Human-pig embryo approved in UK

The "cybrid" or hybrid human-animal embryos are created in the laboratory by Somatic Cell Nuclear Transplantation, using emptied eggs from animals and the nuclear and cellular DNA from humans.. We know that there are currently experiments on-going with the human embryos made using emptied cow eggs (more on the "ease" of making these embryos, here), and now the British have authorized the development of pig-human embryos.

The experimenters admit that the problem will be achieving embryos and embryonic stem cells that do not contain DNA left from the egg. Proving the purity and "human-ness" of the stem cells will be a complication that I do not believe they will be able to overcome, at least for transplantation into humans, except possibly in the case of severe, last-hope disease and trauma.

The ethical debates about xeno-transplants and treatments using living organs, cells and tissues from animals carry the risks of transmitting animal diseases that humans have no immunity for and the development of new strains of disease that cross species lines. Ethicists have predicted that at least the early patients will have to live their lives in isolation at the worst, and have life-long surveillance at the best. (more on the debate, here and here.)

However, the researchers will probably be able to develop other uses, such as the early warning chemical weapon detection systems that are being developed by our own military, using human embryonic stem cells.

Rather than humanitarian and medical hope, I believe that time will show us that the research is the result of pure greed, with each lab hoping to come up with a product that can be patented and sold. I'm disappointed that the courts and "ethics" bodies in the US and UK have allowed these patents of human organisms. The drive to "create" new human cells and artifacts using human DNA is the logical outcome.

Coffee drinkers live longer

If true, I may live forever.

According to the Washington Post,

The researchers found that women who drank two or three cups of caffeinated coffee daily had a 25 percent lower risk of death from heart disease during the follow-up (from 1980 to 2004) than non-drinkers. Women also had an 18 percent lower death risk from a cause other than cancer or heart disease compared with non-coffee drinkers.

For men, drinking two to three cups of caffeinated coffee daily was a "wash" -- not associated with either an increased or a decreased risk of death during the follow up, from 1986 to 2004.

The lower death rate was mainly due to a lower risk for heart disease deaths, the researchers found, while no link was discovered for coffee drinking and cancer deaths. The relationship did not seem to be directly related to caffeine, according to the researchers, since those who drank decaf also had a lower death rate than those who didn't drink either kind of coffee.

Translation of Yamanaka, Yu "induced Pluripotent Stem Cells" (Revised)

Scientists who report their findings are expected to discuss the problems as well as the outcome of their research. This is usually found in the "Discussion," "Conclusions" or "Results" section of the paper. This is the best place to figure out what the researches intended, what they did and what the report means. (Then you go back and check to see if they proved what they "discussed." And then, you wait for other labs to confirm it.)

The actual (Takahashi et al., "Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors," Cell (2007).) Cell article on reprogrammed adult fibroblast skin cells, the "induced Pluripotent Stem Cells) or "iPS," is available for free, here. The Science Magazine report about similar work by James Thomson from Wisconsin (the researcher who reported the production of human embryonic stem cells in the first place) is supposed to be published November 22, 2007. (Editorial note 11/30/07 – Science published the Thompson and Yu report the same day that Tamanaka's report was published, two days ahead of schedule. See my “translation,” here.)

To the best of my understanding, here's a translation into layman's terms about what the Takahashi/Yamaka report means:

While it took a lot of cells and more time than the researchers first expected because the human iPS grew much slower than the mouse iPS,

1. The cells that grew looked and functioned like human embryonic stem cells with a few minor differences,
2. They believe they proved that their technique is responsible for all the new pluripotent cells that were found in their cultures(there weren't any cells from another culture introduced accidentally or on purpose and which would make them look more successful than they were),
3. The cells could be directed to develop nerve cells and heart cells,
4. They were able to use several types of adult specialized cells to achieve iPS, and
5. The researchers suggest several possible ways to overcome the drawbacks of the process.

The authors believe that the inefficiency or the need to begin with lots of adult cells and wait a little longer for a substantial amount of human iPS should not be a "practical" problem because the adult cells are easy to obtain and labs all over the world should be able to reproduce their results. Since the technique should be well-funded (it qualifies for US Federal funding and is ethical, since no human beings have to die), the authors believe it will be possible for lots of researchers to work on them.

If I were to predict the future, I would anticipate banks of iPS - or even specialized or intermediate forms of cells that are produced from iPS - being stored for each of us, just in case. In the very long term, we will learn more about stimulating our on bodies' stem cells from research on these cells, so that we can repair or prevent damage without transplants or waiting for cultures to grow in the lab.

The major hurdle is that the cells were produced by the Recombinant DNA technique, using retroviruses in plasmids.

The retroviruses are a class of viruses that actually insert themselves into the DNA strands of animal or plant cells to become a part of that cell’s DNA and are copied when the cell reproduces. They are manufactured in the lab in the form of plasmids in order to carry genes into the experimental cells.

Plasmids are little bits of DNA, a mini-virus in a circle. Think of a chain with pairs of magnets or interlocking puzzle pieces that connect the ends and make a loop. When open, the plasmid becomes a strand of DNA which has ends that are "sticky.” When placed in a culture with mouse or human cells, the plasmids infect the cells and then move into the nuclei of the cells. The retroviral DNA is inserted or inserts itself into the DNA of the host cell because the sticky ends of the plasmid strand match or mate to certain areas of the host DNA.

Plasmids can be manufactured to carry copies of genes that researchers want to insert into the DNA of experimental cells. The technique is common in commercial and experimental labs for at least the last 30 years. In fact, "Recombinant DNA" is used to induce strains of bacteria and yeast cells in cultures to manufacture vaccines like the flu and Hepatitis B vaccine and the insulin used by diabetics these days. The particular retroviruses used by Tamanaka are said to be "strongly silenced in humans." In other words, they don't normally get reproduced as viruses when the cell divides. Once they are taken up in the cell DNA, the viruses used in research don't break out to become infectious viruses, again. However, some of them can induce the cells to form tumors or cancers if injected in an animal or human.


