To be involved in medical research, a seat belt is sometimes required. The flow of new information coming in from closely allied and distant fields creates its own turbulence. But perhaps the most jarring is the forward-moving research edge colliding with the black hole of our ignorance. Sometimes that collision comes when a great discovery of a prior age is seen through the lens of today.
For example, sometimes a person’s immune system will stray beyond its boundaries and start attacking the body’s own cells. This so-called autoimmunity is what causes type 1 diabetes, multiple sclerosis, and a host of other ailments, including blood diseases. Blood stem cells, red cells, or platelets needed for blood clotting are not uncommon targets. The result can be life threatening. so for ages doctors have sought ways to treat these conditions. A century ago, it was found that infusing animal serum worked. It could raise the blood counts. I teach a course to Harvard freshman called “Blood: From Gory to Glory.” It is about how we constantly re-know things we think we already understand. Blood has been known as the stuff of life since historic time began and yet we constantly are learning new things about it, use old principles to make it better and sometimes scratch our heads at how unbelievably primitive “modern” medical science can be. I took the twelve freshman in my seminar to meet a young woman in the process of getting treatment for her low blood counts. At one of the greatest institutions of medical science in the world, Massachusetts General Hospital, she was getting what could only be considered a primitive therapy: an infusion of horse serum. It worked, but surely we could do better (and, in fact, new approaches have emerged in the intervening three years or so). For the students it was a clear indication of how the forward thinking of one era can seem like magical primitive thinking to another, and how new thinking was constantly needed to improve our condition.
The ancient Greeks opened veins and drained blood from the sick because they thought many illnesses were caused by an imbalance of the “humors,” which also include bile and phlegm. Blood-letting remained part of medicine for more than a thousand years. After he suffered a seizure, England’s King Charles II was subjected to so much bloodletting by his doctors that he lost one quarter of all his blood. His treatment also involved enemas, emetics, and quinine. Of course he died. The same fate met George Washington, who, when he suffered an extreme throat infection, ordered a servant to open a vein before his doctor arrived to continue the procedure. Belief in this therapy persisted until the second half of the 1800s, when Louis Pasteur and other pioneers of modern medicine began to discredit it.
Lacking the ability to intervene with the body, except to manipulate fluids, physicians turned to bloodletting because it seemed rational in the pseudoscience of the day. The ancient Greeks constructed a logical order of things in nature as comprised of earth, air, fire, or water. That four-part rationality was applied to the seasons of nature and of life and to what gave us life in the four humors: blood, black bile, yellow bile, and phlegm. Each was given significance in our personalities and in our health, particularly by Hippocrates, the great proponent of rationality in medicine whose “Oath” is still recited by doctors receiving their medical degrees today. When health failed, it was regarded as an imbalance in the humors and the response was to purge or bleed. Remnants of this seemingly rational, but highly unscientific reasoning continues today with “cleansing enemas.” Physicians commonly used the application of leeches or simple bloodletting well into the twentieth century in part goaded by the imbalance theory, but also because it allowed them to do something dramatic in the face of suffering.
Blood being central to life is something no one could dispute. Old medical practice leveraged that instinctive knowledge and in so doing also indirectly claimed connection to higher powers. Blood is a part of virtually every mythology and every religion, particularly religious ritual. Blood sacrifice was a critical component of ancient Mesoamerican practices as a means to feed the gods so their gift of a good harvest would continue: blood was a kind of restorative fuel. In ancient Middle Eastern traditions, it was often used in sacrifice. The word origin of sacrifice is to “make sacred,” a way of connecting us to what is holy. In South Asian traditions it represented the fearsome power of the gods, as in the terrifying Hindu goddess, Kali. The ancient Greek myths perhaps synthesized the duality of blood’s power to take and to give life in the story of Asclepius, the son of Apollo and a mortal mother. He was taught by the centaur, Chiron, in the healing arts and was said to be given by Athena two vials of blood: one from the right side of the head of Medusa that gave eternal life, and one from the left side that gave instant death. Blood was the basis of both and yet Zeus, angered at the notion that Asclepius could use blood to change the order of things, struck him down with a thunderbolt. No matter what power may appear to be in the hands of healers, it is the fate the gods impose that ultimately wins out.
The duality of blood embodied in the myth of Asclepius is mirrored in the stick he is often depicted as carrying. It is entwined by a snake—a fearful creature, but one that also has great regenerative power; it sheds its skin and creates it anew. That combination of horror and regeneration is associated with blood in a more modern tale, Dracula
The tale of Dracula, first published in 1897 by the Irishman, Bram Stoker, borrows from much older Eastern European tales of vampires. But while Stoker’s nocturnal, pale-faced monster might be considered elegant and magnetically appealing, the traditional vampires that inspired him were hideous, ruddy-faced corpses that became animated and pursued their prey day and night.
Experts in myth say that every monster we invent is a reflection of some basic human fear—most often our fear of death—and that in confronting these creatures in stories we gain some mastery over existential realities. In the case of Dracula and other bloodsucking creatures we can also see that on a conscious and even subconscious level blood is our well-being, both physical and psychological. As Dracula takes the blood of innocents, he converts the victims into creatures of evil, building on the fearful notion that blood can create a contagion. Central to the story is that blood rejuvenates Dracula, not just giving him life but making him younger and more vigorous. This is a theme that permeates all the vampire myths and has gruesomely played out in some historic circumstances. The Countess Elizabeth Bathory of Hungary murdered hundreds of young women in the sixteenth century to bathe in their blood so as to retain her youthful looks. Despite the clear madness of such magical thinking, there is some scientific basis to the idea that in the blood there is youth.
