Tag Archives: human genome

Knock Out Mouse Revolution

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Standing in the New Orleans convention center felt a little eerie. The interior was clean and neat. It looked like an airport. Still, I could not help but recall images of Katrina, when the huge edifice had become a beacon of false hope, luring the populace through its doors with the promise of aid, only to leave those who entered trapped like rats.

We had come to a conference to learn about endocrinology, which I had not considered too creepy before. I was wrong.

The proceedings began innocently. Hundreds of physician scientists, and I, filed quietly into a giant auditorium. I want to make clear my lack of qualifications relative to the rest of the group. I am no scientist, and barely a physician. I would much rather read philosophy books and climb around on crumbly sandstone towers than pipette solutions into a gel matrix.

But my job is mostly about helping people protect themselves from diabetes. Plus my wife had a poster to present. So, there I was, attending as an imposter.

The keynote speaker got a prolonged introduction. He deserved it. He was an important person with important research credentials. It was the kind of introduction where a name is never mentioned, for dramatic effect, and because everybody already knows exactly who the subject is. It is a an effective strategy for generating anticipation in the majority who are already quite familiar with the speaker, as well as in those who have never heard of him. It works for everyone, except my wife. She is honest to a fault, and that means that she is a real subject-object-verb kind of person. When presented with a dramatic, obscure speech, her attention lapses. As the speaker walked onstage to the sound of his name, she asked me who this Francis Collins person was.

After a long moment’s reflection, I told her that Francis Collins was a bad philosopher. She seemed to accept my summary, because she promptly settled back in her theater chair to nap through the rest of the lecture. I could not sleep, though I was feeling a little jet lag as well. The lecture was fascinating. Dr. Collins had been right in the middle of genetic research since the beginning of the human genome project, and he took the audience on a trip through the whole endeavor, right up to the current moment: the Big Data revolution.

The Big Data revolution referred to the use of advanced mathematical and computing techniques to sort through scads of data for druggable targets in endocrine diseases. The special techniques had become necessary because the database had exploded. Dr. Collins and his compatriots had deciphered the genomic book of life, but when they sat down to read it, they discovered that they needed a lamp, reading glasses, bookmarks, and indeed, the semantics of the language. The genes turned out to be active in the context of all sorts of transcription factors, promotors, coactivators, corepressors, etc. There was layer upon layer of conditionals which gave meaning to the genetics.

The source of the Big Data revelation was the knockout mouse. The knockout mouse and its cousins, the knockin mouse and the humanized mouse, were what happened when researchers turned to their traditional test subjects with gene manipulation techniques learned in dissecting the genome. By studying mice with selectively induced genetic defects, the researchers had produced the dense pile of data on gene regulation which advanced computing methods might sort out for us.

By the end of the keynote address, I had mouse fever. I wanted to hear all about the things which these creatures could do, and it turned out that I had come to the right place. Over the next few days, I would hear about mutant mice who could run on a treadmill off the couch like they had trained for months. Mice who developed diabetes. Mice who could turn on their brown fat to alter their metabolism. And many of these mice could serve as their own experimental controls. They had mechanisms inserted in their genomes which could turn their genetic defects on and off in response to substances in their mouse chow.

I’ll admit, when I heard about designer mice and their custom mouse chow, I got a little side-tracked. I had been eager to get out of medicine for a while. It all seemed so futile, and even a bit of a sham. Knockout mice might have been the ticket.

Two incidents elevated that thought to conscious consideration. The first was sighting a booth devoted to mouse chow in the exhibit hall.

To understand the significance of the chow booth, one must understand what the exhibit hall is all about. There is an exhibit hall at every conference. They are huge and opulent sometimes, sometimes modest, but always staffed by beautiful, shiny people and stocked with treats, from lattes to foam-model pancreases. Brands like Coach or Louis V. would feel at home amongst the booths.

Giant pharmaceutical companies ruled the hall, and the mouse kibble guys were right there in the mix. If mouse chow could buy an exhibit booth, the mice themselves must be golden.

The second incident was a conversation overheard in the poster hall.

The poster hall is a huge open space with row upon row of cork boards. Researchers pin up posters with summaries of their investigations on the boards, and attendees walk up and down the rows soaking in the knowledge. Usually there is a clearing in the middle with a nest of round banquet tables where everyone can go to take a break, chat and have a cup of pharma coffee. That’s where I sat while my wife presented her poster. I did not sit randomly.

As I walked up on the tables, I spotted a fat man in a plaid shirt and a yarmulke leaning in to say something to a thin, swarthy, bearded companion wearing a dark olive sport coat and a gold medallion. I needed in on that conversation, so I settled in the chair next to them, and swirled my coffee thoughtfully. Imagine my surprise as I picked up on the subject of their conspiracy.

