When Dr. Andras Nagy, a Senior Scientist at Sinai Health System’s Lunenfeld-Tanenbaum Research Institute in Toronto, set out to catalogue molecular events behind reprogramming — a process of making stem cells in a dish — he did not expect to uncover a new kind of stem cell. But not everyone was enchanted, and Nagy had to fight for the cell’s right to exist.
The newly discovered stem cell was cheaper to grow and could potentially overshadow the currently available cells used for transplants that could one day treat degenerative diseases. You’d think that the biomedical community would have unanimously welcomed the finding with open arms. Not so. Critics argued that the new cell was an artificial product of the reprogramming process and, as such, had no value in biomedical research, prompting a debate over what’s “natural” when it comes to cells grown in a dish.
During cell reprogramming, an ordinary cell, such as a skin cell, is turned into a stem cell capable of producing all other cell types. This process, while opening the door for cell therapy that is free of the controversial use of human embryos that naturally abound in stem cells, remains poorly understood.
To shed light on what happens during reprogramming, Nagy’s team charted a road map of molecular events that turn a skin cell into a stem cell, also called induced pluripotent stem cell (iPSC), which behaves much like a stem cell from an embryo. The study – aptly named Project Grandiose – generated an unprecedented amount of data and concluded with five papers published simultaneously in December 2014, two in Nature, and three in Nature Communications, with two more studies following in 2015.
It was while collecting the cells for Project Grandiose that Nagy’s team made the unexpected discovery. There it was, lurking in a dish, a new kind of cell. Unlike the smooth appearance of the familiar iPSC, the new cells looked fuzzy, inspiring a somewhat less than poetic name: the F-class cells. To be fair, these fuzzy monsters weren’t totally unknown in the field. “People had seen these cells before, but they thought they were artifacts of reprogramming. They thought the cells were garbage and people would discard them,” said Nagy in 2014. Nagy decided to keep the cells and study them side-by-side with the classic iPSC.
To reprogram cells, scientists insert four genes known as Yamanaka factors. These are named after Dr. Shinya Yamanaka who discovered the process that revolutionized stem cell biology and earned him the Nobel Prize in 2012. Switching on the Yamanaka factors forces the cells to undergo a profound state change. Like a computer rebooting after a crash, thousands of genes are turned on or off in order to run a new genetic program, which will take the cell to the new pluripotent, or stem-cell-like, state.
Both the iPSCs and the F-class cells started off as skin cells taken from a mouse embryo. But instead of muting the Yamanaka factors after eight days as is usually done for the iPSCs, the researchers left the reprogramming genes on in some dishes for longer – and the fuzzy cells appeared.
It transpired that the sustained activity of Yamanaka factors drove the F-class cells along a distinct route to becoming stem cells. Some typical stem cell genes were switched off, whereas others were ramped up compared to the iPSCs. Despite the differences, they behaved as true stem cells by being able to turn into all other cell types.
But it was the fuzzy cells’ ability to grow faster than their old-school relatives that made them stand out. They were cheaper too, thriving in relatively simple conditions in the lab. This meant that if human F-class cells could also be established, they could potentially cut both the time and cost it takes to grow billions of cells that would be required for drug discovery and therapy.
Despite the compelling practical advantages of the new cells, Nagy’s discovery was greeted with mixed feelings. According to Nagy, one expert who was judging whether or not the study should be published dismissed the finding as “rubbish,” arguing that the F-class cells were an artificial offshoot of the experiment, caused by Yamanaka factors gone wild, and therefore had no place in biomedical research.
“Some scientists have a paranoia trying to show that what we are creating is the same as what naturally occurs in our bodies. But what’s natural? Everything that we have created, including embryonic stem cells, is just as artificial as our F-class cells,” says Nagy. Despite scientists’ best efforts to imitate the body’s environment, tweaking the nutrients, growth factors or oxygen until they’re just right for growing cells and tissues in the lab, these conditions are man-made and, according to Nagy, could clearly be considered artificial.
“Our F-class cells are this ugly duckling – yes they are totally artificial, but they have a value. They are cheaper to grow and are amenable for industrial-scale production,” says Nagy, who won the argument in the end and published the discovery.
Thanks to advances in synthetic biology, we already have microorganisms that produce all kinds of useful things, such as drugs, biofuels or plastic. The growing ease of genetically engineering mammalian cells heralds a new era of “designer cells,” in which entire genetic circuits can be assembled to create features unlike anything that exists in our bodies.
An early example comes from Switzerland where researchers have created cells that sense inflammation in the blood and release anti-inflammatory molecules, staving off gout and psoriasis in mice. If these principles can be applied to humans, future therapies, rather than resting on mere cell replacement, may involve engineered cells that actively fight disease.
As his team is working to establish F-class cells in the human system, Nagy sees designer stem cells as the future of regenerative medicine.
“We need to disconnect our minds from our own cells, and start making cells with new properties that are better than our own cells. That’s where the breakthrough is going to happen,” says Nagy.
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