Â鶹´«Ã½É«ÇéƬ

ASBMB Annual Meeting

Understanding cellular function to understand life

Gabriela Contreras
By Gabriela Contreras
March 5, 2021

When Geoffrey Hesketh was growing up in Canada, he loved sciences and math and wanted to be a medical doctor. He became curious about molecular mechanisms after he started volunteering in a biochemistry lab in his second undergraduate year at Queen's University, and he realized that his huge curiosity would be more satisfied working as a scientist than as a physician.

Hesketh-445x450.jpg
Geoffrey Hesketh

Since then, Hesketh has wanted to understand molecular processes, especially those that have evolved for billions of years but that we still are far from understanding, such as cellular nutrient uptake. "Experimentally unravelling a previously obscure or unknown biological function is the ultimate scientific achievement," he said.

Now a postdoctoral fellow in Anne-Claude Gingras' group at the Lunenfeld–Tanenbaum Research Institute of Mount Sinai Hospital in Toronto, Hesketh earned a Ph.D. in biological chemistry at Johns Hopkins School of Medicine in Baltimore and then did a postdoc at the Cambridge Institute for Medical Research.

Hesketh is interested in cellular membrane trafficking and signal transduction. "If you are understanding cell function at the molecular level, you understand life," he said.

Using advanced mass spectrometry and cell biology tools, he studies the molecular mechanisms by which lysosomes control cellular nutrient biology. In nutrient signaling, mechanistic target of rapamycin complex 1, or mTORC1, plays a key role.

"Life is largely driven by the flow of key elements — carbon, hydrogen, nitrogen, oxygen, phosphorus, and sulfur — in different chemical states, from organism to organism," he said.

Hesketh is fascinated by how mTORC1 is fundamental to life, participating in the sensing of the key elements, synthesis and degradation of macromolecules.

Many human diseases originate in cellular dysfunction, so Hesketh believes understanding cellular processes is the way to understand disease. Therefore, as a cellular biologist, he is pursuing his childhood interest in medicine and human diseases.

There's more than one way to activate this protein

Amino acids, sensed by the cell, can be derived through lysosomal degradation of external proteins or via amino acids acquired exogenously through cell surface transporters by macropinocytosis. Mechanistic target of rapamycin complex 1, or mTORC1, is activated by both these sources of amino acids, and mTORC1 function is regulated on the surface of lysosomal system organelles.

Exogenous amino acids are sensed by a mechanism dependent on the Rag guanosine triphosphatases, or GTPases, that control the mTORC activation. Geoffrey Hesketh and collaborators at the Lunenfeld–Tanenbaum Research Institute have demonstrated that lysosome-derived amino acids activate mTORC1 through a Rag GTPase-independent pathway. They have shown that both sources of amino acids activate mTORC1 by two different pathways. Using proximity-dependent biotinylation, known as BioID, and mass spectrometry for protein identification, they designed organelle sensors with which they showed the surface proteomes of late endosomes and lysosomes.

In highly lethal Ras-driven cancers, researchers know that macropinocytosis and lysosomal degradation of external proteins fuel cancer growth, but they do not yet know the mechanisms behind these processes. Hesketh's research results may lead to mechanistic insight into how lysosome-derived nutrients fuel the growth of Ras-driven cancers.

Enjoy reading ASBMB Today?

Become a member to receive the print edition four times a year and the digital edition weekly.

Learn more
Gabriela Contreras
Gabriela Contreras

Gabriela Contreras earned her Ph.D. in biology at Heidelberg University.

Get the latest from ASBMB Today

Enter your email address, and we’ll send you a weekly email with recent articles, interviews and more.

Latest in People

People highlights or most popular articles

Elucidating how chemotherapy induces neurotoxicity
Award

Elucidating how chemotherapy induces neurotoxicity

Dec. 2, 2024

Andre Nussenzweig will receive the Bert and Natalie Vallee Award at the 2025 ASBMB Annual Meeting, April 12–15 in Chicago.

ASBMB committees welcome new members
Announcement

ASBMB committees welcome new members

Nov. 29, 2024

Committee members serve terms of two to five years, and a number of new members have joined. We also thank those whose terms have ended.

Curiosity turned a dietitian into a lipid scientist
Award

Curiosity turned a dietitian into a lipid scientist

Nov. 27, 2024

Judy Storch will receive the Avanti Award in Lipids at the 2025 ASBMB Annual Meeting, April 12–15 in Chicago.

From receptor research to cancer drug development: The impact of RTKs
Award

From receptor research to cancer drug development: The impact of RTKs

Nov. 26, 2024

Joseph Schlessinger will receive the ASBMB Herbert Tabor Research Award at the 2025 ASBMB Annual meeting, April 12–15 in Chicago.

Awards for Alrubaye and Dutta; Strochlic named ass't dean
Member News

Awards for Alrubaye and Dutta; Strochlic named ass't dean

Nov. 25, 2024

PSA presents Early Achievement Award for Teaching to Adnan Alrubaye. ASIP honors Anindya Dutta with the Rous–Whipple Award. Drexel names Todd Strochlic assistant dean of curricular integration.

In memoriam: Arnis Kuksis
In Memoriam

In memoriam: Arnis Kuksis

Nov. 25, 2024

He was a professor emeritus at the University of Toronto who studied the complex mechanisms dictating lipid metabolism and an ASBMB member for more than 40 years.