Regenerative Medicine & Pathologist

[HESC]

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Anyone heard of pathologists or pathology departments making progress toward using stem cells therapeutically (besides weissman and stanford)? Ive notice a lot of pathologist are getting involve in embryonic stem cell research and it makes sense that pathologist would play a central role in this field given what they already do with HSC. Any thoughts how this maight play out?

 

[LADoc00]

Anyone heard of pathologists or pathology departments making progress toward using stem cells therapeutically (besides weissman and stanford)? Ive notice a lot of pathologist are getting involve in embryonic stem cell research and it makes sense that pathologist would play a central role in this field given what they already do with HSC. Any thoughts how this maight play out?

Weissman although a Pathologist by training does purely research now. Given his basic science work, I dont think the pathology background for him was all that critical.

I would also add 99% of stem cell reserch is hype. California bond measure brought out alot of hucksters looking for a quick buck (and I almost joined em).

The business of pathology departments is to churn out the slides/tests, the research is really secondary which is why I IF I did do research I would stick to pure pure basic science programs which had no run off into a high volume clinical practice, something like Genetics at Whitehead/MIT or CalTech. I would simply do a postdoc right after medical school.

 

[drbraxton]

I wouldn't say 99% of Stem Cell research is hype. seems like it would create more business for pathologists. Think about when there are clinical applications for these cells. a pathologist would be overseeing quality control for the culture and differentiation of stem cell lines, and verify that the cells where, lets Say... Hepatocyte precursors, before the clinicians would transplant them into a cirrhotic patient. It might be very good business for pathologists.

 

[HESC]

So, I think pathologists have A LOT to gain by this research. This might be the end of the pathology job market dulldrums. Which path dept is going to set up a stem cell bank of patient specific lines first? any guesses?

"Park and colleagues reprogrammed differentiated human cells from various sources (fetal and neonatal, as well as cells isolated from a skin biopsy of an adult volunteer) into what are known as induced pluripotent stem (iPS) cells, which have all the properties of stem cells derived from human embryos.

... The added advantage of direct reprogramming is that it enables patient-specific stem cells to be obtained for studying human disease and for tissue matching in transplantation. What is more, virtually any laboratory capable of carrying out the required cell-culture techniques can now perform direct reprogramming of adult cells."

From http://www.nature.com/nature/journal/v451/n7175/full/451135a.html

another review by the same author
http://www.nature.com/nbt/journal/v26/n1/full/nbt0108-59.html

 

[malchik]

So, I think pathologists have A LOT to gain by this research. This might be the end of the pathology job market dulldrums. Which path dept is going to set up a stem cell bank of patient specific lines first? any guesses?

"Park and colleagues reprogrammed differentiated human cells from various sources (fetal and neonatal, as well as cells isolated from a skin biopsy of an adult volunteer) into what are known as induced pluripotent stem (iPS) cells, which have all the properties of stem cells derived from human embryos.

... The added advantage of direct reprogramming is that it enables patient-specific stem cells to be obtained for studying human disease and for tissue matching in transplantation. What is more, virtually any laboratory capable of carrying out the required cell-culture techniques can now perform direct reprogramming of adult cells."

From http://www.nature.com/nature/journal/v451/n7175/full/451135a.html

another review by the same author
http://www.nature.com/nbt/journal/v26/n1/full/nbt0108-59.html

My optimism is dampened by the observation that this "reprogramming" requires SV40 large T and hTERT genes, which are commonly known to create transformed cell lines, and if I am not mistaken are two of the genes Bob Weinberg has used to define minimal genetic requirements for tumorigenesis. So what you're talking about is a bank of patient-specific cancer stem cells.

 

[HESC]

Indeed they are expressed in immortalized cells. I believe though that the significance of this is not that the factors they used are required for reprogramming but instead we now know more about the mechanisms and validity for reprogramming. The author addressed this problem and mentions transiently expressing these or other factors to do the job, and eludes to the possibility to do this with extrinsic signals/culture conditions. so, not looking past the methods to get to the significance of the study maybe leading to your pessimism.

 

[malchik]

Indeed they are expressed in immortalized cells. I believe though that the significance of this is not that the factors they used are required for reprogramming but instead we now know more about the mechanisms and validity for reprogramming. The author addressed this problem and mentions transiently expressing these or other factors to do the job, and eludes to the possibility to do this with extrinsic signals/culture conditions. so, not looking past the methods to get to the significance of the study maybe leading to your pessimism.

What more have we learned about the mechanism of reprogramming as a result of this paper that we didn't already know? This is a technical advance, not a scientific one, as it simply does in human cells what has already been done in other systems. And it does nothing to address the problems of uncontrolled growth, simply mentioning ideas in a discussion doesn't count. This is not a trivial concern. We have been transforming cells for decades with SV40 large T and still know very little about how it works.

