At a conference in Colorado in April 2007 Professor Jaenisch stood up to give his presentation and announced that he had repeated Yamanaka’s experiments. They worked. Yamanaka was right. You could make iPS cells by introducing just four genes into a differentiated cell. The effect on the audience was dramatic. The atmosphere was like one of those great moments in old movies where the jury delivers its verdict and all the hacks dash off to call the editor.
Rudolf Jaenisch was gracious – he freely conceded that he had carried out the experiments because he just knew that Yamanaka couldn’t be right. The field went crazy after that. First, the really big labs involved in stem cell research started using Yamanaka’s technique, refining and improving it so it worked more efficiently. Within a couple of years even labs that had never cultured a single ES cell were generating iPS cells from tissues and donors they were interested in. Papers on iPS cells are now published every week of the year. The technique has been adapted for direct conversion of human fibroblasts into human neuronal cells without having to create iPS cells first[11]. This is equivalent to rolling a ball halfway up Waddington’s epigenetic landscape and then back down into a different trough.
It’s hard not to wonder if it was frustrating for Shinya Yamanaka that nobody else seemed to take up his work until the American laboratory showed that he was right. He shared the 2009 Lasker Prize with John Gurdon so maybe he’s not really all that concerned. His reputation is now assured.
If all we read is the scientific literature, then the narrative for this story is quite inspiring and fairly straightforward. But there’s another source of information, and that’s the patent landscape, which typically doesn’t emerge from the mist until some time after the papers in the peer-reviewed journals. Once the patent applications in this field started appearing, a somewhat more complicated tale began to unfold. It takes a while for this to happen, because patents remain confidential for the first year to eighteen months after they are submitted to the patent offices. This is to protect the interests of the inventors, as this period of grace gives them time to get on with work on confidential areas without declaring to the world what they’ve invented. The important thing to realise is that both Yamanaka and Jaenisch have filed patents on their research into controlling cell fate. Both of these patent applications have been granted and it is likely that cases will go to court to test who can really get protection for what. And the odd thing, given that Yamanaka published first, is the fact that Jaenisch filed a patent on this field before him.
How could that be? It’s partly because a patent application can be quite speculative. The applicant doesn’t have to have proof of every single thing that they claim. They can use the grace period to try to obtain some proof to support their assertions from the original claim. In US legal terms Shinya Yamanaka’s patent dates from 13 December 2005 and covers the work described a few paragraphs ago – how to take a somatic cell and use the four factors – Oct4, Sox2, Klf4 and c-Myc – to turn it into a pluripotent cell. Rudolf Jaenisch’s patent potentially could have a legal first date of 26 November 2003. It contains a number of technical aspects and it makes claims around expressing a pluripotency gene in a somatic cell. One of the genes it suggests is Oct4. Oct4 had been known for some time to be vital for the pluripotent state, after all, that’s one of the reasons why Yamanaka had included it in his original reprogramming experiments. The legal arguments around these patents are likely to run and run.
But why did these labs, run by fabulous and highly creative scientists, file these patents in the first place? Theoretically, a patent allows the holder access to an exclusive means of doing something. However, in academic circles nobody ever tries to stop an academic scientist in another lab from running a basic science experiment. What the patent is really for is to make sure that the original inventor makes money out of their good idea, instead of other people cashing in on their inventiveness.
The most profitable patents of all in biology tend to be things that can be used to treat disease in people, or that help researchers to develop new treatments faster. And that’s why there is going to be such a battle over the Jaenisch and Yamanaka patents. The courts may decide that every time someone makes iPS cells, money will have to be paid to the researchers and institutions who own the original ideas. If companies sell iPS cells that they make, and have to give a percentage of the income back to the patent holders, the potential returns could be substantial. It’s worth looking at why these cells are viewed as potentially so valuable in monetary terms.
Let’s take just one disease, type 1 diabetes. This typically starts in childhood when certain cells in the pancreas (the delightfully named beta cells in the Islets of Langerhans) are destroyed through processes that aren’t yet clear. Once lost, these cells never grow back and as a consequence the patient is no longer able to produce the hormone insulin. Without insulin it’s impossible to control blood sugar levels and the consequences of this are potentially catastrophic. Until we found ways of extracting insulin from pigs and administering it to patients, children and young adults routinely died as a result of diabetes. Even now, when we can administer insulin relatively easily (normally an artificially synthesised human form), there are a lot of drawbacks. Patients have to monitor their blood sugar levels multiple times a day and alter their insulin dose and food intake to try and stay within certain boundaries. It’s hard to do this consistently over many years, especially for a teenager. How many adolescents are motivated by things that might go wrong when they are 40? Long-term type 1 diabetics are prone to a vast range of complications, including loss of vision, poor circulation that can lead to amputations, and kidney disease.
It would be great if, instead of injecting insulin every day, diabetics could just receive new beta cells. The patient could then produce their own insulin once more. The body’s own internal mechanisms are usually really good at controlling blood sugar levels so most of the complications would probably be avoided. The problem is that there are no cells in the body that are able to create beta cells (they are at the bottom of one of Waddington’s troughs) so we would need to use either a pancreas transplant or perhaps change some human ES cells into beta cells and put those into the patient.
There are two big problems in doing this. The first is that donor materials (either ES cells or a whole pancreas) are in short supply so there’s nowhere near enough to supply all the diabetics. But even if there were enough, there’s still the problem that they won’t be the same as the patient’s tissues. The patient’s immune system will recognise them as foreign and try to reject them. The person might be able to come off insulin but would probably need to be on immuno-suppressive drugs all their life. This is not really that much of a trade-off, as these drugs have a range of pretty awful side-effects.
iPS cells suddenly create a new way forwards. Take a small scraping of skin cells from our patient, whom we shall call Freddy. Grow these cells in culture until we have enough to work with (this is pretty easy). Use the four Yamanaka factors to create a large number of iPS cells, treat these in the lab to turn them into beta cells and put them back into the patient. There will be no immune rejection because Freddy will just be receiving Freddy cells. Recently, researchers have shown they can do exactly this in mouse models of diabetes[12].