mice in spain

I’ve never been to Spain, but this fall I sent four of my special personal representatives. I recently received an e-mail reporting that all four had started having sex with multiple partners. Was I concerned? No—I was delighted. Let me explain, but it’s kind of a long story.

In 1975, my freshman year of high school, I had surgery to remove a grapefruit-sized cancerous tumor from my abdomen. Chemotherapy and radiation therapy followed. A sample of the tumor was sent from Madison to the Mayo Clinic in Rochester, Minnesota, to try to figure out what kind of tumor it was (by the way, pay attention to the places mentioned in this story). The tumor was finally identified as a paraganglioma. Since I’m told that Mayo never throws away people’s tumors, it’s probably still in a warehouse someplace. Paraganglioma is rare and, fortunately, sometimes survivable. Paraganglioma is also a kind of cancer that has the nasty habit of recurring years later. I set that thought aside and pretty much ignored it (we would cue the ominous low sustained cello note if this was the screenplay).

Anyway, although I don’t remember it too clearly (being blindly in love at the time), I’m told that my parents had me go through some scans right before I was married in 1983. I guess this was to make sure that they weren’t going to be accused by my future in-laws of providing damaged goods to their daughter (ha—little did they know!). The scans, though crude, turned out negative, so the wedding proceeded with pomp and flair.

As life played out, I became a molecular biologist. In fact, I was influenced by my cancer experience. In the end, though I had intended to be an MD/PhD physician, I decided to become a research scientist in the lab. I maintained my interest in the molecules within cells, and how these molecules misbehave in cancer. Actually, the cancer part was a more of a stretch—I was really much more interested in the molecules. My surgical scar and I went through PhD training in Madison and post-doctoral training in Pasadena. I began my career as an Assistant Professor at age 30, starting four years at the University of Nebraska Medical Center.

So in 1995, perhaps strangely, we found ourselves moving to Rochester, Minnesota and the Mayo Clinic (remember that name?). It was admittedly sort of a weird choice for a fundamental research scientist like me to move to a more clinical research setting. Call me unconventional, or maybe call the whole thing pre-ordained. Whatever. With wife and two daughters we moved. I resigned at Nebraska and accepted Mayo’s unique no-signature verbal job offer, and then calmly underwent Mayo’s pre-employment physical. Now to those unfamiliar with the world-famous Mayo Clinic, a Mayo physical is unlike a physical anywhere else in the world (in fact, this is literally true). No stone was left unturned. When my interesting juvenile cancer history was mentioned, the already-stunningly-rigorous physical was revved up into a real barnburner. And guess what? They found stuff. To our dismay, the summer of 1995 quickly turned from relocation party to nightmare. A cancer recurrence was discovered in my abdomen, and that was the good news. The bad news was the discovery of metastatic cancer at sites in the bones of my skull and pelvis. We had no way of knowing at the time if this was to be a fast-progressing disaster, or a slow motion (and hopefully boring) epic. The original high school surgery was 20 years (to the day) from the date of the new Mayo diagnosis. We had genuine concern that Mayo would rescind their job offer (again the damaged goods) and that Nebraska wouldn’t want me back.

In the end, things got boring. The cancer is taking its time. Over the intervening 13 years I have survived with only the inconveniences of a couple surgeries, skull radiation, a bald spot, hip radiation, and plenty of expensive scans and tests. Inconvenience is the right word, since all of this has happened within a few minutes walk of my research laboratory. The world famous Mayo Clinic has invested big time in tinkering with my health. I’m not complaining about it.

Several years ago I had an interesting gene test. It turns out that paraganglioma tumors are both rare and mysterious. My endocrinologist knew of my scientific interests, and mentioned to me that there was new evidence that certain genes seemed to be broken in the paraganglioma tumors. In fact, people that carried one of the broken genes were at especially high risk of occasionally losing the other gene in some of their cells. Loss of the second copy somehow seemed to cause paraganglioma. Remember that (warning: deliberate oversimplification) genes are coded recipes telling the cells of the body how to make different protein machines. We get one copy of each of our 25,000 or so genes from dad, and an entirely separate copy from mom. The gene test was based on a truly bizarre discovery. The broken recipe related to paraganglioma was code for a cell machine needed to effectively extract energy from blood sugar. Without these machines, a cell gets only a tiny bit of bang from each sugar molecule, and the rest goes needlessly to waste (kind of like buying a can of Red Bull energy drink, taking a sip, and then pouring the rest down the drain). This seems like a heck of a poor way to run a tumor. After all, tumors are growing fast. They are mean. It seems like they should be super efficient about extracting every bit of sweet energy from sugar, right? Not so much. Paradoxically, loss of this fancy-sounding machine (warning: deliberate use of science jargon) “succinate dehydrogenase” actually hastens the onset of paraganglioma cancers. The gene test showed me that my father had (quite by accident he assures me) passed on to me a broken succinate dehydrogenase B gene, and at least one of my cells had mismanaged the remaining copy at some point, letting the cancer get started (I currently blame this genetic mismanagement on disorientation induced by the cavity-prone years of middle school).

