The Scientific Activist

That could easily have been the shared title of a pair of articles in today’s New York Times discussing the science and political implications of two very significant stem cell papers published online yesterday. The biggest offender was Sheryl Stolberg:

It has been more than six years since President Bush, in the first major televised address of his presidency, drew a stark moral line against the destruction of human embryos in medical research.

Since then, he has steadfastly maintained that scientists would come up with an alternative method of developing embryonic stem cells, one that did not involve killing embryos.

Critics were skeptical. But now that scientists in Japan and Wisconsin have apparently achieved what Mr. Bush envisioned, the White House is saying, “I told you so.”

Conservative Republican presidential hopefuls like former Gov. Mitt Romney of Massachusetts are breathing a sigh of relief. And opponents of embryonic stem cell research are congratulating themselves.

I think I just threw up a little bit.

Oh no… there’s more!

On Tuesday, senior aides to Mr. Bush said he drove the experiments by holding his moral ground.

“This is very much in accord with the president’s vision from the get-go,” said Karl Zinsmeister, a domestic policy adviser to Mr. Bush who kept the president apprised of the work. “I don’t think there’s any doubt that the president’s drawing of lines on cloning and embryo use was a positive factor in making this come to fruition.”

OK, OK, that last part wasn’t Stolberg’s fault: it was just the Bush Administration being completely fucking insane! Yes, that’s right: by doing everything in his power to prevent embryonic stem cell research from happening, George Bush is now inexplicably its savior. The Administration is able to claim this with a straight face despite the fact that (1) this isn’t the end of the embryonic stem cell debate (see below) and (2) one of the two studies reported yesterday (and the original work that directly led to these breakthroughs) comes from Japan! Maybe what the Administration means is that by inhibiting embryonic stem cell research in the US to such a large degree, it all but ensured that this major breakthrough would come from overseas.

Getting back to the media coverage, I should note that although Stolberg has a tendency to write these disappointingly credulous articles, I have to admit that I reproduced only the worst parts here. Surprisingly, though, Gina Kolata’s article in the Times wasn’t much better. This is a shame, because the two papers published today are quite significant and very interesting.

I won’t go too much into detail about the science, since there already some good explanations in the blogosphere (Pharyngula, Denialism Blog, The Daily Transcript, Hope for Pandora) and in Cell. One paper (Takahashi et al.) was published in Cell and came out of Shinya Yamanaka’s group in Japan. The other (Yu et al.) was published in Science and came out of James Thomson’s group in Wisconsin. Thomson’s group was the first to isolate human embryonic stem cells in 1998, and Takahashi’s and Yamanaka’s work last year on mice first validated the approach published yesterday. Both groups yesterday reported infecting fibroblasts from grown humans with retroviruses containing four key genes. The expression of these four genes transforms these fibroblasts into “induced pluripotent stem (iPS) cells”, which are very similar to totipotent embryonic stem cells. Like embryonic stem cells, these iPS cells can differentiate into any type of tissue and (in mice, at least) can give rise to an entire organism. Interestingly, both research teams accomplished this feat with a different set of four genes. Both used Sox2 and Oct 3/4, genes that encode transcription factors (proteins that control the expression of other genes). In addition, Takahashi et al. included two other transcription factors: Klf4 and c-Myc (c-Myc is a notorious oncogene that when mutated or overexpressed can promote cancer development). This was the combination of four genes used in their original mouse studies, and I think that many scientists were surprised that this strategy worked in humans considering some significant differences between human and mouse stem cell biology. Instead of Klf4 and c-Myc, though, Yu et al. used Nanog (a transcription factor) and Lin28 (an RNA-binding protein involved in regulating the translation of RNA into protein). While Lin28 seemed to improve the efficiency of their system, it was not necessary for the creation of iPS cells.

