Note: This is an excerpt of a history/memoir I am attempting to write about our experiences with my son’s two bone marrow transplants. It provides some information on how bone marrow donors are matched to recipients, so I thought it might be of some use to someone facing the same circumstances. The information presented is gleaned from years of investigations into the workings of the immune system, but the details were mostly retrieved from Immunobiology: The Immune System in Health and Disease (6th Edition) by Janeway, Travers, Walport and Shlomchik (2005). It starts with the end of a story about fishing by the bay in Destin, Florida on a trip we took after my son finally went into remission before the first transplant in 2001.
It wasn’t long before we ran out of bait. I debated whether or not I should leave my little bald-headed, moon-pie-faced son (the bald head was because of the chemo, the moon-pie face was due to the steroids he had taken as a part of the induction phase of chemotherapy—it had also made him fat and caused him to suffer routine bouts of heartburn) alone by the bay with the hungry heron standing so close by. I decided to lure the heron away so that he wouldn’t feel intimidated by being alone in its presence. I took the last couple of fish we caught and headed up to the condo. Just like I figured, the heron followed me, going as far as the concrete breezeway, stopping as I started climbing the stairs. When I got to the top, I looked back to see the heron easing back down to the bay, which I didn’t want, so after coming in the front door, fish still in hand, I headed to the sliding door on the terrace, and making sure the heron saw me, deposited the fish on the terrace floor. I had barely closed the sliding door behind me when I saw the heron fly in and gracefully land on the railing of the terrace. It was quite a sight, a bird with about a four-foot wing span landing on the terrace railing of a second-story condo. The bird’s looming presence just outside the living area made the glass doors leading to the terrace seem a bit unsubstantial and perhaps unequal to the task of providing a demarcation line between the structured environment of the dwelling and the anarchy of Nature looming outside. The heron stayed on the rail long enough to ensure things were more or less safe, and then fluttered down to retrieve the two fish from the terrace floor where I’d left them. It gobbled them quickly and flew away. The whole episode probably didn’t take more than a minute, but the close-up view of the heron through the glass doors of the condo as I stood in the living area left an indelible impression on me. Wolves, or in this case, herons, are always crouching at the door. Doors and windows are rather fragile human contrivances for keeping them at bay.
We returned home to the whirlwind of preparation for the transplant. We already were aware that none of us—me, my wife or daughter—matched all six of the markers used in typing bone marrow. My daughter had four of the six, and would have been the best choice in a pinch, but bone marrow transplants work much better with a perfect match.
Determining a marrow match has nothing to do with one’s blood type. Donors and recipients for bone marrow transplants are matched according to genes on chromosome six in the human genome that code for the major histocompatibility complex proteins (the MHC). There are basically six different MHC’s, three of each type, MHC I and MHC II. The MHC’s have the function of presenting fragments of intracellular proteins (and with MHC II’s, extracellular proteins that have been ingested by immune system cells known as “antigen presenting cells”) on the cell surface for inspection by the T-cells—a particular type of immune-system cell that mediates and directs battles against intracellular infections, mainly of viruses. The T-cells “look” at the protein fragments with their own perceptive machinery, called T cell receptors (TCR’s), determining whether the fragment is a “self” protein (belonging to the body), which means the cell is healthy, or is a “non-self” protein, meaning the cell might be infected and needs marking for destruction. When a virus has hijacked a cell’s reproductive machinery for its own propagation, T-cells are alerted to the intracellular coup by fragments of viral proteins that are presented on the cell surface through the MHC’s. TCR’s that read the fragments contained within the MHC’s look also to see whether the MHC itself is self or non-self. Anywhere from 1-10% of T cells in circulation at any one time will recognize a foreign MHC and tag the cell expressing it for destruction, which is why MHC matching is so important for successful marrow transplantation. Without it, the new marrow would attack and destroy the host body’s organs and tissues.
