October is the month when science turns the microscope on itself, recognizing some of the more spectacular sights along the road of discovery. Sure, there’s the Nobel, the top prize in science, but there’s also the Gairdner.

Each year at U of T, since 1959, the Gairdner Foundation has recognized a handful of researchers who have done influential work in the medical sciences. And 71 of the 280 winners between 1959-2004 have gone on to win (or share) a Nobel Prize.

This year, the Gairdner Foundation recognized the work of six researchers, in three areas: memory, obesity, and gene silencing. The six presented their work at a symposium last Thursday, and were feted at a banquet later that evening. These are some of their stories.

The ROM and RAM of human brains

Dr. Brenda Milner is a giant among Canadian neuroscientists, with a career spanning many decades. Fifty years on, she is still a researcher at Montreal Neurological Institute and McGill University.

In the 50s, Milner’s work with Dr. Wilder Penfield showed the role a part of the brain called the hippocampus played in memory. Penfield had been removing the temporal lobes of seizure patients to lessen their symptoms. Although the outcomes were generally good, removing the left temporal lobe occasionally resulted in severe memory loss.

A clue as to why this happened came from patient P.B., who only experienced memory loss after his second operation, when the medial region of his left temporal lobe was removed. Since this region contains the hippocampus, Milner and Penfield surmised that patients with memory loss must have had prior damage to the right hippocampus, and that removing the left hippocampus had left them with no hippocampal function. An autopsy on P.B. eventually verified this.

Milner and Penfield’s findings caught the attention of Dr. William Scoville, who had removed sections of the temporal lobes of a patient named H.M. The operation had left H.M. unable to form new long-term memories, and Milner was invited to study him.

Through a series of experiments, Milner demonstrated that H.M. was in fact capable of certain kinds of learning. One task, for instance, required H.M. to draw inside the outline of a star while watching his hand in a mirror. After repeated trials he made fewer errors, but could never remember having performed the task.

In another experiment, H.M. was shown fragmented drawings, which were progressively completed until he could recognize the object. Again, H.M. did not recall seeing the drawings, but over time he recognized the objects more quickly. Through this work, Milner showed that the brain stores multiple kinds of memories.

-Sabrina Adamski

Dr. Endel Tulving, another renowned neuroscientist, picked up where Milner left off. Over the last few decades, he has studied and described the mind’s three main memory systems: the procedural, semantic, and episodic.

Procedural memory deals with the details of executing tasks and “knowing how.” The most primitive animals rely on this memory for their survival. General knowledge-type memories are encompassed by the semantic memory system. All higher animals possess the first two systems, but episodic memory is a recent, and evolved, addition.

First proposed in 1972, episodic memory is an extension of knowledge memory that allows one to parse through temporal events in subjective time. This “mental time travel” enables humans to turn back the clock, to remember past experiences, or to fast forward, to anticipate the future. Our self-knowledge and identity are also closely linked to episodic memory. The human adaptation of mental time travel-to advance our survival-is absent in other animals and human infants, according to Tulving.

Evidence for separate memory systems come from human amnesia patients. Tulving has worked extensively with patient K.C., a human case of pure episodic amnesia. A brain injury sustained in a motorcycle accident had deprived K.C. of his mental time travel abilities, but not of other cognitive functions involving procedural and semantic knowledge. The patient could solve word puzzles, yet not have recollections of ever completing the task.

Since the discovery of episodic memory 30 years ago, “great progress has been made in memory research”, said Tulving. He is a U of T professor emeritus, and researcher at Rotman Research Institute in Toronto.

-Wendy Gu

What makes us fat?

According to Gairdner International Award winners Drs. Douglas Coleman and Jeffrey Friedman, the answer to the question “to eat or not to eat” and the obesity phenomenon can be revealed from a hormone known as leptin.

