individuals who are distinct. Identical twins are not, in fact, identical.

Waddington recognized this when he wrote, “The task is to discover the causal mechanisms at work, and to relate them as far as possible to what has already been revealed of the mechanisms of development. It is convenient to have a name for this complex. ‘Epigenotype’ seems suitable.”

And while history would not find the word "epigenotype" entirely suitable, the quest to better define and understand that complex interaction between gene and environment had begun. “We might use the name ‘epigenetics’ for such studies,” Waddington went on, and, indeed ‘epigenetics’ was what took. And, thus, the word and the concept of "epigenetics" was born.

I knew none of this as I struggled to find my identity as a physician. I knew none of this as I struggled to understand the mystery of the paintbrush. But, several years later, I started to put it together—with the help of the work of some brilliant research scientists in Montreal.

Michael Meaney, along with colleagues at McGill University, were also aware of the work of Levine and Denenberg. Rather than being stymied by the mystery of the paintbrush, Meaney researched it. What he discovered was that, after the paintbrush, when the pup was reunited with the dam, it was not the pup’s behavior that changed. It was the dam’s. When her pup was returned, the dam would immediately initiate a series of maternal behaviors including licking and grooming (LG) and arched-back nursing (ABN).

Meaney selectively bred dams that naturally displayed the maternal characteristics of either low licking and grooming/arched back nursing (LG/ABN) or high licking and grooming/arched back nursing. He discovered that pups raised by high-LG/ABN dams were emotionally different as adults than pups raised by low-LG/ABN dams. The high-LG/ABN pups, when adults, were less fearful and less impulsive. They were better able to moderate the stress response.

But what accounted for this more controlled response? Was it the pup’s inheritance—the genes—or was it the environment—the behavior of the dam?

The pups were cross-fostered. That is to say, pups that had been birthed to low-LG/ABN dams were switched to the nests of high-LG/ABN dams. Pups birthed to high-LG/ABN dams were given to low-LG/ABN dams.

When mature, the pups showed the characteristics of their rearing (nurture) and not the characteristics of their inheritance (nature). In other words, it was not the result of inheritance that led to greater stress control. It was the behavior of the dams.

The work of Meaney and colleagues demonstrated a specific effect of maternal licking and grooming/arched back nursing on the genome of the pup—in this case, on the expression of a gene that encodes for a receptor that promotes feedback inhibition of the stress response. The more the dam licks and grooms her pup—especially in the first week of its life—the more will the pup encode that gene. The more the dam licks and grooms and nurses her pup, the more will the pup be able to control its stress response when it is an adult. In other words, the presence of active maternal care leads to an animal that when grown is better able to exert feedback control of its stress response. These changes are not due to its inheritance (nature). They are due to its environment (nurture).

These findings were huge. They were the first biological demonstration of the "causal mechanisms" of environmental effects that Waddington had described in his 1942 paper on epigenetics. This was the first biological demonstration of how events outside the cell (the behavior of the dam) could have lasting effects on the workings inside the cell (the expression of her pup’s gene). This was the first biological demonstration of epigenetics and a paintbrush.