New cell synthesis technique makes millions in days

Stem cells are the starting point for all of the cells in the human body and scientists can use to them to replace injured tissues, or to study how certain diseases affect different parts of the body. But it can take a very long time - up to twenty weeks - to turn a stem cell into a mature tissue. Now, scientists at the University of Cambridge and the Wellcome Trust Sanger Institute have reduced that to just a matter of days, thanks to a new technique that can make millions of identical cells at a time.  To find out how, Chris Smith spoke to Cambridge University’s Daniel Ortmann...
Daniel - Essentially we focus on a process called “reprogramming cells” so, essentially, it’s turning one cell type directly into another. So rather than going down this fairly lengthy developmental process, we just convert them directly from, let’s say, a skin cell or, in our case, a stem cell.

Chris - In the old days we used to take a skin cell and turn it back into a stem cell, and then turn the stem cell back into what we wanted to turn it into. What you’re saying is we’re going to short circuit that equation and go from A to B directly, rather than via C?

Daniel - Yeah, exactly. Reprogramming processes are fairly direct because you don’t have to go through these cascades of normal development as it happens in the body.

Chris - Why didn’t scientists do that in the first place then? Why did they go all the way back to stem cells and then turn the stem cells into what they wanted? Why didn’t they do what you’ve now done?

Daniel - People have done similar things before. It’s just that what we have done in our study is rather than putting those genes that control the whole process, putting those randomly into a cell, what we did is we integrated this genetic information in specific locations into the genome - they are called “safe harbours.” In this way, we can ensure that all the cells have the same information, and we can also rapidly turn it on and then switch this programme that’s running into the cell.

Chris - Right. So you embed the reprogramming genetic information into the cell at the get-go, and then you can control what’s turned on, where, and when. So that cell passes all of that genetic information into its offspring so you get a whole clutch of cells that are the same or behave the same way and follow the same instructions?

Daniel - Yes, exactly. So, essentially, we are putting in the information and then it justs sits there until we decide to give it a chemical trigger to then activate those genes, and then the cells rapidly reprogramme and within five or six days they turn into an entirely different cell type.

Chris - When you say there’s a safe harbour, you put in the instructions. You know what the genetic instructions are that turn a skin cell into let’s say a heart cell or something, so you’d put those genes into a specific part of the genome where you know they’re not going to do any damage to the cell putting them in there?

Daniel - Yeah, exactly. There are some defined sites where people studied what are those locations doing? And also, at the same time, those locations are also protected from events like silencing. Usually when you put something…

Chris - What’s that?

Daniel - Something somewhere in the genome it’s very likely that the cell kind of shuts it down so it doesn’t want this strange information to be there and to be read, so it has mechanisms of shutting it off. Whereas when you put in the genomic safe harbours, it’s much less likely that that happens.

Chris - How do we know these cells are safe that you make with this if you wanted to use them therapeutically because, at the end of the day, having enough stem cells or mature tissue cells that can do something has always been a problem? How do you know they’re safe?

Daniel - So you’re talking about cell therapies now?

Chris - Yes.

Daniel -  There are various ways to test whether the cells are safe. Obviously, we can make them in the lab first and then have them there and do all sorts of tests on proliferation and genomic stability to really ensure that the cells would be safe to put into a patient. But, for the more immediate applications, what we can do is we produce all sorts of cell types that are hard to come by from humans like brain cells, heart cells, all those types of cells to make them in a controlled way, in large quantities, so we can use them for drug discovery or screening process within the pharmaceutical industry for example.

Chris - When you say you turn a cell into a muscle cell, how do you know it really is a muscle cell? Because it might look like one but biochemically have you checked that that’s a muscle cell and also epigenetically? Have you looked at the genes which are being turned on and off - is that to all intents and purposes now a muscle cell that you’ve made?

Daniel - What we do is after we turn on those genes, we check other genes that are unrelated to the ones we activated and whether they come up or not, and that gives us an idea of is this programme of being a muscle cell actually activated in those cells?

Chris - It’s got the genetic fingerprint of the muscles and you can be confident in what you’ve got?

Daniel - Exactly. Then you can do also obviously do epigenetic tests, but what we also did was functional tests so we actually gave them the same kind of compounds that make muscle cells contract, for example, in the body. If we add those to the dish and the cells are contracting so, essentially, functionally also they are exactly what we would expect them to be.