Read Present at the Future Online
Authors: Ira Flatow
“And that was where I got the first jarring data that the mice taught us: In these very end-stage mice, we could reverse autoimmunity. We had done the islet transplants, the animals were normal glycemic, and bingo—the big surprise was that when we took the transplant out, the blood sugar stayed flat. And that was like ‘How could this happen?’ and sure enough, how it happened was that islets had reappeared in the pancreas.”
It appeared that once the autoimmune disease could be silenced, the pancreas could regenerate. There was no need for the transplanted cells anymore. But how did the pancreas recover? And why? Faustman suspected that adult stem cells, circulating in the blood, helped regenerate the pancreas. But she wasn’t sure. Stem cells have the capability of becoming almost any cell in the body. But her discovery was so astounding that researchers doubted she had actually cured lab animals of diabetes, doubted that the pancreas had actually regenerated. She dared not speak that way in the research paper she published.
“In 2001 we weren’t allowed to use the word regeneration in that paper. It was restoration of insulin secretion.”
Faustman pressed on, searching for a reason why the pancreas could recover on its own. In 2003, she published a paper saying that perhaps the spleen was the source of those cells. According to her paper, when she injected spleen cells into her diabetic mice, those spleen cells gave rise to new islet cells, showing that not only could they “do it repeatedly in these end-stage animals but [also] there appeared to be multiple mechanisms for why these islet cells could reappear in the pancreas. And one way was without any stem cell transplant; another way was actually putting back in precursor cells from the spleen.”
But in March 2006, three independent studies in the journal Science both succeeded—and failed—to replicate Dr. Faustman’s work. The success: all the teams cured some of their diabetic mice, indicating that there was growth of new pancreatic islet cells. The failure: no evidence that the injected spleen cells were the reason or that the spleen cells gave rise to new islet cells. To Dr. Faustman and her colleagues, the specific failure was unimportant. What did matter was that for whatever reason, the animals were cured of diabetes.
“I must say when I saw the three papers that are, to a great extent, confirmatory of the major results that Denise found over the last four or five years, I was very pleased,” says Dr. David Nathan, professor of medicine at Harvard and director of the Diabetes Center at Massachusetts General Hospital. “The three papers could not confirm what Denise had seen,” says Nathan. “But nevertheless, there are new islets that are secreting insulin and sufficient to cure diabetes. I think that the question of mechanism—where these cells come from—remains an open question.”
Faustman agrees. “Yes, so there’s still debate of how this regeneration/rescue occurs.”
Does Faustman still think there are stem cells floating around in the blood that help an injured pancreas repair itself?
“Yes, absolutely. I think the pancreas is still smarter than us. And I think that it can probably heal by multiple mechanisms.”
She points out that research from another group in Switzerland shows that in human fat tissue, “they had found a similar precursor cell” grown in laboratory dishes that “could form human islets. So these stem cells may be in multiple locations.” That means that if you stop the disease in its tracks, you may also rescue any remaining islet cells in the pancreas.
None of this speculation, says Dr. Nathan, should detract from the fact that mice, for the first time, had been cured of type 1 diabetes. “I think what we need to keep in mind is that the diabetes in these mice, this mouse model of autoimmune diabetes, was thought to be irreversible, incurable at the stage in which it was being studied.”
SO MUCH FOR MICE; WHAT ABOUT PEOPLE?
Now for the $64 question: How soon can such a cure be tested in humans? The mice were given a simple and safe compound of chemicals to knock out their immune system. Could that same brew be given, safely, to people?
“It needs to be determined,” cautions Nathan. “It’s worth pointing out that Denise’s work and the work in Science that’s being published is all in mice. And so the mice community has reason to celebrate: Diabetes is curable in them. But we still need to demonstrate whether these lessons we’ve learned in the mouse are translatable to humans.”
Nathan remains enthusiastic. “It is conceivable that one can use a relatively simple way of manipulating the immune system, at least as the first step, to get rid of that part of the autoimmune response. Deplete these kinds of cells that don’t recognize self from nonself, and that makes, of course, for the ability to do some fairly simple early clinical trials.”
