Cancerland

by David Scadden

  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 rei
gn. 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 retiremen
t 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.