Tomorrow, We Fly: A Story for Blogathon 2006
I actually had some down time this morning, time enough for an entry. An entry for dear friends on a special day, a story about stem cells, and research advances, and hope...
Raghu Kalluri and his colleagues at Harvard had an idea. What if you tried to use bone marrow stem cells to treat Alport syndrome?
In a paper in the May 2006 issue of the Proceedings of the National Academy of Sciences, they share their results...
In the entry Tryggvason's Race, we very-handwavingly outlined Alport Syndrome, the basics of the physiology and molecular biology underlining the disease. To even more handwavingly summarize that entry: the kidneys work by straining toxins out of the blood through a filter called the glomerular basement membrane, and Alport Syndrome is a defect where the body is unable to make critical structual proteins that make up the glomerular basement membrane. Without those proteins, the filter gradually loses function; without the filter, the kidneys gradually lose function; and without kidneys, patients either get replacement kidneys, get artificial dialysis filtration until they can get kidneys, or die.
The term "stem cell" is a very general term, describing hundreds -- if not thousands -- of very different specific types of cells. Recall that all of us originally began life as a single cell -- the resultant fusion of one sperm and one egg. This original cell splits into two, which become four, which become eight, etc. Along the way, these cells begin to specialize -- differentiate -- into different purposes. The end result are billions of neurons and glia arranged into brains, and billions of myocytes arranged into muscles, etc. More about this was explored in the entry Answers Beneath our Feet. It was once believed -- back when I took AP Biology -- that this process was largely irreversible; that once a daughter cell began to specialize, it could not reverse track. Cells that had "chosen" the track that would ultimately lead to neurons could not turn back and then become pancreas. One of the fruits of the NIH-Squared initiative -- the giant doubling of funding to the National Institutes of Health pursued over the 1990's -- were the series of discoveries which blew that conventional wisdom straight out of the water.
To summarize stem cells in a single entry is well beyond the little time I have -- U. Michigan has a nice primer here -- but basically, scientists discovered that the human body had lots of different hidden pools of stem cells which could be potentially be reprogrammed; some cells which had already differentiated could be induced to go backwards and be re-programmed; and cells in their very earliest stages -- the embryonic stem cells -- could be manipulated into specific final purposes. The last category -- the embryonic stem cells -- is of course an area of significant political grand-standing, and a whole different topic. But the former two categories of stem cells -- the ones we all have lying around, and the ones we can make by deprogramming adult cells -- are largely without the same kind of controversy, and so progress continues to be pursued by American scientists on them, free of the complications associated with the stem cells derived embryonically. Such as the work Kalluri and collegues pursued.
To return to Alport Syndrome: the kidney's filter is broken because the cells which make the filter are unable to make the correct protein. In essence, the cells which make the filter are broken. But what if you could insert healthy cells into the kidney which *can* make the necessary proteins? Rather than trying to fix the genomes of the broken cells -- the heart of gene therapy, which has turned out to be a fairly difficult task -- you could just insert new cells. Over the last few years, the millions poured into stem cell research has discovered many interesting facts about their basic biology -- including the observation by a number of scientists that certain classes of stem cells are smart enough to home in on area of injury by themselves.
Injured tissue releases a whole host of signals to summon aid, and scientists have recently discovered that among the cells that respond are various classes of stem cells, which arrive on the scene, and based on cues from neighbors, convert themselves into the appropriate cell type to fill in the gap. It is a bit like how, at our hospital, we have pools of physicans who can be called in on a moment's notice to fill in when a regular physican gets sick -- one day, acting like a nephrologist to plug a hole in a kidney team; the next day covering for a sick Pediatric ICU staffer, and so on. Likewise, very preliminary research suggested that some classes of stem cells were smart enough to home in on areas where there was, for example, heart damage, and convert themselves into new heart tissue.
