Sonenberg: the science of translation

Mark Reynolds | Technically, Nahum Sonenberg's specialty is cancer research. Yet his lab is currently working on projects on everything from virology to obesity and neurology.

Biochemistry professor Nahum Sonenberg
Claudio Calligaris

A scientific Renaissance man? Perhaps, but these seemingly disparate fields are bound together by the biochemistry professor's research on translational control mechanisms.

In a nutshell, Sonenberg studies the process by which the information in our DNA creates the proteins that make up our bodies. To make a protein, messenger RNA (mRNA) binds to our DNA, making a mirror image. The mRNA then binds with amino acids in the cell to create proteins.

"This is called the translation process, because you take a code, which is made of nucleotides, and you make it into a different language, which is proteins," said Sonenberg.

This process of translation has to be accurate and it has to be fast. In biochemical terms it needs to be very tightly controlled: if mRNA makes too much of some proteins, it can lead to diseases like cancer. Not enough of other proteins, and you get diseases like diabetes.

"That's why it's important to know this machinery and how it works. First you want to know the mechanism, and you want to know the components. We think we have most of the components, but we're not sure yet," said Sonenberg.

The extremely basic nature of this work means that there are hundreds of diseases and biological processes that fall under the general purview of his research. He's been at it a long time: as a post-doc 25 years ago, Sonenberg identified a protein (called EA4E) that is over-expressed in cancer cells — up to three to five times more than normal. Other researchers later identified the over-expression of that protein as a cause of cancer.

"Translational research is out to bring that basic research here in the lab, and put it into practice, to improve patient health. The next step is to develop the kinds of drugs that will reduce the amount of this protein or inhibit their activity," said Sonenberg.

Although Sonenberg's deliberate manner of speaking indicates a systematic approach to his work, serendipity has played a large role in his lab's recent work.

An example would be the skinny mouse. In order to investigate the effects of a protein, Sonenberg's team used a "knockout" mouse — one that was manipulated to not express the gene for the protein 4EBP1.

"The surprising thing is that these mice were leaner than the parent mice. So that's very interesting," said Sonenberg.

It turned out that 4EBP1 inhibited the process that turned white fat (which the body stores) into brown fat (which the body burns). For Slim and his knockout siblings, that meant less gain, no pain.

Of course you can't create knockout humans, so Sonenberg's next step was to find a collaborator to create a drug that would inhibit 4EBP1 in humans, and provide a possible treatment for obesity.

It gets even more complicated when you introduce 4EBP2, a related protein that is highly expressed in the hippocampus region of the brain. Researchers have long puzzled over how we store memory, and it looks like 4EBP2 might be key to the process.

"During the process of memory storage, you stimulate the activity of the synapse. So you release neurotransmitters, and you increase translation in the adjacent, post-synaptic junction. This is a hallmark of memory. If you impair this process translation you will impair memory," said Sonenberg, explaining that mice in which this protein had been inhibited showed significant reduction in performance on memory tests.

So with his cancer research leading to obesity research, which is related to memory research —not to mention the groundbreaking work he has done in hepatitis and other virology fields — how does Sonenberg keep on top of it all?

"This poses a great dilemma, because I cannot learn all of this. Just to understand obesity would take two years of reading every day, so of course I cannot be an expert. If you find the right collaborator, you're lucky to do the research."

Of course, Sonenberg has a reputation for working hard. His lab — a large one by Canadian university standards, with 27 students and staff — works late into the night. Sonenberg himself works almost every day of the week, and stays until 7:30 every night. Then he goes home and works some more.

It pays off. Abe Fuks, Dean of Medicine, has nothing but praise for Sonenberg.

"Dr. Sonenberg is one of the finest researchers and scientists in Canada," said Fuks, saying that his research has both basic and clinical value.

"His work is of particular interest to hepatitis, tumour viruses and HIV. In addition to the fundamental science on protein production, his work is especially important in how viruses can cause illnesses in people."

His boss isn't the only one noticing his work. Sonenberg has been nominated for a slew of honours, including being named a Distinguished Investigator of the

Canadian Institute of Health Research, a Howard Hughes International Fellow and a recipient of the Robert L. Noble prize of the National Cancer Institute of Canada.

And although the people in his lab strive to meet his high expectations, they are not without humour. On the lab web page some wag posted a document called "The Wisdom of Nahum." The 12 rules for success include such practical advice as "Always put rubber bands around your Styrofoam boxes." Rule 10 is "You can't be first and wrong or second and right. Always be first and right."

Sonenberg readily concedes he's a competitive person in a competitive field. Private companies have staffs numbering in the hundreds to tackle the same questions he does, and are not bound by the same prerogative to share their data as is a university researcher.

"Either you decide to do less and miss an opportunity, or you try to do the maximum. It's very hard, and you have to be lucky and do all the right things."