One of the possible problems that the article notes is that the new iPS cells each had several copies of the retrovirus included in their DNA. There is a concern that these bits may be responsible for the tumors that were seen in the mice used in the experiments. Before iPS can be used in humans, it will be necessary to learn to remove all the viral particles or to learn to make the cells without viruses that can cause tumors. Otherwise, there is a risk of causing cancer in patients.

The researchers note that another group of scientists have already reported that it is possible to insert one of the genes without using retroviruses and that the hope is to either find a way to insert the other three genes or to remove all traces of the virus.

There's also a suggestion that what they are actually inducing to grow is a sub-set of fibroblasts with the tendency to become embryonic-like stem cells.

Translation of "Induced Pluripotent (Human) Stem Cells"

Please see the revised version of this post, published November 30, 2007.

Reprogramming Stem Cells - Links to Articles

I got the authors backwards. Here's the corrected version:


Takahashi et al. (including Yamanaka), Cell Online, free pdf.

There's a "Preview" article in pdf here.
Still waiting for Science to post Thomson's report online.

Drugs, Sleep, Memory and Ethics

New information on the science of memory may one day finally tell me why I have a hard time remembering names and even faces, but I'll store a patient's potassium level without even trying. As with all science research, we'll have to decide whether and why the information we discover matters and how to use it.

Last night's post was on the bioethics questions in a television show dealing with a patient who asked for help forgetting a trauma - actually, the emotional memories, not the facts. A wide range of articles on memory research is the subject of yesterday's post at Bioethics.net. There are posts to articles and blog entries on old and new information on drugs that affect memory, and disorders of memory.

That post contains a link to this New York Times article (free registration required) on the significance of sleep and memories. (I love the title, "An Active, Purposeful Machine That Comes Out at Night to Play.") The same session at the American Society of Bioethics and Humanities conference that dealt with blunting the emotional memory of trauma also touched on the ethics of new medications that enable people to sleep less. The question asked was whether avoiding the need for sleep would allow time for more worthy pursuits - the question and answer period focused on what to consider a "worthy" activity. According to the NYT article, the question should be what is lost.

As is too often the case, science gives us some of the answers to our questions (those "power naps" are probably good for dealing with facts and later sleep appears to be useful for detecting patterns) and technology or means (propranolol, propofol, Provigil, etc.) to manipulate ourselves and our behavior, before we come to a consensus on the ethics - or even the ethical principles that apply - of using our knowledge.

The old saying "let's sleep on it" may have some measurable truth - and a lot of wisdom, after all.

Rao: Adult Stem Cells "soon to be on the market"

The journal Stem Cells has published an Open-Access review by the former NIH director, Mahendra Rao, MD, PhD, covering last month's "Adult Mesenchymal Stem Cells in Regenerative Medicine Conference" at the National Center for Regenerative Medicine in Ohio.

Another review with summaries of some of the individual talks as well as the history of the National Institute for Regenerative Medicine and Dr. Arnold Caplan's part in founding both the NIRM and Osiris, can be found at Medscape.

Mesenchymal stem cells (MSCs) can be found in bone marrow and other organs. MSCs are proving to be multipotent, meaning that they can be induced to give rise to different types of cells.


Speakers at the conference included virtually every "big" name in stem cell research, including Dr. Rao, Caplan, Anthony Atala, Catherine Verfaille, and Paul Simmons. The program covered the history, basic science and techniques involved in harvesting and culturing mesenchymal stem cells. There were reports covering the multipotent nature of MSC's and some of the treatments and commercial applications that are in use or will soon be available. One company, Osiris, has been in phase III of some clinical trials of stem cells for treatment of heart disease, graft vs. host disease, Crohn's, and cartilage and tendon repair. Veterinarians are already using MSC's to treat horses and other animals.

Take a look at the last page of the review which contains a graphic covering the wide range of topics.

Patients' own adult stem cells in the news

There's hope in the news for future adult stem cell therapies using patients' own stem cells within the next ten years.

The (UK) Times Online reports on the rapid progress in research on tissue regeneration using patients' own adult stem cells to produce heart valves and muscles. The researcher predicts the technology will be available in three to five years for use in humans.

To support this hope, Nature Biotechnology will publish a report on adult stem cells that make muscles in immune deficient mice. The abstract is available here and the UPI report is available here.

Science retracts another

There's good news and bad news.

The good news is that the scientific review process does work. Science is retracting (all of these Science and Nature articles are behind a paywall) an article that has been proven to include forged photographs, due to the questions about these photographs from other researchers. Although the actual research and premise of the research my have some validity, it needs to be replicated and validated in other labs, by other researchers.

The bad news, I'm afraid, is that the reason that the article came under scrutiny in the first place (and the reason we will hear about it over and over and over) is that the findings were hailed as further proof from a study of very early mouse embryology that the embryo is a unique organism from fertilization, since the immediate result of the first division showed different fates and different genetic markers.

There is nothing here to discount the fact that the zygote is an organism. In fact, the cdx2 marker is indeed found mostly at one end of the zygote and most of it ends up one of the cells after division. The article, "Your destiny from day one" in Nature.com (behind a paywall) covered the work by R.L. Gardner and Magdalena Zernicka-Goetz:

Nature 418, 14-15 (4 July 2002)
"Developmental biology: Your destiny, from day one"

by Helen Pearson

The mammalian body plan starts being laid down from the moment of conception, it has emerged. Helen Pearson considers the implications of a surprising shift in embryological thinking.

Your world was shaped in the first 24 hours after conception. Where your head and feet would sprout, and which side would form your back and which your belly, were being defined in the minutes and hours after sperm and egg united.

