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Embryonic stem cell research: from the basics to the hopes for the future

Somewhere a human egg cell is hooking up with a sperm cell.

Whether it be in the Fallopian tube of a woman, or in a glass Petri dish, there is now the full complement of the 46 chromosomes that make up the human genome, all in a single cell. But then again, just about every cell in your body has this full set genes bundled as chromosomes. How is this cell different?

Here again, it depends. It could continue to move along the Fallopian tube while it divides into 8 cells and then implant in the uterus. Or, it could be a thawed embryo from a IVF clinic that is used to generate an embryonic stem cell line. The 8-celled blastocyst in the uterus, as we know eventually grows into an organism that lives for on average 70 years, while the embryonic stem cell line is essentially immortal, but even though that's the term used, it's a little overdramatic. But they can be cultured and grown in labs for what seems endlessly. The other immortal cells that can be grown in labs are cancer cells.

Lets look at the adult for now. (By "adult" I mean "not a fetus." Really it's about differentiated versus undifferentiated tissue,)  There has never been any good evidence that embryonic stem cells exist in the adult human. It's assumed that cells  a little bit along the way of differentiation do exist and are ready to produce the tissue that needs replacing. The liver is good at doing this, the nervous system, no. And there are times when this repair system doesn't always work out the best way for the human.

For instance, during the typical heart attack, a coronary artery is blocked, decreases blood flow to cardiac muscle which needs the oxygen without fail. The result is the muscle cells die, but the problem is they're not replaced with new muscle tissue but with non-functioning scar tissue. If enough of this scar tissue is present, the heart can't work as a pump as well as it used to.

more to follow...

Reprogrammed skin cells replacing embryonic stem cells for research

These images are taken from the Sciencexpress report, "Induced Pluripotent Stem Cell Lines Derived from Human Somatic Cells," whose embargo was lifted minutes ago. I presented the news item in the previous post.

The researchers showed that they could take adult human skin cells, and then introduce 4 genes which would reprogram them into a viable stem cell line.

Here's the visual proof that their experiment worked. These images show the 3 basic tissue types in the human body, ectoderm, mesoderm, and endoderm as they are generated on the embryonic level. The skin cells turned into pluripotent where able to generate these tissue types when implanted into mice. (The type of tumor is called a teratoma).

Imagine a day when you could go in for a skin biopsy, then have a cell line available that could be used to regenerate tissue in the event of nerve damage (ectoderm), heart attack (mesoderm), or even replace a portion of the colon (endoderm).

While this doesn't address the root cause of the diseases, cell lines such as these could also be manipulated to mimick diseases such as Alzheimer's or Parkinson's in an attempt to understand the pathophysiology.

News embargo lifted on stem cell paper

I see a banner on MSNBC, listed as breaking news: "Japanese, U.S. scientists report stem cell breakthrough," about a research paper demonstrating a method for creating a cell with appears to have the characteristics of a pluripotent stem cell from a somatic (skin) cell by the addition of four genes.

By taking a skin cell, and reprogramming it to become a pluripotent stem cell, this solves the problem of immune rejection by the donor if this cell is meant to be used for therapy, for example, to help regenerate cardiac tissue in the event of a heart attack. It's a simpler solution than somatic cell nuclear transfer (SCNT), the technique also known as therapeutic cloning, and was used to create Dolly, the cloned sheep.

The announcement of the lifted embargo:

The AAAS Office of Public Programs is lifting the embargo, effective immediately, on the article "Induced Pluripotent Stem Cell Lines Derived from Human Somatic Cells," by Junying Yu and colleagues, because of an embargo break by the newspaper, The Age. The article will be published online at the Science Express website, at noon today, 20 November.

more to follow...

I just listened to the first 1/2 hour of a conference call with the lead author of this paper, Dr. Yu, and the corresponding author, Dr. Thompson. Both are researchers at the University of Wisconsin. Their statements were very brief since they wanted to get right to answering questions.

First, Dr. Thompson said that this paper is based on the research performed over the past ten years using embryonic stem cell lines, and that embryonic will need to be continued in the future to provide a gold standard against which this reprogrammed somatic cells may be compared.

But he did say that he thought that this marked "the beginning of the end" of generating new stem cell lines. He said that in his lab he has been using around 10 embryonic stem cell lines, but found the need to derive more to test a new medium and culturing technique. He thought that research with the hundreds of ES cell lines available throughout the world will continue, and that there will be a need to derive new cell lines as necessary.