Because none of our MHC factors perfectly matched his (there is a one in four chance that a sibling will be a perfect match), the newly-formed transplant unit (at the same hospital hosting the hematology/oncology clinic where he was being treated), having been alerted in late April when the induction regimen failed that he would need a transplant, set about to find a match. It succeeded in locating a “donor” in a national registry of umbilical cord blood created just for the purpose. Umbilical cord is rich with hematopoietic stem cells, and by the time of my son’s first transplant in 2001, the umbilical cord blood of millions of fetuses that would otherwise have been discarded with the placenta had been MHC-typed, and saved and stored cryogenically for use in bone marrow transplants. (“Bone marrow” and “stem cell” transplant are used interchangeably throughout—stem cells in the context of a bone marrow transplant are hematopoietic stem cells—the precursor cells for all of the various types of blood cells, including other hematopoietic stem cells. These are not embryonic stem cells over which so much controversy has erupted. A hematopoietic stem cell is not capable of growing another complete human. It is only capable of growing more stem cells, or becoming one of the many types of blood cells the body continually manufactures in the bone marrow over the course of one’s life. Spongy pink bone marrow and umbilical cord blood are each rich in stem cells, the cells upon which successful transplantation depends.)
The successful use of umbilical cord-blood for transplants spawned an unfortunate industry specializing in the private storage of umbilical cord blood; unfortunate because spending money to store a child’s cord blood is ineffective in helping the child, while doing so also prevents the use of the cord blood where it might be helpful. Indeed, it is unfortunate, but not surprising. In a wealthy culture of declining birth rates, no expense is spared in raising the one or two children the average wealthy/upper middle class American female spawns, so it took very little persuasion to convince wealthy parents to fork over a few thousand bucks a year to store for their child’s possible later use its umbilical cord blood after cord blood was discovered to be useful for transplanting marrow (and probably because a great many of the parents confused hematopoietic stem cells with embryonic stem cells). It was foolhardy in the extreme, because there is virtually no scenario imaginable where a child would need the stem cells contained in his own umbilical cord. If he needed his own stem cells for a transplant (autologous), which is indicated in some types of cancers, his bone marrow makes them every day. If he needed someone else’s stem cells for transplant (allogeneic), as is indicated in acute lymphoblastic leukemia, among other diseases, then his own cord blood would be of no use to him. But there is no limit to what a modern-day wealthy parent, consumed with the fear that comes from having it all, worshiping all that is had, and not knowing quite why, will do to protect its child’s life from dangers imagined and real, particularly if in doing so it can seem to be poised at the scientific vanguard of pediatric medicine. Fortunately at the time of my son’s first transplant, there were still enough donated umbilical cords that a match for him was found.
But it is somewhat misleading to refer to anyone other than an identical twin as a perfect match. The genes coding for MHC’s I & II, also known in humans as the human leukocyte antigen (HLA), that must be closely matched for a transplant to succeed, have more varieties than any other gene sequence in human DNA. Within the human population, there have been identified over two thousand different alleles (varieties) of the genes that code for the three types of MHC I alone. The possibility of exactly matching one person not an identical twin to another person is exceedingly remote, to the point of impossible. “Perfect” in the context of MHC/HLA matching is an imprecise term. It truthfully means as closely matched as is possible in the premises; and even perfectly-matched identical-twin siblings can suffer transplant complications that are presumed to arise as a result of mismatched donors and recipients, so impossibly complex is the immune system mechanism for identifying self from non-self. This has thus been a greatly simplified explanation of one aspect of the immune system, and of that aspect, only a limited view of its most important part so far as transplant matching is concerned, hardly doing justice to the system’s majestic complexity. The human immune system is far and away the most complex of all the systems in the human body, making it very simply, the most complex entity in the known universe.
We humans commonly fancy that the essence of our being is expressed through our intellect and emotions; in effect, that the nervous system forms the basis of our individuality. The immune system might wish to differ. It alone knows, in microscopic detail, whether something it encounters belongs to us (“self”) or not (“non-self”). The immune system could make a colorable argument that the quick of the human animal (and of other vertebrates) lies in the spongy marrow at the core of its bones. Remarkably, the intelligent barrier between us and the world that the immune system creates is done completely outside of our conscious perceptions. In every normally-functioning human body, T-cells are constantly evaluating short strings of proteins (peptides) tucked in MHC’s on the surfaces of the body’s cells, deciding whether a particular combination belongs to the body or not. Unless and until an infectious agent successfully evades immune system destruction such that it causes illness, we are never consciously the wiser of the existential war carrying on within in us. None of the nervous system’s consciousness and sentience that seem so profoundly us and about which we humans regularly marvel would be possible were it not for the immune system knowing, a priori, the intricacies making us unique from each other and from the whole of the rest of the universe.