The Man Who Touched His Own Heart

by Rob Dunn

  When the body is cooled, Bigelow had come to know, the heart slows, and the body’s demands for oxygen also decline, for the simple reason that cells in the body are metabolizing more slowly, requiring less oxygen. Beginning in 1947, Bigelow did experiments on cold dogs. In one such experiment, thirty-nine dogs (one suspects a fortieth didn’t make the cut) were cooled to 20 degrees C. It was difficult work because the dogs’ shivering made it hard to cool them all the way, but Bigelow did his best. Then, in each dog, Bigelow blocked the flow of blood back to the heart, essentially shutting the heart off. He kept it blocked for fifteen minutes, five times longer than a dog’s body should be able to go without the beating of the heart and its froth of oxygen, at least at normal body temperature. Once blood flow was restored, 51 percent of the dogs survived; they survived with far less oxygen than they normally needed from the heart because each of their cells had slowed down.

  In theory, Bigelow’s results meant that cooled humans could have their hearts stopped for more than ten minutes and still possibly be resuscitated, though with only a 50 percent survival rate, the procedure was still too nascent to be applied to humans. Yet it was all very exciting (albeit not for the dogs). Bigelow announced his idea at an American Surgical Association meeting in Denver, Colorado, in 1950.

  Almost immediately, eager young scientists, led by John Lewis, followed up on Bigelow’s idea and developed an entire subfield in which bodies would be cooled in order to facilitate heart surgeries. The earliest efforts, the first of which was an attempt to repair a congenital heart defect, were made so quickly after Bigelow’s talk that he had not even had time to publish his findings before the surgeries were complete. Lewis, as Bigelow would say, “broke the ice.” The 50 percent survival of Bigelow’s dogs had not concerned Lewis.17 Cooling bodies worked; the first patient survived open-heart surgery. She had been placed on a bed of ice, and her heart was stopped for ten minutes. The historic, three-minute barrier was surpassed, and with it, the possibility of far more ambitious surgeries had opened up. Heart-lung machines would eventually replace cooling for many surgeries, but today the two procedures are sometimes used in concert. Bigelow’s insight was fundamental and correct, but for him, it was still just a sidestep en route to an even bigger lesson.

  After his initial work cooling bodies for surgeries, work others seized upon, Bigelow himself chose another trajectory, one that brought him ridicule for the rest of his life. He had noticed that while human bodies could be cooled and their hearts slowed, their cooling was different from that seen in hibernating animals. Hibernating animals seemed to be able to cool themselves and slow their heartbeats without external help, such as ice. They cooled of their own physiological volition. When they did, they did not experience shivering, and their bodies did not fight the process (a big problem with both dogs and humans). This fact, Bigelow thought, could be used in human surgery and maybe even to extend human lives. The body temperatures of groundhogs could be lowered to 3 to 5 degrees C in the lab, after which their hearts could be disconnected for as long as two hours with zero deaths. While many of the dogs that Bigelow had cooled died, the cooled groundhogs almost never did. When he finally wrote up his 1950 paper (in 1953), Bigelow noted, “A greater knowledge of hibernation may yield useful information on this problem.”18 Bigelow began to think that hibernating animals had evolved a compound—he ambitiously gave it a name, hibernin, even before he discovered it—that triggered the cooling of the body and the slowing of the heart and metabolism. This compound, he thought, allowed these animals to hibernate but also extended their lives. Bigelow hoped to find this compound and use it to extend human lives, whether while surgery took place or perhaps via some other means.

  To find this chemical, Bigelow would study hundreds of groundhogs, devoting ten years of his life. He studied them under the conditions in which they were likely to be producing the mythical hibernin: outdoors, in the winter. This is not an easy thing to do. The warrens go deep and are complex, and groundhogs can react negatively to being yanked out of their holes. Bigelow persevered. He crawled into tunnels on his belly. He pulled animals out. He raised furry little groundhog babies. He set up the biggest groundhog study in history, probably never to be repeated. At its peak, his groundhog facility housed more than four hundred animals, all tunneling, eating, and hibernating just north of Toronto.

  Then, after six long years of research, there was a moment of elation. Newspapers were abuzz in the 1950s with the idea that, according to Bigelow, there was a “strange brown-colored fatty tissue” around the groundhog heart that, if removed, made the groundhogs much more sensitive to cold. Maybe this was the magic stuff of a hibernation gland? Bigelow injected the substance into other animals—both guinea pigs and rats—and successfully cooled their body temperatures to 5 degrees C. Animals without the injections could be cooled to only 14 degrees C.