Of course early is a relative term. “People have wondered: ‘This is about three years old; how come you haven’t started?’”
“Technical difficulties” remain to be ironed out first, he says. It turns out that one of the fundamental parts of Faustman’s studies is that she recognized that there are these abnormal T cells—that is, white blood cells that circulate in the blood and that seem to be the cells that attack the islets. “We have to be able to measure those cells in a reliable fashion in humans before we can go on to human studies. And Denise has spent the last couple of years trying to develop these methods and translate them from measuring them in [mice] to measuring them in humans. As soon as she’s developed that tool, then we can go ahead and do the first part of the clinical studies that we want to do.”
Faustman says she is ready to meet the challenge. “Yes. There’s a great analogy that people with diabetes will understand. If David Nathan was working in 1920 and he announced over in his research lab, down the street here, that he had discovered insulin, but he didn’t know it regulated blood sugars, the chance of insulin ever working in humans and not being able to check a blood sugar and dose it is about zero. So we feel we’re in the same boat, and to really make these compounds work in humans, we have to have a blood-monitoring tool. So the big job assignment that comes back to my laboratory here is taking human blood, isolating these cells, and proving we can count them and quantitate them, before David ever starts the trial over in the clinic.”
Of course when you think about diabetes, an autoimmune disease, you think about the other autoimmune diseases—diseases where the body’s immune system attacks the body itself, thinking the tissues are foreign invaders. Why can’t the same kind of research apply to curing them? No one who works with diabetes misses that point.
“That’s actually why David and I are excited about bringing this forward to the clinic, because as we were doing mouse experiments, other scientists worldwide were looking at the same bad T cells in other forms of human autoimmunity. And it turns out [that] very
similar T cells that die with these same compounds have been found in lupus and scleroderma and indirectly in subsets of patients with Crohn’s [disease] and rheumatoid arthritis. So there may be subsets of autoimmune patients beyond type 1 diabetes [who] might benefit from this same therapy. Obviously, in those patients you don’t need to regrow their islets or rescue their islets, but you do need to rescue their target tissues that are being destroyed in different forms of autoimmunity.”
Is there a risk, though, that this therapy might suppress parts of the immune system that you don’t want to suppress?
“Well, that’s the good news,” says Faustman. Past human trials of treatments for type 1 diabetes have involved the shotgun approach of giving nonspecific immunosuppressive drugs. “And indeed, if you add nonspecific immunosuppressive drugs, you can halt the disease or slow it down, but you’re also halting the good white blood cells and good T cells. The compounds we’re using appear to only selectively kill the bad T cells, so the most simplistic way to view these compounds is kind of like an antibiotic. You take an antibiotic and it only kills bacteria; it doesn’t kill your cells. So the antibiotic-type drugs appear to have specificity for only killing the disease-causing cells—at least in the mice and in tissue culture in human autoimmune cells.”
But wait. We’re getting ahead of ourselves, talking about human cures. Nathan points out that a lot of table setting needs to be done first. “Our first step in human studies, which we’re not quite ready to start, will be looking at whether we can suppress these cells. We never thought, I think, when we designed the very earliest human studies, that they would necessarily cure diabetes. I think that’s really far down the road. But the first step will be to see whether we could duplicate what Denise is showing in the mouse at least with regard to depleting these bad-actor cells. We have a protocol actually to do that very first step. But it is the first step in what will probably be a sequence, or maybe a long sequence, of studies before we get to the point of curing anyone with diabetes.”
THE MISBEHAVING SHOWER CURTAIN
So you step into the shower and turn on the tap. But try as you might, you can’t begin to scrub yourself properly all over. Your shower curtain keeps billowing in the wrong direction, into the tub, and
sticking to your body—grasping your arms, grabbing at your legs, blowing in your face. You’re forced to put it outside the tub and trade a wet floor for a chance to take a shower without being groped by a piece of plastic. To you, especially if you’re running late, this is a big annoyance. To physicists and engineers, it’s a big unsolved problem. No one knows exactly why it happens. But the details suggest you’ve got a mini hurricane in your bathtub!