The latest developments are very significant, and they will have a major impact on embryonic stem cell research. And, they have already made an impact on the debate over embryonic stem cell research, although most of this has been trumped up by the media. This certainly isn’t the first time that some newfangled finding has been heralded as the be-all and end-all to the stem cell debate. Here are a few reasons why those who claim the debate is over now are way out of line:

Although these iPS cells are very similar to embryonic stem cells, they are not identical. Takahashi et al. found that “DNA microarray analyses showed that the global gene-expression patterns are similar, but not identical, between human iPS cells and hES cells.” Yu et al. reported that when injected into mice, different iPS lineages varied in how they tended to differentiate.
The retroviral technology used in the current studies is not appropriate for clinical applications. Scientists cannot control where the retrovirus integrates into the host cell’s DNA, so it can potentially disrupt important genes, leading to complications down the line (cancer being the most likely). Also, Yamanaka reported earlier this year that 20% of the offspring of iPS-generated mice developed tumors at a young age, although this was attributed to c-Myc (one of the four genes used in creating iPS cells) being reactivated. The protocol of Takahashi et al., at least, avoids this particular downfall by not using c-Myc.
This is the big one: iPS cells appear to be totipotent. That means they are fully capable of forming embryos themselves (this has been demonstrated in mice). If these cells are no different from human embryonic stem cells in that respect, I’m not really sure what ethical issues are being addressed here.

In short, these findings in no way validate Bush’s current ban on federal funding for human embryonic stem cell research (in fact, they happened in spite of the ban, since this work would not have been possible without prior and ongoing research on human embryonic stem cells). But, these findings are very cool and very significant. Although the press coverage has focused on clinical applications, these latest advances will be most valuable for basic research, allowing scientists to generate stem cells from patients with a variety of diseases to better understand the basic pathology. And, this will give scientists another effective tool for studying human development. This will surely lead to clinical breakthroughs down the line, and although the technology in its current form is not appropriate for therapeutic uses, after some tweaking it might be. But, not yet.

Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K., Yamanaka, S. (2007). Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors. Cell, 131(5), 861-872. DOI: 10.1016/j.cell.2007.11.019 (free access)

Yu, J., Vodyanik, M.A., Smuga-Otto, K., Antosiewicz-Bourget, J., Frane, J.L., Tian, S., Nie, J., Jonsdottir, G.A., Ruotti, V., Stewart, R., Slukvin, I.I., Thomson, J.A. (2007). Induced Pluripotent Stem Cell Lines Derived from Human Somatic Cells. Science, 318(5858), 1917-1920. DOI: 10.1126/science.1151526

Comments

#1 Beverly Nuckols
November 21, 2007

You misunderstand the Jaenisch methods. The cells were amenable to forming “viable chimaeras, can contribute to the germ line and can generate live late-term embryos when injected into tetraploid blastocysts.” They did not have the self-directed organization of an organism in themselves, any more than any embryonic-like stem cell.
#2 Mike
November 21, 2007

I always assumed the big ethical objection to embryonic stem cells is that they came from embryos, not that they could become embryos. Totipotent stem cells created from something besides embryos may be okay. Of course, once they are made into embryos, then all the claims of importance of embryonic life are in full force. I think the real answer lies in the process to create embryos, and how it’s seen by those who judge it.
#3 Nick Anthis
November 22, 2007

Being someone who doesn’t share those objections and someone who is concerned about the undue consideration that religious ideas are given in formulating our science policy, I can’t really speak to that. I will note, though, that Wernig et al. were able to grow mice that consisted of only cells descended from iPS cells. Sure, they had to inject the iPS cells into tetraploid blastocysts, but if you create an embryo by cloning and leave it in a dish, it’s not going to grow and develop into an independent organism either. The ethical divisions here seem somewhat superficial.
#4 Ex-drone
November 22, 2007

Haven’t you heard? Bush didn’t just cleverly inspire and shape the iPS stem cell discovery. He has planned out the discoveries of the cures for Alzheimer’s and cancer. Be assured that when those discoveries are announced, the social conservative journalists who are in the know will explain Bush’s involvement.
#5 Grumpy Steve...
November 22, 2007

Bush claims what? Are we to hear Bush invented stem cell research?

We have lost the edge in this field. We lost this lead because of political pressure from war criminals claiming the highest ideals, and respect for human life? Godwin prevents me from going further. Further, the comedy of this situation, as blabbered about by Bush administration flak, Herr Zinsmeister, considering that the administration was until quite recently all atwitter in its opposition to chimeras and the indecency of it all, would be side splitting in it’s heartburn hypocrisy if it were not backed by the force of law.

