Thursday, April 21, 2016

Uncertain Health in an Insecure World – 81

“Fog of War”

In the aftermath of the Battle of Waterloo in 1815, Prussian military theorist General Carl Von Clausewitz coined the term “fog of war.” Napoleon's defeat required several lucky (or unlucky) turns of timing and twists of fate, and hung in the balance from hour to hour for three days.

A less famous but more prescient Von Clausewitz observation was that, “Politics is the continuation of war by other means.” Let's explore how the potent forces of science and politics do battle now. 

The capacity of age- or disease-damaged tissues to self-repopulate with stem cells, traced to the blastocyte layer of embryos (above), is part science and part magic. As an embryo matures, these stem cells are responsible for transforming themselves (i.e., differentiating) into heart, brain, lung, skin, etc. tissues.

In 1981, Dr. Gail Martin at University of California San Francisco derived stem cells from early phase mouse embryos (below), and sub-cultured these embryonic stem (ES) cells to differentiate into teratocarcinoma cells (Proc. Natl. Acad. Sci., USA 78, 7634-7638, 1981). The capacity to culture pluripotential ES cells was confirmed by Evans and Kaufman (Nature 292, 154-156, 1981).

Over the following decade, scientists understood that turning genes on and off was critical to making undifferentiated stem cells differentiate.

Stem cells can be manipulated to differentiate, and be transplanted and engrafted onto other organ tissues. Matsui et al (Cell 70, 841-847, 1992) used epigenetic reprogramming to derive pluripotential ES cells from primordial embryonic germ (EG) cells. In the early blastocyst (below), EG cell precursors are specified by signaling molecules – gene-directed proteins that tell the EG cells to reach their so-called ‘somatic fate’. EG cells multiply and migrate within the growing embryo, usually with a unipotential fate (bone, muscle, or kidney, etc.). However, when explanted and cultured, they can be returned to pluripotent EG cells.

Stem cell research advanced steadily until Dr. James Thompson used a similar method to derive stem cells from human embryos obtained from failed in vitro fertilization (IVF, below); human ES cells could be grown in the laboratory (Science 282, 1145-1147, 1998). Dr. John Gearhart also identified and cultured embryonic germ (EG) cells from the gonadal ridge of fetal tissue obtained through elective abortions (PNAS, USA 95, 13726-13731, 1998).

But using failed IVF and abortion-derived stem cells was a political trip-wire.

Speaking to Americans from his Crawford, Texas ranch in August 2001, just one month before 9/11, President George W. Bush presented a mixed pro & con policy position on federal funding of ES cell research. He also announced the creation of a ‘special council’ to oversee stem cell research, and focused much of his speech on the ethics of ES cells derived from IVF procedures. “At its core, this issue forces us to confront fundamental questions about the beginnings of life and the ends of science.” By the time of his 2004 re-election campaign, President Bush had strictly limited federal funding and ES cell lines available for research.

In the private sector, a 2006 research breakthrough occurred at Advanced Cell Technology (Worcester, MA, above) where scientists genetically reprogrammed specialized adult cells into a stem cell like state – so-called induced pluripotent stem cells, or iPSC’s. In 2007, researchers in Japan and the U.S. developed a virus transfection method to reprogram somatic skin cells to function like stem cells (below), and then converted them to blood and other non-skin tissues.

In 2009, President Barack Obama lifted the 8-year federal restriction on IVF-derived ES cell research.

The tissue regenerative capacity of ES cells has created the discipline of cell-based therapy, also known as regenerative or reparative medicine. Diseases that might respond well to this approach include retinal macular degeneration [my mother], Parkinson’s disease [Michael J. Fox], spinal cord injury [Christopher Reeve], stroke, burns, heart attack, type-1 diabetes, osteoarthritis and rheumatoid arthritis.

But results of stem cell therapy clinical trials have been mixed, and disappointing in many cases.

