W’s August of 2001 speech on the evils of embryonic stem cells was an early classic of his presidency, one of the first indications of his deciderish, rather than uniter-not-a-divider, tendencies. All his favorite hobbies were covered–simpleminded and peevish sanctimony, rigid adherence to a bizarre and inconsistently absolutist moral code, and disinterest in any sort of logical, thoughtful or informed critique. In short, it was a delightful preview of the following eight years.

Bush’s policy was to deny federal funding for any research on new embryonic stem cell lines created after August of 2001. This wasn’t a ban. Nor was it a system of regulations, well thought out or idiotic. Research involving any embryonic stem cell line created before August of 2001, all requiring the destruction of an embryo? Fine. Dandy. Not murder. Moral, according to Bush. On a line after August 2001? Murder, as it involves the destruction of an embryo–a murder good decent American taxpayers shouldn’t be asked to participate in, even indirectly.

Put another way: Under the Bush policy, if you have money you can do whatever you damn well please. Commission embryos for the sole purpose of destroying them? No problem. Pay women for their eggs? Sure. Create a jello-mold out of human embryo? If you have the cash, you can do it.

Federal funding of contentious research buys you, the public, the right to set rules and demand oversight. Ask the animal rights activists. Instead of banning federal funding for animal research, they focused on demanding massive regulation and oversight. Killing a mouse in a research lab involves a prodigious amount of paperwork, hours of training and going in front of a panel of vets to explain yourself. Even if your research is privately funded, most non-federal grants require you to follow the federal grant rules. Bush’s innovative policy of “do what you want, just not with our dollars” successfully shoved the most ethically contentious work out of the public’s eye and into the shadows.

Well, weren’t some embryos saved? Hundreds of thousands of fertilized embryos are sitting in cryogenic storage at in-vitro fertilization clinics around the country, largely because it is much more difficult to freeze unfertilized human eggs. Therefore, eggs collected for fertility treatment are typically fertilized with sperm, allowed to develop for a few days into a very young embryo and then frozen. The overwhelming majority of these embryos will eventually be destroyed, after the couple has decided they want no more children and the insurance stops paying for storage.

If you really believe that human life begins when the egg fuses with the sperm–as Bush’s new family planning policy asserts–this is the worst imaginable outcome. At least with federally funded embryonic stem cell research, a few of these embryos destined for destruction could be used to generate new embryonic stem cell lines, advancing medical science and potentially improving human health.

(I think calling an embryo at this stage a human being is a serious stretch of even the most generous definition of what makes a human. These embryos have only developed for a few days, to somewhere around 100 cells. They are not yet individuals. If you cut the embryo in half, you get twins; smash two together, and you get a chimera. Not a single organ has developed, not a drop of blood, not the heart, not a blood vessel, not a single brain cell. An embryo at this point is literally an undistinguished clump of two different kinds of cells. The essense of humanity and human life seems more to me than sets of chromosmes coming together.)

The iPS cell breakthrough this fall seemed to change the game. Simply by adding four genes, we could convert most any adult cell into something that resembled an embryonic stem cell. If we can turn skin cells or swabbed cheek cells into something like an embryonic stem cell, we no longer need to bother with destroying embryos. Right? Discussion of stem cell policy quietly dwindled. The president appeared to be a forward thinking visionary, saving thousands of embryos from doom in the name of science.

Well did he? No.

From a social conservative’s point of view, Bush’s policies were and are a total fiasco. Not a single embryo is saved from ultimate destruction, as the IVF industry remains without serious regulation. By delaying research, human health was harmed. An opportunity for a serious discussion and enduring compromise on both fertility treatments and stem cell research was bypassed for political expediency.

The moment was there, and we had some decent models to apply to this ethical quandary. Take the example of German IVF clinics, where the number of embryos generated and stored per couple is strictly regulated, vastly reducing the number of excess embryos to be eventually destroyed. A slightly more liberal position would be to absolutely prohibit the sale or purchase of human embryos, only allowing donation much like we do with solid organ donation today. Nor did we discuss why there is such a need for fertility treatments–environmental degredation and the costs of having a child delaying pregnancy.

