Tip of the iceberg

How stem cells will reverse the devastating diseases of our time

“When I was first exposed to stem cells, I found it fascinating that they are capable of changing into any type of cells,” says Dr. Andras Nagy, a world-renowned stem cell biologist and the Shawn Kimel Research Scientist at the LTRI. “I wanted to know how far we can push these stem cells. Can we push them to make a whole mouse — not just different types of cells but the whole organism? There’s still something very fascinating to me about these cells, even after more than 20 years.”

Photos of Drs. Rogers & Nagy

It’s little surprise that stem cells continue to be a source of wonder: Pluripotent stem cells can be obtained from any adult human and have the ability to become any type of cell in the body. They thus hold unrivaled promise for treating a wide range of diseases by using a patient’s own cells to replace damaged or deficient cells in the heart, kidney, pancreas and elsewhere.
Stem cell research is both a relatively young field and a rapidly evolving one. Scientists have known about the existence of stem cells for fewer than 60 years, and the technology to reprogram mature adult cells, such as skin cells, into induced pluripotent stem cells (iPS cells) that can become any type of cell, has been available for less than a decade.

Since joining the LTRI in 1989 to work in one of the world’s first laboratories studying stem cells in mouse models, Dr. Nagy has emerged as an international leader in the field and has positioned Canada at the vanguard of stem cell research. He was the first scientist in Canada to establish human embryonic stem cell lines and, in 2009, he discovered a more efficient way to reprogram adult cells to create iPS cells without using viruses, a discovery that set the stage for the real-world possibility of using stem-cell-based therapies to treat human disease.

The tipping point: Project Grandiose

But until very recently, scientists still understood little about how adult cells could be reprogrammed — one set of genes turned off and a different set turned on, activating a whole new cell function and converting, say, a skin cell into a kidney cell.

Photos of Drs. Nagy & Rogers

“It’s amazing that stem cells are able to do this,” says Dr. Ian Rogers, an associate member of the LTRI whose lab is developing stem cell-based treatments for dangerous complications of diabetes, such as non-healing wounds and chronic kidney disease.

Most recently, Dr. Nagy spearheaded an international collaborative study named Project Grandiose that brought together nearly 50 colleagues — including Dr. Rogers and others at LTRI — from four countries to study different components of the reprogramming process, including the cell’s proteins and RNA, as well as functional changes that occur in the cell during reprogramming.

Last year, Project Grandiose culminated in two major stem cell research breakthroughs: the discovery of F-class cells, a new class of stem cells that are easier and faster to grow and can be artificially engineered in very large quantities, and an encyclopedic database documenting every step of the cell reprogramming process in unprecedented detail. These discoveries will accelerate drug screening efforts and bring us closer to developing stem cell-based therapies for diseases and conditions as varied as spinal cord injury, stroke, diabetes and Parkinson’s disease, among others.

Photo of Dr. Nagy & Rogers

“This is just the tip of the iceberg,” says Dr. Nagy. “With cell-based therapies, we will be able to treat and one day cure devastating diseases that are currently incurable. Our work is basic research, but we are always thinking about how we can have an impact on treating disease.”
If anything, the latest discovery has only increased the urgency of Dr. Nagy’s work. His lab is already putting the data from Project Grandiose to use to overcome the most significant remaining barrier to using iPS cells to develop cell-based therapies to treat human diseases: safety.

Applying our new-found understanding of the reprogramming process, Dr. Nagy is investigating the genetic mutations that can occur during this process, resulting in cell damage that can make the cell unpredictable, even potentially cancerous. His lab is working to create a fail-safe mechanism that can “turn off” or eliminate such cells.

“We are working furiously to solve this problem,” Dr. Nagy says. “The data is promising.”

Using stem cells to create healthy organs

Dr. Rogers is also drawing on the resources developed through Project Grandiose to create new, functional, transplantable organs that can be grown using a patient’s own cells to replace a damaged organ — an innovation that will revolutionize organ transplantation by overcoming common challenges such as the lack of a donor match and the need for patients to take immune system-suppressing medications for the rest of their lives. 
His work focuses on developing kidneys that would one day be able to repair or replace those damaged by type 2 diabetes. The process involves removing all the cells from an existing kidney, which leaves the organ’s protein matrix, or structure, intact — “kind of like chicken wire,” Dr. Rogers explains. New cells are then grown and loaded into the new kidney, repopulating it with live, functioning cells that are a perfect match for the patient, making the kidney work like new again.

“The advantage of growing kidneys is that you have the time you need to intervene,” Dr. Rogers says. “People with kidney disease can generally survive with dialysis for a period of time while the organ is growing. There are also a lot of kidneys available for transplant that are too old or damaged or not a match for a particular patient.”

Dr. Rogers has already developed cell-based therapies that effectively use a patient’s own cells to treat non-healing skin wounds, a common affliction among diabetics that can lead to gangrene and, ultimately, amputation. The hurdles to getting these and other therapies to patients, he says, are often more commercial than scientific in nature.

“We forget that great science is not enough to get a product to market; it has to be affordable,” says Dr. Rogers. “That’s why having a deep understanding of the reprogramming process that allows us to make stem cells more efficiently — and thus more affordably — is so critical.”

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Mount Sinai Hospital Foundation

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