Recent animal studies tested whether the changes with age were transferrable by blood. Mice were connected by a skin flap so they exchanged blood over time. Connecting a young mouse to an old one remarkably made the older animal heal better. The blood allowed for rejuvenation, but what in the blood caused this has been difficult to define. A single chemical in the blood may not be sufficient, but candidate molecules are now being tested with some benefit in animals. The fearsome elements of the vampire myth may yet prove to give us hope for healthier aging.
Not long ago, a team led by Harvard geneticist Stephen Elledge announced it had developed a reliable test that would discover, in a single drop of blood, every virus a person had ever contracted. The new technology, which had been tried with patients all over the world, can detect more than one thousand variants of the roughly two hundred species known to infect human beings. In these trials, few people showed evidence of having been stricken with more than a dozen types of viruses, most of which were linked to gastrointestinal illnesses or the common cold. However, signs of other pathogens, like Epstein-Barr, human papillomavirus, or hepatitis, would alert both patients to their increased risk for later disease, including various cancers.
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The blood system begins with the marrow, which I consider a kind of foundry where elements are forged into various cell products. The capacity of this foundry is awesome. It depends, in a primary way, on the ten to twenty thousand blood stem cells we each possess. These make about two hundred billion new red cells per day. But as they say in TV infomercials, “Wait, there’s more!” In addition to these red blood cells, we also make four hundred billion platelets and about ten billion of the immune system cells called white blood cells. Altogether, this production exceeds the population of stars in the Milky Way, every day.
The activity of the bone marrow is stunning both in its volume but also in its importance to our survival. And all this is accomplished by a part of the anatomy that Aristotle believed was a waste depository and which Hippocrates thought provided nutrients for the bones. Eighteen hundred years would pass before Ernst Neumann squeezed the bones of both rabbits and human beings and discovered—in what was called bone “sap”—red blood cells. Neumann reported his discovery in 1868. In that same year, his colleague Giulio Bizzozero proposed that the marrow produced white blood cells. Bizzozero’s theory was correct. He also correctly theorized that the marrow was the site of blood cell destruction. This idea was confirmed in 2017.
In going two for two, Bizzozero’s batting average was astounding given the changing fashions of thought over long stretches of time. Most big discoveries are amended and enlarged by later work, and in many cases, the pioneers in one generation become reactionary naysayers in the next. A century after the Europeans discovered the productive capacity of the marrow, and fifty years after Josef Pappenheim proposed there was a blood stem cell, the Canadians Ernest McCulloch and James Till published their experimental evidence on blood stem cells and advanced the ideas that they were the sole creators of the blood and immune system. When a British scientist named Raymond Schofield suggested in 1978 that things were much more complicated than the matter of stem cells birthing offspring, McCulloch reacted with skepticism that veered into antagonism.
As a giant in the field, McCulloch carried the weight of his achievements into the debate, and Schofield felt quite overwhelmed by the controversy that arose. Schofield had recognized that the stem cells were affected by a variety of inputs from what he called the “niche” they occupied and that these inputs determined much of what the bone marrow foundry created. The power of communication, which occurred in the niche, was the big notion that Schofield advanced. A proud and somewhat acerbic man, McCulloch considered Schofield’s work not a contribution to his own but an affront. Schofield eventually wearied of the argument and decided to retire from science at age sixty. He bought a farm in an isolated corner of Wales and happily raised sheep and cattle. With time, however, his ideas about the way marrow works gained wide support, and his science inspired a generation of scientists, including me.
In 2008, decades after Schofield retired from what he would call “the science business,” I began research for a paper to help mark the fiftieth anniversary of the American Society of Hematology. I was asked to write because my lab had proven Schofield right: we mammals do have stem cell niches. I thought Schofield had been overlooked and should be honored in the record and, if possible, given an award to acknowledge his achievement. Unfortunately, my efforts to track him down went for naught. Then, in 2014, I received an email from him. He reported that he was alive and well and was keeping up with hematology, albeit from a distance. One thing led to another, and I found myself making an appointment to visit him during a planned trip to the U.K. We agreed to meet in the city of Cardiff. Before I left, I bought a small silver Revere-style bowl and had it inscribed for him.
The meeting place Schofield suggested was a cavernous pub called the Prince of Wales, which sat between the Chippy, which was a fish-and-chips place, and a bookmaker’s shop called Coral. The Prince of Wales was close to the central station, where Ray arrived by bus from Aberaeron, which was a town of 1,400, most of whom spoke Welsh, located one hundred miles to the north on the Irish Sea. At age eighty-eight, he was a spry, energetic, and talkative fellow. When we settled into our seats, he told me that in a previous incarnation, the pub had been a legitimate theater—Laurence Olivier, Richard Burton, and Rex Harrison had appeared on its stage—and, later, a cinema specializing in X-rated fare. We would laugh quite a bit in the time we spent together.
Schofield’s humor suggested the playful, creative spirit that makes for first-rate science.
He also recalled a life story that defied the idea that a straight line is always the best pathway to success. Schofield said he dropped out of school at age sixteen and found work as a technician in a pathology laboratory. Excited by what went on around him, he studied mainly on his own to earn a doctorate. Most of his career was spent at the Paterson Institute for Cancer Research near Manchester, England, which was founded to study the health effects of radiation and ways to protect people or treat them after exposure during an accident or nuclear war. Schofield’s more creative methods included using beetles to clean the bones of deceased animals and planting stem cells beneath the membrane that covers the kidney (in animals), where they could be nourished by a blood supply and grow. In another experiment, he used radiation to kill the marrow stem cells in a young mouse and then used some harvested from an old mouse to repopulate the marrow. When the new supply of stem cells functioned normally, he waited for the recipient to age and then repeated the process. The stem cells remained productive as they were moved from mouse to mouse to mouse, which showed the power of these special cells.
