23 replies to this topic

[struct]

http://news.bbc.co.u...lth/7101834.stm

[Johan]

Nice!

So what are the differences between these reprogrammed cells and stem cells made by therapeutic cloning?

[Lazarus Long]

So what are the differences between these reprogrammed cells and stem cells made by therapeutic cloning?

In lay terms these cells are grown from your own cells so they bypass the need to insert your genome into a clone through STNC but they are still ASC (Adult Stem Cells) and their ability to be mutable into all the various types of cells that ESC (Embryonic Stem Cells) is still subject to a lot more study. However they have demonstrated a far greater plasticity than previous methods of manipulating ASC.

In a sense however they are still being reprogrammed, only using your own genotype as the base code so compatibility should be enhanced. The real trick will be developing methods of improved culturing that can not only harvest and cryo store your own stem cells but convert various tissues, skin, fat, and bone marrow for just a few, into significant quantities of matched stem cells, which can then be used to grow specific tissues in vitro while others portions of the harvest are stored.

We are probably still 10 years from those break throughs and maybe more but it is definitely the direction things are going.

Here is a another article on the same subject.

http://www.cnn.com/2...s.ap/index.html

And another I posted previously in a different thread.

http://www.msnbc.msn.com/id/21886974/

[Johan]

Do these cells get their "clock turned back" (i.e. telomere relenghtening) like ESCs derived from SCNT?

[Karomesis]

We are probably still 10 years from those break throughs and maybe more but it is definitely the direction things are going.

Laz, do you think anything could be done to hasten this? or is the realtion to IT/accelerating returns the reason for your comment?

[Lazarus Long]

Do these cells get their "clock turned back" (i.e. telomere relenghtening) like ESCs derived from SCNT?

I believe this is still a very important question but I do not know for sure.

I also remember that early experiments with stem cell therapy went awry and one of the reasons was that the cells soon become cancerous, producing tumors or leukemia and that might have been because the *clock* didn't turn back.

However I also remember reading somewhere that they had located some of the genetic trigger mechanisms for controlling this. I think another advantage to embryonic stem cells will be turning the clock back on the mtDNA, which is something this method still cannot like accomplish.

Karo I am simply looking at the state of what we can do and the rate of both advance and investment. I have no crystal ball but bio doesn't exactly advance like IT, there is not a doubling of knowledge every 18 months like Moore's Law asserts for processing speed. In fact medical advances come in spurts, usually due to breakthroughs that alter our paradigms and open up novel approaches to the problems being targeted.

Our present state of knowledge is really at the beginning of one such period, quite nascent actually with the level of genomic mapping, decoding and associated techniques beginning to develop and brought to bear to achieve the level of organ growth I described. Nevertheless we still need some more new paradigms and methods to be developed.

Due to the level of testing required to confirm theory and results, as well as functional, reliable methodology there is a lag time of anywhere from 5 to 10 years alone. This delay costs lives but rushing things also costs lives and sometimes bad cures are more damaging than the diseases they target so caution is well advised when pioneering radically new medical methodologies such as these. When there are catastrophic failures the public panics and goes strongly into blame mode and this can be a devastating setback at times.

For example I expect the techniques described here are still 2 to 5 years away from producing results that can be used in human trials and the results of those trials are five to 10 years away from reaching the general public even if the researchers involved have good methodologies for applying them to humans right now, which they do not claim to have BTW.

[John Schloendorn]

So what are the differences between these reprogrammed cells and stem cells made by therapeutic cloning?

One rather relevant differences is that mice grown from cloned embryonic stem cells are just fine, while mice grown from these reprogrammed cells quickly die from cancers all over the place, presumably due to the overexpressed oncogenes (this is actual data, which for some reason these news releases don't consider worth mentioning).

[manofsan]

posting transferred from duplicate thread:
----------
For the first time, human skin cells were reverted back into pluripotent stem cells, apparently similar to embryonic stem cells:

http://www.timesonli...icle2908408.ece

This is an amazing breakthrough! Wow, and since it's just a few genes/factors that were required, that could mean widespread replication of these results, as everybody gets in on the act.
Japan's Dr Yamanaka, who led one of the 2 teams that achieved this breakthrough, was also the fellow who'd previously accomplished similar results using mouse skin cells last year, in which he actually produced fully cloned mice.

