To demonstrate the applicability of EOS, Ellis also derived iPS cells from patients who have a neurodevelopmental disorder called Rett Syndrome. Rett Syndrome is an Autism Spectrum Disorder which affects almost exclusively females at an incidence of 1 in 10,000 and is one of the leading causes of mental retardation in girls. These Rett Syndrome iPS cells were green when placed under a fluorescent microscope and Ellis demonstrated that neurons can be generated from these Rett Syndrome iPS cells, the cell type affected in Rett Syndrome.

In conclusion, the EOS reporter will facilitate the generation of iPS and will be particularly useful for new labs going into this rapidly developing field. Furthermore, Rett Syndrome iPS cells that were also generated in this study will be invaluable for future drug screens that may be beneficial to those with Rett Syndrome.

Article:
Hotta, A. et al. Isolation of human iPS cells using EOS lentiviral vectors to select for pluripotency. Nature Methods 6, 370–376 (2009).

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1. The embryonic stem cells were derived from human embryos that were created for reproductive purposes, but were no longer needed for this purpose;
2. The embryonic stem cells were obtained consensually, without coercion or remuneration;
3. The embryonic stem cells were donated for research purposes, and for which the proper documentation can be assured (further details regarding proper documentation).

Importantly, the current guidelines would prohibit the NIH from funding human embryonic stem cell research if:

1. The research involves introducing human embryonic stem cells or human induced pluripotent cells into non-human primate blastocysts (the structure that gives rise to the embryo and placenta:);
2. The research includes the possibility that human embryonic stem cells or human induced pluripotent stem cells may contribute to the germ line (sperm or egg) of a non-human animal;
3. The embryonic stem cells are derived from other sources, such as somatic cell nuclear transfer, parthenogenesis, and/or in vitro fertilized embryos created for research purposes.

These guidelines try to strike a balance between scientists and the anti-embryonic stem cell position: on one hand allowing research involving cells destined for destruction, on the other limiting funding when it comes to other sources of human embryonic stem cells. 

There is no question, however, that these guidelines will allow the NIH to fund human embryonic stem cell research, and not surprisingly there is some objection from the political right.  In a press release the President of the Family Research Council stated: "The research that President Obama supports is not sound science and will destroy human life.”

These guidelines would also restrict funding for scientists pursuing research involving embryonic stem cells derived from non-reproductive in vitro fertilization, or somatic cell nuclear transfer (the cloning technology that brought us Dolly the sheep).  Again, not surprisingly, these limitations have provoked objections from stem cell biologists who argue that these technologies are important therapeutic avenues for the development of disease-specific human embryonic stem cells.

As mentioned above, these guidelines are now open for public consultation (comments to be mailed in the next 30 days to: NIH Stem Cell Guidelines, MSC 7997, 9000 Rockville Pike, Bethesda, Maryland, 20892-7997). 

To quote the fictitious President Josiah Bartlet of NBC’s The West Wing, “Decisions are made by those who show up”.  So, if you feel strongly about human embryonic stem cell research, either pro or con, get out your pen and start writing.  It’s time to get involved.

I would love to hear other people’s opinions on this topic, but to me the idea that someone could be so easily classified as either left or right wing, and then one would presume to know their opinion on all of these diverse topics is highly insulting to their intelligence.  This assumes that people are not gathering information on their own, processing it in an intelligent manner and then coming up with a reasoned and independent opinion.

Perhaps even more concerning, it seems the notion that people can be split along these artificially created lines (left or right) is reinforced so often throughout society that people seem to be more and more inclined to support the view of “their team” and thus become very rigid and entrenched in their ideology.  It’s as if open and reasoned debate has been abandoned in favour of some bizarre sport where two teams of differing policy clash in a no-rules match.

This adversarial approach may make for good TV, but it is doing a disservice to the level of debate on a range of issues.  Reasoned argument has given way to zingy one-liners that rally the troops and score points for your team.  In regards to embryonic stem cell research, if we are to believe this notion of left-right classifications, then left wing people are to feverishly support this research, while right wing people are to vehemently oppose it. 

So with this in mind, I would like to reach out to others that don’t feel like they need to be part of a “team”.  I am curious to hear from people that have thought independently about the issue of embryonic stem cell research and have come up with their own reasoned argument for why it should or should not progress, or perhaps under which circumstance or regulations it should be allowed to continue.  I am particularly interested in hearing from people who have views that might contradict the opinion that one might assume they have.  So (previously classified) right wingers who support ES research, and left wingers who do not, I would love to hear your opinion.  Your thoughts would be a great way to start a well reasoned conversation on this topic.