“Yes,” said the fat man, ” I have been trying to find some of those mice. I need them to finish my work, but you can’t find them anywhere.”

“Yes,” echoed his friend, “those mice are nowhere to be found.”

“The closest I came,” the fat man continued, “was this Korean lady in San Fransisco. She said she had some, even said she would send me a few. But she never came through, and now I can’t get a hold of her anymore.”

The mice must be golden.

But my dreams of becoming a mouse Baron were short-lived. Upon further investigation, I found that genetically altered mice did not thrive. It was hard enough to get them past the embryonic stage. Once they could breathe on their own, they often required special conditions and diets just to survive. Worst of all, most of the really good mice had been patented. You bought the limited rights to a strain of mice when you bought the animals themselves. The patent system was the impetus for the black market discussion in the poster hall. You could trade for mice underground and avoid some costs, at the risk of incurring the wrath of the mouse factory lawyers after publication.

Despite the disappointment on economic grounds, I left the conference optimistic. I still had the image of all those colored bars from Dr. Collins’ slide in my head. Each one was a gene which a mouse model could exemplify, and therefore each one was potentially a druggable target. We had this. It was just a matter of time, and mice.

On my way to work, I have some time to think, though not too deeply. I leave early to beat the traffic, but I never do. Most commutes demand constant attention to collision avoidance. The situation is unfortunate, because the commute is the only time to think. Once work starts, I am behind. Someone constantly needs something from me to satisfy someone else who needs something from them, etc.. My workplace is carefully structured to facilitate this cycle. If I need to communicate with someone, odds are that I can lean over to one side and speak to them directly. Otherwise, my computer contains a messaging system which will pop in on whoever I need to inform or interrogate. Patient rooms cluster around my workstation, so I never need to walk more than 6 steps. However, patient contact occupies only a minor portion of my time. Most of the day is passed on the computer and the phone, addressing questions, requests and lab results. At the end of the day the freeway awaits again. By the time I get home, I am burned out and may or may not have it in me to do some physical training and watch television before retiring to get up and do it all again the next morning.

As luck would have it, traffic was light on the first day back from New Orleans. As I drove, I dreamed of druggable targets; Dr. Collins’ slides with the colored bars swam before me. Most of my patients were already on carefully targeted medications, but reaching down into the genome would ramp up medication effectiveness by orders of magnitude. Yet, not all my thoughts were so happy. Other images kept popping into my head, unbidden. I saw other colored slides, from another lecture by another renowned researcher. They were Dr. Brawley’s slides on the geographic and socioeconomic correlates of life expectancy and the epidemiology of conditions like obesity, cancer and diabetes. I could not banish those intrusive images, and by the time I was walking across the clinic parking lot, my mood had deteriorated.

I made it through the day, and finally got to resume my train of thought as I walked back to the car to drive home. I thought about gene targets and Dr. Brawley’s maps again. Then thoughts of one of the day’s patients joined the fray. She was very overweight, and had the metabolic problems that went with excess adipose tissue. She was on targeted therapy for her diabetes in the form of a monoclonal antibody directed at a counter-regulatory hormone receptor. It was the best science had to offer, but she often missed her doses. She had 2 jobs and no car, so she was up early and home late, and she simply forgot her meds sometimes. She set an alarm, but often could not attend to it, or forgot to reset it. We did not even discuss diet and exercise. She lived on a busy street with non-contiguous sidewalks, had no money for a gym, and no time to travel to a safe park. She could not cook, because she had grown up on packaged foods. In any case, she had grown too heavy by now. Her knees had given out under the weight. She could only mobilize fat stores in the face of severe calorie restriction. To reclaim  her life, assuming that was our aim, she would need two joint replacements and a gastric bypass.

I began to re-experience the rising panic which I had felt at the end of her appointment. Dr. Collins & Co. had let me down; I was not armed for this struggle, nor would I be. I stopped to take a breath and get my bearings. The parking lot was nearly empty. A bad smell rose from a nearby drainage grate, and a noise like water flowing.

I imagined that the noise might be something else. Maybe, instead of waste water, it was all those knockout mice, rising through the  sewers from the depths of the New Orleans convention center where the disappointments of Katrina had flowed down to bring the little fellows back, like a time-delayed Ghost Dance. The mice were coming with their little spectral incisors primed to clip down the cages, the labs, the chow booth, the convention center, and all the rest in a massive, surgical revision. I became convinced that the sound was the mice coming. It had to be. It was the only way that the knockout mice could save us.

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