Anyhow, this latest method still has to insert a cancer gene using retroviral insertion vector, with all the attendant risks, so obviously it's not ready for primetime. But it's sure to bring all kinds of other researchers running in to build on this great achievement.

Wow, I bet there is going to be a chain reaction of new breakthroughs over the coming year, just by building off this work alone. Isn't this spectacular?

Now of course there's a new way to bypass the religious-ethical debate over the use of embryonic stem cells, and this will open the floodgates of new activity.


http://cosmiclog.msn.../20/474428.aspx

Dolly demonstrated that there was something in the egg that could reverse the cell's "strong arrow of time," Thomson said.

When I used to study chemical engineering back in university, we used to consider entropy as the "arrow of time" for physical processes. However, I fail to see why such concepts remain applicable in the highly organized world of cellular chemistry, in which controlled processes can be routed in any which direction, just as easily as a digital clock can be run backwards.

[manofsan]

One rather relevant differences is that mice grown from cloned embryonic stem cells are just fine, while mice grown from these reprogrammed cells quickly die from cancers all over the place, presumably due to the overexpressed oncogenes (this is actual data, which for some reason these news releases don't consider worth mentioning).

Fair enough, but at least this is a foot in the door, which bypasses the legal restriction difficulties from the embryonic route.

I would point out that Dr Yamanaka's previous feat which this latest one was based on, was doing the same thing using mice skin cells. He actually went as far as to create live mice from those skin cells, but as you point out, 20% of those mice died from cancer. But not bad for a first try, huh?

At least now from this starting point, the mechanisms of this reprogramming can be probed -- dare I say mapped?

This achievement has sparked so much attention and so much enthusiasm that it'll be sure to attract a lot of follow-up efforts trying to take it further. I can't wait to hear the news of further breakthroughs.

[niner]

While the cancer rate is a worry, this is still a really exciting discovery. To not have to collect 150 eggs and do the SCNT workup is a huge advantage. I'd like to see research continue on both paths until we know more. The reprogramming route seems so much simpler, plus it lacks the ethical issues, I expect to see a lot of experimentation with it. It shouldn't be terribly long before we have a reasonable idea how it will work out. The rate of advancement in bioscience is impressive. This is a crazy and cool time to be alive.

[manofsan]

Yeah, and it only took just a few factors. Read this:

http://www.nature.co...ll/450462a.html

Introduction of the four 'Yamanaka factors' requires genetic manipulation using viral vectors that health agencies would be unlikely to approve for clinical use. And one of the factors, c-myc, is thought to be responsible for tumours in mice.

Thomson, who was the first to isolate and maintain human embryonic stem cells in culture, has gone part way towards solving these problems. He also used four factors, introduced by viral vectors, to reprogramme human foreskin cells. But only two of the four are the same, and he does not use c-myc. What is more, the discovery that a different recipe resulted in successful reprogramming suggests that scientists might have a greater degree of flexibility in finding clinically acceptable variations on Yamanaka's selection.

So the Thomson group didn't even have to use the oncogene.

Who knows, maybe there are many combinations of 3 or 4 factors that will work.
Time for some brute force trial and error.

Meanwhile, back on the embryonic stem cell side, Mitalipov is preparing to switch to human cloning experiments:

Furthermore, in a move likely to raise fresh controversy, Mitalipov this week began a collaboration with Alison Murdoch and Mary Herbert of Newcastle University, UK. Murdoch's group has a licence to work with human embryos. "I can't just keep modelling," Mitalipov says. "If we show medical progress, society will accept the technology."

[Liquidus]

This story is turning up all over the media wire, I know the story broke to web junkies a few days ago, but it's really starting to grab national and international spotlight. We always hear of all these miracle cancer/disease 'cures' that never seem to end up on the front page of news papers, well I just went downstairs at my building here at work, and the newspaper stand had 2 out of 4 of the newspapers with this story as the front page headliner. The fact that it completes avoids the ethical debate might be a bigger breakthrough than the actual implications of the new method, this could be the bottleneck breakthrough stem-cell research has been in dire need of. Anyway, here's some more press:

http://news.yahoo.co...4HUnH3kQCQPLBIF

http://www.physorg.c...s114773905.html

http://www.newsweek.com/id/71441

Ever since I got into following life-extension, every story that carries this kind of weight holds with it tremendous amounts of excitement. When I was younger, I would have never imagined that I would be reading technology/medicine/science websites for 3-4 hours a day for LEISURE. Never say never!