More proof has been produced in other research, there's some, here, and a review in this article by Robert P. George and Patrick Lee in the New Atlantis. From this year there's the report from M.-E. Torres-Padilla et al. [Nature 445, 214–218; (2007)] described this way in Nature (sorry, also subscription only):

Nature 445, 157 (11 January 2007) Published online 10 January 2007
"Developmental biology: Marked from the start"

Helen Dell

Not all cells in the early mammalian embryo are created equal. Even at the four-cell stage, embryonic cells that follow a particular pattern of division already have their developmental fate assigned to them. No cell will contribute exclusively to a specific cell type in the later embryo. But the progeny of some cells make a greater contribution to the 'inner cell mass' — the stem cells destined to become the fetus — and its surrounding 'trophectoderm', which forms extraembryonic structures such as the placenta. The progeny of other cells will make a greater contribution to other extraembryonic structures.

However, I'm afraid we should expect to see this scandal used against those of us who would protect embryonic human life.

Here's more on the Deb scandal from the Columbian Missourian

Doctors, faith and helping the poor

The Chicago Tribune published an article on a study concerning doctors who help the poor. I haven't read the actual article, yet, but I wonder how the "poor" are defined and question the definition of "religiosity" vs. spiritual.

For one thing, I'm not sure how, as a Family Physician, I would separate my patients into poor and not-so-poor. Currently, I work for other doctors, but their patients seem similar to the ones I cared for when I had my own practice, although the trend is away from Medicaid, which pays very little compared to Medicare and private insurance. (Medicaid pays less than the office overhead for the time it takes to see the patient.)

There seems to be a fair mix in the patients that come to our practices through the hospital call lists because they don't have a doctor. Also, I frequently hear that this patient or that has an agreement with the doc to pay what and when she or he can. I'm also reminded by the staff that the patient is "self-pay." These patients are "coded" or charged as little as we legally can without committing the felony offense of insurance or Medicare fraud. (The law says we can't charge less than we would charge a Medicare patient and we can't charge a "discounted" rate without risking charges of fraud. There is a little bit of lee-way, however, in calculating the risk, history necessary, etc.)

The study, based on a mail survey of more than 1,100 American physicians, found that 31 percent of doctors who described themselves as religious reported that they serve primarily poor or uninsured communities, compared with 35 percent of doctors who had no religious affiliation.

Those two figures were statistically equal, but other comparisons showed that doctors were more likely to treat underserved populations if they considered themselves highly spiritual, felt that their religious beliefs influenced their medical practice, or said they were raised in a family that encouraged service to the poor.

How do you determine "religious" if not by those who "considered themselves highly spiritual, felt that their religious beliefs influenced their medical practice?"

BTW, I've been away while studying for and taking my every-7-years American Board of Family Physicians National Boards. I won't know the results until mid-September, but at least there's no dead lines looming ahead of me for a while. Yeay!!!

"Exaggerated resistance" (Or how not to report science)

Scientific American gives us several reasons to "resist" the information in its pages this month, the August, 2007 issue. Unfortunately, only the Table of Contents is free, but the problem is in the titles given "news" stories themselves.

Under the title, "Roots of Science Hatred," on page 29 we learn that people learn to trust their own experiences, causing us to have "exaggerated resistance" to scientific reports:

For instance, because objects fall down if not held up, kids may have trouble accepting
the world is round, reasoning that things on the other side should naturally fall off.
Intuitive notions concerning psychology also lead children to see everything as designed for some reason—for example, a cloud’s purpose might be to rain—which can lead to opposition to evolution. In reportingtheir work in the May 18 Science, the researchers also note that when both adults and kids obtain knowledge from others, they judge claims based on how much they trust the source of an assertion. It suggests that science will meet exaggerated resistance in societies where alternative views are championed by trustworthy authorities, such as political or religious figures. —Charles Q. Choi (emphasis is mine)

Yeah, and the exaggeration is all on our part, and due to "hate," "religion," and "politics," right?

Since SA can't be engaging in politics, then only someone inclined to hate science would notice the problem with the following headline on page 32: "SciAm Perspectives: Worse Than Gasoline: Liquid coal would produce roughly twice the global warming emissions of gasoline." Couldn't they have used the more correct and less political term, "green house gasses?"

Yes, I'll admit to being a human-caused-global-climate-change skeptic. I remember the '60's and early '70's, when we humans were told that we were the cause of global cooling. I believe it had something to do with clouds blocking the sun's radiation from warming the earth. I'm watching and waiting, although I've always believed in keeping my little micro-climate as clean as possible..


However, for a review of the current "consensus" on global climate change, those of you with access to SA can read "The Physical Science behind CLIMATE CHANGE" (all caps in the original), beginning on page 64.

Global Warming: No Debate? (Reporting bias)

Just one more example of the effects of reporting bias in the scientific literature - and another warning to be wary, even about "consensus."

The journal, Nature, now reviews its own blogs on a web page titled the "From the blogosphere,"a subheading of the "Author" web page., on the homepage of the journal's website. The "From the blogosphere" heading was on this morning's "headlines" that were chosen by my Google search page. Unfortunately, the blogs are behind a paywall.

One of the blogs, "Peer-to-peer: for peer-reviewers and about peer review" has a discussion about the controversy over a meta-analysis published in Science magazine by the science historian, Naomi Oreskes, based on this opinion piece - that is available for free - at the UK Guardian, by Jonathan Wolfe. I believe that the point of Mr. Wolfe's commentary is that non-experts should "shut" our mouths, because we flat don't know enough.

Neither Mr. Wolfe nor the Nature blogger make any mention that the report by Oreskes was severely flawed and inaccurate. However, as the one comment at "Peer to Peer" reports, "This is very odd. The main critic of Oreskes' work was Benny Peiser, who is not a blogger or a think-tanker, but a member of faculty at John Moores University and a fellow of the Royal Astronomical Society."


