We’ve heard it all by now. “Stem cells will cure everything.” “Stem cells kill embryos.” “Stem cells are overrated.” We hear much less about the science of it all. (Oh, no! Not science!) And that’s too bad, because it can tell us a lot about the rest of what we hear. Let’s get to it.

Think of stem cells like tiny organ transplants, and you’ll be pretty close to grasping the essentials. If you could grow a new heart from your own tissues, there wouldn’t be any need to worry about transplant rejection. That’s how adult stem cells work when used in the adult they came from. Used in another person, they’re like a transplant. Anti-rejection drugs need to be taken for the duration.

So, conceptually, stem cells are simple. Politically, it’s another matter. I’m going to try to give the Cliff Notes version of both the science and my take on the ethics, as well as what we can realistically expect in the way of cures in the near term.

Intro … at warp speed

Adult stem cells are a very rare cell type, are hard to grow, and are hard to turn into useful tissues. Embryonic stem cells are easier to find because they’re present in much higher proportions relative to the total number of cells in the embryo. The earlier the embryonic stage, the more stem cells, until at the very earliest stages (zygote, blastula) it’s pretty much all stem cells. Embryonic stem cells are easier to grow and mature. They can generally be coaxed to mature into a wider variety of tissues.

Also, the earlier the stage, the less developed the immune system is, so the less chance there is of rejection even when the tiny cell transplant is given to an unrelated person. However, due to research restrictions in the US, there hasn’t been enough work done here to know whether rejection will be an issue or not. Research is being carried forward elsewhere (Britain, South Korea, Australia, Singapore, China, Brazil, and other countries), but I haven’t heard about definitive results on this question yet.

The downside of stem cells is that they can have a nasty tendency to turn cancerous. There’s some evidence (eg here, and here) that at least some cancers get their start as stem cells that lose the fine-grained regulation necessary to grow and differentiate into something useful. Instead, they just grow. However, it’s still not clear whether so-called cancer stem cells start as normal stem cells or just look like them in some ways.

There are also other down sides. One is that more research really does need to be done. We’re just taking the first baby steps in this field.

Some results are being obtained now, and those are therapies for conditions due to malfunction of a single cell type. Things like macular degeneration blindness (retinal cells), replacing insulin-producing cells, and regrowing damaged nerve cells, such as in Parkinson’s (simpler, here), and brain or spine damage. But we’re years away from growing new organs.

[update, Sept. 4. The hardest thing about writing this post is that the field overtakes me before I have the paragraphs finished. The scuttlebutt is that Israeli researchers have grown a whole heart from embryonic stem cells. So we’re obviously not years away from growing new organs. We’re not even days away, if that report is right.]

Getting a stem cell to mature into one cell type is just a matter of figuring out how to trigger it and then keep the cells alive while they grow. An organ is dozens (hundreds?) of cell types, all of which have to be perfectly placed together in order to function. At this point, we’re miles (but not light years) away from understanding cell growth regulation well enough to know how to do that. Figuring out how far away we are from growing new hearts or limbs is an unknown itself. It’s like trying to figure out how far away a mountain peak is when you’re hiking. If you’re seeing the whole mountain, it’s on the horizon and maybe fifty miles away. If you’re only seeing the tip, then the base is around the curve of the Earth somewhere and it could be 500 miles away. We don’t know enough about growth regulation to know how far we have to go, but we can see the peaks in the distance.

And then there’s the huge downside that people get hung up on stem cells, especially when they’re from an embryo. So let’s just dive right into that issue, since it has to be addressed before anything else can be done.

[Fair warning: this is a long post…]

Ethics of stem cells

The scientific facts are one layer, the ethics a very different layer. Starting with the science, what does the embryo actually feel when dissolved into separate cells in petri dishes?

An amoeba, a somewhat mobile single-celled creature, reacts to a touch at the cell surface by moving away, so it obviously has some way of registering that sensation. Embryonic cells don’t react to touch and don’t show any internal changes I’ve ever heard about. Embryonic stem cells are taken within a few days of fertilization, before the cells have differentiated, since that’s the whole point. You’re trying to get undifferentiated, i. e. stem, cells.