Although some of his techniques were rudimentary, Ray built a truly sophisticated understanding of how the blood and immune systems develop and function. He also rebelled against the reductionist thinking that many scientists are trained to follow. Around the world, many students of science and medicine are encouraged to embrace a commonsense philosophy referred to as Occam’s razor. Occam was a fourteenth-century thinker who favored an intense kind of reasoning that shaved away at superfluous factors to produce the simplest answer to a question. It was based on the Aristotelian notion that favored theories with the fewest variables over those that suggested intricate processes—and even divine intervention—as answers to scientific questions.
In a general sense, the razor worked. The wind is a far better response to the question, “How did those clouds get here?” than an answer that invokes the gods and the labor of spouting whales. However, many problems, especially in biology, defy such a reductionist approach and require, instead, the inclination to delight in complexity. The grandeur of biology can be seen by comparing the ordinary butterfly to the most complex robots fashioned by human hands and minds. The robots can perform tasks in specified environments but eventually require human interventions for refueling and maintenance. Butterflies emerge from caterpillars, respond to myriad changes in the environment, feed themselves, and even reproduce without any help at all. Consider the roach, and the success of vastly complicated organisms like human beings, and it’s plain to see that Occam’s razor doesn’t always cut it.
One sure way to get around reductionism involves learning to take some delight in discovering a new facet of a problem and loving the way that the answer to one question may lead you to five more. Ray possessed this kind of enthusiasm, and it didn’t seem much diminished, even though so many years had passed since his retirement. He had continued to read avidly in both scientific journals and the popular press, and he had stored up plenty of theories and ideas for experiments. When he told me about his life in science, I could hear that his spirit had been as important to his success as his intellect. On a trip to Moscow, when the Cold War still raged, he formed relationships with Soviet scientists who suggested new ways to explore problems. The irony of getting tips from people working for the regime that posed the atomic threat that inspired the creation of Ray’s lab in the first place was not lost on anyone.
In the end, science, like every other human endeavor, may come down to relationships that add to individual creativity. It may sound a bit sentimental in light of the fact that advances depend on devotion to provable fact, but Schofield’s example illustrated the place that friendship and support but also unfair criticism and isolation can play in the process. In my view, Schofield had been denied the recognition he deserved. As we finished lunch, I looked in my bag for the bowl I had brought and presented it to him. Although the gift didn’t carry with it the acclaim of a professional organization or a prize committee, it acknowledged Ray’s true contribution. A tear came to his eye as he read the inscription, which said, “To him who gave stem cells a home.” Minutes later, we walked to the bus station, and he climbed aboard for the journey back to his village.
Ray stayed in touch via email after our time in Cardiff and offered well-informed observations about where stem cell science and society seemed headed. In one email, he seemed as enthusiastic as the most idealistic undergrad as he described his regular efforts to comprehend the ways evolution led, by natural selection, from unicellular organisms to “simple animals and plants, let alone humans.” In another, he complained of the “scientific” (his punctuation) information the popular press feeds the public “about the so-called stem cell ‘therapists’ who seem to think that if they put stem cells” into the body, they cure any illness or injury. As Schofield noted, the world was fairly buzzing with reports on stem cell therapies that supposedly helped people with everything from autism to sagging skin. Hundreds of stem cell clinics had opened across the United States, many of which took advantage of a quirk in the law that allows patients to have their own cells removed from their bodies, processed, and put back in for any purpose at all. (One orthopedic clinic in New Jersey offers to do this to people who respond to their advertisement at a discounted price of $2,000 per joint.) Similar openings in regulations permitted the marketing and sale of stem cell cosmetics and creams, even though there was no evidence that the special ingredients were effective.
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The science of blood, including the work done with blood stem cells, continues to evolve. I am especially intrigued by the progress being made toward the goal of understanding how the variety of these cells protects us from disease, including cancer, but also lose some of this capacity over time. The best way to think of this involves imagining a chess board before the start of a game when each player has a full complement of pieces. This is the immune system at the height of its powers, which exists as we enter adulthood. Some of the cells in this array are quite powerful, like the queen, and can meet a great many threats. Others are pawns that can basically carry out a single mission.
As the body engages with various events like the common radiation exposure from the sun, chemicals, or inflammation, certain stem cells break down and stop producing. Like a chess player who gradually loses pieces, the body is left with a lesser variety of stem cells with which it can create responses to nascent cancer or infections. This process, like the endgame of chess and not simply the passage of time, may explain why older people are more susceptible to diseases as disparate as pneumonia and cancer in most of its forms. Interestingly, the total number of stem cells in the body remains relatively constant, but we see a decrease in the variety needed to maintain health. Understanding the system as a sort of community of cells that is more diverse and powerful at some points in life could lead us to therapies that strengthen the system to fight more diseases over a greater portion of the life span.