When politicians lost in Religio/political tomfoolery decide to play doctor, who will dare practice medicine?
#6 Jim Hu
November 22, 2007

Oh come on, Nick. Zinsmeister’s hyperbole doesn’t justify yours, esp. since you’re a scientist and he’s not. This work wouldn’t have been possible without the human work based on embryos? I think not.
#7 Nick Anthis
November 22, 2007

Without a doubt, I can say that this work would not have been published this week without prior work on human embryonic stem cells. I suppose scientists may have stumbled onto this eventually (who knows how many years down the line?), but to get there they would basically be shooting in the dark without knowing what we already know from prior work about culturing and analyzing human embryonic stem cells.
#8 Beverly Nuckols
November 22, 2007

Perhaps my first reason for deciding that I don’t want to kill members of our species was religious, but I’ve since come to understand the concept of the right not to be killed on several more levels. Surely you aren’t saying that moral reasoning – such as the belief that science is a worthy goal – can only come from religious reasoning?

I’ve always thought the search for pluripotent cells was a distraction – what we want are the multipotent cells and precursors for each specialized cell, tissue and organ.

BTW, Yamanaka proved the concept using murine ES, without hES.
#9 Nico
November 23, 2007

While I share your contempt for the Bush administration, I find some criticism here largely unfair and border on misrepresentation.

Bush was fine with research using stem cell lines already in existence. He was against research using stem cell lines that were yet to be created. He believed that in no way should the federal government participate in potentially life-saving research when it entailed the sacrifice of embryonic life.

In light of that, it doesn’t matter if iPS could develop into embryos. As long as they weren’t harvested from embryos that had to be, in effect, destroyed, no killing was involved. This is a significant difference when iPS research is compared with embryonic stem cell research.

Bush feels vindicated by results of iPS research in Japan. This is not because he claims responsibility for them. Instead, he feels that, because of his policy, federal money was not involved in the killing of embryos that was unnecessary for the development of medical interventions that required totipotent cells. He at least prevented the participation of the federal government in what he believed was an inhumane act.

Lastly, yes, maybe it would’ve taken less time to develop these techniques if scientists were allowed to research on newly created embryonic stem cell lines. But his position is that speed is a price he is willing to pay for saving embryonic life.

I do not share Bush’s belief in many of the premises he has laid down. But in the context of this piece of news, you can’t say he has proceeded illogically from his premises.

I despise Bush with a passion. However, in the interest of fairness, debate can only proceed if ideas are not misrepresented just so it would be easier to dismiss them. It would be stupid to assume that stupid people never make sense. Let us not insult our own intelligence.
#10 Nick Anthis
November 23, 2007

Let’s take another look at the quote from the Administration:

“I don’t think there’s any doubt that the president’s drawing of lines on cloning and embryo use was a positive factor in making this come to fruition.”

The Bush Administration is clearly trying to take partial credit for these advances–a position that is utterly laughable. Since the beginning, Bush has misled the public on embryonic stem cell research, most notably by wildly exaggerating the number and quality of human embryonic stem cell lines available for federally funded research. If you still insist on believing this delusion that he had anything to do with the recent findings, I would encourage you to talk to scientists in the field and see what they think.
#11 Mr. Gunn
November 23, 2007

Well, Nick, I didn’t think it would take long for the Religious Right’s team of blog commenters to find its way here. As you can probably tell, and I can assure you from my experience with her, Mrs. Nuckols is just a Catholic troll.

The last thing she was upset about was how Nature wouldn’t publish her friend’s apologia for the Catholic position on stem cell research.

It’s interesting science that they did, but gee, maybe that effort would have been better spent learning how to actually do something with the cells, instead of finding a different way to make them?
#12 Beverly Nuckols, MD
November 23, 2007

Much worse- I’m a Baptist who finds common ground with pro-life Catholics, atheists and libertarians.

Y’all do realize that far from being hampered, Thomson did his basic science on his own batches of (NIH approved and funded) embryonic stem cells, don’t you?

I guess he could have spent the time figuring out how the elite of the future could have patient specific stem cells through SCNT. But where would he – and the future patients – get the oocytes? Even labs that are buying eggs or offering free IVF for eggs aren’t able to talk women into it.
#13 B. Gillin
November 24, 2007

“Being someone who doesn’t share those objections and someone who is concerned about the undue consideration that religious ideas are given in formulating our science policy, I can’t really speak to that.”