Once a nervous system has differentiated, which is very early on after the first month of pregnancy, the nerves carry signals. There is, at that point, no developed brain to process the signals, but signals can travel through the embryo. The type of signal, though, is very different to what we think of as feeling. The embryo’s nerves are unmyelinated. Myelin acts as an insulator. Without it, the nerve carries the signal the same way an uninsulated wire would carry electricity if it were lying on the ground. The wire is still conductive, but the charge won’t get very far. In relatively primitive organisms like clams, all nerves are unmyelinated. In humans, some nerves remain unmyelinated, and those holdovers from early evolutionary time can’t be anesthetised. So, for instance, if you get novocaine at a dentist’s, you can still feel pressure and vibration. Those sensations are coming via unmyelinated nerves, and give you some idea of the level of sensation in an embryo.

(Myelin sheaths start forming in the fourth month of pregnancy when the embryo becomes a fetus. Because of the magnitude of developmental changes between the third and fourth months, biologists use different terms: “embryo” during months one to three, and “fetus” during months four to nine.)

Biologically, the only objective fact about the feelings of embryos is that they have, at most, the nerves of a clam.

Which brings us out of the scientific weeds and into the ethical ones.

It should go without saying that lack of sensation has nothing to do with whether an embryo is considered a person or not. Just because someone has no feeling, such as a person in a coma, is no reason to deprive them of rights. The discussion from this point on tends to be about the relative rights of embryos versus those other beings who can greet you in the morning. (See, e.g., the reasonable summary on Wikipedia.)

I think there’s a step missing. First figure out whether an embryo actually is a full human being with all the rights thereof, then start weighing whose rights are more important.

That first step is indeed a hugely difficult question. Books have been written about how to define what is human. Socrates struggled with it. In the Cliff Notes version here, it’s enough to say that the more you think about the issue of what actually defines “personhood,” the harder it becomes to figure out. (Bit more on that in an earlier post of mine.) The ultimate fallback definition used by some people is having human DNA, but they obviously don’t really believe it or they’d want people who’ve had transplants to carry two ID cards. The more thoroughly you go into it, the clearer it becomes that there simply is no objective way to define what constitutes a human person. Neither science nor logic has an answer to this question.

That means objectively defining who is a human person with full rights is not a difficult question. It is an impossible one.

The only way to arrive at a definition is by examining one’s assumptions or beliefs about what is essentially human. I have yet to see a philosophical or religious treatise on the subject that doesn’t come down to; “This is what I think (or God thinks) it means to be human.” On an individual level, that can take lots of thought and soul-searching, but on a social level, it simplifies the answer to something totally obvious. The operative word is belief. As in anything based on beliefs, it’s an answer everyone has to find for themselves. And, as in all matters of belief, everyone has to be free to live according to their own.

So weighing the rights of embryos versus adults is an individual decision, and on that level it can be a difficult one.

But on a social level, the question goes away. The freedom to live according your own beliefs is a fundamental right in free societies. The government has no business telling people what to believe. If I have no problem with stem cell research, I must be able to live according to my lights. Someone who does have an issue with it, must be able to avoid therapies based on it. In a free country, stem cell research really does fall into the same category as abortion. If you’re against abortion, then don’t have one. If you’re against stem cell research, don’t use it.

That leaves the question of whether people opposed to stem cell research should have to worry about their tax dollars going to fund it. Ideally, no. But there are also people desperately opposed to war, who have no legal choice but to fund it. People are opposed to the death penalty, and have to fund it. Either all conscientious objectors should be respected, or none should. Exceptions for just one class of objectors look unprincipled to me.

Many people genuinely believe that something with less nervous system than a clam is not a human person. For us, there is nothing ethically dubious about stem cell research.

Stem Cells, Part II: Embryonic Stem Cells

Getting back to the science, stem cells are not all created equal. There are several different kinds.

Embryonic stem cells are naturally capable of differentiating into any tissue (or organ, if we knew how to trigger the right signals). We have no way, yet, of getting them to do their thing inside the body where they’re needed, so they have to be grown in tissue cultures. Tissue culture techniques require the stem cells to grow in association with feeder cells. It’s hard enough getting human stem cells, so in the early research the feeder cells came from mice. The reason that’s important is that DNA can sometimes move around, and especially viral DNA can move around. So the early cell lines potentially have bits of mouse DNA or mouse viruses incorporated into the human DNA of the stem cells. For medical use, this is Not Good.

When Bush turned off federal funding for stem cell research in 2001, almost all the cell lines were still at the early research phase and used mouse feeder cells. So, almost all of them are useless for medical applications (although okay for most medical research).

