Thursday, July 16, 2009

The Strangeness of Cancer

To no one’s surprise but my own, I did not fatally succumb to the flu. After 2 restless nights of sweat-soaked sheets I awoke dry and rested yesterday morning, feeling largely recovered except for a lingering cough.

I make fun of a lot of things in this blog, and partly that’s because I feel that if I can keep it light, a casual reader might be a bit more likely to stick with some of the geeky stuff that I think is so cool about the living world. So if you’re a regular reader, I hope that you’ll cut me a little slack for today’s not-funny post. And yes, not only is it un-funny, but it’s got science in it. But it’s science that any motivated 8th-grader could understand, and it’s important. So stick with it.

LanceCallpic About 2 weeks ago a longtime friend and colleague, who I’ve known and worked with for over a decade, was diagnosed with leukemia. Before I go any further, let me be up-front and say this story turns out largely OK- so far, this is a “good” cancer story, if there can ever be such a thing.

This friend- let’s call him “Lance”*- had recently been diagnosed by an “Instacare”** physician with mononucleosis. But when his symptoms worsened, he returned to his family physician, who ran a series of blood tests. In the 2 weeks since, specialists have conducted further tests, and detected a tell-tale chromosomal anomaly indicating the specific variant of leukemia with which he’s afflicted. But I’ll explain all that in a moment.

*Unlike most of my lame-O-not-really-pseudonyms, this one really is not his real name. I’ve actually mentioned “Lance” a couple of times- under a different pseudonym- previously in this blog.

**This isn’t intended as a slam on “Instacare” physicians or facilities. I’ve received excellent care from healthcare providers in walk-in facilities many, many times.

Two and a half years ago, my favorite uncle* went to the doctor complaining of acute malaise and a nicked-while-flossing gum that wouldn’t quit bleeding. He was diagnosed with leukemia, and was dead 10 days later. By the time we all realized he had hours to live I was in Houston on a business trip, desperately trying to figure out how to get to Boston while he was still lucid. I didn’t make it.

*Twin A is named for him. And yes, I still always plug his book.

In the busy-ness and goings-ons that surround unexpected deaths and memorial services, there wasn’t really ever an appropriate time or opportunity for me to learn what type of leukemia killed my uncle, and none of my close family either asked at the right time or understood the details. To this day I don’t understand specifically what killed him, or why his earlier treatment for prostate cancer (radioactive seeds) apparently precluded what would have supposedly been the optimal therapy.

So when Lance told me he had leukemia, I quickly knuckled down and learned everything I could about it.

Cancer is the most perplexing of diseases because it’s so unlike a “normal” disease. Even in this modern day and age, here in the US most of us still latch on to the age-old concept of a “disease” being something you “catch”- like plague or smallpox or typhus or cholera. And today, with those traditional diseases largely eradicated from our first-world lives, more and more of us, and the people in our lives, manage to live long enough to “achieve” cancer.

When you talk to people about cancer, you quickly notice that most folks (and you probably) are more “comfortable” with the idea of cancers that seem to have some kind of “reason” behind them. The classic example is the long-term smoker and lung cancer. We’re sad of course for the victim, but somehow there’s a bit of comfort for us in that there’s at least some “sense” in it, some explanation, and even something that could have been “done” about it: You should regularly wash your hands if you want to avoid catching the flu, and you should abstain from tobacco if you wish to avoid lung cancer.

But those obvious cause-and-effect cancers from things like smoking, or radiation, or asbestos exposure are only a portion of the myriad forms and types of cancer, and the mysterious “causes” of so many of these cancers just add to the pain and anguish experienced by those touched by them. And yet we so want to understand the cause, because when you get down to it, cancer isn’t simply a disease; it’s a malfunction.

This blog covers a lot of ground, but its overall underlying theme is my fascination with living things. When I started the project, what intrigued me most about living things was hard for me to put my finger on; I used terms like “wonder” and “beauty.” And while those terms are certainly still worthwhile and valid, I feel now that I can better express the object of my fascination: reliable complexity. What amazes me about living things- all living things- is that something so darn complicated can work so amazingly, reliably well.