Just recently, another group reported that they could harvest mouse Germline Stem Cells from both newborn and adult female mice, and grow them long term in vitro (in culture dishes).  Importantly, they could reinject them into ovaries of sterile mice and restore fertility in the recipients.  As evidence fluorescent pups were born from previously sterile, non-fluorescent mothers who were injected with fluorescent Germline Stem Cells.

Together these studies indicate that female mammals have Germline Stem Cells which produce eggs long after birth.  Moreover, these Germline Stem Cells can be harvested, studied and grown in vitro, and injected into ovaries to restore fertility of recipients.  While both these reports used mice in their experiments, it’s very likely that human females have similar Germline Stem Cells that could be harvested, stored and used to restore fertility of a patient.  You can quickly appreciate the implication of this finding:  the future of reproductive technology may not be limited to in vitro fertilization and implantation, but may also include the use of Germline Stem Cells to restore fertility, in particular for people who are sterile from cancer therapy.  Conceivably, Germline Stem Cells could be harvested from patients before rounds of chemotherapy and radiation, and then reinjected after treatment.  An important medical advance, particularly for pediatric cancer survivors!   

Although in both of these examples the rationale behind the research, treatment of human disease, is certainly true, the constant demand to justify research projects in terms of their directly applicable endpoints has become a very real threat to basic biomedical research.  For decades, if not centuries, we have relied on basic scientific curiosity, a desire to understand the fundamentals of the world around us and of life itself, to provide the inspiration for research projects.  Over this time we have come to realize that great medical and technological achievements springboard off of years of basic research, research that is often done with no awareness or indication of the payoff that will follow in the years to come.

Despite the well established link between basic and eventual translational research there has been a creeping negativity and even contempt towards researchers who engage in the most basic of biomedical research studies.  The term “academic research” (commonly defined as research done without a practical purpose or intention) has become a term of derision.

Perhaps then we need a reminder of the great importance of so-called “academic research”.  I found this one publication from the Journal of Biological Chemistry published in 1962.  The title is: “Isolation of a mouse submaxillary gland protein accelerating incisor eruption and eyelid opening in the new-born animal.” Why did the researchers do this project?  Were they investigating tooth development in the hope of one day being able to regenerate adult teeth after facial trauma or tooth decay?  Perhaps.  But perhaps their reasoning was simply that they were just curious about what this protein was and what it did.  I wonder if during the 1960’s people would have made the argument that the tight economic times necessitated that projects like this would have to be cancelled.  After all it seems somewhat pointless or “academic” don’t you think?

Turns out this protein was subjected to further scrutiny over the years, eventually being named epidermal growth factor (EGF).  EGF was one of the first growth factors to be isolated, one of a family of factors later found to be involved in processes such as cell division, cell survival and cell movement.  This work set the foundation for the subsequent discovery that many forms of cancer showed extremely high levels of the receptor for EGF, making them dependent on its activity.  By the early 1990’s compounds that inhibit the EGF pathway were being discovered and put through the clinical trials process. In 2003 the first compound was approved by the FDA for therapeutic use against a specific form of lung cancer, and since this time compounds targeting EGF or similar pathways have entered clinical trials and are now used in the treatment of many different types of cancer.

This example is one of many similar stories, in truth the development of nearly every medical treatment can be traced back to basic research that was undertaken for a completely unrelated purpose, or perhaps for no purpose other than pure scientific curiosity.

As a stem cell researcher in a lab which is actively investigating the function of both normal neural stem cells and brain tumor stem cells, I have generally framed the purpose for my research in terms of the search for a novel cancer treatment.  In our lab we have projects that could be classified as basic fundamental research; where are neural stem cells located, how many are there, how can we distinguish them, how do they decide when to divide and when to stop?  We also have projects that would fit under the term “translational research”, such screening projects to look for new compounds and new pathways to target brain tumor stem cells. 

My personal project involves normal neural stem cells, an attempt to discover how in one division they can produce two progeny cells with vastly different identities.  I initially approached this question with the idea of applying this knowledge to brain tumor stem cells.  Perhaps being armed with an understanding of how normal neural stem cells make these decisions we could find new avenues to attack and if not kill the brain tumor stem cells, at least influence their decisions to produce a more benign cell type.

