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The anatomy of a major discovery


50 researchers, 4 countries, 4 years and over 300 million stem cells: THE ANATOMY OF A MAJOR DISCOVERY

For the first time ever, scientists have access to a high definition view of the molecular events of reprogramming, which is the process of converting adult body cells to stem cells. In five Nature and Nature Communications papers concurrently published today, researchers led by Dr. Andras Nagy at the Lunenfeld-Tanenbaum Research Institute are the first to map out the major biological checkpoints of reprogramming to stem cells, in terms of which combinations of genes and proteins are associated with each step, making it the encyclopedia for this biological process.

The new research papers, which are the brainchild of Dr. Nagy, the renowned geneticist who previously established Canada's first human embryonic stem cell lines, brings us closer to stem cell-based therapies for diseases and conditions such as spinal cord injury, stroke, macular degeneration, diabetes and Parkinson’s disease.

Dr. Peter Tongue, Dr. Ian Rogers, Dr. Samer Hussein, Dr. Andras Nagy, Dr. Mira Puri
Dr. Peter Tongue, Dr. Ian Rogers, Dr. Samer Hussein, Dr. Andras Nagy, Dr. Mira Puri

The new data are already being used by Dr. Ian Rogers’ and Dr. Andras Nagy’s labs at the research institute, where their teams are developing stem cell based treatments for chronic kidney disease. Just imagine taking an old, diseased or non-matching kidney, removing all of its cells, and then repopulating the organ with patient matched stem cells that will make the kidney work like new again.

How it all started…

In 2006, Dr. Shinya Yamanaka discovered that by turning ‘on’ four embryonic genes which are usually turned ‘off’ in adult cells, adult cells can be changed back into stem cells that are similar to embryonic-like stem cells. He won the Nobel Prize in Medicine in 2012 for this discovery, and these new cells were named induced pluripotent stem cells, or iPS cells, for short. These stem cells can be used to create any desired cell type, a property that has tremendous potential to treat devastating and currently incurable disorders.

Until now the molecular details of how skin cells can convert to stem cells was poorly understood – and this is what the group of researchers led by Dr. Nagy set out to study. If this can be understood better, then scientists can harness the power of stem cells to build better cell replacement therapies and drugs in regenerative medicine.

Backed by generous competitive funding and philanthropic efforts of the Ontario government, industry partners and private sector organizations, Dr. Nagy recruited a team of stem cell experts from Canada, South Korea, Australia and the Netherlands. His team at the LTRI, consisting of Drs. Mira Puri, Samer Hussein and Peter Tonge, in addition to Dr. Ian Rogers’ group, collaborated with researchers from the University of Toronto, the John Curtin School of Medical Research in Australia, the University of Queensland in Australia, Utrecht University in the Netherlands, and Seoul National University in Korea.


The various groups studied different components of the reprogramming process, such as proteins, the small and long RNA of cells, and overall epigenetic changes of the cell during reprogramming, but nearly all 50 researchers came together to capture and document the genetic and molecular activities throughout the process of reprogramming.

“It is an enormously enlightening feeling that a single scientific question was able to transcend geographical distances, time zones, international borders and cultural differences. Each of the close to 50 scientists with unique expertise contributed to a unified product which none of us as individuals could even get close to,” says Dr. Andras Nagy.

With the highly detailed molecular profile that has now been built, scientists will be able to understand the fate of reprogrammed stem cells, and their behaviour, better than ever before.

How did they do it?

The Nagy group had previously developed a system where they could easily switch on and off the four Yamanaka factors in skin cells. They collected these cells at regular intervals during their 21-day conversion from skin cell to embryonic-like stem cells.

The team examined DNA for the chemical marks that control changes in gene expression, as well as changes in the type and quantity of proteins produced. They noted that the biggest changes in the cells happened between day 0 and 2, mainly to the protein content.

It was during these studies that the team stumbled upon a new class of stem cells, which they termed F-class cells. These stem cells are easier and faster to grow compared to embryonic-like stem cells, and because they have accelerated growth, the new F-class cells can be artificially engineered in very large quantities, which will speed up drug screening efforts and disease modeling for different illnesses.

“We’re able to mimic any genetic disease,” says Dr. Samer Hussein, a post-doctoral fellow in the Nagy lab, and a McEwen Centre Fellowship recipient. “With the large number of stem cells that we can generate given our new findings, one of the immediate benefits will be drug screening. We’ll be able to test drug therapies for diseases like Multiple Sclerosis and Alzheimer’s.”

What they found

  • defined the molecular differences between two alternative stem cell types, F-Class and iPS
  • documented the molecular signaling pathways that are active during the conversion of skin cell to early reprogramming cells, and during the transition from late reprogramming cells to pluripotency (stem cell stage)
  • identified new and uncharacterized RNA molecules that are now being studied worldwide
  • found, for the first time, that micro-RNAs are regulated in a manner that is similar to other RNAs in the cell, but this had never been documented before in a biological process
  • highlighted important biomarkers in the reprogramming process (one of these markers distinguishes whether cells are on the path to becoming F-Class stem cells, or iPS cells).

What does it all mean?

The new research, which lives in the form of an online database and is available to the entire world, will allow scientists to access data on molecular and cellular events that occur during reprogramming without having to carry out their own extensive and costly experiments.  This will fast track the translation from bench to bedside.

Information within the databases will provide insight into the production and regenerative medicine potential of induced pluripotent stem cells. One of the discoveries made by the Nagy group was that of alternative stem cells, such as the F-class cells. Further interrogation of the database may reveal other classes of stem cells that will have therapeutic potential.

Being able to produce iPS cells from patients will mitigate the need for having to find a suitable donor. Even in the case of a genetic-based disease, the genetic ‘mistake’ that causes the disease can be corrected in iPS cells. The repaired cells can then be generated in a culture dish, and transplanted back into the patient. Since the iPS cells were derived from the patient, these therapeutic cells can, in theory, by transplanted without the risk of rejection, as is typically the case for organ and tissue transplants from donors.

“Having a deep understanding of the reprogramming process allows us to make stem cells more efficiently, which means they will be more affordable,” says Dr. Ian Rogers. “Many therapies die because of cost issues. We forget that great science is not enough to get a product to market; patients have to be able to afford it.” Dr. Rogers also notes that the collaborative effort generated information about reprogramming that was unknown before.

“The research we have published presents so much more opportunity to study and use a novel pluripotent cell type in biology, medical research and future medicine,” says Dr. Peter Tonge, a former Scientific Associate in the Nagy lab who worked with Dr. Nagy for six years. Currently, he is a Scientific Associate at the University Health Network.

Dr. Andras Nagy adds, “This is just the tip of the iceberg.”


What are stem cells

Induced pluripotent stem cells

Embryonic stem cells

iPS cell and disease research

Discovery of F-class stem cells

A resource for the research community: STEMFORMATICS.COM


By Sandeep Dhaliwal

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