4runner Consider my car. It’s a 10-year-old Toyota. I drive it- alone- to all kinds of remote places from which a tow would cost in the thousands of dollars. And so I take reliability and maintenance issues quite seriously. Sometimes when I’m on a long drive in the backcountry I think about all of the hundreds of parts in my car that are all working together: pistons, alternator, water pump, oil pump, radiator, clutch, tires, flywheel, various belts and joints. They all have to work, all the time, and that they do so the vast, vast majority of the time is a testament to Toyota’s fine engineering, manufacturing and quality control.

But compared to a single living cell, my Toyota is a moronically simple device. The complexity and nuances of the biochemical processes going on in a single cell are mind-boggling, far more advanced than any automobile, spacecraft or supercomputer ever designed by human engineers. And yet the cell works, and it works reliably- far more reliably than my Toyota.

Now consider a complex, multi-cellular organism, like a person. We’re talking trillions of these cells, each one a masterpiece of “engineering”, all working together in a well-functioning machine that performs tasks of dexterity and analysis unmatched by any robot or computer, running at levels of reliability Toyota engineers could only dream of, most often for several decades, with practically zero maintenance.

The instruction manual for this machine is of course the genes in the nucleus every one of your cells*, and of all the amazing tasks these instructions carry out, probably the most daunting and impressive is how they manage to drive, guide and limit the growth and development of those trillions of cells compromising your body. And when you step back and think about this awesome complexity, it makes you regard cancer in a different way. Because the strangest, most remarkable thing about cancer isn’t that it strikes so many of us- it’s that we all aren’t already long dead of it.

*With some obvious exceptions, such as red blood cells and sex cells… and I’m ignoring mitochondrial DNA here.

I once read a statistic that if humans were immortal, the average life span would only be about 600 years*. That’s how long on average it would take for any one of us to get killed in a car-wreck, bike-accident or coyote-attack. Another interesting statistic would be: if we didn’t die of anything else, how long on average would it take us on average to die from cancer? I don’t know that anyone’s done the math, but I’ll bet it’s a lot less than 600 years. Multi-cellular organisms have evolved sophisticated mechanisms to detect and repair genetic damage or copying errors that give rise to cancers, but someday, in the face of a long life plagued by tobacco, UV exposure and a gazillion other potential carcinogens, our repair mechanisms will eventually fail to keep up. If we were all to live long enough, it’d be a virtual certainty that we’d all ultimately experience cancer of some sort.

*No, I can’t remember where I read it. It was years ago, and might well be BS, but certainly there is a number, and I’d be shocked if it were greater than 1,000 years.

When you think about it, that makes sense. Living things evolve features and abilities in response to pressures, and over something like 99.99% of the time people have been around, there was never any meaningful selection pressure to evolve DNA-repair machinery that reliably worked for 70 or 80 years; people just didn’t live that long. It would be like Toyota designing a water pump that lasted for 30 years. They could probably do it- but why?

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 36.

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.)

Philchrom 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*.

*His words.


Kristin said...

Thanks for the detailed explanation, Alex. "Lance" is lucky to have a friend like you.

Betsy said...

Nice bio lesson! Welcome to the world of Cancer Research.

BTW, Fast Jimmy lost the belly, so you'll need to post an "after" pic.

Glad you're feeling better.

Ski Bike Junkie said...

All my best to Lance. Cancer sucks. I'm with you on the healthcare thing. I think it stifles entrepreneurship in this country not to have a better system. Over the years I've worked with some brilliant people with wonderful ideas who didn't dare go it alone because of healthcare. You get one guess as to where those ideas are today. And that doesn't even begin to address the cases like Lance and Elden where families would be bankrupt were they not employed by a place with a good plan.

