Tuesday, May 31, 2005

Differentiation and Determination

(This is installment #3 of a series on cloning. The beginning of the series is here.)

After fertilization, the zygote begins to divide, duplicating all 46 chromosomes faithfully each cell division so that every daughter has the same genetic material. At first there is no growth, and all the cells are the same, so that the size of the cells gets progressively smaller as their number increases. The cells keep dividing until there is a ball of cells. At this stage, every cell is pluripotent, meaning that any one of these cells, if separated from the others and placed in a nurturing womb, could develop into a normal baby. This means that the cells are not yet determined to become a particular type of cell, and since they are all the same, and not specialized yet into any particular type, they are also not yet differentiated. Identical twins occur at this point when something causes the undifferentiated, undetermined small ball of cells to come apart into two, each of which then continues to develop normally. Since all the cells have the same genetic material, the resultant individuals will be genetically identical. One could take this ball of cells and separate it into three parts, getting identical triplets. One could separate it into four parts, and get identical quadruplets. The point is, each of these cells, and any group of these cells, is capable of building an entire, normal individual. They are pluripotent stem cells, one of the types of embryonic stem cells you have heard so much about.

As the cells continue to divide, the ball begins to hollow out, and soon the hollow ball loses its complete symmetry as one side pushes into the interior of the ball so that some of the cells are on the “outside” of the ball and some of the cells are on the “inside”. At this stage, the cells begin to be determined, meaning that their instructions in their nuclei begin to be “set” irreversibly so that they become destined to become a certain class of cell, and lose their original capability to make every possible type of human cell. If you think of each type of cell deriving from some other type of cell, like branches off a tree with each smaller branch representing a more particular type of cell, the zygote (fertilized egg) is the trunk, and has the capability of developing into every type of human cell. It is therefore the ultimate “stem cell”, since all other cells “stem” from it. At very early stages, when the embryo is still microscopic, some of those cells become committed to become skin and lining cells, some commit to becoming nerve tissue, and some commit to becoming bones and muscles, though at this stage they still all look the same. The fact that they are committed means that they have become determined, and cannot go back to being pluripotent zygote-like stem cells. They are still stem cells, because they will give rise to yet more specific cells and retain the capability of being several types of cells, just not ALL types of cells. They might, for example, become a bone cell or a muscle cell, but can’t any longer develop into skin cells or brain cells. Since they aren’t yet actually bone or muscle cells, they are not yet differentiated, but their internal program is now set for a certain pathway of development, so they are determined.

The rest of the development of the embryo is a matter of continually narrowing capabilities of the stem cells, as they become more and more narrowly committed to a certain type of tissue. Also, the cells begin to look and act differently from one another, becoming differentiated into specific mature cell types. By the time of adulthood, the individual still has many stem cells scattered throughout (probably) all his tissues, which serve to heal injuries and replenish losses. Most of these stem cells are still very determined (that is, they are committed to a certain type of tissue), however, and very hard to isolate. The different types of blood cells are being continually formed from stem cells in the bone marrow, but these stem cells can only “branch” into specific types of blood cells, and couldn’t become skin cells. There are other stem cells scattered in our skin that can regenerate a few types of skin cell. For example, it is now thought that there may be some stem cells even in the heart, so that under the right circumstances cardiac muscle might be regenerated. Our livers already do a pretty good job of regenerating themselves, presumably from residual stem cells that are capable of becoming the various types of liver cell.

Returning to our metaphor of the nucleus as blueprint library, we can think of the librarians (the regulatory proteins that "tend" the DNA) as controlling very tightly the set of blueprints that can be accessed in each cell. One can think of them unlocking and locking various drawers, so that only certain blueprints are available in that library (that cell nucleus). At fertilization, they gather together the filing cabinets from the father and the mother's germ cells, and begin to open certain drawers that contain plans for molecules and building materials needed for formation of the ball of cells, and they lock up the drawers that have plans for very specific cell structures like nerves and bone and skin, that are not yet needed. As the contractor molecules come in for plans, they can only get those that have to do with being an embryo and setting up the framework for the organism as a whole. At some point, for reasons we do not completely understand, having to do with size and age of the embryo and with the position of the cell within the embryo, some of the librarian molecules in some of the cells open some new drawers, and lock up some old ones. The new drawers have plans for new structures, new molecules, new cellular machinery that will make the cell differentiate into a particular kind of cell, and the locking of the older drawers means that there is no going back now; the cell has been "determined" to the extent that the drawers for the earlier functions are now locked and inaccessible. As the cell divides and the "libraries" are duplicated, the librarians are duplicated also, so that the daughter cells will have the same drawers open or locked. An adult stem cell is a cell that keeps some of the earlier drawers open, in case injury necessitates the small-scale regeneration of some particular tissue.