Even from a scientist’s point of view, this was a total fiasco—far worse than an outright ban. At least with a complete ban, those with private funding sources, such as endowments, would not be at such an advantage. All efforts could focus on alternatives. Japan had a near total ban on embryonic stem cell research; iPS cells were developed in Japan.

Whatever you think of the status of an early embryo, the Bush policies were a disaster–achieving the neither the desires of the infirmed seeking therapy nor the social conservatives seeking protection of very early embryos. When considering the long lasting societal costs of demonizing scientists, medical research, patient advocates and rational discussion, the whole situation becomes  emblematic of the entire contemptible George W Bush presidency.

(Image from Takahashi et al., Induction of Pluripotent Cell form Adult Human Fibroblasts by Defined Factors, Cell (2007), doi:10.1016/j.cell.2007.11.019)

Ok. Now I believe.

Two groups working independently–Dr. Yamanaka’s lab in Japan and Dr. Thomson’s Lab in Wisconsin–have converted human cells into embryonic stem cell-like cells. This tremendous accomplishment is on par with the initial creation of human embryonic stem cells about ten years ago, the completion of the human genome project and development of gene knockdown technology.

With this trick, skin cells can be converted into embryonic stem cell-like cells that can become any cell type in the body, including difficult to acquire human heart and brain cells.

I’ve written about this technique rather skeptically in the past. All of the previous work was with mouse cells. Now with two groups independently showing it works also with human cells, I’m pretty convinced. Yes, these two papers are pretty sloppy. The Thompson one reads like it was written over the weekend and the Yamanaka paper has a few glaring flaws. Still, the evidence has tipped in this case.

Embryonic stem cells–created from a few hundred cells in a very early human embryo–have the ability to become any cell type in the body, including heart and brain cells. Adult cells, like those found in your skin, are restricted to doing only a few things at a time.

After adding four genes–Oct4, SOX2, cMyc, and Klf4 according to Yakanama; Oct4, SOX2, NANOG and LIN28 per Thompson–to differentiated cells and growing the cells in careful culture conditions, some of the cells in the culture become quite like embryonic stem cells. Both groups went on to show these “Induced pluripotent cells” (iPS cells) can be turned into useful cell types just like embryonic stem cells. For example, the iPS cells were efficiently turned into beating human heart cells–all in a dish.

The technique still isn’t perfect. The four genes are still being added with retroviruses that permanently change the cell’s genetic material. Additionally, the proper differentiation of the cells requires these added genes to be silenced by a process that is still not entirely understood. Finally, at least one of the genes, Oct4, is cancer-causing. Therefore, this new technique is more useful for the lab than the clinic. None of these problems are unsolvable.

Why are these iPS cells so exciting?

The ability to make patient- or disease-specific stem cells should give a boost our unraveling of how complex combinations of genes cause illness or change responses to medications–particularly in combination with the human genome project and the ability to selectively shut off genes in cultured cells through RNA interference.

Let’s say you have two patients, one who responds to a cardiac drug and another who doesn’t. If you want to figure out why, you could now pluck some skin cells from each patient, and create iPS cells from each. In turn, iPS cells can be differentiated into heart cells (or blood vessel cells, or neurons, or liver cells and so on.) The heart cells can then be tested with the drug in a dish. Genetic differences between the two sets of heart cells–both in what genes each patient has, as well as which are on in their heart cells–can be determined and compared to the reference human genome sequence. The likely candidate genes can be turned off to figure out which ones are required.

Right now, iPS cells would be too dangerous to treat patients. Still, with a few relatively straightforward improvements, iPS cells could easily be a new cell source for treatments.Thus far, the techniques developed for embryonic stem cells–how to turn them into brain or heart cells–seem to work for iPS cells. That’s fantastic news. New heart cells made from iPS cells–all from a skin stem cell plucked from the patient–could replace the billion or so lost in a heart attack, for example.

The clinical medicine stuff is pure speculation. The impact on modern molecular biology of this technique–if it hold true; please hold true–is hard to understate. I’m excited. You should be too.

What’s being done with the money: A course to train young scientists, training grant to fund them and community outreach (ethics); pilot grants to draw in other scientists; three cores–one on human embryonic stem cells, one on advanced imaging technologies, and one using robots to screen drugs. Two floors of laboratories in a new building in South Lake Union will house most of the show. Eventually the hope is to form a department around this center.

