Leukemia, as most people know, is cancer of the blood or bone marrow. Most of the early symptoms are caused by excessive numbers of white blood cells- Lance’s most pronounced symptom was an enlargement of the spleen- but some types are asymptomatic for many years and are only detected through routine blood tests. Right now Lance has about 25 times as many white blood cells in a given volume of blood than you or I do. There are several different forms of leukemia, which are described as either “acute” or “chronic.” Both adjectives sound pretty bad to me, but it turns out that “acute” means “wicked bad” and “chronic” means well, if not “good”, then better than “acute.”
Lance’s leukemia is one of the chronic forms. Specifically it is chronic myelogenous leukemia (CML) and it turns out that this is one of the most fascinating of all cancers for 2 reasons. First, it was the first cancer to be linked to a specific genetic cause and second, it’s one of the best cancer-research-success stories.
Like other leukemias, CML manifests itself through an abundance of white blood cells. It appears later in life, usually after age 40*, and afflicts more men than women. But though it appears well into adulthood, its origins lie far in the past, all the way back past childhood, birth and even conception.
*Lance is 38.
About 1 out of every 600 humans is born with a reciprocal chromosomal translocation, which is where some of the parts of one chromosome wind up on another non-homologous chromosome. (The real number of such translocations is thought to be much higher, but some underdetermined proportion of them result in spontaneous miscarriages.) Translocations occur during meiosis, the process through which haploid* sex cells (eggs, sperm) are created.
*”Haploid” means having ½ the “full” or “diploid” number of chromosomes. So the sperm from your father and the egg from your mother each carried 23 chromosomes, giving you your “diploid” total of 46.
Side Note: The “non-homologous” bit means that the exchange is between 2 different chromosomes in different locations. Remember, we have chromosomes in pairs, one from each parent. Homologous chromosomes- meaning the two at the same location- routinely exchange genes during meiosis through a process called chromosomal crossover. Occasionally there can be problems in chromosomal crossover, but they’re different problems than the kind of translocation problem we’re talking about here.
About 1 out of every 100,000 people is born with a specific translocation in which parts of chromosomes #9 and #22 wind up in each other’s place. Specifically a piece of chromosome # 9 known as the ABL1 gene winds up in a stretch of chromosome #22 that is part of what’s called the “Breakpoint Cluster Region”. The modified chromosome #22 is known as the “Philadelphia* chromosome” and its presence is considered a firm diagnosis of CML**.
*The research that lead to the discovery of this anomaly took place in Philadelphia.
**About 5% of CML cases don’t seem to involve the Philadelphia chromosome. The cause behind these cases is not clear, but other, similar translocations are suspected.
The ABL1 gene is responsible for encoding a protein that controls several aspects of the cell lifecycle, including cell division. On the other hand, geneticists aren’t exactly clear on the function of the BCR region over on chromosome #22. But they’re very clear on what happens when that hunk of ABL1 winds up in BCR. An alternate protein is created- a protein that doesn’t exist in the rest of us. (I pulled this graphic from the University of Bonn Medical Center site. It’s way better than anything I could’ve cooked up.)
This protein, called the BCR-ABL fusion protein, “works”, but works a little differently from the standard (ABL1) protein. It doesn’t require activation by another protein; it’s active from the get-go. It activates several other proteins related to cell lifecycle, effectively speeding up cell division. And on top of that, it seems to work against some of the very same DNA repair mechanisms that prevent cancerous cell growth.
Tangent: The various “mistakes” in genes and gene replication is in itself a fascinating topic. Translocations, copying errors, deletions and other anomalies have played a huge role in the evolution of life. Here’s a quick example from the very same chromosome- #9- that effects far more than 1 out of 100,000 of us. One of the genes on chromosome #9 is the ABO gene, which determines your blood type. People with blood type O, which includes about 40% of Europeans (including me) are actually missing a single “letter” in their ABO gene. This one-letter ancestral deletion shifted the relative positions of a whole bunch of other “letters” within the gene, and dramatically altered the way ABO is expressed; specifically our blood cells are different.
The interesting thing about blood types is why there are multiple types around. If the A/B/AB types are better than O, or vice-versa, why wouldn’t one or the other come to dominate over time? The likeliest reason seems to be disease resistance. If you have type A, B, or AB blood, you have probably stronger resistance to cholera than I do. But it seems likely that my resistance to malaria is better than yours.
CML’s probably been around forever. Most people who have ever lived didn’t make it till 40 anyway, and those of our ancestors who did presumably got their baby-making and child-rearing out of the way before then. But today most of us in the developed world make it well past 40, and as recently as a decade ago, CML was most often something of a slow death sentence. It was usually treated with various chemo-type drugs (cytarabine) and in younger patients, sometimes bone marrow transplants*.
*Bone marrow transplants can cure CML, but there’s a good chance of the transplant killing the patient.
Chemotherapy (and radiation) treatments are intended to “work” by killing cancerous cells. The obvious problem with these therapies is that it is extremely hard to kill cancerous cells without killing lots of healthy cells in the process, which is why chemotherapy is so terrible for the patient. When most people think of a cancer “cure”, they often think of some miracle drug that would somehow recognize and kill only cancerous cells, but since cancer takes so very many forms, this seems like a tough dream to realize.
In 2001, the FDA approved a type of drug called Imatnib, marketed by Novartis under the name Gleevec. Gleevec doesn’t kill cancer- or any-cells. Rather it inhibits the action of the BCR-ABL fusion protein. The development was an excellent example of Rational Drug Design, a methodology pioneered in the 1990’s of designing drugs by understanding their specific biological targets.
Gleevec therapy is not without its downsides. In its early phases the medication causes significant nausea and body aches. It’s also expensive; without insurance it costs ~$5,000/month. And you take it forever. Lance has insurance; hopefully he’ll be paying more like $500/month. So that’s like a sports-car payment for the rest of your life, which I guess isn’t a bad deal seeing as you get a life. But it’s worth thinking about what would it would mean if Lance had been between jobs, or without coverage; treatment would likely bankrupt him and his family within a few years*.
*Yes, this is my plug in support of public-option healthcare reform. If all those other little crappy** countries can do it, surely we can.
**Special Note for Non-US Readers: Forgive me. I don’t really think your countries are “crappy” at all. That’s just the kind of ra-ra jingoistic trash-talk we Americans use to get each other riled up about doing important stuff, like putting people on the moon, curing diseases or invading other countries.
But chances are (97%, according to Lance’s oncologist) that within a couple of months the Gleevec will get Lance’s renegade protein under control, his white-blood cell count will decline, and he’ll be feeling well again, quite likely better than he’s felt in a year or more.
Cost, bureaucracy and hassle aside, there are great cancer stories, and Gleevec is one of them. Lance isn’t out of the woods yet, but there’s light at the end of the tunnel*.
No comments:
Post a Comment