Understanding the cells that provide us with resilience or susceptibility to disease is one thing; modifying the stem cells we have to protect us is another. Both are themes of active, early-stage research. What is closer to application is the use of cells to rebuild damaged tissues. Indeed, some stem cell approaches are moving forward on rebuilding whole organs. The idea of doing so immediately comes to mind simply by looking under a microscope at stem cells that have human heart muscle cells, grown in a laboratory, beating with telltale rhythm. Experiments generating cardiac cells mainly use induced pluripotent stem cells (iPSCs), of the sort developed by Shinya Yamanaka from skin cells. They can be encouraged to form cardiac cells and will start beating. They can then be taken from the culture plate and used to populate a heart “scaffold.” The scaffold is derived from an animal heart where the cells of the heart have been dissolved by detergents. What remains is a fine web mesh of proteins exactly outlining the fine structures within the heart and its blood vessels. This 3-D matrix appears to convey important information as the cells that are applied organize and take on the features of a mature heart.
The excitement that attended stem cell work that created human heart muscle was informed by the prevalence of heart disease and the limits of our current therapies. Heart failure, as a group of conditions is generally known, can be treated partially with lifestyle changes, drugs, implantable devices, surgeries, and transplanted organs. At any given time, more than four thousand Americans are on waiting lists for heart transplants, but in most years, fewer than twenty-five hundred procedures are performed due to the small number of healthy hearts made available when people die. Overall, about nine people waiting for organ transplants die every day. If labs could take skin cells from individuals, turn them into iPSCs, and then create usable organ cells, they might be used to treat a wide number of diseases.
The ultimate dream of scientists who addressed the problem of organ failure involved manufacturing entire genetically specific hearts, kidneys, lungs, and other organs that would spare many patients the wait on the transplant list. In 2016, a thoracic surgeon, Harald Ott, reported on a project that involved using human hearts that were not suitable for transplant to create scaffolds. His team created scaffolds out of the left ventricles and then seeded them with five hundred million reprogrammed human skin cells. They placed individual scaffolds in chambers, where they were bathed in nutrients that allowed the cells to develop. The chambers, called automatic bioreactors, also stimulated the scaffolds and cells with intermittent pressure to simulate the functioning of a real heart. Fourteen days later, they used an electrical current to stimulate the cells, which started to beat like mature tissue. Imagine the team’s excitement as they saw the organs that they had created and suspended in the bioreactors flexing.
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Photos of the partial heart, suspended in the clear plastic bioreactor and illuminated by bright lights, look like nothing less than a small human heart. Construction of a full-size, functional heart and testing its durable function will take years and overcoming engineering and biologic problems. However, Ott’s success has made it much easier to imagine the leap from lab to patient. Ott’s lab, which was allied with both the Harvard Stem Cell Institute and the Center for Regenerative medicine at Massachusetts General Hospital, was also working on creating lungs, kidneys, and tracheas. In a step that could be regarded as a halfway point in the effort to produce transplantable organs, Ott and others produced three-dimensional representations of organs—they are called organoids—that mimic many functions of organs as varied as the tongue and the thymus. Scientists in the Netherlands have used organoids grown from people with cystic fibrosis to test how their bodies might respond to certain drugs. The process eliminated the time, expense, and discomfort of trying medications as therapies and waiting to see if they worked.
Other stem cell projects did not require constructing either organoids or organs built on scaffolds. In 2014, Harvard Stem Cell Institute cofounder and my close friend, Doug Melton, reported that he had used stem cells to create pancreatic cells—called beta cells—that could produce insulin. He transplanted these functioning cells into diabetic mice where they cured the disease. Melton and his group were able to produce these cells in the millions, which would be required if they were to be used as a treatment.
In nature, beta cells function with exquisite perfection, maintaining insulin levels in a way that is impossible to match with blood monitoring and injections. However, the early animal tests determined that the implanted cells stopped functioning because the immune system identifies the implants as unwanted invaders and eventually destroy them. This action, a mistaken immune response that degrades normal insulin production, is the cause of type 1 diabetes, which is usually diagnosed in children and young adults.
One creative workaround for the immune response problem called for encapsulating new cells in a substance that would protect them from immune system attacks while letting in key cell nutrients and letting out the insulin that the beta cells produce. Melton’s team worked with a bioengineering group led by Robert Langer of the Massachusetts Institute of Technology to test nearly eight hundred substances. They discovered one that seemed to act as a cloak of invisibility for the cells, which meant the immune system wouldn’t attack them. Beta cells were packed into little spheres of this gelatin and the package was tested in animals. It worked for six months. Melton thought the system could be tweaked to last a year or longer. If the problems of cell production and packaging are solved, it is possible to imagine a time when people with diabetes will get cells to replace the continual testing and insulin injections used by millions of people.
The Melton lab and others are also looking at type 2 diabetes, which is linked to obesity and marked by a breakdown in the body’s ability to use insulin. A huge advance was made in this area of science when iPSCs were induced to turn into human brown fat cells. Brown fat, unlike regular white fat cells, burn energy rather than store it. They could lead to people getting thinner and more in metabolic balance.
The other advantage of iPSCs is that they offer human cell models of disease rather than depending on mice or cancer cell lines that have been passed in culture for years the way Henrietta Lacks’s (HeLa) cells are. Too often a treatment that helps a diseased mouse does nothing for human beings. Some of these disappointments may be avoided by having cells from individuals with the disease providing iPSC that can then be made into the cells that participate in the disease. Neurological diseases can be extremely complex, but some of them have particular cells that appear to be central to the process. Parkinson’s disease and amyotrophic lateral sclerosis (ALS) represent two such diseases and are a point of focus for many laboratories using stem cells. Replacing the damaged cells with those grown from iPSCs is a dream that will at least be tested as laboratories in New York ramp up to do just that. Other options for the use of the cells is to test how they behave compared with cells from people without the disease and to try and identify medicines that may improve their behavior. It sounds like fishing and it is, but at least it’s fishing for a drug using the right hook (human cells) and bait (abnormal function).