In 2001, David P. Schmidt, assistant professor of mechanical engineering at the University of Massachusetts Amherst, was honored with an Ig Nobel Prize for physics for publishing a paper entitled “A Partial Solution to Why Shower Curtains Billow Inwards.” The Ig Nobels are awarded annually by actual Nobel laureates, one week before the real Nobel Prizes are announced. All Ig Nobel Prize winners are actual scientists who’ve done real science that’s been reported in a published article or presented to other scientists for feedback. Like Schmidt’s paper, Ig Nobel research sounds ridiculous, but the prizes are meant “to make you laugh, and make you think.”
Schmidt gamely accepted his Ig Nobel wearing a shower cap and fessed up that “my own shower curtain doesn’t billow inward. If I want to observe the phenomenon, I have to go to my mother-in-law’s house.” But Schmidt picked his paper’s title because he says the problem sounds much simpler than it really is. He’s part of an international community of researchers puzzling over why shower curtains have that pesky tendency to billow in and stick to your arm or leg. So far, there are mostly theories, no complete answers.
Schmidt is a founder of Convergent Thinking, LLC, a software firm that makes computer programs that mimic how sprays, such as shower sprays, act in real life. He is an expert on sprays, fluids thrust out of small openings into an unpredictable environment. Schmidt tries to predict what happens next. Most of the time, he looks at how sprays work in combustion engines, such as the diesels in trucks and airplanes and the gas turbines in automobiles that carry countless
people and cargo every day. By learning more about how sprays work, Schmidt would like to find how much pollution is formed in an engine. Then he’d know which kinds of engines could help reduce global air pollution.
So far, Schmidt has found that a spray and the nozzle it bursts out of affect each other in very complicated ways, especially in a high-speed spray like the one you get blasted with if you turn your shower tap on high. Once the water bursts out of the shower nozzle, it breaks up into droplets. But what happens next, Schmidt says, is anyone’s guess. The droplets can break down into even smaller mini droplets or they can collide with other drops. They can evaporate and turn into heat. They can get swirled around in eddies in the warm air in your shower.
To predict the unpredictable, Schmidt works with computer simulations of sprays that he has designed himself. As a “fun exercise” and a pleasant break from studying fuel injection, he decided to tackle the familiar shower curtain problem. He set up a mathematical model of his shower curtain on his home computer, dividing the curtain into 50,000 tiny sections. He simulated the shower running for 30 seconds. He ran yards and yards of numbers—just like the opening credits of The Matrix. After two weeks, he had part of the answer, something he could prove. It boiled down to this: When you step into a running shower, you step into a mini “horizontal hurricane.”
The way the shower spray and the surrounding air interact, says Schmidt, “a vortex sets up, a hurricane of air turned on its side. In the center of the spinning column of air, just like in the eye of a natural hurricane, there’s low pressure, and it pulls inward near the middle of the curtain.” But besides the hot spray and warm air, there’s the added factor of the shower curtain itself, something a real hurricane never has to consider. Schmidt says that “because of the way tension works in a hanging curtain, because the curtain is restrained by the rod, and because the bottom of the curtain is much
freer to move, the bottom is pulled inward.” Soon you find yourself taking your shower with the curtain. If you feel sorry for yourself because your shower is a daily struggle, try to save some pity for Schmidt and his colleagues, who are still trying to figure out the details of what’s going on.
WHY AN AIRPLANE FLIES: DEBUNKING THE MYTH
Fly the airplane. Don’t hit anything.
—THE PILOT’S TWO RULES OF FLYING
Air travel these days is a harrowing experience. From the full-body frisk to the shoe X-ray to the nonexistent food (maybe that latter part is not a bad thing?), getting from here to there by air is frightening, risky, and unnerving. At that’s even before you set foot on that airplane. So why make the rest of the trip even more unnerving by worrying about the actual flight? Yes, but what miracle of nature keeps us aloft?