McGill Biochemistry Professor Nahum Sonenberg likes asking simple questions. He believes that every problem can be broken down into pieces and put together like a puzzle to answer a bigger issue.
“Always ask a simple question to get a simple answer,” Sonenberg said. “If you […] want to look at the mechanism by which cancer kills cells, well, that’s too vague.”
Sonenberg speaks deliberately, and at first, slowly. As his thoughts come together, however, they seem to bubble with excitement and come quickly tumbling forward, like the crest of a wave crashing ashore. His desk reflects this excitement. It is cluttered with papers, letters from Universities around the world, and piles of books. His office is lined with bookcases, filled with binders of information about the topic he knows best: Protein translation regulation.
“Always ask a simple question to get a simple answer,” Soneberg said. “If you […] want to look at the mechanism by which cancer kills cells, well, that’s too vague.”
“I started [my PhD] on something that I’m still working on,” said Sonenberg. “Ribosomes.”
Ribosomes are the very large and very complex molecular machines that make proteins. In the body, proteins are responsible for a variety of tasks, like transporting molecules, breaking chemical bonds, and building new compounds. To make proteins, ribosomes rely on a molecule known as mRNA for information. mRNA is a macromolecule synthesized using DNA as a template. This ‘reading’ of mRNA to make proteins is known as translation. The process of DNA to mRNA to protein is so fundamental to the study of molecular biology, it is called the “Central Dogma.”
The basis for understanding much of human disease, and in particular, cancer, relies on understanding defects in this process; however, in order to spot the anomalies, a person must first know what is normally there. Consequently, for years, researchers have been examining every step of this process in the hopes of understanding it fully to treat human diseases.
The bits and parts of these reactions were just beginning to be discovered when Sonenberg was born in 1946. His parents had been Polish textile workers, who, during the second world war, had sought refuge in Russia. After the war, they migrated to Germany to find a temporary home.
“I was born in [Wetzlar, Germany],” Sonenberg said. “My parents [had] come from Russia [to a] displaced persons camp [in Germany]. In ’49, we immigrated to Israel on a ship from Marseille.”
Sonenbergs’ earliest memories are from Israel. He recalls going to the beach in Jaffa with his parents, feeling the sun on his face, and swimming in the Mediterranean. Here is also where he would begin his life as a scientist.
“The one thing that [my parents] always told me was that you have to get an education,” Sonenberg said. “They weren’t educated in Poland, and so, [for them], education was the most important [thing].”
After finishing high school Sonenberg spent two years in the Israeli Armed Forces as part of Israel’s mandatory conscription policy, and throughout his studies, his experience with the army was never forgotten.
“One thing that […] you learn from the army is discipline,” stated Sonenberg. “If you have to study something, you don’t do anything [else].”
Sonenberg then completed a master’s degree in Microbiology and Immunology at Tel Aviv University, and later completed a PhD at the Weizmann Institute of Science in Rehovot, Israel.
“At Tel Aviv, I had a fantastic teacher in Biochemistry that inspired me so much that I went to do my PhD in Biochemistry at the Weizmann Institute [of Science],” Sonenberg explained.
His PhD was focused on the enzymatic activity protein peptidyl transferase, found in the ribosome. Peptidyl transferase is responsible for connecting amino acids—which are the building blocks of a protein—together using a special kind of linkage, known as a peptide bond. When Sonenberg was doing his PhD, however, much of this was unknown.
“My project was to identify the peptidyl transferase—the protein that make the peptide bond,” Sonenberg explained. “I was a little naïve, I thought I can solve this—I can find the protein.”
“Whatever experiment you’re [doing], you have to be persistent,” said Sonenberg. “Rule number one is ‘Do not despair.’”
Ultimately, the structure and mechanism of the ribosome was solved via X-ray crystallography rather than biochemical assays, and in 2009, the Nobel Prize in Chemistry was awarded to Venkatraman Ramakrishnan, Thomas Steitz, and Ada Yonath for their discovery of the structure of the ribosome.
“My biggest fear was that I [wouldn’t] be successful,” Sonenberg said. “Experiments don’t always work.”
But Sonenberg overcame this fear by doing what he knew how to do best—persevering.
“Whatever experiment you’re [doing], you have to be persistent,” Sonenberg said. “Rule number one is ‘Do not despair.’”