How did we get the grant? By some impressive science. Almost everyone working on stem cells in Seattle gave a ten minute presentation of their work. Here are some highlights:

* Tony Blau can control stem cells after transplantation through a nifty bit of genetic engineering. While he started controlling the production of red blood cells, my friend and colleague Kelly Stevens has successfully controlled the growth of muscle cells grafted into an injured heart using Tony’ engineering.

* Beverly Torok-Storb is busily working creating (first in the world) dog embryonic stem cells. Why? Because dogs are one of the few animals with as much genetic diversity as humans. If you want to get around the immune system when transplanting human embryonic stem cells into humans, dog embryonic stem cells into dogs are probably the best place to work it out. It worked for blood stem cells a few decades ago, making Seattle the first place in the world where bone marrow transplantation worked.

* Carol Ware’s human embryonic stem cell core, currently limited by Federal restrictions, cultures fourteen of the “Bush blessed” lines. Beyond those, she also managed to maintain virtually all other available mammalian lines, including mink, mouse, cat, rhesus, fasicularis and marmoset. This is a remarkable technical feat. Dr. Ware also developed an impressive new technology improving the freezing and thawing of embryonic stem cells.

* Pam Becker is already running clinical trials using genetically modified (bone marrow derived) stem cells, a key bit of infrastructure to getting basic scientific findings to patients. The amount of paperwork–to this basic scientist at least–is terrifying. She works on treatments for both Gliomas and Fanconi Anemia.

* Provost Phyllis Wise warns that “California overpromised to the voters about cures” and that Washington should focus on basic science, understanding and building “nodes of expertise.”

* Thalia Papayannopoulous is figuring out a way of deriving blood-forming stem cells from embryonic stem cells. By first transplanting blood-forming cells into an immune-mismatched patient, we might be able to protect the cells from rejection.

* David Russell is a master at genetically modifying stem cells–useful for studies, preventing tumors from forming, and enhance transplantation. Foamy virus vectors. AAV gene targeting. HPRT locus as a model. Goal to modify the immuno-compatibility genes to make embryonic stem cell lines that will be accepted by many patient immune systems.

* Robert Hevner showed that exercise more than doubles the number of new neurons formed in the memory-regulating hippocampus (of mice). Add in the observation that living in an “enriched” environment increases the survival of the neurons and conclude: if you want a healthy brain get off your ass and do something interesting.

* Billie Swalla gave a fascinating talk about worms and other tiny animals that can or cannot regenerate themselves after injury. One must love any organism that can regrow it’s head. Choice quote: “This is a scary experiment for undergraduates. You cut the worms in half, and they just die.”

* Some shared problems repeatedly came up. The limited number of pre-August 2001 lines means those in use are aging. Chromosomal abnormalities are increasingly common.

I’ve just returned from a week long trip to Germany (Düsseldorf and Dresden) for scientific meetings on stem cell research and regenerative medicine–the land of cheerful public artwork, amazing cab drivers and tear-inducing-good mass transit. How many hybrids did I see? Zero

Some thoughts:

I.

Human embryonic stem cell research in Germany is under tight restrictions. It is a criminal offense to destroy an embryo—defined quite conservatively as a fertilized egg after the fusion of the sperm and egg pronuclei. No stem cell line created after January 1st 2002 may be used at all, with private or public funds. Nor can research in Germany encourage the destruction of embryos elsewhere. In contrast, while public funded research is restricted in the United States to lines created before August of 2001, with private funds one can do essentially anything. The Germany policy, while more restrictive, is at least ethically consistent.

The policy reflects underlying conflict in the Germany constitution, between requirements to respect human life and the independence of science. This duality is reflected in North Rhine Westphalia Stem Cell Network’s structure, combining both scientists and ethicists together in a cohesive program. As one of the local scientists delicately put it, “concerns over the lingering consequences of Nationalism-Socialism cause conservatism on the use of human tissues in research.” Slowly, the policy is liberalizing.