Both scientists were key figures in the understanding and identification of leptin and how it regulates the amount of fat stored in the body. At the Jackson Laboratories in Maine during the 60s and 70s, Coleman, a Stratford-born Canadian, discovered a factor that was the metabolic basis of obesity and diabetes.

Coleman used a method called parabiosis. Pairs of mice are stitched together so that they share blood circulation.

When two strains of “fat” laboratory mice-a mouse genetically predisposed for diabetes (db), and one genetically predisposed for obesity (ob)-were stitched together, the db mouse gained weight, whereas the ob lost its appetite and eventually starved to death. From such experiments, Coleman deduced that the obese mouse must be lacking a so-called “satiety factor” that controls food consumption. Also, the diabetes mouse is unable to properly respond to this “satiety factor,” increasing its appetite.

Flash forward to Rockefeller University in New York, in 1994. Using positional cloning, Friedman and his team identified the mutation responsible for the ob mouse, and named the gene “leptin,” from the Greek word for “thin.” Friedman had put a name to Coleman’s “satiety factor.”

Leptin is a hormone secreted from fat tissues in the body and its function is to control food intake. This hormone also “maintains weight within a range, keeping the organism from being too heavy or too thin,” said Friedman.

Leptin travels to the hypothalamus, telling the brain there is enough fat being stored. This in turn rewires the neural circuitry of the brain to inhibit feeding and to reduce hunger.

While some obese individuals respond well to leptin therapy, most actually have high levels of leptin in their bodies. However, these individuals are unable to put the leptin to use, so the brain signal to inhibit feeding is never created.

“Most obesity is a result of leptin resistance,” Friedman explained.

Drug companies are now targeting the neural transmitter that controls feeding, hoping to design a therapy for obese individuals. But perhaps the most significant contribution of Coleman and Friedman’s work on leptin is to change public perceptions of obesity.

“It establishes there is in fact a powerful biological basis for obesity,” Friedman concluded.

-Mandy Lo

Shhh! (What the marauding virus said to its host’s mRNA.)

To stop a dangerous message, kill the messengers-or silence them, at least.

That is the rough idea behind RNA interference (RNAi), a cell process that can be used to shut down, or “silence,” the effects of a gene. The term was coined by Drs. Andrew Fire, of Stanford University, Craig Mello, of the University of Massachusetts, and others, who first described it in a brief Nature paper in 1988.

Fire and Mello’s work shed new light on the way the immune system works, and may make possible a new class of drugs. These would fix problems that stem from DNA, without causing changes or damage to the DNA itself.

For if the double-stranded DNA contains the master blue print for life, then RNA, its single-stranded kin, is its molecular agent that carries out these instructions. One important player is so-called messenger RNA (mRNA), which carries the instructions for producing proteins-what living cells need-that they gleaned from the DNA master plan.

Fire and Mello figured out how to use an odd sort of RNA, one that is double-stranded, like DNA, to interfere with the workings of mRNA. They worked with Caenorhabditis elegans, a simple kind of worm, and a favourite among molecular geneticists, who like to tinker with its genes.

Double-stranded RNA enters the cell, and gets sliced down the middle by a type of molecule called (appropriately) DICER. Fire explained why the cell’s enzymes chop incoming RNA into such short ribbons. To identify a virus, you only need recognize a small part of it, which cannot cause harm on its own.

The single-stranded RNA gets chopped into even shorter pieces, and makes its way into the nucleus. Nonetheless, if one of the chopped-up pieces ends up as the mirror image of a piece of mRNA in the nucleus, the two of them lock together. The mRNA is disabled. No protein is produced. The gene responsible for producing that protein is effectively silenced.

Some types of viruses use RNAi to fight a cell’s anti-viral mechanisms. If the virus can block the production of proteins designed to fight it, victory is assured. So organisms and viruses are locked in an eternal arms race. One seeks to interfere with the workings of its host’s mRNA, while the other tries to throw a spanner into the invading RNA’s works.

-Mike Ghenu