 

[docbiohazard]

Before this turns into a huge debate about the merits of stem cell research, I wanted to tell the OP that when I interviewed at UPenn that definitely seems to be a strength in their department, and the main research interest of their chair, if memory serves me correctly. So you might look there...

BH

 

[HESC]

What more have we learned about the mechanism of reprogramming as a result of this paper that we didn't already know? This is a technical advance, not a scientific one, as it simply does in human cells what has already been done in other systems. And it does nothing to address the problems of uncontrolled growth, simply mentioning ideas in a discussion doesn't count. This is not a trivial concern. We have been transforming cells for decades with SV40 large T and still know very little about how it works.

ok... lots of virus products do what the SV40 large T does (ie adeno E1A ) it interacts with cell cycle controls (pRb etc). Without getting into the gorey molecular bio of the cell cycle and hES cell bio here is why this developement is awesome.

1) Before, we knew a couple of transcription factors are required for pluripotency (oct4,nanog etc) and knew some of the extracellualr signals that induce them (WNT.. PDGF..)
2) we did not know that a differentiated somatic cell COULD become pluripotent (aka reprogrammed) and thought that the condensed chromatin would not allow such
3) we knew cell cycle control (pRb, p300, p53...) was tightly linked to differentiation in cell models but did not, and still dont know, how this is linked to pluripotency.
However, these papers shows that the regulation of pluripotency is not completely separate from cell cycle control and manipulation of differentiated somatic cells into pluripotent cells IS possible.

Admittedly, more work needs to be done to address your concerns, which would constitute overcoming a technical barrier.

dont get distracted by the basic science, we should leave it to the PhDs anyway. But if/when it does come through and a simple skin biopsy (or already banked cord blood cells ) can be induced to become patient specific pluripotent cell lines that can yield cardiomyocytes, hepatocytes, pancreatic islets... dont you think a pathologist is going to be HEAVILY involved in this? dont you think that there will be some profit there for pathology??

and thanks for the actual info biodoc...

 

[SaltySqueegee]

I always thought they would eventually transform the cells using genes behind a Tet-on system, or some other pharmacological agent for inducing. So that the appropriate transcription factors were selectively inducible. (as an aside, that would be kind of crappy, that you would get a teratoma anytime you were treated with tetracycline type compounds for an infection, if you had Tet-On iPS cells in your body).

Additionally, what about transient transfection to attain iPS state? Then culture conditions to maintain the state...

Something tells me these kinks will be quickly worked out. I don't think it will have the types of stumbling blocks that viral delivery of gene therapy has been experiencing, since the creation of these cells is exogenous to the organism.

Of course, right know the best to be hoped for is treatment of bone marrow type disorders. Not likely to be of help in the near, near future for organ level diseases that have a very specific matrix or complex tissue organization.

Just a few thoughts...

 

[malchik]

ok... lots of virus products do what the SV40 large T does (ie adeno E1A ) it interacts with cell cycle controls (pRb etc). Without getting into the gorey molecular bio of the cell cycle and hES cell bio here is why this developement is awesome.

1) Before, we knew a couple of transcription factors are required for pluripotency (oct4,nanog etc) and knew some of the extracellualr signals that induce them (WNT.. PDGF..)
2) we did not know that a differentiated somatic cell COULD become pluripotent (aka reprogrammed) and thought that the condensed chromatin would not allow such
3) we knew cell cycle control (pRb, p300, p53...) was tightly linked to differentiation in cell models but did not, and still dont know, how this is linked to pluripotency.
However, these papers shows that the regulation of pluripotency is not completely separate from cell cycle control and manipulation of differentiated somatic cells into pluripotent cells IS possible.

Admittedly, more work needs to be done to address your concerns, which would constitute overcoming a technical barrier.

dont get distracted by the basic science, we should leave it to the PhDs anyway. But if/when it does come through and a simple skin biopsy (or already banked cord blood cells ) can be induced to become patient specific pluripotent cell lines that can yield cardiomyocytes, hepatocytes, pancreatic islets... dont you think a pathologist is going to be HEAVILY involved in this? dont you think that there will be some profit there for pathology??

and thanks for the actual info biodoc...

I'm probably being pedantic, but it's only because I agree that this is interesting stuff. To respond to the underlined above, John Gurdon showed in 1962 that differentiated nuclei from frog intestinal cells can be reprogrammed upon transfer into an egg to not just become "pluripotent," but produce viable frogs. So conceptually, this recent study has not taught us anything, it is as you put it a technical hurdle. I just find it annoying that incremental, technical advances on anything remotely related to stem cells gets in to Nature/Science, because it is fashionable. Don't get me wrong, I agree that there is great potential, but let's be realistic about where we are and where we are not. We don't know how to reliably produce tissues of interest from ES cells, we don't know how to deliver them in a way that cures disease, and we don't know what the risk of giving the patient tumors is.

I agree that it would be great if pathology is instrumental in patient-specific stem cell treatment, but it is certainly not a given, other fields know how to culture cells. I think more pathologists should work in this area to see that it happens though.