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.
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