For clinical uses, the stem cells must also be shown to function normally (i.e., heart muscle cells must contract), while also avoiding harm to recipient tissues from triggering immune rejection, or DNA damage that increases future cancer risks. These hurdles remain a real challenge to basic and clinical research towards the use of stem cells in human disease sufferers. 

Use of pluripotential stem cells – of embryonic or somatic origin – in biomedical research has significant ethical repercussions.

Related societal and cultural concerns have creative divisive politics and aggressive advocacy on both sides of the stem cell research issue. In response to this, related governmental policies have evolved, or twisted, in the white-hot crucible of public opinion. Whether or not embryos are going to be discarded by IVF clinics, pro-life groups strongly assert the “sanctity of life” beginning at the moment a sperm fertilizes an egg. Human cord blood and amniotic fluid derived stem cells are less controversial for research purposes, in that they do not require the direct manipulation of embryos. However, these stem cells are not inherently pluripotent.

Anti-abortion politicians tend to vote against the use of ES cells for research purposes.
In the current U.S. Presidential Campaign, there has been political push back against fetal tissue research. Republican candidate Carly Fiorina’s (above) anti-abortion position in the early debates was awkwardly counter-posed with her highly paid 1999-2000 service on the Merck & Co. board of directors, when the big Pharma company was making vaccines using fetal ES cell lines derived from aborted tissues.

The Republican-controlled U.S. House Select Investigative Panel on Infant Lives is now behaving as if fetal tissue research is a national security matter. Representative Marsha Blackburn (R-Tennessee, above), who chairs the Panel but opposes most fetal tissue research, favors subpoenaing researchers, saying “We are going to review the business practices of these (fetal tissue) procurement organizations and do some investigating of how they have constructed a for-profit business model from selling baby body parts.

The panel is now compelling fetal tissue scientists and their institutions to release identities and other personal information. Their disclosure demands apply to researchers, graduate students, healthcare providers and staff with ANY involvement – scientifically significant or not – in fetal tissue research. University of California San Diego, for one, has complied with the committee’s demands, but redacted the names of individual researchers. Given the heated emotional debate and a history of targeted violence, including a November 2015 attack on a Planned Parenthood clinic in Colorado that killed three, there are grave concerns about the safety of individuals and institutions identified in such activities.

Only 0.25% of the National Institutes of Health budget funds fetal tissue experiments. But the effect of such subpoenas on stem cell and fetal tissue research could still be chilling.

Medical school and research university advocacy organizations have strenuously objected, on the basis of a lack of compelling cause, and the lack of assurance that such information would be adequately safeguarded.  The Association of American Medical Colleges, a Washington D.C.-based academic healthcare and medical school advocacy organization, warned of such restrictions causing “serious downstream effects,” including “limiting research on vaccines not yet developed, for treatments not yet discovered, for causes of diseases not yet understood.

Not surprisingly, U.S. Democratic Party politicians have called this a “witch hunt.”

Republican political outrage over videos of alleged Planned Parenthood fetal tissue sales ground the 2015 U.S. budget process to a halt, costing then House Speaker John Boehner his job.

A 2015 report from the Union of Concerned Scientists titled “Freedom to Bully: How Laws Intended to Free Information Are Used to Harass Researchers” that predated the Congressional panel subpoenas, pointed out other widely shared concerns. Public universities and publicly funded research grants & contracts are subject to freedom of information act (FOIA) and open records requests. While using the public purse is a good reason to publish federally funded research in peer-reviewed scientific journals, these researchers should not be subjected to fishing expeditions by those with a narrow anti-science agenda.

Scientists usually carry out ethical research to advance human health.

But Superman died a mere mortal, without a medical miracle to regain the use of his legs.

Post-revolutionary politicians promote societal advancement in the guise of war.

But Napoleon died a prisoner, isolated from a fearful society on a deserted island.

We in the Square see through this fog of war. We are mindful of the march of science on human disease, and fearful of the confluence of political extremism.

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