The interest in stem cells derives from the observation that some animals, such as salamanders, can regenerate entire limbs, while we cannot. Why can we not? It appears that whatever stem cells we have retained, there are none “primitive” enough, none close enough to the original embryonic stem cells, that can recapitulate the original process and generate and direct the whole set of cells and processes needed to reconstruct the damaged limb or organ. The irony, of course, is that we know that the whole instruction set is “in there” in the DNA, we just don’t know how to push the “reset” button, so to speak. Those early blueprints, the parts that originally constructed our nervous system, musculoskeletal system, GI tract and skin all from a single featureless cell, are somehow there but “locked up”. Stem cell research is all about trying to learn how to turn these organ-construction programs back on again. It is about identifying those circumstances that push the "librarians" to return a given cell back to a pluripotent state, unlocking the very early file drawers and undoing its determination as a particular type of cell.

(This continues here...)

Chromosomes and Fertilization

(The link above will take you to the latest NYTimes article on the Korean human cloning project.) (This is installment #2 of a series on cloning and the beginning of life. The first installment is here.)

Now for some details about what goes on in the nucleus of our cells, where our genetic information comes from, and how it is handled normally in the course of cell division, generation of sperm and egg cells ("germ" cells), and in fertilization. This section is long, but I believe that these basic concepts are truly necessary to consider issues relating to cloning and reproduction.

All cells, including bacteria, are constructed according to information that is contained as a type of code on extremely long molecules called DNA. Just as Morse Code contains only two distinguishable elements, a “dot” and a “dash”, so DNA contains only four elements, (A, T, C and G) that spell out strings of three-letter words that each signify a particular amino acid in a sequence. Most cells contain the entire instruction set for the entire organism in a structure called the nucleus, and even those cells that have lost all these instructions (have no nuclei), like red blood cells and platelets, were made from or within other cells that had the whole set.

In mammals and most other complex organisms, these long molecules of DNA are attended by, and in various ways attached to, many specific proteins and sugars whose job is to maintain and interact with the DNA so as to translate its message into actual structures and events in the life of the organism, and this combination of DNA and its associated proteins is called a “chromosome”. The complete set of instructions for each organism is divided into several chromosomes, and the number of chromosomes is species-specific, meaning that any particular species has a certain number of chromosomes, no more and no less. Humans have 23 different chromosomes, numbered 1-22 plus the sex chromosome, which together contain all the information necessary to build and maintain a human being. However, all mammals (actually almost all multicelled organisms) have two samples of each type of chromosome, one from the male parent and one from the female parent, so that for every instruction and every gene (except for a few genes on the X chromosome) each cell has two instances of that instruction or gene, one from each parent. This is a type of protective redundancy; if one of the samples of chromosome #3 is faulty, for example, the chance that the same gene is faulty on the other sample of chromosome #3, from the other parent, is exceedingly small, provided that the parents are not closely related to each other. So, while humans have 23 different types of chromosomes, they have two versions of each type, one from each parent, making a total of 46 chromosomes in each nucleated cell.

A useful metaphor for the contents of the nucleus in each cell is a large library of blueprints, complete with very focused and protective librarians. There is no other reading material…only blueprints. Each blueprint contains the plans for a molecule, which can be either a building-block or structural material, or a molecular machine that manipulates other molecules. Certain molecules that we might think of as “contractor” molecules can come into the library and get copies of each of these blueprints, but only if the librarian molecules allow it. The librarian molecules themselves, of course, were made from blueprints in the library, the complete set of which is called the organism’s “genome”. The blueprints are organized very specifically in certain locations on certain chromosomes, which might be thought of as specific drawers in specific filing cabinets.

Whenever a cell divides, it first makes a complete copy of each of its chromosomes, one for each daughter cell, and utilizes a complex but very reliable process to keep track of each chromosome and make certain that each daughter cell gets only one copy of each chromosome. All the filing cabinets are duplicated, so to speak, and each copy of each one is moved to one end of the library or the other, and then the library divides in half, one for each daughter cell. The only exception is when reproductive or “germ” cells are made, in which case the number of chromosomes is reduced back to only one instance of each of the 23 types, so that sperm and eggs each have only a single version of each chromosome. It is important to realize that there are several “shuffling” steps in the generation of germ cells, so that the 23 chromosomes in any given sperm or egg are a mixed set of genes from both parents, and, statistically, no two germ cells contain exactly the same set of genes. Not only are the maternal and paternal filing cabinets “shuffled”, but the drawers in each filing cabinet are shuffled, so that each cabinet in the end has the same number and type of drawers, but some of the drawers are from Dad and some from Mom. There are no longer any purely “Mom” filing cabinets or “Dad” filing cabinets in the germ cells. When sperm and egg come together, each brings (in humans) 23 chromosomes, so that the resulting “zygote” (fertilized egg) has 46 chromosomes again. The reason mules are infertile is that horses and donkeys have different numbers of chromosomes, so that the resultant mule does not have a “matched set” of chromosomes and hence cannot make useable germ cells from its odd number of chromosomes.