The personhood of the human embryo is far from a “religious idea,” unless, perhaps, you suspect that the authors of dozens of biology textbooks are secretly doing pro bono work for the Christian Coalition?
#14 udo schuklenk
November 24, 2007

With re to the discusison re the personhood of fetuses, you might find a commentary on my blog useful reading. http://ethxblog.blogspot.com/2007/11/stem-cell-wars-its-science-stupid.html
#15 B. Gillin
November 24, 2007

So…what you have there is the presentation of an idea I’ve already refuted. Useful reading? Eh…no.
#16 Jim Hu
November 25, 2007

Hope you had a good Thanksgiving and got to see the Ags beat Texas! Back to the disputation…

Without a doubt, I can say that this work would not have been published this week without prior work on human embryonic stem cells.

You’re still just asserting this without pointing to anything that is specific to human ES cell studies that would not have been figured out from a combination of prior work on mouse ES cells and the same final step with human cells. Also, going from “not possible” to “not published this week” is a pretty big goalpost move.

The operative point here is that a huge amount of what we know about ES cells in general is from mouse model systems, for the usual reasons why model systems are useful. Including the earlier work you cite. I’d hardly call the immense amount of prior and ongoing mouse work “shooting in the dark”.

Now, maybe I’ve missed something that specifically was needed from human ES cell studies…after all, I’m not in the field. You make it sound like there are lots of things in this class. Just name some. It doesn’t have to be comprehensive.
#17 Nick Anthis
November 25, 2007

Hi Jim,

Happy Thanksgiving to you too. I went down to London to watch the game with the London A&M and UT clubs. It was glorious!

Getting to the point about differences between human ES cells and mouse ES cells, I’m certainly not a stem cell biologist either, but a few key points emerge from examining the two papers. This is from the Takahashi et al. paper:

hES cells are different from mouse counterparts in many respects (Rao, 2004). hES cell colonies are flatter and do not override each other. hES cells depend on bFGF for self renewal (Amit et al., 2000), whereas mouse ES cells depend on the LIF/Stat3 pathway (Matsuda et al., 1999; Niwa et al., 1998). BMP induces differentiation in hES cells (Xu et al., 2005) but is involved in self renewal of mouse ES cells (Ying et al., 2003). Despite these differences, our data show that the same four transcription factors induce iPS cells in both human and mouse. The four factors, however, could not induce human iPS cells when fibroblasts were kept under the culture condition for mouse ES cells after retroviral transduction (data not shown). These data suggest that the fundamental transcriptional network governing pluripotency is common in human and mice, but extrinsic factors and signals maintaining pluripotency are unique for each species.

These could be trivial differences, but they are specific, and we would not be aware of them without previous work on human ES cells. One of the differences listed here (the differing role of bFGF) is particularly significant, because this was used directly in both papers. If you look at the protocol for generating human iPS cells in Takahashi et al., for example, a few days after retroviral transduction, cells are cultured in a medium containing bFGF. As the process takes a full month from transduction to harvest, I would argue that it would have taken them much longer to optimize their protocol without this one piece of information. And, this is in the paper that one would argue came most directly from mouse work.

Yu et al. based their protocol on the Thomson lab’s preexisting protocols for working with human ES cell. This also included bFGF, but, more significantly, they identified the four genes they used in their protocol by examining genes known to be upregulated in human ES cells. How much this varies between human and mouse, I don’t know, but this approach apparently paid off, as the Yu et al. procedure on the surface appears more promising. And, of course, it would be very difficult to argue that the Thomson lab’s expertise with human ES cells did not contribute to their findings in a major way.
#18 Apikoros
November 26, 2007

In regard to the question of whether the human iPS cells could have been created without prior work on human ES cells, I think it’s important to point out that mouse ES cells were first reported in 1981. Human ES cells were not published until 1998.

The biggest reason that it took 17 years of effort to create human ES lines is the requirement for bFGF instead of LIF as a mitogen. The morphology and growth characteristics of human ES are also quite different.