Furthermore, normal cells can’t grow forever. Only cancer cells can do that. So embryonic stem cell lines can be maintained for many cell divisions, but certainly after a few years, it’s time to start over. And mutations accumulate with each cell division, which is also medically Not Good.

It’s essential to have a high diversity of stem cell lines to use in research. Otherwise there’s no way to be sure that results are generally applicable. A somewhat analogous situation might be making only kidney transplants legal. There would be no heart, lung, liver or corneal transplants. Also, for some applications like pharmaceutical testing, results can’t be obtained unless specific lines are available.

For all these reasons, limiting the embryonic stem cell lines to be used in research does not show “balance” or “compromise.” It shows the ignorance we’ve come to expect from this Administration. It’s also very bizarre to believe that using such cells is murder, and then saying that some murder is okay. I’d say it shows that even they don’t believe the things they spout.

Recently, a new kind of embryonic stem cell has been generated. Scientists found a way to trigger cell division in egg precursor cells. (Cloning and Stem Cells Journal, 2007, vol 9, no 3 (pdf), or a simpler summary.) These are egg precursor cells that still have the full complement of 46 chromosomes. They’re genetically matched to the donor, like any other cell in the body, and could be used for therapies in that woman without requiring anti-rejection drugs.

Ethics … again

The cry has gone up from people who don’t know much about it that it’s not just the traditional egg+sperm combination we need to be concerned about. A dividing egg by itself could develop into a complete human being, someday, when we have the technology worked out. The problem with this scenario, of course, is that the dividing egg only has half the chromosomes. Given the complexities of mammalian development (about which there’ll be a bit more below, under Adult Stem Cells), the dividing egg isn’t going anywhere all by itself. What these people are really worrying about is egg precursor cells, and those, as we just saw, are already being coaxed toward complete development. This is not a problem coming in the future. It’s here right now.

The problem in the future is much worse than that. Once we have the technology worked out, we’ll be able to take any cell in the body, de-differentiate back to the equivalent of that egg precursor cell, and then have it grow into a human (who would be an identical twin, or clone, of the cell donor).

Let me say it more clearly: soon many cells in the body will have the potential to turn into a complete human being.

So what are the people urging us to “Think of the cells!” going to do? Start holding funerals for each cell left on the sidewalk when anyone scrapes their knee after a fall?

That’s the problem with muddled thinking that can’t distinguish potential human life from actual human life. Before technology, muddled thinking didn’t matter because the two were functionally equivalent. Even a few weeks of prematurity was a death sentence. Then technology kept pushing back the date of viability. Then it occurred to some people that potential humanity goes right back to the fertilized egg. Now science has pushed the potential beyond that, to the proto-egg alone. Some day, it’ll be every single cell.

Science has taken away the easy conflation of potential and actual. The two were never equal, any more than the fact that I’m a potential Nobel Prize winner makes me an actual one. But science is making that fact of logic painfully obvious. It’s forcing people to come to grips with the difficult question of what they mean by “human.” If I were them, I’d think it through consistently enough to avoid absurd conclusions. Such as having to find a name for every one of the millions of intestinal lining cells sloughed off with every bowel movement.

Stem cells, Part III: Adult stem cells

Adult stem cells come in several different varieties. They are already partly set on a path toward some specific tissue. For instance, there are stem cells capable of forming new brain cells, but they cannot form new liver cells, and so on. After we’re born, all our stem cells are “adult,” except for egg or sperm and their precursors. Even babies have only adult stem cells, except for the sex cells. Therapies based on adult stem cells involves triggering these partially differentiated cells to form their particular mature cell types.

The hard part is finding those adult stem cells to begin with, because they’re very rare. Once they’re found and tissue cultured, the harder part is getting them to multiply without differentiating until there are enough cells to make a difference. It does you no good to find ten retinal stem cells, painstakingly start culturing them, only to have them turn into proper retinal cells after one division. You have twenty cells after all your trouble, which aren’t enough to cure anything.