  Bigelow was overwhelmed with excitement. He suspended his surgical practice to focus on the groundhogs and hibernin. He even injected the substance into two human patients, both of whom survived very low temperatures but seemed drunk. This was an odd finding and, it would turn out, a telling one. Bigelow submitted a patent for hibernin. It was then that he realized something had gone terribly wrong: The patent was rejected. The substance he had submitted a patent for had already been discovered and patented by someone else, and it was not a miracle compound. It was a plasticizer, a compound used in laboratory tubing, safety goggles, and other laboratory plastics to keep them pliable. Some plastic from the lab equipment appeared to have gotten into the samples. It was that compound that he had been injecting—a compound whose active component was butyl alcohol (hence the drunken behavior). With this, Bigelow became known as the man who had inspired the use of cold in heart surgery only to lose himself among the groundhogs.19

  But science is complex. One decade’s loss is another’s gain. Bigelow eventually retired, but not before planting a few seeds. The field he inspired progressed, as young scientists continued to study hibernation, metabolism, and heart rate. Scientists abandoned the quest for something so simple as hibernin but not the attempt to figure out what makes groundhogs and their kin so special. Then, in 2012, a team at the University of Alaska, led by Tulasi Jinka and Kelly Drew, discovered hibernin. Working with ground squirrels, Jinka and Drew had been trying to answer the same question Bigelow posed, but they had the advantages of the major advances in scientific technology that had occurred in the past fifty years. Jinka and Drew isolated a compound that, when released in the ground squirrels’ bodies, caused the animals to hibernate. Jinka and Drew are now able to perform an amazing trick with this compound. They wake hibernating ground squirrels up. Once awake, the ground squirrels stay awake, thinking they have found spring, until Jinka and Drew give them the magic compound, which causes them to go right back to sleep. The compound is called adenosine, not hibernin, and yet it does exactly what Bigelow had suspected hibernin might.

  Could adenosine be used to slow the metabolism of humans? Could it be used to extend lives or put people, Rip van Winkle–style, into suspended sleep to wait for new cures? Maybe. The good news is we actually know a fair bit about adenosine. It is used clinically to slow heart rates in certain kinds of dangerously fast heart rhythms. In nature, it induces hibernation in ground squirrels, but interestingly, it does so only during the winter (and it doesn’t do so if they have been given caffeine).20 It appears that during the winter, the receptors to which adenosine binds become more receptive or responsive, making hibernation possible. This may mean that in order to use adenosine more effectively in humans, we need to figure out how to use both it and its receptors. More remains to be discovered, as always, and yet a big corner has been turned. Sadly, all of this was realized seven years after Bigelow’s death, in 2005. He had been on the right track. He just needed more time.

  As Bigelow had intuited, hibernators have something to reveal, but so do many other wild species. The past few years have produced a richness of example
s of what can be learned from the hearts and blood of other species. Burmese pythons, for instance, have hearts that wax and wane with meals. Could lessons from these pythons be used to help us figure out how to regrow parts of human hearts? Yes. The groundhog, ground squirrel, and python are just three species from which we can learn, three out of millions. Further study of the hearts of other species will teach us about the limits (or maybe even advantages) of our own.

  A big lesson we’ve already learned from the experiments of Bigelow and from Geoffrey West’s laws of scaling is that the life expectancy of an animal is, on average, equivalent to one billion heartbeats. The beats can be slow, like a tortoise’s. Or fast, like a shrew’s. Or in pulses of fast and slow, like a hibernating animal’s. But that is all most animals get.

  Still, exceptions can be found. Some wild animals live longer than would be expected given their heart rates. In some cases, this appears to be related to how their mitochondria work and just how, at the finest scale, they wear down. Then there are humans. When Bigelow began his work, in the 1940s, humans lived lives of just over a billion beats. Now, in the United States and much of the developed world, the average human gets about 2.5 billion heartbeats, 1.5 billion of which are extra, bonus years thanks to the successes of modern public health and medicine. One perspective on this change is simply that we are extending our lives; another is that we are living out more heartbeats than any species on Earth ever has. In terms of an internal, biological clock, each of us lives, on average, two full lives.

  Our bodies break with the same frequency as those of other species, but we can mend them before they fall apart (as with the treatment of congenital diseases) or, better yet, find ways to prevent them from breaking in the first place (as in the case of statins). If you are lucky enough to be born in a fortunate part of a fortunate country, if you get sick, your body can be tended to. Much of the success, at least sixty years’ worth, is due to improvements in how we care for our hearts.

  People like Bigelow, Gibbon, and all the others have given each of us a chance at a second life, a billion and a half heartbeats with which to do as we please. Taussig used hers to keep making discoveries. Bigelow used his with the groundhogs. Time will tell what Geoffrey West will do, though it seems likely he will keep walking to his office, struggling with life’s data. Time will also tell what the rest of us do with our beats, those billion gifts, moments in which to change the world or just sit back and admire it.

  Postscript: The Future Science of the Heart

  I have a strange job. I get to wake up and study the species that live on humans and around humans and how they affect human lives. This is work I do with the public. Who better, after all, to study bodies and homes than the people who inhabit them? In studying the species around us, my colleagues and I have discovered a large number of things no one ever knew were there. One day, we find fifty unnamed bacterial species in someone’s belly button. Another day, we find a totally new kind of animal living in the pores on a teacher’s face. In houses, we have discovered a wasp that no one can name; what we know of it, we have garnered based on what is known of its relatives—namely, that it likely makes its living by laying eggs in the body of some other animal, where they then develop and eat the other animal, the host, from the inside out. This wasp is very common in homes but goes unnoticed. Elsewhere, we have discovered a thumb-size cricket that has spread basement to basement across North America without note. Everyone thought someone else knew it was there.