Edited by G Snake, 21 November 2007 - 08:44 PM.

[Johan]

I wish they'd write about this in Swedish newspapers too...

I just hope these cells are as good as real ESCs. My main question is if iPS cells have their telomeres relenghtened ("clock turned back") just like ESCs. How hard would that be to do without an egg?

Edited by namingway, 21 November 2007 - 10:14 PM.

[maestro949]

One small step on a long journey albeit an important step.

[manofsan]

Here's some commentary that goes really into detail on experimental methods used:

http://scienceblogs...._cells_into.php

And here's his previous commentary on Yamanaka's previous experiment with the mice:

http://scienceblogs....wedge_issue.php

Edited by manofsan, 22 November 2007 - 04:52 AM.

[manofsan]

So I just want to get one thing straight here -- didn't Yamanaka's previous experiments with the mice skin cells show that their derived IPSs were totipotent, and not merely pluripotent?
Because after all those reprogrammed skin cells were grown into full clones of the mice.

Obviously nobody's going to go so far as to grown a full blown human clone from skin cells (hopefully they won't), but I presume that totipotency can be verified without having to go that far.

Furthermore, with the recent breakthroughs on the monkey cloning, I'd assume the way is open to attempt to create full-blown monkey clones using this skin cell method. That's still not human cloning, but monkeys are a comparably complex organism thru which to demonstrate proof of principle, right?

[manofsan]

I also liked this commentary:

http://www.futurepun...ves/004807.html

... By finding ways to turn the knobs on genetic switches in the cell it was inevitable that scientists would figure out how to make cells change state into embryonic cells. They will next find more genetic knobs to turn in order to convert embryonic cells into precisely desired cell types and they will even find ways convert between various non-embryonic cell types while totally avoiding an intermediate state where the cells are like embryonic cells. Cells are just complex state machines. The next few decades of advance in biotechnology can be seen as a series of advances in techniques for causing desired and useful cell state transitions.

These are my feelings exactly. It's just a matter of finding the correct "switches" and "circuits", and you'll be able to switch a cell from one state configuration to another.

So it's important to try out as many switches as possible, in order to figure out which switches do what.
Just like the old school pioneer days of chemistry. We're probing a black box.

[Luna]

I highly doubt we asre 10 years away from the breakthrougs.
5-7 top.

[AdamSummerfield]

Well if we're managing to convert multi/unipotent stem cells into toti/pluripotent ones, I think this technique should be harnessed further, since of course totipotent cells are so much more useful.

- Adam

[Live Forever]

I saw an article on this the other day. I am not sure how close or far it is, but it certainly would bring a lot more religious (and social conservatives in general who are opposed to destroying embryos) on board. I totally disagree with them, but having them come on board with the issue will lead to many more breakthroughs than if they opposed it. Hopefully the drawbacks that have been mentioned can be minimized sufficiently.

[Lazarus Long]

Because I am an alumni of the school where this research is taking place I get a lot of info from them. This article is in my online journal and for those of you interested in a great graduate program in this field it is full of links directly to the department where this work is happening. This article is also considerably more in depth I find then many I have seen in the general press. IMHO the issue of ASC versus ESC is getting way too hyped in the general press and not really as relevant to the importance of this issue scientifically. Check out the link for links on the page.



The scientific team from the University of Wisconsin-Madison created genetic modifications in skin cells to induce the cells into what scientists call a pluripotent state — a condition that is essentially the same as that of embryonic stem cells. Junying Yu, James Thomson and their colleagues introduced a set of four genes into human fibroblasts, skin cells that are easy to obtain and grow in culture.
Hi res photos

http://www.news.wisc...?clickcode=2923

UW-Madison scientists guide human skin cells to embryonic state

Nov. 20, 2007

by Terry Devitt

In a paper to be published Nov. 22 in the online edition of the journal Science, a team of University of Wisconsin-Madison researchers reports the genetic reprogramming of human skin cells to create cells indistinguishable from embryonic stem cells.

The finding is not only a critical scientific accomplishment, but potentially remakes the tumultuous political and ethical landscape of stem cell biology as human embryos may no longer be needed to obtain the blank slate stem cells capable of becoming any of the 220 types of cells in the human body. Perfected, the new technique would bring stem cells within easy reach of many more scientists as they could be easily made in labs of moderate sophistication, and without the ethical and legal constraints that now hamper their use by scientists.

