Undelivered items go to BAG6

A story of how bin men work at the post office in our cells

Our cells produce all sorts of proteins with all sorts of functions. But to fulfil these functions the proteins must be in the right place. There’s no use for a protein that should be in the nucleus to stick around the outer membrane and like wise. When a protein needs to go to a specific compartment of the cell, this information is encoded in the protein itself. It’s like the address on an envelope. And interestingly, the machinery responsible for protein delivery starts working even before the synthesis of the protein is finished. It’s like we addressed an envelope, then started writing a letter, and before we finished it, our personal postman was already putting the address from the envelope into his sat nav.
Because there is so many various proteins being synthesised in the cell at any given moment, these postmen sometimes can’t keep up and happen miss a “protein letter”. The protein would then just stick around and clutter the wrong compartment of the cell. Now obviously, apart from post men, our cells are also equipped with bin men, who take care of such undelivered protein mail. A recent discovery (1) found that these bin men are actually very vigilant and work in a fashion very similar to the postmen. They hang around the protein factories, and as soon as they see a protein addressed to the membrane that wasn’t spotted by any of the postmen, they grab it and put it in their trash bag. Interestingly, one of the proteins responsible for this process is called BAG6.
You might wonder, is this discovery really that important? Isn’t it science just for the sake of it? Would a cell really mind having some litter laying around its protein synthesis offices? Well, actually, it would. Apart from just not being able to fulfil its function at the right compartment of the cell, a protein that isn’t where it’s supposed to be, can behave in an unpredicted and sometimes harmful way. This is one of the causes for Creutzfeldt-Jakob disease, otherwise known as the human form of mad cow disease. A so-called prion protein, the cause of this disease, is normally supposed to find itself in the cell membrane. But when it doesn’t and stays in the cell cytoplasm (where protein synthesis occurs) it tends to form aggregates which are very resistant to being cleaned up. These aggregates start affecting the functioning of the whole cell, and because the protein is mainly produced in the brain cells, the brain’s function gets severely impaired. If this research goes further, maybe the scientists will be able to better understand the onset of the disease, and maybe even come up with novel therapies to either treat patients affected by it, or prevent its development in people who have a family history.
So that’s the story. In our cells, bin men work as fast as they can to remove junk proteins which are undelivered. And wouldn’t it be great if all the junk mail we receive was binned just as it’s being put in its envelope?

1. Protein targeting and degradation are coupled for elimination of mislocalized proteins.

Trans-differentiation: cells in trance do things they haven’t dreamt of

Our bodies get injured, get damaged, get old and we’d like to be able to regenerate them. Modern medicine has for quite some time been on it’s way to help us with this. It’s all about the stem cells! The magnificent almighty stem cells that can turn into any adult cells that need replacing. The road to actually achieving this magical regeneration has been quite bumpy and riddled with ethical issues, because embryonic stem cells – which have the biggest differentiation potential – are generated from undeveloped human embryos. But with the whole idea of “manufacturing” cells for regeneration – have we got the wrong end of the stick from the beginning? Recent findings suggest we could have took a much more straightforward approach. But only if we had dismissed what our professors told us when we were students and done some procedures in spite of them saying they had no chance of working. And seen them actually work in the end.

Embryonic stem (ES) cells obtained from many species, including human, have been around for quite some time (1, 2). We’ve seen them differentiate into neurons, heart muscle cells, liver cells and so on . We’ve also seen them raise serious ethical issues of whether obtaining them from very early-stage embryos is killing or not. We’ve seen them cause a see-saw changes in US law imposing and lifting bans on ES cell research. So the scientists had a look at another kind of stem cells – the adult stem cells. These can be obtained from an adult person without killing them, so there was no strong ethical objections against these. But many researchers argued these cells had very limited potential of differentiation. Our body organs develop from one of three layers of an embryo – the outer, the inner, and the one in between. Some scientists strongly advocated the idea that when you isolate adult stem cells from, say, bone marrow – which comes from the middle layer – they will never be able to give rise to neurons (originating from the outer layer) or liver cells (the inner). So the bottom line was, adult stem cells – ethical, but not so good.

Then came the induced pluripotent stem cells, or iPS cells (about which I wrote some time ago). They are generated from adult tissues, as easily accessible as skin, but they behave like embryonic stem cells, i.e. can readily differentiate into all kinds of cells from any embryonic layer. It was a big wow in the scientific society, as these cells were as plastic as the unethical embryonic stem cells, yet as ethical as the crappy adult stem cells. Win-win? Not exactly. One practical issue scientists experience with both ES and iPS cells is that we can never achieve full differentiation of all the cells while they’re in culture. Say, you have a patient who suffered a bad liver damage so you need to inject them with liver cells. You can culture the ES or iPS cells, differentiate them into liver cells and then inject them into that patient. But the few cells that failed to differentiate in culture, will start doing it after being injected. And the problem is – they can go crazy and out of control in the process. They can differentiate into weird tumour masses called teratomas, which can contain any sort of tissue. Some teratomas were even found to contain hair or teeth. Now, you don’t want that in your liver, do you? Neither do the doctors who treat you. This is the main reason why both ES and iPS cells, even though we’ve been culturing the former ones for about three decades now, have been struggling to be actually accepted for clinical trials.

Recently, there is a new wave of cell differentiation research, which stays away from stem cells altogether and is in opposition to what they taught us at our university courses. They used to tell us that once a stem cell differentiates into a specialised cell – that’s it! There’s no becoming a another kind of cell. Or in scientist’s words – there’s no trans-differentiation. This is in line with the argument that adult stem cells from one embryonic layer can’t differentiate into cells from another. However, recently there are more and more scientific reports showing how not only adult stem cells can trans-differentiate into other-layer cells, but adult specialised non-stem cells can do that too. Apparently, you can take a skin cell, and genetically reprogram it to become a neuron cell (3)! That’s very exciting, but skin and neurons actually come from the same embryo layer – the outer. But other researcher have broken this boundary, and transformed fibroblasts (the middle) into liver cells (the inner, 4). And even more importantly, the newly generated liver cells were shown to be working in living organisms. For instance when the skin-turned-liver cells were injected into mice with liver damage, they took part in reconstituting the organ tissue. No embryo killing so it’s ethical. It can be done without changing the adult cells into the iPS cells first. No iPS cells, no risk of teratomas. Win-win? Hopefully!

The research is still in early stages and a lot more testing needs to be done. Also, because of a short life span of a mouse, we can’t really predict how would these cells behave, say, ten years after injection. Would they still be functional? Would they form some kind of tumours or cancers? We can’t exclude these possibilities yet. But you know what we scientists are like. We will keep trying until we get the answer. And hopefully the answer will be – the trans-differentiated cells are long lasting and safe.

1. Establishment in culture of pluripotential cells from mouse embryos
2. Embryonic Stem Cell Lines Derived from Human Blastocysts
3. Direct generation of functional dopaminergic neurons from mouse and human fibroblasts
4. Direct conversion of mouse fibroblasts to hepatocyte-like cells by defined factors