I hope Mr. Wolfe or the Nature bloggers will follow up on the Oreskes article and the controversy surrounding it, because there appears to be a secondary theme: bias can lead to error, even in peer reviewed, scientific journals.

Oreske's article, originally published in Science in December, 2004. This review of the scientific literature is often quoted to support the position that there is no disagreement among scientists about whether the earth is warming due to the increase of "greenhouse" gases, and that those greenhouse gases are due to the influence we humans have on our environment. However, the problem appears to be a flaw in both the professor's methodology and her reporting. She mis-reported her search terms, and those terms - the use of the three words, "global climate change," rather than "climate change" - make a huge difference.

Here is the "Erratum" published in January, 2005 by Science:

Essays: “The scientific consensus on climate change” by N. Oreskes (3 Dec.2004, p. 1686). The final sentence of the fifth paragraph should read “That hypothesis was tested by analyzing 928 abstracts, published in refereed scientific journals between 1993 and 2003, and listed in the ISI database with the keywords ‘global climate change’ (9).” The keywords used were “global climate change,” not “climate change.”

The choice of search terms seems to make a huge difference. From a web page entitled, "The Letter Science Magazine refused to publish," by professor of anthropology, Benny Peiser, we learn,

On December 3rd, only days before the start of the 10th Conference of Parties of the United Nations Framework Convention on Climate Change (COP-10), Science Magazine published the results of a study by Naomi Oreskes (1): For the first time, empirical evidence was presented that appeared to show an unanimous, scientific consensus on the anthropogenic causes of recent global warming.

Oreskes claims to have analysed 928 abstracts she found listed on the ISI database using the keywords "climate change". However, a search on the ISI database using the keywords "climate change" for the years 1993 - 2003 reveals that almost 12,000 papers were published during the decade in question (2). What happened to the countless research papers that show that global temperatures were similar or even higher during the Holocene Climate Optimum and the Medieval Warm Period when atmospheric CO2 levels were much lower than today; that solar variability is a key driver of recent climate change, and that climate modeling is highly uncertain?

These objections were put to Oreskes by science writer David Appell. On 15 December 2004, she admitted that there was indeed a serious mistake in her Science essay. According to Oreskes, her study was not based on the keywords "climate change," but on "global climate change" (3).

Her use of three keywords instead of two reduced the list of peer reviewed publications by one order of magnitude (on the UK's ISI databank the keyword search "global climate change" comes up with 1247 documents). Since the results looked questionable, I decided to replicate the Oreskes study.

***

DISCUSSION:
According to Oreskes, 75% of the 928 abstracts she analysed (i.e. 695) fell into these first three categories, "either explicitly or implicitly accepting the consensus view". This claim is incorrect on two counts: My analysis shows that only 424 abstracts (or less than a third of the full data set) fall into these three categories.

It also shows that many abstracts on "evaluation of impact" and "mitigation" do not discuss which drivers are key to global climate change, instead often focusing exclusively on the possible effects of elevated CO2 levels on plant growth and vegetation. Many do not include any implicit endorsement of the 'consensus view' but simply use certain assumptions as a basis for often hypothetical impact assessments or mitigation strategies.

Quite a number of papers emphasise that natural factors play a major if not the key role in recent climate change (4). My analysis also shows that there are almost three times as many abstracts that are sceptical of the notion of anthropogenic climate change than those that explicitly endorse it (5, 6, 7).

I guess our lesson should be to be skeptical of "consensus," just as we are becoming skeptical of "peer reviewed" journals that rush to print on "hot" stories about cloning and stem cells.

Why most Published Research Findings Are False

Chasing links today, I somehow stumbled upon found this very interesting title:
John Ioannidis, “Why Most Published Research Findings Are False,” PLoS Medicine, vol. 2 (2005), pp. 696-701.

Brush up on your statistics and ability to evaluate scientific literature (and those that report on the same).

Prolonged culture of embryos, stem cells and more Free Stuff

This week's (June 27) Nature.com "Advance Online Publication" contains two "Letters" describing the production of embryonic stem cells from "epiblast" cells, one in mice and rats, one focusing on mice.

Full content is restricted to subscription-only, but you can listen to a discussion about the studies on the free podcast from Nature, here, and the first paragraph of each is available for free, here and here. I believe you can also download the pdf of the Supplementary material for the articles here and here. You can find old podcasts and the English transcripts of previous podcasts, here.

One point that I find interesting is the statement on the Podcast that "what we thought were mouse eS Cells (embryonic stem cells), probably weren't." The second is that, beyond the obvious concerns about increased interest in growing human embryos to a later stage, this research was carried out in human embryos before moving on to mice and rats. From the first reference:

We initially determined that prolonged culture of human ES cells in chemically defined medium (CDM) containing activin A and FGF2 (CDM/AF) maintained their fundamental characteristics (See Supplementary Data). We then tested similar conditions for derivation of pluripotent cells from pre- and post-implantation rodent embryos.

The good news is that the scientists are convinced that these "EpiSC's" - or Epiblast stem cells - will be useful as models for the study of embryonic development and substitute for the human embryonic stem cells, without the limits on US Federal funding. (I'm always fascinated by the interest that British publications have in our US funding schemes and politics.)

If I'm correct in interpreting the importance of this information, scientists should find it easier to do experiments that they've been wanting to do by using rodent embryonic stem cells, now that they know how to find the actual cells, themselves. We will also hear more advocacy for the "culture" of human embryos longer than the previous 3 to 5 days, in order to harvest truly pluripotent eSC's, from what one article calls the "embryo proper" or the body of the would-have-been-born individual. One researcher tells us on the Podcast that these cells from embryos at the stage when the embryo would naturally implant are the "universal stem cells" that scientists have been searching for.

Racism, politics, and really big numbers

Last week's announcement that three different labs have managed to not only reproduce work showing that certain genes are responsible for embryonic-stem-cell-ness, but actually managed to turn adult cells into embryonic-like stem cells has been widely reported and comment upon.