When an adult human makes a germ cell (actually, a woman’s eggs are all made while she is still a fetus in her own mother’s womb, but a man makes sperm continually), each germ cell therefore should have 23 chromosomes, one of each type. Some birth defects, such as Down’s syndrome and XYY syndromes, occur because one of the germ cells had an extra chromosome, so that the resultant individual has 47 chromosomes instead of 46.

Let us consider the germ cells. These are properly cells that are part of the human being that made them; every one of their chromosomes is a copy of one of the human’s own chromosomes, their substance came from the cells that divided to make them. They are hence “human” cells, and cannot be thought of as belonging to any other organism than the one that produced them. Most of these cells die without issue; they do not reproduce, and most of them never meet a germ cell of the opposite sex to form a new individual. A male produces millions of sperm a day, all but three (in my case) dying without producing a new individual, and a woman likewise “wastes” all but a few of her eggs.

Fertilization refers to the merging of the nuclei of the sperm and the egg to form a single nucleus, containing a set of 46 chromosomes, 23 pairs, one member of each pair from each parent. For millennia, this occurred only within the body of the woman, usually in the fallopian tubes, as a result of normal sexual intercourse. Now it can occur within the woman as a result of artificial insemination, or outside the woman “in vitro” (“in glassware”). “In vitro” fertilization is similar to the manner in which fish and amphibians fertilize their eggs; the egg is outside the female, and the sperm is dumped over the egg to fertilize it. The egg chemically attracts the sperm; the sperm have no “eyes”, and therefore rely upon chemical signals from the egg in order to locate it. The egg is swarmed by thousands of sperm that work to penetrate its outer layers, and as soon as the first sperm penetrates a threshold, the egg raises a membrane-like structure to repulse all the other sperm so that only a single male nucleus can fuse with the egg nucleus to make 46 chromosomes. My point here is to note that the egg is not “passive” in fertilization, but interacts with the sperm. A normal egg and a normal sperm “do something” specific to effect fertilization. We will see that this is not the case in cloning.

The fertilized egg is called a zygote. At this time, since we cannot duplicate either sperm or eggs, every egg and every sperm is unique, no matter how obtained and no matter where fertilization takes place. Therefore, every zygote, at this stage, is unique. We will note that this is not the case in cloning.

(Next: Determination and Differentiation, here)

Sunday, May 29, 2005

(Pause to admire the Mini Cooper)

Andy Crouch on the Mini Cooper and other "devices as focal things". Just some fun. (By the way, while we do have a Mini Cooper, we have neither a TiVo nor a Viking range...just a middling Whirlpool and Panasonic DVD/VCR. Have to keep that Bobo impulse under some control...)

Saturday, May 28, 2005

Conception and Embryology: Intro

In forthcoming blogs I hope to explore beginning-of-life issues as they relate primarily to cloning, in vitro fertilization and abortion. My views have been gradually changing over the past decade, and one of the reasons for laying out some thoughts here is to get them “out there”, on paper, so that I myself may evaluate them in a manner more systematic than I can accomplish in my head. I will be exploring some ideas that have occurred to me, and am quite willing…even eager…to have them challenged.

Many readers will already be familiar with the details of human conception and embryology, at least those aspects that bear directly upon the moral and theological issues I will be considering here. However, on the possibility that some will not be familiar with the processes involved, and the likelihood that many will not be familiar with terms that have very specific meanings in this domain, I would like to quickly sketch the overall process of mammalian conception and early embryology. A few of the terms, such as differentiation and determination, are very important when discussing stem cells, but do not typically appear in the popular press and are therefore probably unknown to most non-medical readers.

Please note that I am consciously trying to avoid using terms that are “at issue”, specifically such terms that beg the question by presuming the outcome, such as “human being” and “person”. “Embryo” has a specific scientific meaning that predates the abortion controversy, as does “fetus”, referring to the developing organism in the early and late stages of gestation (pregnancy) respectively, and need not be taken to imply that the developing organism lacks human rights or does not deserve protection.