Although the motivation for my research remains in the context of finding a novel treatment for brain cancer, in light of the historical twists and turns of research discoveries I have to admit that I don’t really know how the knowledge that I acquire will eventually get used.  Likely the knowledge gained from my work will add to what others find over the next 5-10 years, clarifying the pathways and processes that neural stem cells use to produce new neurons in the brain.  This knowledge might be applied to cancer research but it is equally likely that it will instead be used to design a treatment for Parkinson’s or to repair areas of the brain damaged after a stroke.  Or someone might draw a connection between what I find in neural stem cells and what they find in cardiac stem cells and the research may take off in an entirely new direction.  Or as in the example above, perhaps the eventual application of this research is so distinct from my original quest that I can’t even envision what it might be right now. 

So in light of this uncertainty, when asked about why I do the research I do, maybe I should cease to describe my research in terms of cancer treatment. In support of the principles and historical success of basic research I should be proud to simply say “because I’m curious”.

Stem cells can be derived from many adult organs- for example the stem cells derived from the blood and the nervous system.   These cells have tremendous capacity/potential to treat once incurable diseases.  The best treatment for some forms of leukemia remains a bone marrow transplant from a healthy donor after completely erasing the patient’s bone marrow (and hopefully any leukemia cells).  This technology has been around for many years, and is now being applied to other diseases such as multiple sclerosis and is based on using healthy adult stem cells to replenish the diseased blood of a patient.  The same can be said for neural stem cells of the central or peripheral nervous system, though for clinical application these cells remain unproven.   The idea here is that adult neural stem cells could be harvested from a patient, or donor, and used for the treatment of spinal cord injury, or neurological diseases such as Parkinson’s.

Due to the success/potential of these stem cell therapies, the idea that embryonic stem cell research is no longer required is being promoted in comments posted on this blog, and on many others that discuss stem cell research.

Critics argue that, all current stem cell based treatments use adult stem cells, demonstrating that embryonic stem cells aren’t needed for today’s therapies.  More importantly, they advocate that even if adult stem cells are deficient in some way, there now exists reprogramming technology where mature cell types (like skin fibroblasts) can be changed to induced Pluripotent Stem (iPS) cells which behave in many ways like embryonic stem cells. Proponents of this position argue that this discovery means that iPS cells can be substituted for embryonic stem cells in any current or future therapy.  Following the example above for the treatment of spinal cord injury or Parkinson’s disease, iPS cells can be made from the patient’s own skin cells, reprogrammed into neural stem cells, then potentially used for therapy.  They state, accordingly, no embryonic stem cells need be used, ever, for research or therapeutic purposes, for any disease.

On the surface this is a reasonable argument, one which many people are inclined to support.  But it comes with some significant concessions which undermine the basic premise of this argument.

The first is that current adult stem cell and iPS cell technologies are largely based on research using embryonic cells.  For example, therapy utilizing adult blood stem cells (like bone marrow transplants) would not exist without understanding how the blood system develops and operates - work done with human embryonic tissue dating back as far as the 1800s.  Similarly, iPS cells would not exist if not for our understanding of human embryonic stem cells, and the factors/techniques required to support their growth.  So the first concession must be that embryonic stem cell research HAS had a major and beneficial impact on our current medical technologies, and without research using embryonic cells we would not have the knowledge needed to use adult stem cells or iPS cells in medicine.

The second concession has one of two components: either the belief that we currently know everything of value that we will ever know from embryonic stem cell research, or that iPS cells and embryonic stem cells are totally and completely equal, in every aspect.  Fundamentally, there can be no other SCIENTIFIC argument for abandoning their study, unless there is there is nothing else to learn from their use, or something completely equivalent can be used as a substitute. 

No reasonable argument can be made to suggest that there is nothing else that can be learned from studying embryonic stem cells, but what about the argument regarding the substitution of iPS cells?

Dr. Yamanaka is a world expert when it comes to iPS cell technology.  His lab was the first to report the generation of iPS cells from both mouse and human skin cells.  In his analysis of human iPS cells, he reported that the difference between skin cells and embryonic stem cells is, at least, a five-fold difference in the expression of ~6000 genes.  This result means that dramatically changing the expression level of at least ~6000 genes is the difference between skin cells and embryonic stem cells.  Interestingly, when the same analysis was applied to iPS cells and embryonic stem cells, they discovered that at least ~1200 genes showed five-fold differences in gene expression levels.  This means that over 1000 genes expressed by iPS cells are expressed differently in embryonic stem cells.  Clearly then, the anti-stem cell research position must concede that iPS cells are not identical to embryonic stem cells in their gene expression profile, and one might wonder in what other ways the two cell types differ.  This is a fundamental principle in all scientific research.  No experiment can be interpreted without the proper controls.  The only way we will ever be able to understand the differences between iPS cells and embryonic stem cells is to use both types of cells and compare them to each other.