Brain cells for modeling or treating disease using iPSCs is promising and paralleled by developments in studying brain stem cells in the brain itself. The very idea that humans possess brain stem cells was rarely even considered prior to the late 1980s. Back then scientists knew that neural networks developed early in life and believed that that once they were established no new cells were created. In 1989, a neuroscientist named Sally Temple reported the discovery of stem cells in mouse brains. Next came the discovery of similar cells in the human brain. Out of this early work grew a new understanding of the brain and nervous system as dynamic and, perhaps, capable of self-repair.
For generations, physicians have noted that people who suffer in injury that causes partial paralysis may recover some function as inflammation recedes, but rarely regain all that was lost. This observation was in keeping with the long-standing belief that neurons were fixed in number and function beyond adolescence. Based on observing behaviors, though, the famed nineteenth-century psychologist William James argued that the brain was more than a machine which, once built, never changes. Evidence of a growth-and-repair process called neuroplasticity accumulated as experiments showed that the brain could adapt to injuries or deficits. One of the most remarkable reports on this process was published by neuroscientist Paul Bach-y-Rita in 1969. Bach-y-Rita, whose work was inspired by his father, who had suffered a stroke, designed a machine that used a scanning camera and that sent signals to tiny vibrating devices attached to a chair. Blind subjects who trained with the machine developed the ability to decipher words and recognize pictures as if they were viewing them. The experiment suggested that the adult brain could develop a new network.
Proof of neuroplasticity poured out of laboratories beginning in the 1990s. Some of the most persuasive work used imaging technology to document changes in the brains of medical students engaged in what experimenters called “extensive learning.” These events reflect dynamism that is likely due to the forming and remodeling of connections between neurons. The cells do have an arbor of cell extensions that connect over long distances with other neurons’ extensions, forming a network. The network changes but that does not necessarily mean the cell numbers change. Just because we have stem cells in the brain does not mean that they are active in making new cells in adults. But it is now clear that we can, in fact, make new neurons. It was discovered by a brilliant use of information derived from military events. Aboveground testing of nuclear weapons in Russia created clouds of radioactive carbon that wafted over northern Europe. Jonas Frisén, a neurologist and stem cell biologist in Sweden, realized that people born when the cloud was around would have levels of radioactive carbon far higher than people born before or after. If the carbon was used to make the molecules in cells, then measuring the amount of radioactive carbon in cells would determine if the cell were made when the person was being born or later. If the cells had less carbon they would likely be descendants of the original cells. Frisén measured the carbon in human brains. Most of the neurons all had the same amount and were like the model predicted. But some in places predicted by the model, did not. They had less and suggested that we do have brain stem cells that make some new brain cells. Now the issue is how to get them to make more, and particularly to make more when people need them after a brain injury. One thing that appears to encourage the formation of new neurons is exercise. Whether medicines can be found that do the same is an ongoing quest.
Making more brain cells of particular types is an important goal, but for them to function properly their connections to other neurons is key. It is the web of interactions that allows the processing of information we call thinking. It is also the maintenance of connections that is critical for memory. Enhancing those interactions with stem cells is not something we can currently imagine doing even though few health problems evoke more fear and anxiety than Alzheimer’s and other forms of dementia. The experience, which includes memory loss, cognitive decline, personality changes, and physical symptoms, can be devastating to people with these diseases who feel as if they are literally fading out of their own lives. Family and friends bear a similar burden. For every one person with Alzheimer’s, roughly three people are involved in unpaid caregiving, which is both physically and emotionally demanding. The cost associated with the medical services needed by people with dementia exceeds $230 billion annually. Increases in life span, primarily due to improved health care, have contributed to a rapid increase in the number of people living with this disease. At the current rate of diagnosis the number of Americans with Alzheimer’s will grow from about five million today to fourteen million in 2050. The call to action is undeniable, but this aspect of aging is not going to yield to a cell replacement the way Parkinson’s might.
Loss of cell function that we associate with aging was generally thought as inevitable. But the studies connecting the circulation of young and old animals suggest that there might be something in young blood that can change that inevitability. Also, it is now clear from studies we and others have done that there are genes that cause at least some of what we call aging. Inhibiting those genes improves how cells and the tissues they inhabit perform with age. Why we have genes destined to compromise our function seems to defy what evolution should accomplish. But some of these genes keep us from getting cancer. Thus, evolution probably chose wisely. However, it does suggest that deterioration with aging is not a fixed attribute. It also may allow us to think about aging and longevity as different. Aging is the decline of function, but longevity is determined by collapse of the entire system. The maximum possible human life span is estimated to be about one hundred and twenty-five, but only extremely rare people will live beyond one hundred and fifteen. Barring an unexpected breakthrough, science and medicine are more concerned about providing healthier aging than adding significantly more years at the end of life. Indeed, many of us share concerns about the desirability of adding decades onto the life span. Would delayed mortality cause us to regard life as less precious, since we would possess more of it? What about the impact of life extension on the natural environment and human communities? If the old stop making way for the young, will we exhaust the Earth’s carrying capacity?
Political scientist Francis Fukuyama, who once declared prematurely the “end of history,” gazes upon the science of longevity and sees big problems. Fukuyama points out that ultra-longevity would be so expensive that only the wealthiest or most powerful people could afford it. A dictator could purchase extensions on his reign. With this outcome in mind, he says that “extending the average human life span is a great example of something that is individually desirable by almost everyone but collectively not a good thing.” I think he is right.