Times Magazine displays blatant racism and not a little naivete in their report, "Japan gets ahead of the curve":

But it was March 2006, just months after the South Korean stem-cell scientist Hwang Woo Suk—who had become an international sensation after claiming to have cloned a human embryo, a first—had been exposed as a fraud. As another Asian stem-cell scientist announcing a surprise advance, Yamanaka knew his peers would put him under the microscope. (emphasis mine)

Yep, all them furinner's look alike to us.

Actually, the Times reporter mentioned the most important factor in any increased scrutiny and pressure from Yamanaka's peers: ". . . because Yamanaka did not use human embryos, his technique offered researchers everywhere a way to sidestep the ethical controversies that have dogged the field since its birth."

We've been treated to examples of politics in science each time non-destructive stem cells news breaks out. I reported on the comments at the American Society of Bioethics and Humanities meeting last October. David Stevens, MD, CEO of the Christian Medical and Dental Association describes the scenario:

. . . proponents rushed to the microphone to do damage control and claiming we must continue embryonic stem cell research since we can't predict which technique will provide cures. With 1,200 clinical studies underway using adult stem cells and none using embryonic ones as well as these two breakthrough studies in the last year, it is becoming a pretty sure thing on simple pragmatic grounds where we should be putting our tax money. It is like predicting whether the San Antonio Spurs are going to beat your local Saturday afternoon pick up basketball team.

The emperor has no clothes but continues to ride smiling through the public. Sooner or later the people notice."

(Go, Spurs, Go! Yeaaay Champs! Sorry, couldn't resist.)

We've read that the results we keep seeing from adult stem cells are simply a matter of the numbers - more US tax dollars are spent on adult stem cell research than on embryonic stem cell research, and embryonic stem cell research is much newer than adult. But let's look at the facts: Yamanaka did his work in Japan, and Nature is published in the United Kingdom. Nope, no influence from US tax payer funding or the lack there of. Perhaps it's just that non-destructive stem cell research actually produces reliable, frequent results?

But maybe, just maybe, if we get out our tin hats and/or risk assuming a duty to die, we might contemplate there's Something Else going on. A UK conspiracy? Or is Someone higher up messing with the United States Congress?

Dr. Stevens:

Ironically, the day this bill passed last fall, the news announced the breakthrough study that showed that amniotic stem cells could become endoderm, ectoderm and mesoderm. They have all the benefits of embryonic stem cells but none of the risks. They don't turn into cancers, they are readily available, genetically stable and easier to control. This year, the ground breaking study on dedifferentiating mouse skin cells into embryonic stem cells hit the front pages and TV screens the same day as the House vote and stole its thunder. Though this technique has a number of hurdles to cross before being applicable in humans, I'm beginning to wonder if God has a great sense of humor!

(Go, God, Go! Had to do it.)

And Dr. Stevens is not the only one to notice that there are just too many coincidences, what Yogi Berra called, "Deja vu, all over again."

A very funny Washington Post Op-Ed by Rick Weiss, entitled "Darn cells, Dividing Yet Again!" could be used to discuss humans' need to attribute natural phenomena with supernatural explanations with these guys, over at The Edge. Or at least a cosmic conspiracy.

Go read the whole thing, but here's a bit:

Is there a plot afoot?

Lots of lobbyists, members of Congress and even a few scientists are starting to think so.

"It is ironic that every time we vote on this legislation, all of a sudden there is a major scientific discovery that basically says, 'You don't have to do stem cell research,' " Democratic Caucus Chairman Rahm Emanuel (Ill.) sputtered on the House floor on Thursday. "I find it very interesting that every time we bring this bill up there is a new scientific breakthrough," echoed Rep. Diana DeGette (D-Colo.), lead sponsor of the embryo access bill. Her emphasis on the word "interesting" clearly implies something more than mere interest.

"Convenient timing for those who oppose embryonic stem cell research, isn't it?" added University of Pennsylvania bioethicist Arthur Caplan in an online column. (The bill passed easily, but not with a margin large enough to override Bush's promised veto.)

Even some scientists, those exemplars of rationality, couldn't help but wonder if somebody, somewhere, was -- if not out to get them -- at least taking some pleasure in irritating them.

"I don't think this is the most sensitive timing for Nature to release these papers," said Harvard stem cell scientist Kevin Eggan, the lead author of one of the articles that appeared in the London-based journal on Thursday.

Twice in six months. What are the odds?

Corrigendum - or "Correction in Print"

I've learned two new words in the last two days: eponymous ("self-named" or named after the thing itself) and "corrigendum" (a correction of an error found after printing, which is corrected with a separate printed page.) I just had to use the latter in my title.


The journal Nature has retracted (sorry, subscription only) a single figure from a 2002 report (free abstract, here) on the successful identification and culture of multipotent adult stem cells, from the lab of Catherine Verfaillie, Ph.D., formerly of the University of Michigan. Besides witnessing an example of scientific integrity on the part of Nature and the authors, we may also be witness to a demonstration of integrity and ethics within the scientific community.

It's important to note that the actual data and the conclusions of the report are no longer in question, if they ever were. The problem was with this single picture, depicting the results of flow cytometry of the cells identified as multipotent adult progenitor cells (MAPCs). The existence and significance of the MAPCs is not in question. The description of the methods and results of the original team has been blamed for the difficulty of reproducing the experiment.

The Scientist reports that Irving Weissman, Ph.D, formerly skeptical of the conclusion that the adult cells were indeed multipotent, has since worked with and published another report on the MPACs with Dr. Verfaillie's team and now supports her conclusion, at least tentatively:

Irving Weissman, director of the Stanford Institute for Stem Cell Biology and Regenerative Medicine in California, co-authored a 2007 study with Verfaillie, and said he believes Verfaillie is innocent of any foul play. Verfaillie "has a long record of solid, reproducible work. I can't conceive that, if there is a systematic error, she participated in it," he said.

