Stories from the Road: A Quarter-Century Gift
- In the care of the suffering he needs technical skill, scientific knowledge, and human understanding. He who uses these with courage, with humility, and with wisdom will provide a unique service for his fellow man and will build an enduring edifice of character within himself.
The physician should ask of his destiny no more than this; he should be content with no less.
- -Harrison, Principles of Internal Medicine
It was a grand setting for a grand story.
- The rebuilt Philadelphia Convention Center sits on multiple city blocks near the very heart of the city, where William Penn's statue stands atop it's 500-foot tall spire; at the heart of the Convention Center is the Grand Hall, a vast expanse of grey marble overarched by a nine-story-high hangar-like roof, the space between filled with the whimsical steel and glass loops of the largest suspended sculpture in the United States. Terraces rise up three stories from the south portico of the Hall up to the Grand Ballroom like the face of an ancient temple, and within the double doors three thousand could seat comfortably. That Friday evening, the room was packed end to end with scientists gathered for the Greep Award lecture of the Endocrine Society. And in that huge, packed ballroom, this year's physican-scientist laureate told a number of tales, one of which I share here...
A gentleman was brought into Yale University Medical Center after an auto accident. Strangely, despite the severity of the incident, he had no broken bones --which was explained, upon examination, by the thickness of his bones. His bones were far thicker than most people's --much more than five standard deviations thicker than average. If you put him in a random crowd, statistically speaking he would have thicker bones than his nearest two or three *billion* neighbors. His bones were built like the composite spars of a modern fighter jet. Intriguingly, one of his relatives had also been noted to have the same trait. Upon more detailed examination of the patient's family, it was noted that a lot of his relatives too had extremely strong bones. One patient might be an accident --but an entire family is no conincidence. Somewhere, clearly, there was some gene being passed along that resulted in bones like steel, and from that beginning Dr. R. Lifton began hunting...
In the entry Dawn of the Coming Age I outlined just how one would go about tracking down a gene; Dr. Lifton used the same concept to identify a single mutation shared by all the family members with extra-strong bones, a single difference in a gene called LRP5. The role of LRP5 is to help turn on molecular switches called Wnts. When Wnts are turned on, all kinds of cell growth events happen. LRP5 is itself turned *off* when a second switch called Dkk-1 latches on to LRP5. Or, put another way, Wnts are the starter motor of the car, LRP5 is the ignition switch, and Dkk-1 is the key that turns the ignition switch off.
The mutation found in LRP5 caused a very small change in shape in a chunk of the LRP5 protein that esentially served as a keyhole for the lock. With the change in shape, Dkk-1 no longer fits in the lock, so Dkk-1 cannot turn LRP5 off, so Wnt switches stay on, and down the road you end up with extremely strong bones. More importantly, the *only* thing this all seems to result in is extremely strong bones --with no other untorward side effects. This is a critical point --there are many other mutations that cause extra-thick bones, but they *also* usually cause extra cancers, or neurological defects, or metabolic problems, or a whole raft of other downsides. In contrast, this family appears to be perfectly healthy.
Over the last few years, now that we know where to look, many other mutations like the one Dr. Lifton and his laboratory found have also been identified. All of them cluster into the same small part of the LRP5 keyhole. All appear to work by blocking the Dkk-1 key from entering the LRP5 lock. All appear to result in super-strong bones with no other observable bad side effects. What if we created a small molecule --a drug-- that could jam the LRP5 keyhole? In theory, if you took such a drug that very specifically jammed the LRP5 keyhole, you would end up with super-strong bones.
As we get older, among the damning curses of age is that our bones tend to get more brittle. Osteoporosis is a real problem, especially for women. My own mother and aunts take various drugs in an attempt to stave off the gradual thinning of bones with age, but our current therapies don't work very well. Fractures are a major fear of the elderly --indeed, over a million patients a year suffer severe fractures from bones weakened by age, and a significant fraction of those patients will die of them or of complications resulting. Even without, the dangers posed severely limit what many elderly patients can do. We do not yet have any treatments that can actually *strenghen* bones...but the LRP5 story clearly suggests one possible route *to* develop one. We are just entering the age of science when building drugs from scratch against specific targets is just barely doable. It will become easier as time goes along. So there stands a fairly reasonable chance we'll be able to build a drug to target the LRP5 keyhole --and a chance that drug might in fact work as we hypothesize it will.
Dr. Lifton, who told the story and did the work, is an MD/PhD, like mdrnprometheus and resonance42 and I. The entire scientific progression in this story from patient to molecular target to drug is all science and clincal medicine that we are trained to do. I understand exactly how Dr. Lifton got from one step to the other; they are all experiments and progressions that I've learned how to design and evaluate. The LRP5 story is exactly the sort of discovery that is well within the capabilities of what we are trained to do as physican-scientists --it's exactly the sort of thing we're *supposed* to be able to do. It's the entire point of training MD/PhDs.
I could describe what the implications of the LRP5 story mean for my mother, my aunts, and the other women of my family whom I love dearly, but as only one of you out there has ever met my family in person, that might not mean that much to you. Instead, let me frame the implications in ways that those of you who read my diary perhaps can relate to more personally....
Those who have read my diaries have followed my adventures into the magical world of dance. Of all the wonderful memories of happy times, shared with so many wonderful women for whom dance of all kinds is a passion. I've had an extraordinary, memorable year of memories and laughter in my times dancing. One can only imagine the joy it brings to the lives of dancers like them --or your own. But elderly people can't do most Latin or vigorous ballroom dances --not with the risk of snapping a age-thinned hip or breaking an ankle like brittle glass; age weakened-bones bring down for far too many an inevitable curtain to the beautiful art of dance.
Now imagine being able to give to so many of my close friends the gift of dancing for twenty-five extra years.
If the LRP5 story pans out, it might enable my lady friends to step the wild Charleston or Korabushka or Road to the Isles even when they're ninety years old. Imagine all of the stories, all of the memories, all of the joy -- an MD/PhD like Dr. Lifton really can single-handedly make possible a gift like that. It is, fundamentally, what physican scientists *do*. People talk all the time about the difficulties in becoming and being a scientist, a physican, or both. But for a chance to give a gift like that to those you cared most deeply about, what would you put on the table? What price would you be willing to pay? What would you be willing to ante up to the line, just for the chance to see an elegant lady with long grey hair spinning across the floor with her beloved just as she had eighty years before?
I've been lucky enough to know magic of all kinds in my life --the magic of family, of friends, of dancing with a beautiful woman across a ballroom floor. And if I can, in the lab, the clinic, and the activist forums, fight to make possible that gift of an extra quarter-century, it's a gift well worth fighting a lifetime for. :-)