Over the years, Sonenberg’s habit for giving short, motivational, and practical tips to survive in the lab evolved into a loose set of rules, known as ‘The Wisdom of Nahum for the New Millennium.’ Partially as a joke, a student in his lab wrote up the set of commandments officially.
“Rule number six: Trust no one: You have to see it with our own eyes. Rule number ten: You can’t be ‘first and wrong’ or ‘second and right.’ Always be first and right. Rule number nine: Ask simple questions to obtain simple answers,” some of the ‘commandments’ read.
Rule number nine is what led Sonenberg to discover the eIF4E protein.
“The simple question was: There’s a cap structure on mRNA, what’s the protein that binds to it?” Sonenberg said.
In 1979, Sonenberg answered that question while working at the Roche Institute of Molecular Biology. This was the greatest discovery of his life.
“The simple question was: There’s a cap structure on mRNA, what’s the protein that binds to it?” said Sonenberg.
“I discovered the protein called eIF4e—the cap-binding protein,” Sonenberg said. “It turns out that this protein is involved in cancer, so now scientists and companies are devising drugs to fight cancer based on this protein. This protein is [also] involved in autism [….] If it plays a role in a large number of autistic children, [then you] can design a drug. These are all milestones. It’s [really] something [when] other researchers look at [that] and they want to continue and find out all the details and then find drugs that will cure human disease. I am very happy when companies start project based on eIF4E.”
eIF4E plays a critical role in protein translation regulation. It is responsible for directing ribosomes to a part of the mRNA known as the cap structure, and almost all cellular proteins require it for their translation. When problems with eIF4E arise, cells will not translate proteins properly, which can result in many kinds of illnesses, like cancer. Consequently, researchers around the world study eIF4E, and Sonenberg has many collaborators.
“I always look for collaborators because I can’t be an expert in everything,” Sonenberg said.
Ten years ago, the Sonenberg lab began working on brain research, and needed to reach out to those with more expertise in the field. When Sonenberg was initially beginning his studies on eIF4E, his assays were not working and he approached chemistry professor Charles Cantor from Columbia University for help. He has started working on microRNAs, which are heavily being used in the field of genetic engineering, and seeks help from those who understand it best.
This communication between scientists has been vital to the survival of the field. Originally, the study of science was the study of details. To understand singular cellular processes, a scientist would isolate one protein to examine, and then see how it would respond to different stimuli. Today, the approach is very different.
“Everything that we are studying now is system-wide,” Sonenberg said. “We understand a simple problem through the whole system. When we look at things like heart disease, we want to see the effect on every organ in the body.”
Take for example the bacteria in the gut, known as the microbiome. Originally, researchers paid little attention to these bugs; however, over time, scientists began to realize that individuals with different microbiome compositions would respond differently to drugs. In fact, fecal transplants—which would introduce new bacteria and change the stomach bacterial composition—could even induce weight loss. Humans actually have 10 times more bacteria than human cells in their body, and the composition and success of these bacteria can play a crucial role in an individual’s health and well-being. Gut bacteria have even been shown to be linked to autism. Today, there is considerable amount of research being done to understand this field. These types of discoveries take time, luck, and money.
“You have to work very hard and be very passionate in order to succeed in science,” Sonenbeg said. “The message is simple. You have to invest in order to get returns.”
Basic research is the study of natural phenomena in order to simply better understand processes. Unfortunately, this type of research does not always have an immediately obvious profitable end product. Investors and government agencies are reluctant to give money to this type of research because there might not be a return.
“The message is simple. You have to invest in order to get returns.”
“We have to do much more to educate the public and politicians and other decision makers about the enormous value of investing in basic research,” Sonenberg said. “In the end, this will change everything.”
Basic research has led to the discovery things like recombinant DNA technology. Recombinant DNA processes are now used to produce enormous amounts of human insulin, which is indispensable in the treatment of diabetes, and today yields large amounts of profit; however, money and glory do not drive most scientists. It is a careful mixture of altruism, intelligence, and selfishness that pave the path to discovery.
“We don’t do science for awards,” said Sonenberg. “We do science for the sake of science. To find how the body [functions] and how to fight and cure disease and how to better humanity. If you get awards, that’s a bonus.”
There is no doubt that the life of a scientist is as rigorous as the scientific process itself. It requires long days, and even longer nights. But for someone like Sonenberg, the journey has been worth it.
“In the end, when [I] think about this, I would do it all over again,” Sonenberg said. “I had the opportunity to do important things in science. I don’t see it as a sacrifice. It is something I had the privilege to do.”
