Stem cell tears

Will researcher have to look for other jobs now that federal funding for human embryo research in the US may dry up?

Imagine you’re a lawyer working for a death row inmate whom you believe is innocent. You spend ten years of your life appealing and re-appealing, interviewing every person remotely connected to the case, poring over the evidence time and again. Finally, you think you’re within a stone’s throw of victory and your client is killed… by a heart attack. There’s no closure, no sense of accomplishment, no thank-you. You feel like you just wasted ten years of your life.

Now, take those same emotions and apply them to a scientist. You spend ten years of you life reading about your topic, going to conferences, working long hours in the lab, thinking about your chosen puzzle from every angle imaginable. Finally, you think you’re within a stone’s throw of a solution and… your funding is cut, dried up, gone. There’s no closure, no sense of accomplishment, no thank-you. You have to choose a new project and move on. You feel like you just wasted ten years of your life.

Does it now make more sense that scientists are desperate to maintain federal funding of human embryonic stem cell (hESC) research?

Here’s the history. Embryonic stem cells were discovered in mice in 1981. Seventeen years later, in 1998, scientists were finally able to replicate that work in human embryos.  With that development came two different dreams. First, we, the public, learned to hope that we had a source of cells that could become any type of cell in the body. Doctors had been using adult stem cells (ASCs) to treat diseases since the 1970s but they were limited in their ability to become every different cell type. There were many types of mature cells in the adult body that we couldn’t replace. Maybe ESCs were the answer! Oh, the therapeutic possibilities!

Second, scientists dreamed that they finally had the tool they needed to answer some of biology’s most fascinating and fundamental questions: if all cells contain the same genes, how is it that the right genes turn on at the right time? If the entire human body is created from a single cell, how does each cell know what to become? Previously, answering these questions may have required dozens of human embryos per experiment. Now, since ESCs multiply so rapidly, scientists could do multiple tests on cells coming from a single embryo. Maybe they could finally unlock the mysteries of human development and cellular differentiation! Oh, the scientific possibilities!

How do possibilities become realities? With money, of course. And therein lay the hitch.

Every year, a budget for the US federal government must be passed by Congress and signed by the president. The appropriations bill for fiscal year 1996 was signed by then President Bill Clinton. Attached to the bill was a clause known as the Dickey-Wicker amendment (DWA). Various congressmen had become increasingly concerned about the number of human embryos existing in labs and freezers throughout the country due to the burgeoning in vitro fertilization (IVF) industry. (The first IVF baby was born in 1978.) A large fraction of the federal budget funds scientific research. The DWA assured that none of those funds would be used for “research in which a human embryo or embryos are destroyed, discarded, or knowingly subjected to risk of injury or death greater than that allowed for research on fetuses in utero…”. The same rider has been passed with the federal budget and signed by each president every year since.

Two years after the DWA was first passed, hESCs were discovered. The excitement of the biomedical community was palpable.

All of a sudden, President Clinton had a policy problem. American researchers had become dependent on federal funds for much of their work. Here was a new field opening up therapeutic horizons never dreamed of before. But it seemed that the DWA might inhibit its progress. Was it an obstacle that could be circumvented, or a roadblock not to be moved? Clinton’s panel of advisors argued that it was merely an obstacle. As long as the hESCs were extracted (and the embryos destroyed) using other funds, federal funding could be used to study the actual hESCs. Before this legal maneuver could be implemented, though, Clinton’s term ended and President George W. Bush inherited the problem.

After consulting his own advisors, President Bush addressed the nation on August 9, 2001 with his resolution. He fundamentally agreed with the Clinton work-around but was uncomfortable with the incentive that it would provide for the further destruction of human embryos. Since scientists all over the world had been experimenting with hESCs for three years, there were already in existence dozens of stem cell “lines” (populations of cells that originate from the same embryo and can be grown perpetually). Thus, he declared that the government could fund research only on those hESC lines that had been generated before the date of his address.

You might not realize how radical this was.

Science is slow. For example, we often don’t give Nobel prizes in science until at least 20 years have passed, proving the veracity of the discovery, its breadth of application, its impact on the rest of science. Here, just three years after a discovery was made, two presidents had been thoroughly briefed on it, created panels of advisors to study it, and chose to endorse and support it with federal funds.

Why were ESCs able to capture the attention of the nation in this unprecedented way? Not since the race to the moon had Americans cared so much about scientific pursuits.

The answer lies in the “pluripotency” of ESCs. Since the cells of an early embryo are capable of multiplying and maturing into all 220 or so cell types in the adult body, the hope of hESCs is that we will be able to create replacement cells for any body part we need. At the time, ASCs had been around for several decades and were being used in therapies for multiple diseases, but they had not been found in every tissue type and they seemed incapable of becoming types of tissue outside of their tissue of origin. So scientists called them “multipotent”, indicating their inferiority to ESCs.

Apparently the ASCs were not to be outdone by their embryonic predecessors. Over the next few years, researchers discovered ASCs in nearly every tissue searched. They also began developing cocktails that could coax the ASCs to become other types of cells outside of their tissue of origin.