"Nevertheless at the very least, the markers associated with the cells [in the Nature study] can't be taken as gospel," Weissman continued. In the case of Verfaillie's MAPCs, he said, "it is conceivable that [Verfaillie] found a way of tissue culture isolation of pluripotent cells that was difficult to reproduce."

There must be room in everything we do for correction of mistakes. We are once again reminded that science is the process of discovering what can be discovered and reproduced in different labs, at different times, using the same methods.

Virtual science vs. actual experimentation (Emergency Contraception)

There's still no evidence that Plan B interferes with implantation, and lots of evidence that it doesn't.

There have been reports that Drs. Mikolajczyk and Stanford ("Levonorgestrel emergency contraception: a joint analysis of effectiveness and mechanism of action." Fertility and Sterility R. Mikolajczyk, J. Stanford, access to free abstract available, here) have proven that there is an abortifacient effect from the morning after pill ("Emergency Contraception," EC, or the levonorgestrel-only pill protocol, LNG EC).

In fact, they do not "prove" anything. Mikolajczyk and Stanford derived an equation from actual results from observing oocyte follicle development and ovulation in women. They then used statistical, "virtual" models,to estimate they effects of LNG:

We simulated random samples of 10,000 women presenting for EC for a single cycle each, and we calculated the number of ‘‘expected’’ pregnancies for each simulated cohort of women using both sets of the daily fecundity data. We assumed that women ‘‘presented’’ for EC treatment with equal probability on days –10 to +5 around the day of ovulation
(day 0).

For each of the women within the fecundity window, we used the follicular growth equation to estimate a follicular diameter, which in turn was used to estimate the disruption of ovulation by LNG EC based on the data from the Croxatto study (Table 1). We assumed that effects observed for 12–14 mm, 15–17 mm, and R18 mm groups reported by Croxatto et al. (15) apply to follicles of size up 11.51–14.5 mm, 14.51–17.5 mm, and R17.51 mm, respectively. When LNG EC was administered on a day when follicular size was below 11.5 mm, we assumed that there was zero probability of pregnancy. These conservative assumptions maximized the possible effects of LNG EC to disrupt ovulation and prevent fertilization.With this information, we estimated the ‘‘observed’’ pregnancies within the simulated cohorts.

Durand and Croxatto's teams studied how LNG EC actually worked in the bodies of real, live women, using biopsies, exams, assays of hormones and serial ultrasounds, as well as animal studies. Mikolajczyk and Stanford actually refer to the Durand study on human women, "On the mechanisms of action of short-term levonorgestrel administration in emergency contraception," (available free on line, here), but say the evidence from biopsies are "mixed."

On the contrary, Durand reported on actual labs, ultrasounds and even biopsy samples from actual observations:

The results were highly consistent with the chronological date of sampling because differences longer than 3 days between the histologic diagnosis and the day of the cycle were not observed. A total of 24 out of 33 biopsies from treated cycles with ovulatory features were studied. The rest were excluded because of insufficient tissue sample (one from Group B and D) or because sampling did not correlate with the cycle day (three from Group A and four from Group D). Table 3 summarizes the morphological findings in Groups B, C, and D. No significant changes were observed between treated and control specimens in any of the studied parameters. No significant differences among groups were observed. Of particular importance was the finding that the predecidual changes as evaluated by the
presence of prominent spiral arteries, which are considered
crucial for implantation [24], were not altered by LNG.

The post ovulatory mechanism is most likely explained by the finding in many studies, including Durands', which have demonstrated a strong effect on mucus thickness and sperm motility from the Levonorgestrel protocol (LNG EC). Practitioners of Natural Family Planning are familiar with this (natural) effect of (natural) post ovulatory rise in progesterone: when the progesterone levels rise after ovulation, the cervical mucus becomes thick and fertility goes down because the sperm can't get to the egg for fertilization. The movement of the oocyte down the fallopian tube is slowed also, because the cilia in the tube are affected. The combination of these two phenomenon explains the increased rate of ectopic pregnancy in women who do become pregnant using levonorgestrel only EC and daily pills.

There are definitely problems with EC. It only works when it works for 4 or 5 days before ovulation and, possibly on the day of ovulation. (The oocyte only lives about 24 hours.) This is the first time that contraceptive pills have been made available to men as well as women. For some reason, women don't use the pill correctly, even when they have them at home. And we have tons of evidence that neither the pregnancy rate nor the abortion rate are affected by making the pill available over the counter. And there's the increased risk of ectopic pregnancy described above.

However, this "study" appears to be statistics used to argue against observations derived from real life medical experiments in order to prove a pre-conceived position.

Austin Texas Patients In Adult Stem Cell Research

The Austin, Texas TV station, KEYE, has a report on the research trial using donated adult stem cells from bone marrow in patients within 10 days of a heart attack. (I've highlighted the part about the bone marrow.)

Seema Mathur
Reporting

(CBS 42) AUSTIN

A clinical stem cell trial involving Austin patients has some doctors saying it may change medicine forever.

The trial involves heart attack patients using adult stem cells. The stem cells are from the donated bone marrow of healthy adults.

The trial is in its first phase, with just 10 sites around the nation. Doctors are already saying the results hold the promise of doing what has never been done before, rebuilding heart muscle of heart attack patients.

Ben Calvo, a math teacher, was willing to take what he considers a calculated risk. He's one of 53 heart attack patients in the nation taking part in an adult stem cell clinical trial.

“I don't feel like a guinea pig,” Calvo said. “I don't want to say I feel super human, but I feel just great.”

Dr. Roger Gammon is director of research at Austin Heart, cardiologist providers in Central Texas. He says that in the double blind study, within 10 days of a heart attack, some patients received adult stem cells from donated bone marrow and other patients received a placebo.