The new study was conducted in the laboratory of UW-Madison biologist James Thomson, the scientist who first coaxed stem cells from human embryos in 1998. It was led by Junying Yu of the Genome Center of Wisconsin and the Wisconsin National Primate Research Center.

"The induced cells do all the things embryonic stem cells do," explains Thomson, a professor of anatomy in the University of Wisconsin School of Medicine and Public Health. "It's going to completely change the field."

In addition to exorcising the ethical and political dimensions of the stem cell debate, the advantage of using reprogrammed skin cells is that any cells developed for therapeutic purposes can be customized to the patient.

"They are probably more clinically relevant than embryonic stem cells," Thomson explains. "Immune rejection should not be a problem using these cells."

An important caveat, Thomson notes, is that more study of the newly-made cells is required to ensure that the "cells do not differ from embryonic stem cells in a clinically significant or unexpected way, so it is hardly time to discontinue embryonic stem cell research."

The successful isolation and culturing of human embryonic stem cells in 1998 sparked a huge amount of scientific and public interest, as stem cells are capable of becoming any of the cells or tissues that make up the human body.

The potential for transplant medicine was immediately recognized, as was their promise as a window to the earliest stages of human development, and for novel drug discovery schemes. The capacity to generate cells that could be used to treat diseases such as Parkinson's, diabetes and spinal cord injuries, among others, garnered much interest by patients and patient advocacy groups.

But embryonic stem cells also sparked significant controversy as embryos were destroyed in the process of obtaining them, and they became a potent national political issue beginning with the 2000 presidential campaign. Since 2001, a national policy has permitted only limited use of some embryonic stem cell lines by scientists receiving public funding.

In the new study, to induce the skin cells to what scientists call a pluripotent state, a condition that is essentially the same as that of embryonic stem cells, Yu, Thomson and their colleagues introduced a set of four genes into human fibroblasts, skin cells that are easy to obtain and grow in culture.

Finding a combination of genes capable of transforming differentiated skin cells to undifferentiated stem cells helps resolve a critical question posed by Dolly, the famous sheep cloned in 1996. Dolly was the result of the nucleus of an adult cell transferred to an oocyte, an unfertilized egg. An unknown combination of factors in the egg caused the adult cell nucleus to be reprogrammed and, when implanted in a surrogate mother, develop into a fully formed animal.

The new study by Yu and Thomson reveal some of those genetic factors. The ability to reprogram human cells through well defined factors would permit the generation of patient-specific stem cell lines without use of the cloning techniques employed by the creators of Dolly.

"These are embryonic stem cell-specific genes which we identified through a combinatorial screen," Thomson says. "Getting rid of the oocyte means that any lab with standard molecular biology can do reprogramming without difficulty to obtain oocytes."

Although Thomson is encouraged that the new cells will speed new cell-based therapies to treat disease, more work is required, he says, to refine the techniques through which the cells were generated to prevent the incorporation of the introduced genes into the genome of the cells. In addition, to ensure their safety for therapy, methods to remove the vectors, the viruses used to ferry the genes into the skin cells, need to be developed.

Using the new reprogramming techniques, the Wisconsin group has developed eight new stem cell lines. As of the writing of the new Science paper, which will appear in the Dec. 21, 2007 print edition of the journal Science, some of the new cell lines have been growing continuously in culture for as long as 22 weeks.

The new work was funded by grants from the Charlotte Geyer Foundation and the National Institutes of Health. In addition to Yu and Thomson, authors of the new study include Maxim A. Vodyanik, Kim Smuga-Otto, Jessica Antosiewicz-Bourget, Jennifer L. Frane and Igor I. Slukvin, all of UW-Madison; and Shulan Tian, Jeff Nie, Gudrun A. Jonsdottir, Victor Ruotti and Ron Stewart, all of the WiCell Research Institute.

More information: Learn more about stem cell and regenerative medicine research at UW-Madison by visiting the Stem Cell and Regenerative Medicine Center Web site.
http://www.stemcells.wisc.edu/

[Mind]

G9a Gene Triggers Differentiation Of Embryonic Cells

In a recent paper in Nature Structural and Molecular Biology, Professors Yehudit Bergman and Howard Cedar of the Hebrew University-Hadassah Medical School have deciphered the mechanism whereby embryonic cells stop being flexible and turn into more mature cells that can differentiate into specific tissues. Bergman is the Morley Goldblatt Professor of Cancer Research and Experimental Medicine and Cedar is the Harry and Helen L. Brenner Professor of Molecular Biology at the Medical School.