  I mention all of this because there has been a consistent lesson for me in studying these species. It is a lesson that rings out loudly and unambiguously every time I go to work: we humans are far more ignorant than we imagine. I wrote a whole book about this reality earlier in my career, and still it strikes me. What I didn’t realize when I was writing that book was that the more focused we are on our daily lives, the more likely we are to miss big discoveries. You expect big discoveries in the rain forest and so look for them. In your house, they run under your feet and you miss them, or perhaps you figure that someone knows what they are even if you do not.

  Here, at the end of the book, I’d like to be able to tell the future of our hearts, and the one thing I am most sure of is our ignorance and, hence, the future’s uncertainty. We know far less about hearts than doctors, scientists, and everyone else thinks. Helen Taussig posited that out there, flying near your house, there might be a bird with two hearts beating in unison (or maybe not beating in unison). The existence of such a bird seems unlikely, and yet we can’t really rule it out. By the same measure, we can’t rule out the existence of many kinds of hearts far different from those we know, or features of our own hearts that we haven’t yet understood. Generation after generation of scientists have assumed the body was, if not perfectly understood, nearly so. They were wrong. Our generation will be no different.

  Part of dealing with our ignorance is humility. But there are also practical ways of improving the odds of making big new discoveries. When it comes to understanding how our hearts work and fail to work, it is a good idea to try to understand the hearts of other species. Nissi and Ajit Varki are starting to compare chimpanzee hearts and human hearts, but they have really just begun. We know very little of the other apes, much less the other primates in general. Given how much light a modest understanding of chimpanzee hearts has shed on the understanding of our own hearts, it is easy to imagine the light from other apes will also be clarifying. And it isn’t just the apes. There are more than five thousand mammal species on Earth, each with a different type of heart. There are around twelve thousand bird species. And then the fish; there are tens of thousands of kinds of fish, and millions of insects. Each of these species carries some lesson to be understood.

  But there is more. Cyclosporine, it is worth remembering, comes from a fungus that immobilizes the immune systems of beetles. Statins come from fungi, a product of their wars against other microbes. Antibiotics that kill off the pathogen that causes rheumatic fever, bane of the heart, come from other fungi fighting other bacteria. In the millions of wild species are millions of answers.

  Predicting the future of medicine may well be more difficult than predicting the future of discovery. It depends not only on science and technology but also on governments, policy, and culture. Bless those who imagine they know the future of policy and culture. The past, though, offers some insight. For one, we do not have to squint too hard to notice that in the story of the heart, there are repeated cycles of hubris, the appearance of accomplishment, and then prolonged or even ultimate failure.1 I’ll speculate that, similarly, part of what seems like the light of progress today is illusion; humans are drawn to the bright light of accomplishment more strongly than to the subtler candle of reason.

  The trick is distinguishing progress from illusion. Brighter minds than mine have tried and failed. Today, one hope on the horizon involves stem cells. In labs around the world, researchers are racing to use stems cells, sprinkling them on the heart or injecting them into the heart to regenerate its muscles. Stem cells are all-powerful cells; they can be anything. These new treatments seek to convince these cells to become part of the heart.

  In petri dishes, entire beating heartlike blobs of cells have been created out of heart cells left to grow on a scaffold. Some researchers are now talking of making hearts in the lab out of human cells. We could, they say, grow thousands of hearts. We could grow parts in general. We could grow ourselves into eternal lives. No one is so bold anymore as to mention eternity or immortality, but quite a few folks are talking about extending lives decades more on top of what they are today.

  Right now, the ability to get stem cells to regrow heart tissue is as exciting as the first heart transplants done by Shumway and Lower on dogs in the 1960s were. Just as with the dogs, it is immediately clear what the intent is, what the future might be. In fact, clinical trials are already going on around the world. More than a thousand people have had stem cells released into their hearts. So far, th
is sprinkling of new, potent cells has not helped the patients. It turns out that, like the ladybugs you release into your garden, stem cells have a wandering jones. Release them into the heart and they wash away, travel elsewhere in the body. Now folks are using mice to try out devices that slowly release the stem cells. In mice, these seem to work better. We wait. The field is full of both hope and contention about these new approaches.2

  Hundreds of researchers are working on stem cells and hearts, and so progress might happen quickly. But these hundreds, in addition to giving me hope, also remind me of the other thing I can predict, this time with certainty. Although society invests heavily in projects that appear likely to result in immediate medical treatments, it invests far less in research that gives context to the need for such treatments. Only a handful of scholars study why our hearts are prone to atherosclerosis in the first place. No one is following up on the hearts of Taussig’s birds. Essentially, no work is being done on how and why human hearts might differ from one population to the next around the world (they almost certainly differ). We have left the study of who we are and why to a handful of diligent folks whose work has the potential to fundamentally rearrange our understanding of our bodies and yet is little known and poorly funded.