Even more remarkable, in 2007, Japanese researchers found that they could take a fully mature skin cell and genetically tweak it to act like an ESC. They had induced pluripotency in non-stem cells! These new “induced pluripotent” stem (iPS) cells again caught the attention of the president. iPS cells were not only better than hESCs because they were ethically uncontroversial; iPS cells also had more therapeutic potential than ESCs -- not that they could become more types of cells than ESCs but they could be generated from a patient’s own cells and thus avoid the problem of immune rejection that beleaguers all ESC advances.

Maybe to emphasize his support of all non-hESC stem cell research, President Bush immediately issued an executive order to encourage the Department of Health and Human Services to fund and support iPS projects.

Stem cell research was in a great place. ASCs were gaining ground every day; an embryonic-like stem cell had been created which avoided all ethical controversy; and hESC research was legal, had no restrictions when privately funded, and had minimal restrictions when federally funded. As of January 2009, the first American hESC clinical trial in human patients had even been approved. (That approval was temporarily withheld that August but was just reinstated on July 30 of this year.)

As good as this scenario may sound, scientists were unhappy with it for several reasons.

First of all, the hESC lines that were created before August 9, 2001 (78 lines) were grown on top of layers of mouse cells that mysteriously kept them alive and aided their proliferation. Even if hESC therapies were developed with those cells, they couldn’t be used because of fears of contact with mouse cells.

Secondly, scientists were captivated by their ability to induce pluripotency in mature cells and wanted to be able to compare the induced pluripotency of iPS cells to the natural pluripotency of ESCs. Scientists care very much about the therapeutic benefits of their work but they are also motivated by a desire to solve the puzzles of nature; and here was a complex puzzle indeed! However, the original supply of hESC lines available had dwindled for various reasons (to 21 lines), so their ability to compare the two types of cells (with federal funds) was limited.

Finally, scientists were fundamentally unhappy that they were being told what they could and could not research using federal funds.

Enter President Barack Obama. Two months after taking office (March 9, 2009), he issued an executive order that negated Bush’s order (yes, even his encouragement of funding for iPS research) and allowed federal funds to be used for hESC research as long as NIH guidelines were followed. Those guidelines boiled down to requiring informed consent from the donors of the embryos. So the nation backpedaled from the faulty logic of Bush to the even more faulty logic of Clinton.

Yet not all stem cell researchers are pro-hESC research. Two American ASC researchers, James Sherley and Theresa Deischer, challenged the presidential logic in court. On August 23 of this year, US District Court Judge Royce Lamberth declared that “as demonstrated by the plain language of the [DWA], the unambiguous intent of Congress is to prohibit the expenditure of federal funds on 'research in which a human embryo or embryos are destroyed’… If one step or 'piece of research' of an ESC research project results in the destruction of an embryo, the entire project is precluded from receiving federal funding by the Dickey-Wicker Amendment.”

Of course, the ensuing outcry suggested that it was all politically inspired. Here were Republicans legislating from the bench just as they accuse Democrats of doing. Here was the beginning of the end of religious liberty. Et cetera. Et cetera.

It probably was at least somewhat politically inspired: I am not aware of the same suit being brought against Bush even though his logic was only a slightly tempered version of Obama’s. But just because a suit is politically inspired does not mean that it is illegitimate. Do those opposed to Lamberth’s decision honestly think that federally funding hESC research is allowed under the DWA? If so, honesty in this country has taken a more severe blow than I realized.

So what now? The Obama administration is appealing the decision in court. If it fails, the only option for them will be to remove the DWA from next year’s budget, an unlikely possibility in today’s political climate since it relies on congressional approval. So hESC researchers may just have to do without federal funds. Not such a bad deal for taxpayers opposed to the research, or really for any taxpayers in this economy.

What will it mean for the hESC field? Competition will be much stiffer and only the most promising projects will get funded by the private sector. Not such a bad deal for patients awaiting hESC therapies. Really, hESC scientists are the ones who will suffer the most. They will either have to find other funding sources (not such a bad deal for those states, most notably California, that have their own hESC funding) or they will have to let go of a project that they may have been working on for many years. Like the lawyer whose death row inmate dies prematurely of a heart attack, this would be a major letdown for any scientist to bear.

It’s also likely that the projects that get funded by the private sector will be those that have the potential to bring in a profit, which means that basic science research will suffer more than therapy-driven research.

While I admit that there are probably some fascinating secrets to be discovered by comparing hESCs and iPS cells, what is the value of this knowledge compared to that of human life? Sure, this knowledge may one day be used to improve other human lives but, for all we know, the embryo that we use as a stem cell source today could have grown up to discover a cure for cancer. Maybe we should let the hESC issue go and start questioning why we grow human embryos in our labs…

Michaela Kingston is the nom de plume of an American scientist who holds a PhD in stem cell science from Johns Hopkins University.  She is currently an adjunct professor at Montgomery College, Maryland where she is fulfilling her goal of science education of the public.

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