He said in response to a question that his research was not driven by a wish to avoid the ethical controversy of using ES cells for research. He also denied that this new advance would result in "pulling the plug" on current ES cell research, as one reporter put it.

Thompson said that a patent would be sought for this procedure and that it would be assigned to his institution.

Dr. Yu described their use of fetal fibroblasts, then adult skin fibroblasts (from a 46-year old woman) in proving that their derived cell lines, now lasting more than 22 weeks, could form teratomas in mice, the proof that these cells can differentiate into all three basic tissue types, and are therefore pluripotent. It was later noted that these cells could not used for reproductive cloning if implanted in a uterus. These derived cells are more like the primitive ectoderm part of an embryo, said Thompson.

Thompson also forecast that research into therapies would likely follow the rhesus monkey model for experiments.

The spin in the popular media that this somehow avoids the ethical dilemma, for the time being at least, is not a good way to view this breakthrough. The definitions of a ES cell, or a pluripotent derived cell are only functional now. It's not clear what makes them what they are.

Of course, the big hope is for a therapy that might alleviate or cure a condition such as Alzheimer disease. But Thompson emphasized there is still much more needed to be known about the disease process itself. This might be possible through created a line cell mimicking the disease, but it's not known if or how this can be done. The basic point is that there will have to be more basic research before therapies will be found.

 

Induced pluripotent stem (iPS) cells derived from fibroblasts

In the inaugural issue of the Cell Press Cell Stem Cell, is the article "Directly Reprogrammed Fibroblasts Show Global Epigenetic Remodeling and Widespread Tissue Contribution" (abstract). The lead author is Dr Hochedlinger of the Harvard Stem Cell Institute.

This essentially confirm a study published in 2006 by Shinya Yamanaka of Kyoto University. The researchers were able to take mature body cells, in this case mouse fibroblasts, and by inserting four genes for transcription factors, they are able to induce a reversion to a pluripotent state (able to produce all cell lines). Pluripotency is the hallmark of the embryonic stem cell.

Two other teams also published papers in Nature reproducing this technique. One team was led by Dr Yamanaka, and the other by Dr Jaenisch, a scientist at the Whitehead Institute for Biomedical Research in Cambridge, Mass.

However, according the the Nature news site, the stem cells create are not quite equivalent to natural stem cells:

But the iPS cells aren't perfect, and could not be used safely to make genetically matched cells for transplant in, for example, spinal-cord injuries. Yamanaka found that one of the factors seems to contribute to cancer in 20% of his chimaeric (a mix of iPS cells and natural stem cells) mice. He thinks this can be fixed, but the retroviruses used may themselves also cause mutations and cancer.

This technique, if it can be performed reliably in humans, also ensures that the stem cells generated with have identical DNA to the patient's cells, thus allowing a perfect match for transplantation, if a therapy can be developed to repair damaged tissue, for instance, cardiac tissue destroyed due to a myocardial infarction.

"None of us are for cloning..."

This is a quote from yesterday's Iowa townhall meeting by John Edwards in the context of answering a question about stem cell research.

In all probability, every other presidential candidate will take a similar stance in supporting the go'vt funding of embryonic stem  cell research,  so the distinquishing factor in my mind would be which candidate has the better understanding of the science of this and other medical or technological topics.

I would like to ask Edwards if he could explain the difference between reproductive cloning and somatic cell nuclear transfer (therapeutic cloning), or even what a stem cell is. It's important for the person running for the highest office in this country demonstrate the intellectual curiosity needed to grasp these subjects rather than deliver a scripted answer. His or her term will face question about other technological advances that will require more than a superficial understanding.

John Edwards on stem cells

This is a post about the John Edwards townhall meeting in Des Moines, Iowa which happened tonight at 6 p.m. Eastern Standard Time  which I watched via a webcast from his website: www.JohnEdwards.com.

This I found out from Robert Scoble who is covering Edwards' announcement of his presidential bid. I was particularly interested in finding out what his views were on embryonic stem cell research.

Edwards responds to the question about the federal funding of embryonic stem cell research by saying (this is a pretty faithful transcription):

"I think it's critical. I think that the limitations that have been put on federal funding of embryonic stem cell research are driven by ideology and not by science and not taking the kind of steps that need to be taken to create at least the possibility of making real progress on the diseases that we can have a real impact things like Parkinson's, Alzheimer's, and spinal cord injury all of which scientists believe we have at least a great potential of doing good work. I think it's a mistake for America to place limitations on the research which can be done.

