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Ever since the first successful transplant was completed in 1954, patients in need of new organs have had to wait – sometimes for years – to receive an organ from either a deceased or, more recently, a living donor.
But what if clinicians could make one for you, potentially out of your own cells, so you wouldn't have to wait? It sounds wild, but it could be a reality in the not-so-distant future thanks to researchers at UHN's Ajmera Transplant Centre who are at the forefront of this groundbreaking organ-building research.
Clinicians there have been trying to find ways to make organs from scratch. It's been a long, painstaking process, but one organ that's seen some significant progress is the kidney, in part because it's the organ in highest demand for transplantation.
According to the Canadian Institute for Health Information (CIHI), as of December 31, 2019, 76 per cent of the 4,352 people waiting for an organ transplant in Canada were waiting for a kidney.
Dr. Markus Selzner, Surgical Director of the Liver Transplant Program and a scientist at the Ajmera Transplant Centre, is working with stem cell researcher Dr. Ian Rogers, who, several years ago, put out what he calls an "audacious" challenge to his lab team to build a kidney.
"There wasn't any technology at the time to suggest this was even possible," he says.
The first step was to figure out how to grow kidney cells, which they did by using what are called induced pluripotent stem cells – stem cells that have been reprogrammed from adult cells and can regenerate to become any kind of cell.
"Now I can take cells from people's skin or urine and put them in a dish and make them into kidney cells," says Dr. Selzner, who is also part of UHN's Sprott Department of Surgery.
Next was figuring out how to take cells in a petri dish and turn them into kidneys – a feat that appeared more feasible after they discovered another researcher had figured out how to strip all the cells from a non-human organ, leaving only the protein framework, called a scaffold, behind. Researchers can then put human cells in this scaffold, where those cells can repopulate.
"The human cells are quite happy sitting on this framework," says Dr. Rogers.
Dr. Selzner explains it this way: "You would have a hybrid kind of kidney, but the portion of it that the recipient's body would touch would be entirely human."
Now the team is fine-tuning the kidney-building process by experimenting with different ways of putting human stem cells into the kidney framework and encouraging them to repopulate in a bioreactor, a chamber that can grow organs under controlled conditions.
So far, they've been able to put two rebuilt kidneys in an
ex vivo organ perfusion system – a device that allows an organ to live outside a human body for several hours – developed by Dr. Selzner. While the rebuilt kidneys only survived for 15 minutes in the
ex vivo system, the process yielded valuable insights.
"It allowed us to ask, 'What went wrong?'" says Dr. Rogers.
Bioengineered kidneys aren't far off. "In five to 10 years, we will have something that can be tested in humans," says Dr. Selzner.
The liver is another organ in high demand, with 610 liver transplants taking place in Canada in 2019 – the second-most out of any organ, according to the CIHI. The process to build a new liver is similar to the kidney, but researchers were one big step behind when they started: they didn't know what cells made up the liver, so they couldn't begin to rebuild it.
"The liver is complicated," says Dr. Ian McGilvray, abdominal transplant surgeon and scientist in the Ajmera Transplant Centre and the Head of Liver and Pancreas Surgery in the Sprott Department of Surgery.
Huge strides were made when, in 2018, Dr. McGilvray, together with Dr. Sonya MacParland, an Ajmera Transplant Centre scientist, published a map of the human liver using a new technology at the time – single-cell RNA sequencing – to look at the individual cells that make up the liver.
"Previously, we were able to map out the average of all the cells in the liver, but we couldn't do it at an individual level," explains Dr. MacParland.
Key to getting this data was a change Dr. McGilvray made about 10 years ago in how surgeons at the Centre do liver transplants so that they now routinely remove an unneeded portion of the liver in order to study it immediately.
Now that they know what cells to grow, another colleague, Ajmera Transplant Centre scientist Dr. Shinichiro Ogawa, is working in the lab to build liver cells out of stem cells. It's a daunting task.
"An individual has 120 billion to 150 billion liver hepatocyte cells, which make up 80 per cent of the liver," says Dr. Ogawa, who is also part of the McEwen Stem Cell Institute at UHN.
The next step is to see if diseased livers in animal models can be fixed using these new healthy liver cells made in the lab.
"If you could infuse cells into the scaffolding and have them stick and regenerate, then you might be able to recreate the liver," explains Dr. McGilvray, who is also working on ways to rebuild a human liver in its entirety.
Growing lungs and tracheae
While kidneys and livers may be the most needed organs, Ajmera Transplant Centre researchers also want to either build or regenerate lungs and tracheae – the latter being the tube that carries air from your throat to your lungs.
Once again, they would take a trachea or lung from non-human samples, get rid of all the cellular material that would cause an immune response and then grow new cells over the existing structure, says Dr. Golnaz Karoubi, scientist at the Ajmera Transplant Centre.
So far, researchers have repopulated a non-human trachea with human cells.
"The lung is more complicated," Dr. Karoubi says. "There are more than 40 different cell types within that organ."
Her main challenge is figuring out how to efficiently get the various cells into the lung structure and encourage them to repopulate in such a way that they create an organ that can perform gas exchange.
To do this, "we're looking at how physical forces, like gravity and movement, affect cellular behaviour," explains Dr. Tom Waddell, a lung transplant surgeon and scientist with the Ajmera Transplant Centre and the Richard and Heather Thomson Chair in Thoracic Translational Research.
"Which genes do they turn on?" Dr. Waddell says. "What chemicals do they secrete? And, to some extent, what shape does the cell adopt?"
Dr. Waddell, who is also part of Sprott Department of Surgery, is working on ways to acquire the cells in the first place, adding that while induced pluripotent stem cell technology is useful, it's expensive.
"I'm looking at taking lung cells and only partially reprogramming them," he says.
Instead of turning cells into stem cells, scientists would harvest lung cells that would stay lung cells.
Another approach is to have what's called universal designer donor cells, where the cell is modified so the immune system doesn't reject it. The ultimate goal is to have a surgically transplantable lung that does not require immunosuppression.
The possibility of made-to-order organs would completely transform patient care for people with organ failure.
"There's a chronic organ shortage, and as a result, regardless of what organ we're talking about, there is significant attrition on the wait list because people die waiting," explains Dr. McGilvray.
"Building organs from a patient's own cells really is the holy grail of transplantation."