Announced today:
My understanding is that these are actually the same genes that are activated in embryonic stem sells, so why aren’t they already in the cells?
And further… are the human genes the same as those found in mice (on which this procedure was first performed earlier this year)? I’m thinking they probably are. We do share something like 90% of our DNA with rodents.
The same genes are present, but they are switched off in these adult cells. Ultimately, it would be easier to switch on the native genes, but that’s not really possible until you know exactly which genes you need. This approach is a first step, showing that these specific genes are sufficient to create a stem cell equivalent. Next, researchers will try to tease out the relevant regulatory circuits, and hopefully find an easy way to turn on the native copies of these genes for future therapies.
The genes are the same as those used in the mouse attempt, though they are probably slightly different in humans. And, as a nitpick to the article you link, retrovirus insertion always has a possibility of causing mutations, since the virus stuffs its payload essentially randomly into the host genome. A given cell line created by this technique may be free of harmful mutations, but overall some won’t be.
But they had to know which genes they were, since they put them into the virus. I’m still unclear about this.
They know what genes are turned off, but that doesn’t allow them to turn them back on. The process of diabling genes is very complex, in most cases it’s a cascade sequence, and in the case of totipotency in mammas it isn’t even clear that it can be reversed. IOW once the genes are disabled it may be that they can thay can never be reactivated. That’s why there’s a need to insert new functional copies of those genes that are still open to transcription.
Think of it like having a library where all the index cards have been superglued together. The cards are all still there, they still contain all the original information but thety can never be read ever again so they may as well not exist. The only way you are ever going to find anything in that library is to take with you a replica of the index system. The fact that the original index system still exists and still theoretically contains all that information you are taking in is irrelevant because the information can’t be read.
Well, two groups did this independently, and each had a slightly different approach. I can’t get through the paywall from here, so I can’t skim the actual papers, but I can get at the abstracts. Basically, one group (publishing in Cell) just did a repeat of what worked for them in mice. There was probably a whole lot of trial and error involved in finding those genes in the first place. There are plenty of examples where something works one way in mice, but completely differently in humans. I’ve heard it said that scientists can cure your cancer, but only if you’re a mouse. So, when they switched from mice to humans, they had to reconfirm everything, especially for something of this magnitude. Research has to be very slow and methodical, and relying on untested assumptions can lead to a lot of trouble (or wasted time at best).
The other group, publishing in Science, started with a larger set of candidate genes, and probably tried a whole bunch of combinations before finding one that worked. So, while they had a good idea of what genes might be involved, they needed to come up with proof.
Basically, you have to confirm everything, especially for a discovery of this magnitude.
What makes these genes “functional” in the new environment, and not get “turned off” like the native genes?
They are functional because they have nevr been turned off.
They don’t get turned off because the cells are never allowed to go through the developmental process that triggers the shutdown cascade. In a natural environment the zygote divides a few times and then the cells start to differentiate more and more. At some point in that differentiation cycle they lose there totipotency and become locked into a very narrow devlopmental stream. They may be able to beocme various type sof blood cell, but they can never again become nerve cells for example. If you prevent normal development the cells never get the signal to differentiate and so they never lose totipotency. They just remain generic cells forever.
Think of it like making coin blanks for a mint. So long as the metal discs remian blank you can use them for any coin you like in future. Once you’ve stamped just one side you’ve limited the future possible uses, and once you’ve stamped both sides you have defined what that coin is forever. These cells are being kept in a blank state. So long as they never get the hormonal triggers that “stamp” them they will remain blanks that can be inmpresed with any design you like.
So the genes are physically altered to be “turned off”? Where do you get non-turned-off genes? I assume they didn’t come from embryonic stem cells, since we are to assume that “no embryos were harmed during the performance of these experiments”, so to speak.
Nope, it’s actaully quite tricky because the DNA itself has to be readable during cell replication but not accesible for RNA trancscritption and protein production. So you can’t physically alter the genes. Like I said, it’s not well understood and there seem to be several different mechanisms that render genes non-functional in certain cell lines.
A large part of it is that the DNA gets “capped” with proteins, so they can no longer be transcribed. It’s like gluing a sheet of cardboard over a page of writing. The page isn’t physically altered and the writing is still there but you can’t read it. Various other methods also seem to be at play, includding reconforming the DNA strand itself so that it folds in on itself and the start codon for those genes are no longer accesible to the transcription machinery. There also seems to be a prion component at work that mops up any proteins that do manage to get transcribed.
Don’t know, I can think of several possibilities. They may have manufactured them from nucleotides, they may have extracted them form non-human embryos, they may have extraced them from non-emrbyonic stem cells, either adult or infant, they may have extracted them from gametes or they may have extracted them form adult cells and “cleaned” them so they are functional. You’d have to read the article for the details.
There are basically two overall types of mechanisms. Epigenetic controls are where the DNA backbone (but not its sequence) and associated proteins are modified to allow or prevent gene expression. They’re involved with the longer term shut down that happens during development. This is only present in eukaryotes: plants, animals, and other “higher” life; bacteria and viruses lack these mechanisms. Blake is mostly talking about this.
Second, you have the more traditional and universal regulatory controls, which is on top of the epigenetic control in humans. For example, a gene is typically associated with a sequence called a promoter. A type of protein called a transcription factor will bind to that promoter, under a specific condition like early development, and then allow the expression of that gene. Thus, you have genes that can be turned on or off under certain conditions. There are a seemingly infinite number of types of regulation, but they all work the same way: in the presence of some signal, a regulatory protein will block (or stop blocking) the expression of some other gene, thus turning it on or off.
It turns out that you can easily attach a promoter of your choice to the gene you want. In this way, researchers can add in a gene that is always on, or just on in the presence of some specific added chemical.
And, on preview, Blake beat me again.
Think of it this way: with current technology, it’s much much easier to put in genes complete with attached “ON” switches than it is to go in to the genes already there and turn the switch from “OFF” to “ON”.