Adult stem cells are valuable for research and therapeutic purposes, and their clinical application must be pursued for every possible disease.  iPS cells are a burgeoning and promising field and their use in medicine and research must be supported in every way, but they are not currently a substitute for embryonic stem cells.  Further, the technologies that support the therapeutic application of adult stem cells and iPS cells are based largely on embryonic stem cell research, and it remains unknown which cell type will be most applicable for treating different types of disease.

You might ask yourself the following questions: What if in the 1800s we had abandoned the research which revealed how the blood system develops; would we currently have the knowledge to perform bone marrow transplants for the treatment of leukemia?  Or would we be dependent on radiation and chemotherapy which, all too often, fail to cure the disease?  Similarly, if we forsake embryonic stem cell research today, what future therapies might never have the opportunity develop in the next 100 years?  Of course time will tell, but one fact is certain: if we abandon the research, we will never find ways of using it for therapeutic purposes.

One disturbing trend though, on both sides of the debate, is the continued use of highly inflammatory words or statements in order to sway, or scare, people to agree with a particular viewpoint.  I have repeatedly heard from the anti-embryonic stem cell research side that it is wrong to exploit or kill "babies" for this research.  The term “baby” seems to be more emotional than precise, used to conjure up an image of a newborn to distract from the issue at hand.  Even a cursory look into the current source of embryonic stem cells, frozen embryos left over from in vitro fertilization, would reveal that this tiny ball of cells in no way resembles a human baby.  Indeed, a recent publication identified the time period 6 days after fertilization in a culture dish, a point in which the blastocyst is a tiny ball consisting of between 75 and 145 cells, as the optimal time to isolate ES cells. Clearly a tiny ball of cells growing in a culture dish cannot reasonably be equated to a human baby.

On the pro-embryonic stem cell research side though one must admit that the blastocyst does have the potential to implant and develop into a human baby if it was placed into the right environment.  So in essence the debate distils down to determining at what stage of human development one becomes a “person”, with all the rights and protections that this entails.  How would one determine this?  General characteristics that can be ascribed to a “person” would certainly include consciousness, self-consciousness, and the ability for thought and reasoning.  Does a ball of cells possess these characteristics?  Undoubtedly not.  But can we accurately define exactly when these characteristics arise during human development.  Again the answer is no.

On the pro-embryonic research side an argument can be made that although we do not know exactly when the developing human becomes a “person”, it is definitely not at the early blastocyst stage in which ES cells are harvested, and thus research should continue unfettered.  On the anti-embryonic research side there is an argument to be made that if we don’t know when “personhood” is attained, perhaps it is safer to error on the side of caution and offer protection from the moment after conception.

This issue is complex, overlapping the domains of the biological sciences and philosophy, and certainly worthy of rational, reasoned debate.  The reality is that many of us have preconceived ideas of where we fall on the political and social spectrum, left or right wing, designations that ironically often have more to do with where we were born, and how we were raised, rather than a conscious and thoughtful decision.  So I will not attempt to sway your decision, but I urge you to step away from previously held positions, and the undue influence of inflammatory propaganda, to take some time to consider the issue for yourself. Consider how your decision might impact not only future research, discovery, and health care, but other related issues such as assisted reproduction, end of life care and euthanasia, where the definition of what it means to be a “person” also plays a central role.
 

 Much has changed in human embryonic stem cell research scene since 2001. An estimate of 400 to 1,000 new human embryonic stem cell lines had been established in other countries or on US soil through private funding. These lines provide many advantages to the Bush’s approved cell lines, such as ease of culture or ease of differentiation into therapeutically relevant cell types. Newer lines are also made without non-human animal material. Of the most the interest, many of these lines have genetic predisposition to certain diseases, which allows the study of the progression of these diseases from early development, all in a petri-dish. However, until now, federally funded American scientists, and their collaborators, were restricted from working on these cell lines.

What President Obama’s executive order means, essentially, is that American researchers can now apply for NIH funding to work on the new derived cells that had been created since the 2001 ban. Scientists would have more resources to study these lines and further understand basic human development.  Furthermore, President Obama has asked the NIH to develop guidelines which would regulate human embryonic stem cell research using federal funding. A legislation that allows the research using new human ES cell lines, using federal money, from leftover IVF embryos, is also under progress.

