In recent years, we've come to understand that there is far more to DNA than just the sequence.
Human diseases whose root lies in the control of cell operations by DNA -- like pediatric cancers -- have driven the need to understand exactly how a diseased cell's DNA differs from their normal counterparts. And we have come to better understand that those differences often go beyond differences in the actual sequence *of* that DNA. For example, it is becoming clear that one mechanism by which DNA activity is regulated by cells is through carefully controlled methylation -- the addition of a methyl group -- to sequences of DNA.
Thus, being able to map DNA -- not just it's sequence, but it's modifications like methylation and many other characteristics -- would be an extremely useful tool for being able to compare, for example, cancer cells to normal cells. Being able to map them across the entire genome would be especially useful, to give us clues on why cancer cells do what they do -- and what we can do about them. This, however, is a substantial challenge. There are approximately three billion base pairs in the human genome, after all. To have any reasonable shot at routinely doing this kind of mapping would require the development of machines that can process vast quantities of DNA in rapid succession.
As it happens, there already *are* machines that can process vast quantities of DNA. Our cells, after all, do it every single second of our lives. The nuclei of our cells contain a whole arsenal of tiny, complex protein machines which spindle, fold, assemble, disassemble, and label DNA with extreme speed and fidelity. So why re-invent the wheel -- or the polymerase, helicase, gyrase, methylase, etc? Why not just take these molecular DNA-handling machines from our cells and strap them onto microscopic assemblies of electrical sensors, micro-fluid chambers and pumps, building a half-biological, half-mechno-electrical machine that can scan DNA for the characteristics of interest with a cell's speed? After all, electrical engineers are very good at fabricating millions of complex machines at a molecular scale. Why couldn't them incorporate biological molecular machines into their computer-chip assemblies? It's just chemistry, after all. MacGyver the cell's own machinery into a computer matrix, like a bacteria-sized cyborg?
The first machines to do just that are just beginning to appear as prototypes in some of the most cutting edge research laboratories in the world. They've quietly, silently been spending the last few years working the kinks out of the process, and now they're ready to actually unleash the new technology on real discovery. It's like ship builders who have spent years learning how to build ships that can sail against the wind, and now they're ready to actually take their vessels out over the horizon to see what's there. Engines of discovery so radical they aren't even available for commercial sale yet. Technology so advanced only the working prototypes are in operation in a select few laboratories in all of the world, just waiting for scientists to use them to apply them to the study of cancers still resistant to everything we know.
And that's the sort of stuff I got a sneak peek at, over four days in October of meeting potential research mentors at Johns Hopkins and the National Cancer Institute @ NIH. A peek at the kinds of work I have the chance to join in a year's time.
The work that has already been published is groundbreaking. But the stuff that hasn't been published *yet* -- the stuff that is being written up, the stuff that is still secret, the stuff still underway -- is totally mind-blowing. To crack the unsolved, unconquered, uncurable problems in oncology is going to require radical new techniques, radical new advances, and radical new technology. And the investigators and engineers at the furthest forward edge of medicine are rising to the challenge, looking at cancers in ways totally beyond what we know now, and doing it with machines like something out of a cyberpunk novel.
Investigators identifying novel biochemical pathways cancer cells use to turbocharge their metabolisms, firing up energy-processing systems their normal neighbors can't touch. Investigators making cells dance between the normal mature state, their forever-young stem cell origins, and their Mr. Hyde cancer counterparts. Investigators diving into the vast sequences of our genome which don't directly code for genes, and exploring the constellations of regulatory mechanisms hiding out in what was once thought to be "junk" DNA. Across four days at Hopkins and NCI, I got the chance to meet with over a dozen faculty, each allowing me a chance to look at *all* the revolutionary projects and data they have, well beyond the stuff they've already published or shown, well beyond the stuff *anyone* in the world has yet done. Professor after professor, laboratory after laboratory, each taking a totally different approach, looking at wild new angles in oncology with prototype machines custom built for the purpose. And inviting me to come aboard for the journey.
We have made tremendous progress torwards the treatment of cancer. When my most senior pediatrics attendings began their careers, pediatric leukemia was a total death sentence. Now, forty years later, 90% of our kids diagnosed will walk away cured. That progress was made possible by generations of systematic, national clinical trials, decades of courageous patients and their families, the effort detailed in the story
Legion of the Brave. But it depended upon generations of basic science advances making those cures even possible, generations of research which form the foundation for the ground-breaking, mind-blowing, "holy $%#%!!" work I was invited to take a sneak peek at. And as far as we've come, we still haven't gotten far enough.
Our best as a profession still isn't enough for too many of our patients and their families. A 90% survival rate for pediatric leukemia is just another way of saying one out of ten of our children will die. And for most other cancers, the survival rate varies from nowhere near as good to absolute zero. Not good enough. Until every child with cancer has the chance to grow up -- not good enough.
We've come a long way. We have much farther to go. Somewhere over the horizon lies the scientific keys to defeating not just cancer, but all the other devastating diseases which threaten those we love, bound together by the common science and biology that links them all. In hunting for what makes cancer cells go bad, we will learn too how to fix broken kidneys and broken nerves and broken brains and everything else. Knowledge is power, and to hunt for that knowledge -- to push forth after those cures -- bold engineers and scientists have built engines of discovery beyond anything anyone outside of the very greatest research centers in the world have ever seen or even dreamed of. They await the next generation of physician-scientists to grab hold of the wheel and set sail. And I am humbled to have the chance to earn a place as one of them.
Twenty years of work from eighth grade to the end of my pediatrics residency was just to get to this point. Now the real adventure begins.
The future stretches forth like the vast undiscovered country it is, a journey to places barely imagined and glimpsed. On a personal level, I hope that I might yet earn the privilege of a lady wife's love, of a child's hug. On a professional level, I hope that I might yet be able to make a difference in the fight and cause I am grateful to be given the chance to serve. I have no illusions about the challenges or my chances, but no road worth travelling was ever either easy or certain. And I excited about the new wonders we'll see along the way, voyaging on the furthest edge of the scientific unknown; and the company of the friends and family we'll share the journey with.
Come, my friends,
'Tis not too late to seek a newer world.
Push off, and sitting well in order smite
The sounding furrows; for my purpose holds
To sail beyond the sunset, and the baths
Of all the western stars, until I die...
Though much is taken, much abides; and though
We are not now that strength which in the old days
Moved earth and heaven; that which we are, we are,
One equal-temper of heroic hearts,
Made weak by time and fate, but strong in will
To strive, to seek, to find -- and not to yield.