Though my lab interests remained focused on other kinds of molecular machines, I found the idea that inept cellular sugar digestion could cause cancer to be irresistibly bizarre. And to my great fortune, one of my pioneering graduate students, Emily H. Smith, also found it irresistibly bizarre. So irresistible (and/or bizarre), in fact, that she did her PhD thesis research by engineering smaller organisms to have the same genetic defect as her mentor (OK, bizarre is the better word). She made considerable progress by studying lowly baker’s yeast cells. This friendly domesticated single-celled microorganism is a wonderful lab subject with its fully sequenced and cataloged genes, its ease of manipulation, and its willingness to grow fast and furiously on cheap nutrients in Petri dishes. This is not to mention the billions of yeast that selflessly offer up their lives for bread products every day (cultural diversity note: the yeast are given a fungal reprieve at Passover in observant Jewish homes). Anyway, Emily H. Smith discovered and published that there were several very interesting problems going on inside yeast cells when the succinate dehydrogenase B machines were broken. Some of the ideas might even make it to further tests for relevance to human tumors someday, even though (regrettably) yeast cells don’t seem to get cancer.

So what does this have to do with Spain? It turns out that Emily H. Smith’s other project was to make a different small organism with the same gene problem that I have. Emily H. Smith built mice like me. Mind you, they still look like normal brownish lab mice (much to our relief, and to theirs). Having worked for some years with lab mice, I must admit that I have pulled rank and left the breeding, care and feeding of these (warning: deliberate use of science jargon) gene-trapped heterozygous succinate dehydrogenase B disruption mice to (now Dr.) Emily H. Smith (now PhD), and her capable protégé, Emily M. Bystry (yes, it is confusing that they are both named Emily). I also must admit that I have sometimes peeked into the mouse lab to look appreciatively at these mice that (unwillingly) share an aspect of my genetic blueprint. Anyway, the hypothesis was that at least some of these innocent mice would, like me, get paraganglioma tumors. Then we could use the animals to study ideas for new therapies and all sorts of exciting things (and get rich and famous). Not so much. The mice have so far had the last laugh, I mean squeak. After months of breeding, and plenty of invested time and money, the animals refuse to mismanage their remaining succinate dehydrogenase B genes, and they are living to ripe old ages and dying of other things (like ripe old age). We’ve even made new super-duper versions of the mice that should be especially prone to losing their remaining succinate dehydrogenase B gene copies. A whole colony of these fancier mice are up in the mouse lab now, also, unfortunately, living happily to ripe old ages without paraganglioma.

I suppose not many scientists actually care much about paraganglioma. It is a rare and bizarre disorder. But guess what—there are paraganglioma enthusiasts in Seville, Spain. And they have bred special mice. Their mice have a different kind of broken succinate dehydrogenase gene (succinate dehydrogenase D), and their mice are also kicking back and living to ripe old ages without dying of paraganglioma (although I am told that they are surviving in a more exotic environment where it doesn’t get to -80˚ F outside when it’s winter). So what do research groups on two different continents do when they both have fancy mice that were expensive to make but uncooperative about getting cancer as intended? Correct—they try to figure out a way to intermingle the two kinds of broken succinate dehydrogenase genes (B and D) to double the chance that the mice will get the cancer. Conveniently, it turns out that mice have devised and perfected a great solution to this challenge: it’s called mating. The only trick is to get some of the Rochester heterozygous succinate dehydrogenase B mice to make the trip to meet (and greet…) the charming and comely specialty heterozygous succinate dehydrogenase D mice of Seville, Spain. We haven’t yet figured out how to accomplish this using the internet (we’ve asked Google to start working on it).

It was a warm (but not-too-warm) fall day when a very expensive air mail shipment of four male gene-trapped heterozygous succinate dehydrogenase B mice were sealed into a pleasant ventilated container with bedding, food and water, and driven to the Rochester airport. When I say expensive, I’m not kidding. It would have literally been cheaper for both Dr. Emily H. Smith, PhD and Emily M. Bystry to buy round-trip tickets to Seville, Spain, and carry the four males (mice) distributed among their carry-on bags (my thought had been to use 1-quart capacity zip-lock bags—and claim, if challenged, that mice are somewhere between gels and liquids). I also briefly toyed with the idea of installing a wireless web cam in the shipping cage to see what kinds of experiences the boys had with the TSA officers en route, not to mention the customs agents in Spain. Given the expense, the unpredictable jostling, and the potential for extended siesta time stranded on the sunny Mediterranean tarmac, it was with some considerable relief that I received an e-mail from my Spanish colleagues informing me that the guys had arrived safely and were “in quarantine.” This brought to mind an image of the Apollo astronauts looking out from a silver trailer window on an aircraft carrier after returning from the moon. Fortunately, like the astronauts, the four Rochester banditos emerged within a week without anything contagious. It wasn’t long before I got the second e-mail that I mentioned at the start of this story (obviously gaining enviable dramatic impact by leaving out the detail that I was talking about mice).

Based on past experience I’m not holding my breath about paraganglioma incidence among the spawn of this mousey Rochester-Seville junket. I do wonder if the four guys (now tired and smiling and the founders of their very own colony) recall their lives in the staid confines of Rochester. I suspect they still have their attention focused on the mousey heterozygous succinate dehydrogenase D females of Seville. Like I said, I’m not holding my breath. I won’t be at all surprised if the mice will again refuse to succumb to paraganglioma. One of these days I expect to get an e-mail from my Spanish colleagues conveying (with the appropriate euphemism en Español) that the new succinate dehydrogenase B/D hybrid mice are all living to a ripe old age (in Spain).

11/08