Seeing Human Embryos - Two Different Perspectives

The NY Times today has a profile on Shinya Yamanaka, the senior author on one of the recent papers reporting the creation of pluripotent stem cells by expressing 4 transcription factor genes in adult fibroblasts. Yamanaka (who "is known on campus for refusing to join colleagues for lunch, choosing to eat by himself so he can keep working" - unfortunate, since informal conversations with colleagues can really be quite useful) has without question achieved something significant by successfully creating stem cells, first from mice and then from human fibroblasts. However I take issue with Yamanaka's outlook on the ethics:

"Dr. Yamanaka was an assistant professor of pharmacology doing research involving embryonic stem cells when he made the social call to the clinic about eight years ago. At the friend’s invitation, he looked down the microscope at one of the human embryos stored at the clinic. The glimpse changed his scientific career.

'When I saw the embryo, I suddenly realized there was such a small difference between it and my daughters,' said Dr. Yamanaka, 45, a father of two and now a professor at the Institute for Integrated Cell-Material Sciences at Kyoto University. 'I thought, we can’t keep destroying embryos for our research. There must be another way.'"

You might expect Dr. Yamanaka to be concerned about the much greater destruction of embryos that takes place in fertilization clinics - far more human embryos are destroyed there than in research labs. A petri dish is not exactly the most natural environment for an embryo, and the very act of creating embryos in vitro puts those embryos at risk.

While I'm not belittling Dr. Yamanaka for his views, and realize that he's just giving his impression and not necessarily making a strong ethical statement, I do think we should realize that his reaction is not universal. I've seen human embryos as well - and two of them became my youngest daughters. Several others never made it that far. I don't feel traces of sorrow for those lost embryos.

I suspect most physicians who work in fertility clinics feel the same way. Many, if not most scientists whose views I personally know, share this persepctive. We're happy for the ones that become human beings, but we don't lose sleep over the millions of little clusters of cells that are lost each year, both in and outside of IVF clinics.

Stem Cell Researchers Respond to Bush's Claim

The White House has claimed that Bush's firm stance against embryonic stem cell research helped to stimulate the recent breakthroughs in creating pluripotent cells without destroying embryos.

In an editorial in the Washington Post, stem cell researchers themselves respond.

We Can Reprogram Skin Cells Into Stem Cells - So Do We Still Need Embryos?

This month we've witnessed the first-time success of two important stem cell research techniques in primate cells. Both techniques were previously developed in mice, but their success in humans and monkeys is important. Stem cells from cloned embryos have been generated from macaque cells. And now this week, two papers (here and here - this last one is a PDF file) have been published that are reporting that adult human skin cells can be reprogrammed to become stem cells. However, do the results of this week's papers mean that we no longer need to get stem cells from embryos? The answer, for now, is a resounding no - reprogrammed skin cells currently have some serious drawbacks that need to be overcome before they can become worth trying in disease treatments.

How do you reprogram a skin cell (in this case, fibroblasts - a very generic, easily handled cell commonly used in labs) to become a stem cell? The key step is to induce 4 genes that produce important master regulators, the transcription factors named Oct3/4, Sox2, Klf4, and c-Myc. These transcription factors are proteins which switch large sets of genes on or off, thus initiating a cascade of genetic signals that enable the fibroblast to transform itself into a stem cell. It's amazing that just these 4 genes can initiate so many substantial changes, but this is a common phenomenon in biology, found even in yeast.

But does this technique now eliminate the need to take stem cells from embryos? Not yet. Contrary to statements by the White house, this research was not a result "the president’s drawing of lines on cloning and embryo use." Without research on embryonic stem cells, we would have had a hard time identifying the role of the 4 transcription factors in the first place. And even with no restrictions on embryo use, researchers would have still tried these important experiments. Science at its best attacks problems using a variety of strategies.

And it's not clear that this technique is going to produce better results in the near future. The process of transferring the 4 regulator genes into fibroblasts involves a type of virus (not a health-threatening virus - it's basically a handy lab tool), which deposits multiple copies of these genes almost at random around the genome. These four genes can end up in good places or bad places in the genome. In bad places, stem cell transplants can develop into cancers, with the c-Myc gene being an especially frequent culprit (it's a gene known to be involved in a variety of cancers). In mice, up to 20% of stem cell recipients develop cancer.

So our ability to manipulate these cells for a useful purpose still lags. We can do a somewhat better job manipulating embryonic stem cells, but in general we have a hard time getting any plutipotent stem cells to produce the exact kind of desired differentiated tissue, such as nerve or heart cells. To improve the process we need to keep working on reprogramming, but we also need to study how stem cells actually work in nature - that is, in embryos.

Monkey Stem Cells From Cloned Embryos - Humans Are Next...

Headlines last week reported that researchers successfully produced stem cells from cloned monkey embryos. Using a process that has become almost routine with mice, scientists can now make make primate embryonic stem cells that are genetically identical to a given DNA donor. Once we learn to do this in humans, the possibility of stem cell based treatments for heart disease, neurodegeneration, and more will be closer to reality. But in the US and elsewhere, can we develop the political will to let this research move forward?

In case you missed the headlines, the story is this: a group of researchers at the Oregon Health and Science University led by Dr. Shoukhrat Mitalipov used the process of somatic cell nuclear transfer (SCNT) to create cloned Rhesus macaque embryonic stem cells. SCNT involves taking the DNA from an adult skin cell and implanting this DNA into an egg cell from which the DNA has been removed. This DNA transplant procedure can produce an embryo without the need for a fertilized egg - and most importantly, it produces an embryo genetically identical the DNA donor, which means that potential therapies using SCNT-derived stem cells wouldn't be rejected by a patient's immune system.

SCNT itself is old news; what is impressive in this research is the new ability to do SCNT with primate cells. This breakthrough was enabled by better imaging technology. SCNT is like a heart transplant where you just rip out the old heart with a giant tug, leaving a lot of damage behind. With the new technology, Dr. Mitalipov's team was able to better see what they were doing as they carried out the procedure.

If it can be done in monkeys, it's just a matter of time before it can be done in humans. Back in 2004 the world thought that human stem cells had been created from such cloned embryos, but that research turned out to be faked. The researcher behind those studies, Woo Suk Hwang from Seoul National University, was exposed as a crook and the already controversial image of human stem cell research was tarnished. Because of this history, Nature and Dr. Mitalipov went to great lengths to prove that the macaque embryonic stem cells reported in this paper are real, including requesting genetic confirmation from an independent group.

Where does this research go from here? Scientifically, we're still some way off from using these cells to replace ailing nerve or heart tissue in patients with terminal diseases. The many political and legal hurdles are even more formidable in the immediate future. To take just one example, at SCNT's current success rates you need hundreds of eggs from donors before you get just one successful embryo. Egg donation is not a pleasant process, and laws in some states prevent researchers from financially compensating donors, unlike other types of research volunteers who are paid for their time and trouble. Success rates will no doubt improve as researchers learn important tweaks in the procedure, but that can't be done without lots of trying. If the US doesn't develop the political will to make it possible for stem cell researchers to do their work, future treatments will be developed elsewhere and the US will lack the expertise in both research and patient treatment. The macaque stem cell paper indicates that the day when we will know how to use embryonic stem cells for medical treatments looms ahead, and unless we make changes in this country, we won't benefit from them.