The leading edge of the science devoted to maximizing healthy aging, regenerative medicine deals with the challenges of translating discoveries in stem cells, bioengineering, genetics, and other disciplines into therapeutic interventions. More progress has been made in regenerative medicine than most laypeople recognize. Some of the big advances involve technologies beyond biology. Robotics labs are already producing light, silent, battery-powered exoskeletons and joints that allow paraplegics to walk. (More modest devices restore movement to a single joint.) Even more dramatic than the exoskeletons are the technologies enabling paralyzed people with a condition called complete locked-in syndrome (CLIS) to communicate.
Although it can be caused in several different ways, CLIS is tragically common in cases of advanced amyotrophic lateral sclerosis. In this condition, people are even unable to blink their eyes in response to questions. For decades, scientists have tried to help patients communicate via electroencephalograph machines, which measure brain activity. When brain waves were studied, these experiments never produced “yes” or “no” replies above the rate of chance. In 2016 scientists in Switzerland worked with four CLIS patients who were connected to sensors that detected the blood flow that corresponds with neural activity. Accurate answers to questions such as “Is your husband’s name Joachim?” exceeded the chance-response rate.
CLIS is a terrifying condition to observe and it is easy to assume that it produces despair in people who live in its confinement. However, the lead scientists in the Swiss-based study told the press that replies from study subjects showed they often existed in a positive state of mind. “What we observed was, as long as they received satisfactory care at home, they found their quality of life acceptable,” said Niels Birbaumer. “It is for this reason, if we could make this technique widely clinically available, it would have a huge impact on the day-to-day life of people with complete locked-in syndrome.”
Birbaumer’s work is just one example of efforts to bridge the mind-machine connection. Much of it is inspired by trying to relieve the suffering of those with brain disorders, but it has a more fantastical side. Some in the world of high technology envision that machine learning, done now in ways that are affecting our lives and will replace many current human jobs, has the capacity to mimic human thought. In its most extreme, some think it can recreate consciousness sufficiently so that we could essentially “download” our brains. Ebay cofounder Peter Thiel and Oracle’s Larry Ellison seek to create what’s called “life extension” using computers.
Ellison, who has said “death makes me angry” and “death has never made any sense to me,” has put hundreds of millions of dollars into research on how we might forestall the end of life. This now-ended program was a superb way to gather scientists and fund their best ideas on overcoming age’s effects. I was fortunate to be one of those, though I confess my ability to significantly improve aging is yet to be realized.
The work of others is impressive in both connecting computer technology to humans and in using manufacturing technology and applying it to biology. On the computer side, there is increasingly common news about hardware allowing the brain to direct action even when normal nerve connections have failed. Brain control of artificial limbs has been fashioned to operate in ways that seem quite human. A prosthetic hand can pick up a sheet of paper without crumpling it. A software driven leg takes a steady step.
In cell biology the progress is even more impressive. Functioning, laboratory-produced bladders have been placed successfully in people with congenital defects. Eye surgeons in Japan have found some success in repairing damaged human retinas with stem cells coaxed to become the tissue that supports sensory neurons. Cartilage made from samples taken from human trial subjects has been used to repair knees. New tissue and organ “printing” technology has been used to assemble living cells into bone, muscle, and even an artificial ear. When a printed muscle was implanted in a mouse, blood vessels and nerves engaged it to keep it alive. The machines used to create these tissues are similar to the 3-D printers that have developed to make objects out of metal, plastics, and other materials. Although the software required to run them is complex, the hardware is not. One creative scientist at the Scripps Clinic in La Jolla, California made his own machine out of an old ink-jet printer and managed to use it to manufacture animal tissue.
Engineered organs represent just one possibility for renewing the body. Another can be glimpsed in the animal world, where zebrafish regrow lost tails and starfish create new limbs. Human beings can regenerate liver tissue, blood, and skin, but our bodies do not reactivate the programs by which stem cells make new tissues to nearly the same level that zebrafish and starfish accomplish routinely. Why do humans lack this ability? One reason may be that we are better engineered to repair, not replace. We scar. At Harvard, my colleague Leonard Zon and others have rooms filled with rows of fish tanks that are populated with zebrafish. The quest is to study how zebrafish can remake a damaged heart or kidney while we cannot. These fish have now gone from good tools to the study the genetics of how repair is governed, to testing for drugs that might improve regeneration. Zon may not discover ways for humans to regenerate lost fingers, but he has used the fish to discover a drug that increases blood stem cell regeneration and is being tested in blood stem cell transplantation.
Sometimes the promise of regenerative medicine can make it seem like human beings will soon be treated like machines—motor vehicles come to mind—and that the future of care will involve removing worn-out parts and installing new ones. The analogy is a limited one, but it’s not completely inaccurate. We have long been replacing worn-out parts with better one with transplants. If bioengineering frees us from the constraints of using organs taken from the deceased and permits the production of custom ones, we should embrace the technology. And I would like to take the machine analogy one step further. It is increasingly apparent that we all accumulate genetically abnormal blood stem cells over time. It is also apparent that this imposes increased risk of heart disease and death. Many diseases once thought to be those of a specific organ now implicate the blood. Therefore, I can imagine a future when commonplace periodic replenishments of blood stem cells may in an effort to prevent deterioration. Perhaps it will allow our bodies to function better longer and suffer fewer breakdowns. Think of it as an oil change.