As a member of the research community, I am very excited about the future potential to understand normal development using human embryonic stem cells, and the administration’s effort in redefining stem cell research guidelines in this ever-changing field. At the present, embryonic stem cells remains our best tool to study normal development and progression of diseases.  Even with induced-pluripotent stem cells, which are made from adult cells that were reprogrammed to a pluripotent state and made to be “identical” to ES cells, we are still at the early stages of fine-tuning such programming and understanding its regenerative capacity - and it will be impossible to study iPS cells without cautious study of natural embryonic stem cells. President Obama’s order to lift the previous ban opens avenues for such studies, and brings hope to the use of stem cells as potential therapies for many devastating diseases.

Main sources- http://www.nature.com.myaccess.library.utoronto.ca/news/2009/090309

Dear House Republican Leader John Boehner,

I am writing in response to your public statement released March 9th, 2009 regarding President Obama’s decision to reverse the limits on federal funding for human embryonic stem cell research.  Specifically your comments:

“The president has rolled back important protections for innocent life […],  I am hopeful that the president will re-evaluate this and other controversial decisions that put government at odds with the sanctity of human life […]Congress and the Administration should support bipartisan solutions like Rep. Randy Forbes’ Patients First Act, which would promote stem cell research that is actually getting results.”

On Monday, President Obama reversed President Bush’s policies prohibiting the use of federal funds to support research involving human embryonic stem cell lines created after August 9th, 2001.  This change in policy now allows NIH funds to be directed to American researchers to pursue the groundbreaking science that is hoped to generate better, longer lasting therapies for the most serious health issues facing North Americans: diabetes, heart attack and stroke, Alzheimer’s disease, and spinal cord injury to name a few.  This decision in no way “rolls back important protections for innocent life” as you assert, and your statement does a disservice to, and misinforms the constituents you represent and the American electorate as a whole.

Strictly speaking the United States Federal Government has no limits regarding the source of human stem cells, and has no laws affording any protections to the American people when it comes to the tissue and techniques used in embryonic stem cell research.  As such, President Obama cannot “roll back protections”.

On two separate occasions however, legislation which sought protections to prenatal life and patients was passed by both House and Senate, but vetoed by President Bush.  And, it is interesting to note, also opposed and voted against by you.  Your own voting record demonstrates that when it comes to bipartisan, reasonable and safe limits to the source of human embryonic stem cells, you favor socially conservative partisan politics rather than the protection of vulnerable people and tissue.

Your support of the Randy Forbes’ Patients First Act is equally disingenuous.  Despite the title, this legislation would enact no protections to patients, tissue donors, doctors or scientists; rather it seeks to ban the use and derivation of human embryonic stem cells for research and therapeutic purposes.  As I am sure you are aware, the first clinical trial using human embryonic stem cells for the treatment of spinal cord injury is now underway.  This trial is fueling the hope that loss of function from spinal cord injury might be partially, or fully reversible.  Yet, the legislation you support would quash any such possibility for the sake of your personal ideologies.  From this it is abundantly clear that you do not have patients’ best interest in mind.

Finally, as someone who is pursuing stem cell-based scientific research, it is disheartening to read your prejudice against this work.  You would seek to support “stem cell research that is actually getting results” however you also seek to ban some of the most promising therapeutic approaches.  Scientific research is the pursuit of knowledge and application of discoveries, and predicting what preclinical strategies will and will not actually get results is arrogant and presumptuous, especially when these predictions are guided by personal standards.  If you are truly devoted to improving the lives of your constituents and their children, I call on you to oppose any outright bans on the use of stem cells in research and therapy, and support legislation that actually protects donors from coercion, tissue from exploitation, and doctors and scientists from harassment while promoting therapeutic avenues that patients so genuinely long for.

Respectfully,

Ryan Ward
PhD Candidate,
University of Toronto,
Toronto, Canada.

Ryan Ward is a Ph.D. Candidate in the Lab of Dr. Peter Dirks at the Hospital for Sick Children in Toronto, Canada.  He studies cancer stem cells in adult and pediatric brain tumors and regularly draws upon knowledge and methodologies generated from the study of normal stem cells.
 

President Obama is planning to sign an executive order on Monday rolling back restrictions on federal funding of human embryonic stem cell research, according to sources close to the issue.

Although the exact wording of the order has not been revealed, the White House plans an 11 a.m. ceremony to sign the order repealing one of the most controversial steps taken by his predecessor, fulfilling one of Obama’s eagerly anticipated campaign promises

For the rest of this article, please see here.