In an attempt to find richer sources of stem cells, people have been trying other approaches. Umbilical cord blood stem cells are one source which is richer than adult tissue. Since the perinatal immune system is still not fully developed, there are fewer rejection issues than with cells taken from people with fully developed immune systems. Using them in the originating individual, i. e. with no rejection issues, would mean storing the cells frozen under perfect conditions for years or decades, and hoping they still worked when they were needed. Obviously, that’s expensive. So, also obviously, there are plenty of companies trying to convince people they need to store cord blood “for your family’s health.” Cord blood stem cells are partially differentiated blood cells, so their primary use is the same as a bone marrow transplant, i.e. for cancers of the blood, like leukemia, and for other blood disorders. Recent research is also finding ways to differentiate the cells into other tissue types, such as insulin-producing cells. (E.g., breathless news report.)

The ultimate workaround is to cheat. Cells have two main components, nucleus and everything else, called the cytoplasm. The nucleus contains the DNA, and with the usual cognitive predisposition to fixating on hierarchies, we tend to see the DNA as the master program in the cell. In reality, though, the DNA is more analogous to a library. It’s the library staff who actually determine how accessible the books are and what’s done with them. Those functions are out in the cytoplasm somewhere, and are still very poorly understood. So the easiest way to cheat is to take the nucleus of a cell of interest, and inject that into an egg whose own nucleus has been removed. This is called somatic cell nuclear transfer (SCNT), i.e. transfer of the nucleus of an ordinary body cell, or “somatic” cell. The egg cytoplasm has the ability to make all the DNA in the nucleus accessible again, and to read off any part of it, and therefore theoretically to make any cell type or organ desired.

Or, theoretically, SCNT can make a whole new human being. This is the human cloning you hear about now and again. It’s worked in mice and, famously, sheep. However, “worked” in this case means “shown to be feasible,” not “worked just like normal development.” Some 30% of naturally produced zygotes (fertilized egg+sperm) result in births, most of them developmentally normal. In cloned mice, the success rate is between 2%-15%. In cloned sheep, it’s less than 1%. From a human cloning perspective, the most difficult question is not the high failure rate, but what to do with all the abnormal births. Those are much commoner than normal ones (more on that in a bit), unlike the natural system. So a cloned animal could be born with, say, underdeveloped lungs. If it’s a sheep, it’s put out of its misery when the researchers realize it won’t survive. What would you do in that case with a human clone?

Development in clones is often abnormal because the gene regulation involved is mindbogglingly complicated. In natural development, egg and sperm have the correct “imprint” on their DNA. Think of the imprinting as little tags flagging the important books in the DNA library. The tags are in all the right places to go through the complicated process of embryonic development. As the cells mature, it’s essential to move the tags around. Whole sets of genes are tagged “Do Not Use.” Never, for instance, make another arm again. In cloning, all those tags have to be rearranged back to the pre-embryonic state before anything can be done. Furthermore, DNA derived from sperm is tagged differently from that of eggs, and the contribution of that tagging is subtle but is increasingly recognized as important. The egg’s “librarians” do their best, but too often the task seems to be too big to handle.

Cloned cells also show too much variation in telomere length, which is another cell development issue, and which may indicate long term problems with the health of the resulting clone. Because of the large differences between species in clonability, it won’t be possible to know the implications for humans until there’s a large sample size of great ape clones. At present there are none.

Cloning of humans and great apes (collectively called primates) hasn’t reached even a sheepish level of success. People aren’t sure why yet, but there is some evidence that the way the cell aligns chromosomes during cell division operates within even narrower parameters in primates than other animals. (For the scientists among you, “primate NT (nuclear transfer) appears to be challenged by stricter molecular requirements for mitotic spindle assembly than in other mammals.” Simerly C, et al. Molecular correlates of primate nuclear transfer failures. Science 2003; 300: 297 (behind paywall). Via pdf by K. Illmensee, Journal fur Reproduktionsmedizin und Endocrinologie, an excellent (English) summary of the current state of mammalian cloning.)

Finally, there’s the holy grail of adult stem cells: taking an ordinary cell, de-differentiating it back to the point where it can create any cell, and then using it to grow the needed cells or organs — or a complete new human being. Well, the grail has already been sighted. I started writing this interminable series of posts about stem cells over three months ago, and new research keeps coming out that forces me to rewrite, and add!, whole chunks. Such as the fact that this has been done. They even have a cute mouse they grew from a mouse fibroblast, a type of connective tissue cell. Abstract, Nature, June 6, 2007)

Even more recently as reported in ScienceNews (currently, only the references are freely available), that original lab plus two others have managed consistently to identify completely retagged stem cells. (They use the word “reprogrammed.” You might also see it called “reimprinted.”) That’s a big breakthrough in itself. Selected cells were implanted into an existing early-stage mouse embryo — which means they’re still “cheating” somewhat by using the regulatory processes of natural embryos — and the fibroblast-derived stem cell formed a baby mouse.