I feel very cautious about the term, “human being”. This term means, at least, some discreet entity that exists (being) and is of the human species. Some also take it to mean, as if by definition, a being created in the image of God and hence possessing all the rights of any such being vis-à-vis other similar beings, and all the duties owed to God by such a being. This is to identify the English words “human being” with the Hebrew word “adam” in Genesis, an identification that is not necessary and which drives many arguments about abortion and embryonic issues, which arguments often boil down to simply using the same words differently.

We will start with biology, simply so that we understand the terms and the processes about which we are speaking. Once we have surveyed the territory, we will begin to dig in more philosophically and theologically.

(The next installment of this series is here.)

Friday, May 20, 2005

The "Dark" Side

For those of you who enjoy "dark" films (and I know you're out there...), my son David has recently posted reviews of "Blade: Trinity" and "Fight Club" on his film-and-book-review web site, Tears in Rain. I have not seen the second or third Blade installments; and quit Fight Club about half-way through (before the denouement.) The latter got too raunchy for me. Yet, this is clearly the stuff of twenty-somethings' discussion these days. Hmmmm...

How I Think

Short version: I maintain a working account of reality, which some might label a "worldview", that I seek to keep as coherent as possible across all the domains about which I know anything. New ideas are integrated into this worldview to the extent that they increase coherence and explanatory power. Once integrated, most ideas lose their individual history...ie, I forget the source; the idea becomes "mine" insofar as it is simply part of the way I think.

Long version: I do not have a "good memory". By that I mean that I do not easily remember facts that are not part of an integrated framework of other facts and ideas. For example, though I am a physician and use certain medications every day, after 25 years I still have to look up dosages almost every time. This is because the dosage of a particular drug is not derivable from any other characteristic of that drug; it is idiosyncratic, so to speak. I can remember the general "potency" of a drug, such as whether it is used in gram or milligram quantities, but cannot remember if it is 20 mg/kg or 40 mg/kg. That's what reference tables are for, in my opinion.

Therefore, I do not easily remember names, dates, or terminology that does not emerge from the concept itself. Instead, I remember relationships, structures, and causal sequences. Though I started out my college career in Biology, I abandoned that science for Chemistry within one semester, because (at least as a freshman) biology was all about remembering nomenclature (King Phillip Came Over From Green Shores, you know...) There was no reason that a particular worm should be segmented or flat. In chemistry, however, one simply had to understand a few principles and then could derive secondary and tertiary principles. One could create an explanatory "account"...a system or model...and use that account to predict and explain additional observations or "facts". Physics was even better. Remember a few definitions, a few principles, and everything else lines up. I would remember F=MA, the concepts of momentum, mass, velocity and energy, and derive all the other formulas on the fly during a test. There was no way I could remember all the various specific formulas; I had to derive them all from the handful of fundamental "laws" of physics as I needed them. The downside was, this was slower than simply "knowing" the particular formula needed for a particular problem. The upside was, I could see the inter-relatedness of all the particular formulas. I understood. I had a "vision" of the material (mechanical) world that was coherent and, in a sense, "concentrated" into a handful of elegant and simple relationships. This vision, incidentally, is one reason that I am convinced of the existence of God, and one of the ways I understand Him. I believe it is why, in most universities, the atheists are in the humanities and not in the sciences. Ironically in an age in which science is popularly believed to be inconsistent with faith, a large proportion of working scientists are, and have always been, believers in a creator god. Even those who don't believe are troubled by the evidence of Mind and Design in the material world. Read a little Hawking; he fusses about God on almost every page.

As I have continued to read, think, and experience life over these decades, I have continued to build my account of the world, which includes ideas of its origin, destination, and creator. There are lots of loose ends, of course. As I encounter ideas, I evaluate them against and from within this account. If an idea seems to provide more coherence, ie. ties up more loose ends, or seems to reconcile or explain apparent paradoxes, or is simply more "elegant" (which is an aesthetic judgment that has to do partly with simplicity and scope) then I will tend to "adopt" it. By that I mean, it becomes part of the framework of my thought, joined to other thoughts in various mutually-supportive ways. As time passes, and I "use" it more, ie: I reason through it on the way to other ideas, its distinctiveness is blurred. A really useful idea becomes connected seamlessly with other ideas in my way of thinking, and its original connection to a particular book or conversation is lost. Hence, it is precisely the ideas that I find most useful whose origins I am most likely to forget. An idea that doesn't "fit" anywhere might be remembered if I have a sense that it is really elegant or promising but I just haven't yet figured out how to use it. It might be remembered if it is one that is often opposed to my own thinking in actual discourse. But the history of really useful ideas is usually lost to me rather quickly.