This big news came from a five-year, $30-million endeavor called Blueprint, which engaged researchers at forty-two European universities and sought to discover how genetic changes in bone marrow cells affect the blood cells that they produce. The target of interest here was what is called the epigenome, which is comprised of all the chemicals that turn genes on and off. The epigenome helps cells differentiate into different tissues and then helps drive their activity. Heredity determines much of the epigenome, but it can also be affected by environmental influences like diet and exposure to chemicals. The epigenome may also be changed by infection and even stress. This process, which once would have been regarded as an impossibility by many scientists, gives support to the notion of a connection between our experience of life and our physical state. Blueprint drew on the records of 170,000 people and identified thousands of epigenetic changes that altered the characteristics of blood cells. This data was then compared with health records.
For more than a decade a small study in Canada has tested immune system restoration via bone marrow stem cell transplant as a treatment for MS. About 70 percent of the twenty-four enrolled patients, who were suffering extreme symptoms when they underwent transplantation, showed marked improvement in their symptoms. Forty percent experienced either increased muscle strength, improved vision, or better balance. Some have had no progression in this otherwise progressive disease for years. The greatest recovery saw one woman go from retirement at a nursing home to a fully active life, including downhill skiing. Brain scans showed that inflammatory processes had been halted, and the rate of brain atrophy was slowed to the normal range.
Bone marrow transplant is currently a high-risk procedure. One of the patients in the Canadian study died from complications. For this reason, it has not become a standard of care for people with MS. However, the therapeutic benefits seen in the trial are almost impossible to deny, and the results illuminate where new science could change lives. My lab has tried to take the specificity of antibodies to create an approach to transplantation that reduces the “collateral damage” seen with current methods. We have shown that it is extraordinarily effective with little toxicity in animals. We tested it in animals with sickle cell anemia. If we could reproduce the same results in humans with that disease, it could dramatically change the outlook for those who have that disease. We also have developed a method for rapidly getting stem cells from the bone marrow into the blood, where they can be collected in the blood bank. That could make being a stem cell donor much simpler and, we think, safer. It also yields stem cells that seem to be overachievers. These highly effective stem cells would be ideal for doing gene therapy or gene-editing manipulations. My lab could never scale these up to test and develop them as medicines. We are a discovery shop. To do so, we have had to team with inspired venture capitalists to create a company, Magenta Therapeutics, that is rapidly moving these forward toward clinical testing. One of my greatest joys is that it is doing so under the leadership of a former postdoctoral fellow from my lab, Jason Gardner. Jason and I worked together over twenty years ago and I have long admired his passionate commitment and energetic approach to move things forward for patients. Importantly, he also gives complete confidence in his moral instincts. He has created a company culture that reflects values we share, focus on patients, partners with doctors taking care of them, and builds platforms of excellent science that are a foundation for therapies. Together we hope Magenta will transform stem cell transplant to make it so safe, so well tolerated that the oil change concept may become a reality, and the use of gene therapy for blood disorders will become commonplace.
Having lab work move from discovery to application is the dream for virtually all the scientists with whom I work. I have the good fortune of other recent work moving in that direction. It involves a lengthy project in which we decided to test whether our understanding of normal stem cell biology could give us novel insight into cancer. One of the young geniuses who came to train in my lab came up with the method to do just that. David Sykes is a physician-scientist in the group who reasoned that leukemic cells likely fail to shut off genes that must turn off for a stem cell to move through the steps of maturation necessary to make a functioning blood cell. He found such a gene and created a system that allowed us to test hundreds of thousands of chemicals to find any that might overcome the blockade in differentiation that cancer imposes. He found just a handful and then discovered that most of them targeted the same unexpected enzyme (an enzyme is a protein that modifies its neighbors and so is usually involved in turning things on or off in cells). That enzyme is one previously targeted by a drug company for other indications. It was safe but wasn’t active as tested so it was abandoned. We wanted to resurrect it so we could quickly get it to people to see if we could improve their leukemia. We had strong motivation because a rare subset of myeloid leukemias (AML), in which drugs could be used to overcome a differentiation blockade, had shown remarkable results. This type of leukemia (acute promyelocytic leukemia) was the worst form to get and I recall taking care of patients who died miserable deaths from this rapidly lethal disease when I was in training. It didn’t respond to standard cancer drugs that are basically cell poisons. When drugs were found that induced differentiation (one was an acne drug), it flipped the situation entirely and now 98 percent of patients are cured without ever receiving a standard cancer chemotherapy drug. We wanted to do the same for the rest of the leukemias and thought we might have identified a drug that could do it. Safe enough for acne, strong enough for leukemia was our goal.
When doing research, partners are needed because the path is long and the resources needed are enormous. We eventually teamed up with colleagues at the Broad Institute and with Bayer Pharmaceuticals. We had all agreed that our greatest goal was to find something that could help people with leukemia. We soon learned that meant different things to different parties. If we took the old drug and revitalized it, it would be faster to patients, but less lucrative since the patent was expired. David and I were confident that we could get the drug, and we did all we could to convince our partners that we could do this together and find a creative business model so that all could be rewarded. We just did not think it right to waste time waiting for new, previously untested drugs when we could re-employ an old, well-understood and well-tolerated one. People would die in the interim. For over eighteen months, we repeatedly made our case and were met with silence or worse, even by our academic colleagues. We parted ways. Patients first, as long as money really came first, was not the way we wanted to live. Fortunately, we found some inspired funders and a passionate CEO and are making the drug and finalizing the clinical study as I write. Also, the paper announcing our findings also inspired four other companies to move forward and we hope that at least one will find the right medicine to flip the outcome for patients with leukemia. That is the dream and all that went into it will fade away if it can be realized. If so, we hope it will pave the way for thinking about other cancers in similar ways: as rogues that have gotten stuck in development. Rather than bludgeoning them to death, maybe we can find drugs that encourage their arrested development, allowing them to mature to the point where they no longer invade and destroy, but quietly reside as good neighbors.