The bad news is that 20% of the fibroblast-derived mice died of cancers. There seems to be a thin line between good stem cells and those that have gone over to the dark side. Who knows, maybe when they solve the problem of stem cells causing cancers they’ll solve the problem of all cancers.

Mice, as I’ve been saying, work rather differently than humans, but, still, it all goes to show that it’s just a matter of time before any cell can be turned into an embryo-generating cell. The people I was talking about at the end of Part II really need to get to work on sorting out the difference between potential and actual human beings. They don’t have too many years left.

Current applications in medicine

A constant refrain in all these stem cell posts should be “more research needs to be done” because I want to be real clear on the fact that most of this stuff is neither here nor now. However, it’s not all somewhere over the mountain. Some of it really is here and now. I’ll give some examples, but first a caveat on how likely we are to see these methods widely applied.

Because of the restrictions on embryonic stem cells, all the currently applied therapies use stem cells taken from the person who needs the therapy (called “autologous” cells), so that there are no rejection issues. That also means the therapies have to be individually tailored, which makes them expensive, and makes pharmaceutical companies unhappy. It’s the same problem they have with using genomic testing to find the most effective drug for a specific patient. It’s also why they try to pretend that any anti-depressant will work in any patient, although that’s clearly not the case. The ideal drug for big companies is something expensive that works for everyone. That’s how you sell blockbuster profit-makers. So I’m not sure how widespread any of these therapies will become, no matter how successful they are.

Immune system stem cells have been taken from blood, bone marrow, or umbilical cord blood, and grown together with cancer cells from the same patient. That primes the mature immune cells produced in the culture to attack that particular cancer. The mature cells are injected back into the patient, and do a rather amazing job of dissolving tumors. Since it’s highly experimental, it’s only been used against tumors that would have been fatal otherwise in some brain cancer patients, for instance. (That link no longer works. Similar information in 2007 at NCBI)

[Stem cells are different from another cutting edge biotech innovation, monoclonal antibodies, but they do share some similar lab techniques, and they tend to show up how little we really know. That last fact was made horribly obvious during safety testing of one monoclonal antibody during which six British volunteers nearly died. Months later, the cause still wasn’t known, and that was still true in the last report I saw.]

“Sperm” cells have been made from bone marrow as an infertility treatment. Autologous adult stem cells have been successfully used to block type 1 diabetes (i.e. juvenile diabetes). (Summary of the original research.) Stem cells have been activated in skin to improve wound healing, and activation of specific genes in the cells has also led to the growth of new hair follicles. So the research gets reported as a “cure for baldness.” Heart valve repair using stem cells is becoming a reality.

Ethics … yet one more time

We’re at the very beginning of using stem cells in medicine, and we already have treatments for some forms of cancer, blindness, neurodegenerative diseases, diabetes, and the list goes on. In all the talk of stem cells and ethics, I haven’t seen much about the ethics of keeping people sick because somebody doesn’t think they should have a cure.

The very people going on about ethics are the ones who seem to be ignoring the gigantic ethical issue of forcing people to die for somebody else’s beliefs.

Because that’s what is going on here. This isn’t about the rights of embryos versus adults. This is about one set of adults deciding what it means to be human and then imposing their beliefs on other people. Nobody has proved or can prove that an embryo is a human person. That is a matter of belief. It’s something everybody has to decide for themselves. It’s something nobody can decide for anyone else.

Imposing beliefs on others is not an individual ethical issue. It’s not something we decide for ourselves. It’s a huge social ethical issue, and therefore can be and should be prevented by law. When one set of adults starts imposing their beliefs on other people, sometimes fatally so, it runs counter to the bedrock of any free society.

There are laws against that. And if familiarity has bred contempt for the original laws, it’s past time to make some new ones.

Technorati tags: stem cells, ethics, bioethics, politics

Other related links:
earlier post on stem cells

Crossposted at shakesville: Part 1, Introduction; Part 2, Embryonic Stem Cells; and Part 3, Adult Stem Cells.