Now, it has taken less than a year for Yamanaka’s mouse iPS method to be successful in human cells. Without the knowledge of how human ES cells grow, what they look like, and what mitogens and nutrients they require, reprogramming of human cells would also have taken years.
#19 rbmoney
November 26, 2007

One simple question I would like to pose. Why was George Bush allowed to have such an influential input into something that is purely scientific, of which he has absolutely NO knowledge of what so ever? I’m no scientist and understand very little about stem cell research. Even at that, my morals would not prevent me from allowing science to do research into any field that might save lives or allow persons to lead more productive lives. This idiot of a President we have seems to think he possesses such God-like qualities, that everything that is done in this country must have his blessings or it is a no-go.
Along with Reagan, the daddy Bush, and the current Bush, we have been set back at least 20 years in the scientific and environmental fields. Those idiots with their comic book mentalities have all but destroyed this country. It pains me terribly when I think of how far we could be right now, if only the country had been ruled by people with real vision.
You scientists’ had better figure out a way to get around Big Oil and our Fascist government or you’re going to have to move where the real science is. . . in Japan, Germany, and Russia.
I suppose I have strayed quite a bit from the stem cell issue, but it all boils down to the same problem. Big Oil and our Fascist(like it or not)government!!
#20 Jim Hu
November 27, 2007

Thanks for the clarification, Nick and Apikoros.
#21 Kumi
December 4, 2007

Successful
Thanks…
#22 Dov Henis
January 19, 2008

On Stem Cells And Human Cloning Research
or
On Settling A Scientific Issue in nature.com
18 January 2008

Comment On Human Cloning Research

http://www.nature.com/news/2008/080117/full/news.2007.350.html

It is about time that science make the Life Evolution mental leap, that scientists swallow and digest the common-sense realization that it is not cells that are the organisms, that the outer cell membrane is an organ, plain and simple, and that it is the genome that is a living complex organism, consisting of (by now) interdependent symbiotic living member genes.

See http://blog.360.yahoo.com/blog-P81pQcU1dLBbHgtjQjxG_Q–?cq=1&p=372

Therefore there is still a vast empty void of knowledge/experience which is a prerequisite for orderly progress of work on cloning. The still missing required knowledge is the assessment of effects-relationship of the age of the genome-genes on its-their constitution and functioning.

Dov Henis

PS: Following rejection of most of my posted above blog title #372 by Nature News Moderator because ‘it’s too long’, I suspect that I now meet another rejection mode:

When I’m cookie-identified, upon entrance to nature.com, and ‘submit’ my above comment posting, the reaction is ‘Page not found’. I reckon that this time the Nature News Moderator rejects it because the comment is too short…

Dov Henis
#23 Dov Henis
August 3, 2010

Cost Of Disregard Of Genome’s Definition

A. “Setback in non-embryonic stem cell use”
http://www.bionews.org.uk/page_67367.asp?dinfo=rWfnKzZO4tkhJf38jsJ5EeJo

B. From “03.2010 Updated Life Manifest”
http://www.the-scientist.com/community/posts/list/54.page#5065

- Genome: a multigenes organism, comprising the genes operational replicas-work-patterns, an organ of the primal Earth’s genes, consisting of a cooperative commune of its member genes. (2nd stratum organism)

- The RNA genes are life’s prime strata organisms. They evolved their DNA-images as their organ, their continuously updated operational worklogs primal Earth’s organisms libraries, and genomed them, i.e. nucleusized them, and celled them with their other organ, the outer cell membrane.

- It is the RNA genes and their DNA replicas, life’s prime strata organisms, that evolve, and the evolution of genomes, the 2nd stratum of life, and of the 3rd life stratum cellular organisms, is an interenhancing consequence of their genes’ evolution.

C. These are some of the costs of the obstinate continuous disregard of the “Life Manifest”.

Embrionic stem cells are formed and imprinted in embryo, with a clean history slate. Other stem cells are formed and imprinted in an organ, with the imprinted organ history slate.

Dov Henis
(Comments from 22nd century)

Cosmic Evolution Simplified
http://www.the-scientist.com/community/posts/list/240/122.page#4427

http://profiles.yahoo.com/blog/2SF3CJJM5OU6T27OC4MFQSDYEU?num=5&max=160&start=0