The embryonic stem cell ‘debate’ in the United States, between absolutist scriptural moralists and absolutist libertarians, is distressingly silly and unserious in comparison. (I personally favor an approach modeled from solid organ transplantation, in which the creation and distribution of human embryonic stem cells should be strictly decommercialized and regulated by an independent agency. And, I work on a near-daily basis with human embryonic stem cells.) The asinine Bush policies have guaranteed we will not have a quality debate on this subject. For that, one must go to the country where, not so long ago, my relations were processed into candles, buttons and soap.

II.

The universality of English in science was startling to experience firsthand. Deep within the former East Germany—where Russian still predominates over English as the second language for “political reasons in the past” as per my host—scientific talks are given in English, even when no native speakers are present. Without fluency in English, one cannot publish in the most widely read journals, attend the highest quality conferences, or even access the vast repositories of biological data available online.

Here is where the NIH’s budget (comparatively paltry to the military budget) really pays off. For the decades following World War II, the brightest minds in the world have been drawn here, studied in American Universities and occasionally settled in our country. Those who return home become powerful ambassadors for American policy and worldview in the highly influential technocratic class. After now experiencing this effect firsthand, I’d gladly drink George Marshall’s bathwater.

With our newly punitive immigration policies–everyone gets fingerprinted and eyeball scanned upon arriving, a deeply unwelcoming act–, startling xenophobia of many Americans and steady cuts of the NIH budget (in real dollar terms) might finally kill off this effect. We’re fools for risking it.

III.

Even more acutely than the the United States, Germany is facing an aging population and abundant heart disease. Right now, the best available treatment for congestive heart failure is heart transplantation. The problem: not enough hearts to go around. The strong restrictions on embryonic stem cell research in Germany have resulted in the most aggressive trials of adult stem cell based therapies for heart disease that can be found in Western medicine. The results so far are mixed at best, with weak evidence for any benefit and some potential risk to patients.

These trials are shockingly audacious–going straight from (unreproduced, and largely unreproducible so far) trials in rodents directly to humans, skipping the typical large-animal studies. Here is where the strong concern for protecting embryos results in adult human beings–unquestionably human life–being put at risk. Looking at all the evidence so far, embryonic stem cell derived heart cells are superior to adult stem cells in helping rodents recover from heart attacks. Large animal trials of the embryonic stem cell therapies are just now beginning–properly so–before trials in humans begin. The FDA might be a pain-in-the-ass, but they still can do a decent job of protecting human life, including adult human life, from harm during trials.

(Full disclosure time: I was a small contributor to the grant, including preliminary data, experimental design and writing. The lab I work in will be receiving some of the funds. Writing this, I am the eponym for conflict of interest.)

Hearing the news, Eric Earling at Sound Politics noted:

And a reminder that despite the annoyingly simplistic campaign rhetoric one hears around election time, there actually is federally funded, embryonic stem cell research already occurring in the country.

Not so quick Eric. Added to the bottom of the press release is this defensive notice:

The source of human embryonic stem cells is limited to federally approved stem cell lines listed on the National Institutes of Health Human Embryonic Stem Cell Registry.

Only lines created before August of 2001 may be studied with federal funds, as per the president and his infinite wisdom. Twenty-one are still around, and only ten are actually available for purchase right now. Federal research on human embryonic stem cells is limited the oldest lines, the lines where culture techniques were perfected, and the lines from a very limited genetic pool. (Fun fact: Three of the more popular lines (H1, H7 and H9) all started as embryos from the same in vitro fertilization clinic in Israel. How’s that for genetic diversity?)

What’s wrong with refusing to federally fund the creation of new embryonic stem cell lines? When government opens the purse, it gets to set rules. New lines are still being created (and pre-implantation embryos destroyed) — just with private dollars, behind closed doors and without any federal governmental oversight. For anyone seriously concerned about the ethical implications of this research, this is the worst possible outcome. Rather than a real national debate to hash out some reasonable rules and guidelines, we’ve simple swept the whole problem under the rug.

Solving some of what stops us from using human embryonic stem cells clinically — purifying out desired cell types from the differentiating population, delivering and integrating cells into target organs, avoiding grafting undesired or undifferentiated cells, protecting the genetic and epigenetic stability of the aged existing lines, and evading immune rejection — will require the creation of new embryonic stem cells. So long as the asinine Bush policy remains in place, we cannot forge a coherent and ethical means of doing so.