As of 2017, it seems clear that we are advancing cell biology at a pace that will dramatically improve our approaches to malignancies and diseases that have long defied science and medicine. The changes are happening now. There were twenty-five new drugs in 2015 in my field and twenty this year. I have finally hung up my stethoscope because of it. I seemed to always be catching up on new medicines to simply keep up. The residents and medical students I taught needed to know vast amounts of information on these emerging therapies and when I was on call, I spent hour upon hour poring over journals to make sure I was ready to handle any emergency that might arise. I always knew I had the backup of superb physicians at the MGH. One, David Kuter, who is head of hematology at Mass General, was always available to discuss particularly gnarly cases with me. (I would find is reassuring, were I a patient, to know that doctors do this.) But, I felt a little like the ballplayer who has reached the end of his athletic career and has begun to fear that he’s not carrying his weight for the team. I called Kuter and said, “I need to talk to you about stepping away from the clinic.” He answered, “What took so long?” He knew before I did—or at least before I could accept the fact that I might not be a clinical doctor.
The decision wasn’t easy. The greatest rewards in my professional life have involved caring for patients who, every day, reminded me of what truly matters in life. But I didn’t want to put patients at risk for selfish reasons. I dropped clinical care, but will never drop being a doctor at heart. I am now a lab director, a department chair, an institute coleader, and a professor. I have to be a manager of diverse teams, but the skills of clinical medicine transfer well.
An attentive bedside manner, which includes confidence and optimism, is essential if I’m to give young scientists the support as well as the structure they require. The same is true for the financial partners that make science possible. Governments and big pharmaceutical firms supply much of the funding to keep America’s labs running. However, every year private philanthropies, some of which are managed by individuals and families, also donate tens of billions of dollars to medical science. Many of our consistent donors have personal experiences with cancer, diabetes, and other diseases and they give in order to help spare future generations. Others, who have larger sums to give, are looking for a big breakthrough to give them the sense that they have done something substantial, for all of humanity, with their fortunes.
Partnering with individuals of such means can be extremely exciting. No one accumulates an immense fortune without possessing real intelligence, and some of these philanthropists can ask extremely challenging and interesting questions. People want to have some confidence that their investment, even if it’s a charitable donation, has some chance of yielding a big return like, say, a new drug or a durable discovery. Some will even shop around for just the right institute or individual, as if they are studying the racing form to pick the winning thoroughbred. Meeting with these folks is not for the faint of heart, but just as we evaluate research proposals to find the ones with the best promise, philanthropists must get answers to their questions before they choose between a seemingly endless number of worthy proposals. The Harvard name (you could even call it a brand) might get us in the door, but no one will write a check on the basis of that alone. With this in mind, I worked to develop my ability to make the science understandable and discovered I enjoy it.
I have also come to enjoy even the difficult aspects of managing scientists, which often means helping brilliant young people stay on track in the face of technical and personal challenges. Everyone who comes to our labs is hoping, in the end, to develop medicines that cure. The best people for this work are fiercely independent and feel a powerful drive to achieve. The problem is that fiercely independent people sometimes struggle to take advice, even when it’s in their best interest. In one recent case I spent a year counseling a truly brilliant person who cannot see he has reached a scientific dead end. In every conversation my advice has been met with a proposal to test one more compound, and then another. The trouble is that each test can take months to complete. Before you know it, a gifted mind has wasted a year chasing a chemical ghost. My task in these situations, which arise quite often, is to serve as mentor, parent, boss, and coach. In this instance a new teammate, added at my suggestion, has helped set the project on a new, Plan B course. In the process the original scientist is developing a bit more emotional intelligence.
This may be the moment to note that even with all the technical resources at our disposal, from instruments to artificial intelligence, science still needs the human touch. The best example may be in the hard-to-quantify but nevertheless significant force of intuition. What most of us experience as hunches can turn out to be signals from the brain, which is observing developments and making connections at a rate faster than we can comprehend. That nagging feeling about a hypothesis or an experiment can be an emotional prod, deployed by the subconscious. Studies of the brain done with FMRI (functional magnetic resonance imaging) machines have located parts of the brain that fire when intuition is sparked. The best theories suggest that the feelings produced in these moments of inspiration represent the brain’s effort to snap the conscious mind to attention to something that engages its computing capacity at its highest levels. This process was understood by Albert Einstein to represent the “leap in consciousness” that is more valuable to the process of discovery than the intellect.
Although it’s not medicine, modern biology is a passionate pursuit that engages as much of you as you can give and requires an expansive and generous style. The idea of the isolated scientist alone with his or her thoughts and experiments has been eclipsed by the model demonstrated to me decades ago by Adel Mahmoud, who was as good with people as he was with ideas. I see this quality in many of the younger scientists affiliated with the stem cell institute. In addition to their scientific brilliance they are resilient and effective at leading team talents. However, there is plenty of room for improvement. Some of our young scientists have to be drawn out, encouraged to think big, and prodded along the path. Others must be mentored in the art of letting go. We have to kill projects, which is fine because there’s value in checking off the answer to any question, even if it’s disappointing.
Fortunately, there is always the next idea. And in time you will see your work added to others to create a better and longer life for many. This is the result I hoped to realize when I first recognized the power of blood and bone. It seems to be coming faster every day.