They found in their experiments, using embryos from laboratory mice and cells that grow in culture, that this entire process is actually controlled by a single gene, called G9a, which itself is capable of directing a whole program of changes that involves turning off a large set of genes so that they remain locked for the entire lifetime of the organism, thereby unable to activate any further cell flexibility.

[Lazarus Long]

You beat me to the punch with that one Mind, so here is another link to that article on cell differentiation and I will raise you one more from your backyard, though it is a cautionary one.

Patient-derived induced stem cells retain disease traits
MADISON – When neurons started dying in Clive Svendsen's lab dishes, he couldn't have been more pleased.

The dying cells – the same type lost in patients with the devastating neurological disease spinal muscular atrophy – confirmed that the University of Wisconsin-Madison stem cell biologist had recreated the hallmarks of a genetic disorder in the lab, using stem cells derived from a patient. By allowing scientists the unparalleled opportunity to watch the course of a disease unfold in a lab dish, the work marks an enormous step forward in being able to study and develop new therapies for genetic diseases.

As reported this week in the journal Nature, Svendsen and colleagues at UW-Madison and the University of Missouri-Columbia created disease-specific stem cells by genetically reprogramming skin cells from a patient with spinal muscular atrophy, or SMA. In this inherited disease, the most common genetic cause of infant mortality, a mutation leads to the death of the nerves that control skeletal muscles, causing muscle weakness, paralysis, and ultimately death, usually by age two. (excerpt)
BBC on the same study

Well make a two.

Mutations common to cancer and developmental disorder examined in a novel disease model

[crayfish]

So what are the differences between these reprogrammed cells and stem cells made by therapeutic cloning?

In lay terms these cells are grown from your own cells so they bypass the need to insert your genome into a clone through STNC but they are still ASC (Adult Stem Cells) and their ability to be mutable into all the various types of cells that ESC (Embryonic Stem Cells) is still subject to a lot more study. However they have demonstrated a far greater plasticity than previous methods of manipulating ASC.

In a sense however they are still being reprogrammed, only using your own genotype as the base code so compatibility should be enhanced. The real trick will be developing methods of improved culturing that can not only harvest and cryo store your own stem cells but convert various tissues, skin, fat, and bone marrow for just a few, into significant quantities of matched stem cells, which can then be used to grow specific tissues in vitro while others portions of the harvest are stored.

We are probably still 10 years from those break throughs and maybe more but it is definitely the direction things are going.

Here is a another article on the same subject.

[url="http://www.cnn.com/2007/HEALTH/11/20/stem.cells.ap/index.html"http://www.cnn.com/2007/HEALTH/11/20/stem....s.ap/index.html"]http://www.cnn.com/2007/HEALTH/11/20/stem....s.ap/index.html[/url]

And another I posted previously in a different thread.

http://www.msnbc.msn.com/id/21886974/

Skin biopsy -> iPS cells; propagate in culture, freeze some. Inject clonally expanded cells into same person (or good immune marker match; I saw an estimate from one group reckoning that cells from 100 donors could be a match for over 90% of people). Frozen stocks can be awakened for subsequent treatment.

But, the big question is, does an injection of stem cells / iPS cells do anything? Do they home in on the right tissues and differentiate all by themselves in response to the local microenvironment? Would [url="http://<a%20href="http://www.nlm.nih.gov/medlineplus/news/fullstory_82799.html"] targeting injections to specific sites[/url] help with this? Is there [url="http://<a%20href="http://news.bbc.co.uk/1/hi/health/7985142.stm"%20target="_blank">http://news.bbc.co.u...stm</a>"] anything else we can do to help this along? [/url] Would periodic injections maintain a constant supply of youthful progenitor cells and retard ageing or allow youthful levels of regeneration? Or will the aged humoral milieu / postmitotic tissues limit or prevent any benefits that could be garnered in this way?

Maybe removal of senescent cells combined with stem cell injections and a decent anti cancer therapy would help as regards cellular ageing.

Although actually, stem cell transplantation may help to eliminate cancer too (presumably by improving the immune system) .

Edited by crayfish, 19 April 2009 - 11:26 PM.