This is one of the reasons I dislike discourse that uses authors or technical labels as shorthand for the ideas themselves. Even if I've read the author, if it has been more than a year or two, I will have incorporated the useful ideas, without "labels of origin", and forgotten those I rejected. There are always exceptions, of course, especially if the author has a memorable style like Chesterton, or is so richly useful that I have read the works several times, like Lewis. I have also had the experience often enough of someone quoting an author or a book without really having understood either, but understanding simply where the ideas ought to go, understanding the context of the ideas without really comprehending the ideas themselves. A person can sound quite educated and erudite by using such quotations to stand for ideas that he does not quite comprehend and could not really integrate into any in-depth discussion. It is my experience that most books contain at most a handful of unique ideas, and usually only one or two fundamental ones from which all the others are derived. If one can't actually articulate one of these ideas in the discussion, quotation of the author or book suggests, to me, a slavish reliance on implied authority.

So what? Well, as I embark on some discussions of controversial issues, I will be attempting to reason closely, and will certainly utilize ideas that some readers may have encountered in a particular author or in a "school" of thought. I probably will not attribute the idea explicitly. I also will not be able to engage you in a "He said...She said" kind of dialogue, ie: "Didn't Descartes address this? and didn't Hume reject this? or Doesn't postmodernism say...?" The fact that I don't respond in kind, or don't understand a question framed in this way, does not mean I haven't read the author or can't address his issues. It may simply mean that I have digested what I read, incorporated the parts that seemed right and ejected the parts that seemed wrong. I would prefer to engage the ideas themselves, articulated specifically.

Thursday, May 19, 2005

Human Cloning Proceeds Apace

Here we go! this is coming as fast as we expected! This NY Times article shows our manifest inability to stop this technology. Should we stop it? Suppose we can't, as I suspect is the case. How should we respond to the presence of this technology in our world? If we cannot stop it, can we regulate it adequately? What theology is applicable?

I hope to begin some on-line thinking about these issues soon. I will be reading Human Dignity in the Biotech Century by Colson and Cameron, From Souls to Cells -- and Beyond by Malcolm Jeeves, Body and Soul by Moreland and Rae, and Clones, the Clowns of Nature, by Gareth Jones. I will also offer some reflections of my own, derived from mybackground in medicine and also from my reading of scripture and various philosophers. Should be a wild ride!

(Sorry, the NY Times link generator is apparently down.)

Monday, May 16, 2005

I'm Back...

Well, my classes at St. John's are over, for now. I received my Master of Arts in Liberal Arts on Sunday. I will miss the very stimulating discourse, but will not miss the twice-a-week round-trips to Annapolis. That was getting old, even with great listening matter in the car. St. John's has a deal whereby Graduate Institute graduates can take a fifth semester for half price. I may consider this in a year or so, but for now I'm glad to be finished.

What to do now? Derek and I have been considering building some type of center for cultural engagement in this area, perhaps affiliated with CCO and our large, well-educated and generally affluent church. Perhaps a type of hosting organization, with weekly cafe-style discussion groups, monthly visiting speakers, offshoot studies in local prisons, medical ethics discussions for local medical school, etc.

Sometimes the above seems pretty free-form, and I wonder if I have the self-discipline to stay focused and productive with such a ministry. It also doesn't explain how my wife and I will secure health insurance or income from this activity. We have built up some substantial investments, but probably not yet enough to live on. I can provide both sufficient income and also health insurance by continuing to work as an emergency physician two days a week, but my heart seems divided here. More often lately the ER is overwhelmed, the patients are hostile and demanding while a good portion of them are abusing an expensive community resource by seeking convenience care at all hours of the day and night for problems that could wait for days or weeks, or that would resolve in a few days spontaneously (like colds). There's a part of me that is simply tired of it.

With a degree in chemistry, a doctorate in medicine, and a master's in the classics I could perhaps find a teaching position in a local college. This appeals to my love of teaching. But I worry that I will find entry-level positions in academia frustratingly full of multiple-choice tests and superficial survey courses. I'd love to be a tutor at St. John's, but beside the rarity of positions there, and the doubt whether I would qualify without a PhD, there is the relocation to a very high-cost city which would break our ties with this community of twenty-five years, and completely consume a lifetime's savings just for a home.

It is odd for me to be in this position. All my life I have known what was the next step. We shall see what the Lord has in store.

In the meantime, I can start blogging again....