“We hang a bag that has millions of stem cells in it,” Gammon said. “They infuse through the vein and travel to where there is an injury. It's just a simple intravenous infusion over 30 minutes.”

Calvo thinks he received the real thing. According to recent images of his heart, so does Gammon.

“Now, his whole heart is moving well,” Gammon said.

The image of Calvo’s heart is amazing because, up until this study, nothing could repair damaged heart muscle.

“They don’t just patch the problem, they actually become heart tissue that starts beating,” Gammon said.

“I feel that I can breathe better,” Calvo said.

Gammon says there was no rejection. He says some patients also had unexpected improved lung function and less irregular heartbeats.

“There seems to be an amazing homing mechanism with these cells to where they can figure out where there is an injury in your body and they go there and start to heal it,” Gammon said.

Calvo believes healing heart muscle is exactly what he experienced. Calvo also had some stents put in after his surgery.

Before this can become an approved treatment, many more people need to be studied to see if the results continue to be promising. But if they do, Gammon suspects this treatment may also help other inflammatory conditions like Alzheimer’s.

(© MMVII, CBS Broadcasting Inc. All Rights Reserved.

(Un)Ethical Science Journals

I guess the first question should be, "Where is the scientific and ethical justification for demanding public funding of science without public restraints?"

The next is, "When there is public disagreement, what is the ethical way to conduct the discussion about the disagreement?"

I'm sure that the answer to the second is not "hit and run."

Wesley Smith adds a new bit of information to the story I wrote about last week, concerning an attack on Maureen Condic, PhD, for her informational article on the lack of promise of embryonic stem cells.

It seems that that the journal Nature Neuroscience has refused to allow Dr. Condic, a respected neuroscientist herself, to respond to the editorial on their pages.

Why, Wesley, the editors didn't display enough courage to sign their names. I'm not surprise that they continue to take the less courageous road.

Religion and zealotry of one sort or another

The National Review has published an editorial by Colleen Carroll Campbell on the resignation of St. Louis' Archbishop Raymond Burke from his position on the board of that city's Children's Hospital foundation. The Archbishop objected to the invitation to the outspoken (and vocal) proponent for abortion and embryonic stem cell research, Cheryl Crow.

Ms. Campbell states the problem well:

Today’s religious leaders increasingly face a double standard when it comes to their public pronouncements: They can say what they want as long as they express politically correct views or stay mum on hot-button social issues. Where secular pundits and celebrities are given free reign to plead their case to the public, religious leaders are derided as theocrats for injecting religiously derived moral principles into political debates. This stifling of religious voices is intended to prevent religious conflicts in the public square. But it also prevents the most fundamental form of deliberation necessary to the functioning of a pluralistic democracy: honest debates about right and wrong, good and evil, truth and falsehood.

However, I would add that the zealotry of some who complain about activism by any and all religious people in any public dispute is near-religious in itself.

A case in point:

The journal, Nature Neuroscience published an unsigned, unattributed essay in the April, 2007 issue, entitled "Shaky arguments against stem cells: Recent attempts to use scientific findings to discredit embryonic stem cell research are distorting the state of the field." (I'm not sure whether this requires registration to view.)

(Amazing, huh, that the editors could afford so much space for their title, but none for their own names?)

The editorial is nothing but a call for all embryonic stem cell research and nothing short of the same, without comment, without restrictions.

In order to illustrate their point, the authors (whoever they are), discuss an essay written to inform the readers of First Things. The authors (whoever they are) state that the content of the article is "correct," but feel it necessary to stress that the journal is a "conservative Roman Catholic magazine" and cite Maureen L. Condic, Ph.D. for "trying to spin science—both its problems and successes—to fit an anti-scientific purpose."

In fact, they seem most offended that Dr. Condic commented at all.

As I wrote the editors, the editorial reflects a deep bias and a "spin" of its own, discrediting their journal and "distorting the state of the field," indeed.

If we knew who these anonymous authors were, perhaps we could ask them why their own position is "right" and the Dr.s' is "wrong." I would also ask them why they insist on bringing religion and politics into the debate, when Dr. Condic so obviously - as they state - avoided both.

Vaginal approach to gallbladder removal

Or removal of the appendix through the mouth?


I finished my residency training in 1993, and was privileged to witness some of the first "laparoscopic" gallbladder removals on one of my rotations with some private surgeons. After 5 years or so of observing and assisting with the old technique that required a 7 to 10 inch incision at the right upper abdomen and months of recovery, I was used to patients lying very still and needing encouragement to breathe after the surgery. I nearly fell apart myself when, just an hour after we removed her gallbladder, one of my patients sat up in bed. I've never moved faster than I did that time, trying to catch her before she tore her wound or fell out of bed when the pain hit!

My first reaction to this story was one of alarm about possible harm due to trying a new, risky maneuver, just because it's surgically possible.

I wasn't sure how much of my distaste was a woman's reaction to invasion through the vagina. After I read the description of the appendectomy through the mouth, I decided that it's a true caution about the risk of such a route.


The biggest problem with recovery from surgery is the trauma to the tissues surrounding the surgical site, especially the muscles that are cut and sewn.

I finished my residency training in 1993, and was privileged to witness some of the first "laparoscopic" gallbladder removals on one of my rotations with some private surgeons. After 5 years or so of observing and assisting with the old technique that required a 7 to 10 inch incision at the right upper abdomen and months of recovery, I was used to patients lying very still and needing encouragement to breathe after the surgery. I nearly fell apart myself when, just an hour after we removed her gallbladder, one of my patients sat up in bed. I've never moved faster than I did that time, trying to catch her before she tore her wound!

The new technique allowed for us to remove the gallbladder - and later, the appendix (and other stuff) - by making 3 or 4 cuts, all less than an inch and using instruments and a camera that allowed remote or video-guided surgery. Without all that cut skin and all those layers of muscle, patients got better, faster.