"None of us are for cloning, and none of us are for violation of ethical standards. But, those things can be complied with, and still do the research that needs to be done. And, if we don't do something about the circumstance we are in now, if you go to our research universities around the country, they will tell you that this work is going somewhere else. It's going to other countries... the circumstance were in today is for America to remain a powerful force, economically and technologically. We have got to be on the cutting edge of everything. It's what makes us strong. And that includes science and technology, and medical research. I mean these are the places where we've had relatively stagnant funding for the NIH, relatively stagnant or decreased funding for the medical research at our universities. That's a mistake. Because actually if we want to remain strong over the long term, we need to be increasing not decreasing funding in areas that make us the most creative and innovative country on the planet. Which we still are today, but if we want to stay there, but we are going to have to keep pushing the envelope, and then includes in this area."

I expected him to continue his pledge to support funding for this type of research. I wanted to see how well he could articulate his understanding of the subject. His faux pas from '04, when he said something to the effect that people like Christopher Reeve would be able to arise from their wheelchairs if the gov't had supported embryonic stem cell research. Bill Frist was quick to counter the scientific basis for this claim which cause false hope, calling the statement "crass" and "shameful."

Tonight I wanted to see if Edwards had a more nuanced view. He spoke very generally, but did not make any exuberant claims about the prospect of stem cells therapies. He did add that it was important for the gov't to support other medical research in the context of global competition.

Weird Al annotated

Wouldn't you know it that when I turned on the radio this am, I'd hear Weird Al Yankovich singing "I think I'm a clone now":

Isn't it strange? Feels like I'm looking in the mirror

[This would suggest opposite chirality (handedness). Not true. But it's even harder to believe that your clone would automatically achieve your current age.]

What would people say if only they knew that I was
Part of some geneticist's plan

[Your self-esteem shouldn't be dependent on what others think.]

Born to be a carbon copy man

[Carbon paper became obsolete with the electric typewriter. Bad metaphor.]

There in a petri dish late one night
They took a donor's body cell and fertilized a human
egg and so I say:

[Somatic cell nuclear transfer doesn't involve fertilization.]

I think I'm a clone now

[If you have any doubt, you can see if your karyotype matches your "master."]

There's always two of me just a hangin' around
I think I'm a clone now
'Cuz every chromosome is a hand me down

[Not entirely true. You do inherit the mitochondrial DNA from the egg cell.]

Look at the way we go out walking close together

[Would this be narcissism?]

I guess you could say I'm really beside myself
I still remember how it began
They produced a carbon copy man
Born in a science lab late one night
Without a mother or a father
Just a test tube and a womb with a view
I think I'm a clone now
There's always two of me just a hangin' around
I think I'm a clone now
'Cuz every chromosome is a hand me down

Stem Cell Research Living Will

This piece of satire was written by Mike at his Crooks and Liars blog.

The Culture of Life Pledge

I hereby certify that neither I, nor any member of my family, including but not limited to: children, grandchildren, cats, dogs, etc. and any "after acquired" family will never, ever, under any circumstances (even with my fingers crossed) take or ingest any form of drug treatment or medical breakthroughs that are in any way associated with or connected to Stem Cell research. I am morally opposed to this type of medical malfeasance that our lord and Savior and Dr. Dobson most assuredly rebuke. I declare that I am of sound mind and body (as so it is hence with respect to the aforementioned family members) as we execute this irrevocable document and thusly said, this document shall not be challenged in a court of law. This is so despite the fact that I or said parties, would either now or in the future, be the beneficial recipient of such a repugnant life enhancing treatment . Only the Devil's greatest tool, i.e. "temptation" could lead us into sinful thoughts of partaking of this reprehensible policy.

____________________________
XXXXXXXX

____________________________
Rest of Family

____________________________
Pets

____________________________
Notary Public

____________________________
Witness

The question it doesn't raise is if federal funding, i.e. Medicare and Medicaid, will be used for these therapies.

"My View" piece in Metro New York

This is a section of the piece published in the Metro New York newspaper on cloning as it applies to stem cell research. I wanted to dispel some of the negative connotations associated with this word.

Here, you can read the piece in its entirety.