Now, in Alport Syndrome, the problem is in the DNA -- a broken gene prevents the kidney from making proper filter proteins. Because the problem is in the DNA, and because all cells in a patient share the same DNA (recall that cells are different not because their DNA is different, but because different sets of genes are activated in different cells), an Alport patient's stem cells would *also* have the broken gene, and any replacement kidney cells born of a patient's own stem cells would be equally unable to make the correct protein. But, Kalluri and his colleagues wondered, what if you took *someone else's* stem cells -- stem cells from someone who *can* make the correct proteins -- and transplanted them into a patient with Alport Syndrome? Could those transplanted stem cells, each with a correct Alport gene, home into the broken kidneys, turn themselves into the appropriate kidney cells, start making functional protein, and in essence cure the disease?
Obviously, they didn't jump right to humans. Instead, they studied mice which had their Alport gene broken, and which subsequently develop Alport Syndrome and die just like human Alport patients do. To do an insane amount of handwaving, they then transplanted stem cells from normal mice into these Alports mice and then watched what happened. In Sugimoto et al (PNAS vol. 103 pg. 7321-6), they provide preliminary evidence that, in fact, the whole crazy idea actually might work.
There's a list of caveats as long as your arm, of course, and a ton of unanswered questions. But the paper suggests that the general concept is there -- that there's at least some evidence to suggest that, if you can work through the problems, you *could*, in theory, take normal stem cells, put them into someone with Alport syndrome, and at the end of the process you have what might be new kidney cells making functional protein, with improved filter function and improvement in condition. Maybe.
- We can work with "maybe".
This paper is in no way definitive proof of a cure -- not even close (which is why I take issue with the title "Bone-marrow-derived stem cells repair basement membrane collagen defects and reverse genetic kidney disease") -- but it at least suggests another real way forward. There are lot of unanswered questions and barrier problems, but questions were meant to be answered and problems were meant to be engineered around. That is, after all, what biomedical science is *for*. To work out the kinks, solve the problems, and get the damned cure is the whole point of spending money on biomedical research. Getting this far is the fruit of the billions previously spent on dozens of different fields. Getting the rest of the way will take billions more. One dollar at a time.
Molecular biology and biomedical science is not, in general, a "big iron" sort of enterprise. We largely make progress one experiment, one culture, one gel, one slide at a time. Every paper is a series of small experiments, each costing a few bucks a piece. People wonder what a few dollars here or there can do. Biology is in large part *all* about the few-dollar steps, the one experiment leading to the next. By in large, we don't put three-hundred million into a single space probe or giant accelerator to get our answers in one big lump. We assemble answers one five dollar PCR reaction at a time. Hope is built of such little steps, paid for with pocket change.
And that's why my dear Sedai is busily typing away all today, over in Moozie's Kitchen.
In even just the few years since I wrote Tryggvason's Race, molecular biology has advanced dramatically. Our knowledge of stem cells, for example, has grown exponentially. This entire line of research pursued by Kalluri wasn't even, in large degree, more than the craziest brainstorm just those few years ago -- and now is an actual, practical, on-the-ground research effort. We have a tremendous distance to go, but we've come a tremendous distance already, and the more basic knowledge we attain, the faster the next discoveries will come. The battle against disease is not simply a footrace to the finish line. We run as fast as we can not merely to close the distance but to get wind underneath our wings. Today we run. Tomorrow, we fly.
I wondered which icon I should use for this essay -- the science icon? The med icon? But in the end, I thought that the most appropriate was the one I used for friends. Because, in the end, this story is less about science and about discovery, and ultimately more about this thing we're all in together. Because, when all is said and done, that's what the story is all about.
A world without cancer, without AIDS, without Alports -- this is the world we fight for, all of us, together. Whether it's raising money one blog entry, one foot race at a time; or running research projects on screensavers; designing and building the next generation of Grid supercomputers and exquisitely sensitive analytical devices; pursing nature's secrets in lab or at the bottom of the sea; or fighting to save lives day and night on the wards -- all of us, every one of us, is in this together.
- Together, we fight.
- And together, we'll win.