It's almost routine to perform hysterectomies through the vagina these days. But let's face it, in this case, everything's right there. The surgeon just has to watch for the blood vessels, the bladder and the rectum, and virtually no muscles have to be cut, at all.

Either of these operations would require muscles and "surface" tissues to be cut, and each require that the surgeons' instruments pass other organs. There's also the problem of making the surgical field sterile and maintaining infection control.

With removal of the gallbladder, there is also the risk to the liver, and especially, the common bile duct from the liver to the intestines. For that matter, an oral approach to the appendix would require reaching past the lungs, the diaphragm, the liver and the intestines, unless the instruments can be passed through the esophagus and stomach. (How would you intubate this patient, protect her lungs, or handle the leaks of acid from the stomach into the abdominal cavity?

The surgeons quoted in the New York Times article are proponents of "no scar" surgery.

I'm a little concerned about the way they "read":

Dr. Bessler said his patient agreed to the procedure (two others had declined) because he told her he thought it would have advantages for her, and she accepted his judgment. She was the first in a study that is to include 100 women who need gallbladder surgery, appendectomies or biopsies taken from inside the abdomen. All the procedures will be done through the vagina.

Dr. Dennis Fowler, another surgeon who participated in the operation, said the team began experimenting on women because “incisions in the vagina have been used for a variety of procedures for decades, and proved safe with no long-term consequences.”
. . .
The operation took about three hours, twice as long as the usual laparoscopic surgery, but it was the team’s first operation on a human, and the time should decrease with practice, Dr. Bessler said. Also because it was the first time, to be on the safe side, the doctors did make three small openings in the abdomen for surgical tools. But their ultimate goal is to perform the operation entirely through the vagina.

How not to question research

What bothers me most about this controversy is that the whole thing began when the authors announced that they were about to release their raw data. Where is the discussion about the evidence in question, rather than historical questions without the numbers.

(I'll admit that the numbers boggle me - I'm not sure how one source could differ from one another by one third to one million deaths, without other groups noticing.

However, I can't help wonder how even 5 teams could interview 38 families during the violence that those teams were reporting.)


Last October, the journal Lancet published a report (available by subscription only and I don't have access) by Les Roberts and Gilbert Burnham claiming that Iraqi citizens suffered hundreds of thousands of "excess" deaths due to the war. Last month (Feb 28th online and in the March 1 issue), Nature published a news article (available by subscription only, excerpts below) critiquing the study:

On paper, the study seems simple enough. Eight interviewers questioned more than 1,800 households throughout Iraq. After comparing the mortality rate before and after the invasion, and extrapolating to the total population, they concluded that the conflict had caused 390,000–940,000 excess deaths (G. Burnham, R. Lafta, S. Doocy and L. Roberts Lancet 368, 1421–1428; 2006). This estimate was much higher than those based on media reports or Iraqi government data, which put the death toll at tens of thousands, and the authors, based at Johns Hopkins University in Baltimore, Maryland, and Al Mustansiriya University in Baghdad, have found their methods under intense scrutiny.

Much of the debate has centred on exactly how the survey was run, and finding out exactly what happened in Iraq has not been straightforward. The Johns Hopkins team, which dealt with enquiries from other scientists and the media, was not able to go to the country to supervise the interviews. And accounts of the method given by the US researchers and the Iraqi team do not always match up.

The authors of the original study have answered and Nature has published it:

In our opinion, your News story about our Lancet paper "Death toll in Iraq: survey team takes on new critics" (Nature 446, 6–7; 2007) has confused the matter rather than clarified it. You outline three criticisms of our work: that there was not enough time to have conducted the survey; that the sampling method suffered from a 'main-street bias'; and that the study team fabricated the data (the last being attributed to anonymous "researchers"). These criticisms have been previously addressed, and have little merit.

On the first point, the 1,849 interviews in 49 days described in our study suggest that 38 interviews had to be conducted each day by our eight interviewers. Although introducing themselves and explaining the confidentiality agreement might have taken interviewers several minutes, the five-question interview would take only a couple of minutes for most households that reported no deaths. The idea that eight interviewers could not conduct a total of 38 interviews in a day is not credible.

Second, we dismiss the suggestion that our sampling over-represented main streets, where car bombs are more likely. As stated in our paper (G. Burnham, R. Lafta, S. Doocy and L. Roberts Lancet 368, 1421–1428; 2006), when excluding the statistically outlying cluster of Falluja from the first report, we estimated 98,000 (95% c.i.: 8,000–194,000) excess deaths versus 112,000 (95% c.i.: 69,000–155,000) over the same period with the second survey. The first survey was done selecting random starting points with a Global Positioning System unit. The second used the random street-selection process, which is being criticized as biased. It rarely occurs in the field that two sampling methods are used allowing for comparison, and here the results are nearly identical. Moreover, there is no plausible mechanism for a significant main-street bias to operate, because only 15% of all deaths are from car bombs and other ordnance, and because most violent deaths are believed to occur away from the home.

Third, as for the accusation that researchers fabricated the data, we are ready, willing and eager to have an established international authority take a sample of the cluster forms and go to the field with our interviewers to verify the findings. Until that time, the Coalition and Iraqi governments' statements that during the first three years of occupation, Iraq's violent-death rate was lower than those of Russia, Estonia, Latvia, South Africa and Kazakhstan remain an implausible contrast with our findings.

When Nature called one of our study members in Iraq and asked if local officials joined them during the survey, that individual later clarified to Nature by e-mail that 'local officials' did not mean local clinicians and colleagues. This was inaccurately reported in the Nature summary along with a statement by our co-author that interviewers often worked alone. These points were wrongly cited as contradictions between the study team members in your News story.

All reports will eventually have "criticisms that dogged the study", if previously addressed criticisms with so little merit are given a voice in the press.