We also need to do something about obesity in this country, but that's another argument for another day. Could you get working on that benevolent dictator thing? I'd vote for you.

KanyonKris said...

I have the same reoccuring thought: the human body is so complex, I'm amazed there are so many healthy people. Astounding.

Enel said...

Great post.

Cancer sucks.

I like your explanation of it though. I especially like your appreciation for how amazing it is that everything goes right so often.

Thanks for the review of stuff learned many years ago that left me just as awestruck then.

You should do a post on how muscles contract. I remember studying the actin/myosin complex in college and just being blown away in wonder by it.

Now the philosophical question: You easily accept that your Toyota was designed, but not the far more complex cell, or the amazing written code of DNA?

I don't think science can or ever will prove God, but man it seems like there are fingerprints everywhere.

We can explain how a lot of this stuff happens by natural processes, but the wonder that it actually, really, honestly does happen blows me away.

Also, while I am making requests in this long winded post, how about a post on how the first cells came about. last time I studied it 20 years ago it seemed no one was so sure how things went from simple amino acids to a functional cell.

Anyway, keep up the great work and thanks for the reminder of why I have always loved science.

Phil O. said...

One of your best posts.

(As an aside: I predict that we won't get comprehensive health care reform this year. We'll get it from a Republican president in 8-16 years, and it will look a lot like the one being proposed now. We might get something symbolic this year, but nothing major).

Watcher said...

Enel- thanks for your comment, kind words and suggested post topics. I’ll add your (great) suggestions to my ever-growing request list, but I’ll try to briefly address (if not answer) the philosophical question right now.

Jokes aside, I try to keep the blog away from religion. The middle-aged-atheist-ranting-blog has been (and is being) done about a gazillion times, by people far more learned, and wound up (on both sides) about the whole religion thing than me. And if a reader’s looking for that kind of “stimulating debate” there are lots of good places to find it.

Any regular reader of this blog has probably long since realized that I’m not a theist. But I have no stake in convincing others to see the world my way. I’m not on a mission or trying to change or destroy anyone’s beliefs. And so I'll try really hard to answer your question in a way that doesn't insult, attack or make light of your beliefs.

When you say “You easily accept that your Toyota was designed, but not the far more complex cell, or the amazing written code of DNA?”, a non-theist hears, “Cell biology is really complicated. Don’t you think it had to be created by a magic guy in the sky?”

For me, that’s just not an explanation. Attributing some thing or occurrence to the supernatural because I don't understand it seems a bit of a cop-out. It’s humbling to think of all the mysteries in the world that smart people haven’t yet- or may never- explain. But if previous generations of (way smarter than me) people had accepted that the explanation for other “really hard” things was just “magic” or the “supernatural”, then we would have never figured out things like Maxwell’s equations or General Relativity or air-conditioning or pasteurization or Gleevec.

Many, many people gain huge strength and support from their religious faith, and I don’t begrudge them that for a moment. I just don’t think we should use faith as a reason not to try and figure out hard stuff.

Enel said...

Thanks for the incredibly gracious reply. I am not at all interested in debating.

I really like what you are doing on this blog and hope you will consider a second career in science education of some sort in the future because you are gifted at it.

I am certainly a theist, but make my living in applied science and have a rigorous scientific educational background. This puts me in the awkward position of many times defending science and the scientific method while debunking bogus "creation science" to my church going friends. Many of whom have an inherent suspicion science for some reason. They are wonderful folks, I love them dearly, but.....anyway.

The supernatural is not an explanation (other than for the big why of it all). I just find it amazing that everything is balanced just so in the physical laws of the universe and the environment of this planet that life (unbelievably complex at all levels) abounds ridiculously here.

Did life come about because everything is just so, or is everything just so so that life can come about? The question is unanswereable with any certainty.

I will worship a God who I believe made the conditions "just so". I do not expect or require that of you or any one else. And I don't think that religious belief necessarily hinders rigorous scientific discovery.