Read The Epigenetics Revolution Online
Authors: Nessa Carey
Tags: #Science/Life Sciences/Genetics and Genomics
The Epigenetics Revolution (6 page)
The obvious thing of course would be for someone to repeat Yamanaka’s work and see if they could get the same results. It may seem odd to people working outside science, but there wasn’t an avalanche of labs that wanted to do this. It had taken Shinya Yamanaka and Kazutoshi Takahashi two years to run their experiments, which were time-consuming and required meticulous control of all stages. Labs would also be heavily committed to their existing programmes of research and didn’t necessarily want to be diverted. Additionally, the organisations that fund researchers to carry out specific programmes of work are apt to look a bit askance if a lab head suddenly abandons a programme of agreed research to do something entirely different. This would be particularly damaging if the end result was a load of negative data. Effectively, that meant that only an exceptionally well-funded lab, with the best equipment and a very self-confident head, would even think of ‘wasting time’ repeating someone else’s experiments.
Rudolf Jaenisch from The Whitehead Institute in Cambridge, MA is a colossus in the field of creating genetically engineered animals. Originally from Germany, he has worked in the USA for almost the last 30 years. With curly grey hair and a frankly impressive moustache, he is immediately recognisable at conferences. It was perhaps unsurprising that he was the scientist who took the risk of diverting some of the work in his lab to see if Shinya Yamanaka really had achieved the seemingly impossible. After all, Rudolf Jaenisch is on record stating that, ‘I have done many high risk projects through the years, but I believe that if you have an exciting idea, you must live with the chance of failure and pursue the experiment.’
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
3
. This is equivalent to rolling a ball halfway up Waddington’s epigenetic landscape and then back down into a different trough.
3
. 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.
Follow the money
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.
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.
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
4
.
4
.
It won’t be that simple of course. There are a whole range of technological hurdles to overcome, not least the fact that one of the four Yamanaka factors,
c-Myc
, is known to promote cancer. But in the few years since that key publication in
Cell
, substantial progress has been made in improving the technology so that it is moving ever closer to the clinic. It’s possible to make human iPS cells pretty much as easily as mouse ones and you don’t always need to use
c-Myc
5
. There are ways of creating the cells that take away some of the other worrying safety problems as well. For example, the first methods for creating iPS cells used animal products in the cell culture stages. This is always a worry, because of fears about transmitting weird animal diseases into the human population. But researchers have now found synthetic replacements for these animal products
6
. The whole field of iPS production is getting better all the time. But we’re not over the line yet.
c-Myc
, is known to promote cancer. But in the few years since that key publication in
Cell
, substantial progress has been made in improving the technology so that it is moving ever closer to the clinic. It’s possible to make human iPS cells pretty much as easily as mouse ones and you don’t always need to use
c-Myc
5
. There are ways of creating the cells that take away some of the other worrying safety problems as well. For example, the first methods for creating iPS cells used animal products in the cell culture stages. This is always a worry, because of fears about transmitting weird animal diseases into the human population. But researchers have now found synthetic replacements for these animal products
6
. The whole field of iPS production is getting better all the time. But we’re not over the line yet.
One of the problems commercially is that we don’t yet know what the regulatory authorities will demand by way of safety and supporting data before they let iPS cells be used in humans. Currently, licensing iPS cells for therapeutic use would involve two different areas of medical regulation. This is because we would be giving a patient cells (cell therapy) which had been genetically modified (gene therapy). Regulators are wary particularly because so many of the gene therapy trials that were launched with such enthusiasm in the 1980s and 1990s either had little benefit for the patient or sometimes even terrible and unforeseen consequences, including induction of lethal cancers
7
. The number of potentially costly regulatory hurdles iPS cells will have to get over before they can be given to patients is huge. We might think no investor would put any money into something so potentially risky. Yet invest they do, and that’s because if researchers can get this technology right the return on the investment could be huge.
7
. The number of potentially costly regulatory hurdles iPS cells will have to get over before they can be given to patients is huge. We might think no investor would put any money into something so potentially risky. Yet invest they do, and that’s because if researchers can get this technology right the return on the investment could be huge.
Here’s just one calculation. At a conservative estimate, it costs about $500 per month in the United States to supply insulin and blood sugar monitoring equipment for a diabetic. That’s $6,000 a year, so if a patient lives with diabetes for 40 years that’s $240,000 over their lifetime. Then add in the costs of all the treatments that even well-managed diabetic patients will need for the complications they are likely to suffer because of their illness. It’s fairly easy to see how each patient’s diabetes-related lifetime healthcare costs could be at least a million dollars. And there are at least a million type 1 diabetics in the US alone. This means that at the very least, the US economy spends over a billion dollars every four years, just in treating type 1 diabetes. So even if iPS cells cost a lot to get into the clinic, they have the potential to make an enormous return on investment if they work out cheaper than the lifetime cost of current therapies.
That’s just for diabetes. There are a whole host of other diseases for which iPS cells could provide an answer. Just a few examples include patients with blood clotting disorders, such as haemophilias; Parkinson’s disease; osteo-arthritis and blindness caused by macular degeneration. As science and technology get better at creating artificial structures that can be implanted into our bodies, iPS cells will be used for replacing damaged blood vessels in heart disease, and regenerating tissues destroyed by cancer or its treatment.
The US Department of Defense is providing funding into iPS cells. The military always needs plenty of blood in any combat situation so that it can treat wounded personnel. Red blood cells aren’t like most cells in our bodies. They have no nucleus, which means they can’t divide to form new cells. This makes red blood cells a relatively safe type of iPS cell to start using clinically, as they won’t stay in the body for more than a few weeks. We also don’t reject these cells in the same way that we would a donor kidney, for example, because there are differences in the ways our immune systems recognise these cells. Different people can have compatible red blood cells – it’s the famous ABO blood type system, plus some added complications. It’s been calculated that we could take just 40 donors of specific blood types, and create a bank of iPS cells from those people that would supply all our needs
8
. Because iPS cells can keep on dividing to create more iPS cells when grown under the right conditions, we could create a never-ending bank of cells. There are well-established methods for taking immature blood stem cells and growing them under specific stimuli so that they will differentiate to form (ultimately) red blood cells. Essentially, it should be possible to create a huge bank of different types of red blood cells, so that we can always have matching blood for patients, be these from the battlefield or a traffic accident.
8
. Because iPS cells can keep on dividing to create more iPS cells when grown under the right conditions, we could create a never-ending bank of cells. There are well-established methods for taking immature blood stem cells and growing them under specific stimuli so that they will differentiate to form (ultimately) red blood cells. Essentially, it should be possible to create a huge bank of different types of red blood cells, so that we can always have matching blood for patients, be these from the battlefield or a traffic accident.
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