Cancerland
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Engineered mice can be used to define how a gene might affect the response to particular challenges like infection or injury or even how drugs are metabolized. There continue to be new ways to use genetic modification to understand genes and their impact on disease, and they all depend on the original definition of mouse embryonic stem cells by Martin Evans. Those stem cells could be grown indefinitely and can be genetically modified. They are then injected into a newly formed ball of cells that will become the mouse embryo and eventually become mice capable of breeding and growing whole colonies of these highly valuable models for understanding and treating human disease.
What Evans enabled was undeniably good. What he also spawned was an effort to find whether embryonic stem cells could also be made from humans and that was laden with more controversy. For scientists, it would be a landmark achievement and open the possibility that embryonic stem cells might be able to produce human tissues in a petri dish—making their study possible. For others, it raised the issue that embryos were somehow being manipulated and destroyed for research—many mistakenly equated it with abortion. Embryonic stem cells were eventually made from humans using the discarded material from in vitro fertilization (IVF) clinics or, in some early experiments, material from an abortion. Generation of human embryonic stem cells after those first efforts was always from IVF; abortion was not involved. Certainly legitimate ethical debate was warranted around whether IVF material represented life, but it could not be regarded as the same as abortion: the IVF material was a collection of a few hundred cells that were not in the womb and could not survive without being so.
Although embryonic stem cells do not require material from abortions, other research does. For example, the immune-deficient mice that could allow human blood stem cells to make human blood cells do not make T cells. That requires human thymus tissue. By implanting thymus and blood stem cells from aborted material, mouse models of human immunity were made much more useful. That has allowed vaccine studies and work on HIV vaccines in particular to move forward. The area is controversial, to be sure, and qualms even among researchers are common. However, the reality is that the material would be incinerated. Using it in research at least offers some positive purpose. To me, that respects the dignity and sanctity of human life. Opponents of such research argue that fetal cell donation somehow encourages women to end pregnancies that would otherwise go to term. In fact, the decision to donate tissue is always made after someone has chosen abortion. Critics also raise a religious argument revolving around the belief that conception creates a supernatural soul that merits extraordinary protections. This idea is guided and validated by one’s religious faith and so is not subject to debate. I personally do share reverence for the seemingly miraculous series of events that lead a single fertilized egg cell to become the complex, thinking organism that is us. Nothing is more awe-inspiring. Even when “lower” organisms are studied in the lab, the sense of reverence is there, for no matter how much we learn about the processes involved, exactly how cells know when to start or when to stop their actions, it is still profound.
For much of the world, the first hint that we might be able to unlock the secrets of life and perhaps even intervene arose when doctors began to treat infertility. As artificial insemination became a treatment for infertile couples in the twentieth century, social critics imagined a host of possible problems. Most alarming to social critics was the notion that one day egg and sperm could be united outside the body—in vitro fertilization—and then implanted in the womb. Aldous Huxley made “test tube” babies part of his dystopian view of the future in his novel Brave New World, and this writing contributed to moral objections to any effort that seemed like interference in procreation. By 1969 a Harris poll determined that a majority of Americans believed IVF was “against God’s will.”
As many religious and political leaders took stands against IVF, scientific progress was slowed but not halted. At the University of Cambridge, a gynecologist named Patrick Steptoe and a scientist named Robert Edwards were determined to discover, as Edwards would say, whether reproduction would be controlled by “God Himself” or “scientists in the laboratory.”
They got their answer when the first IVF baby was born in England in 1978. A Harris poll done months later found a change of heart across America. Sixty percent of respondents said in vitro fertilization should be legal and half said they would opt for it if they needed it. Today more than 60,000 babies per year are born in the U.S. with the help of IVF and, Huxley notwithstanding, no social crisis has arisen.
Because it was aimed at a specific, narrowly-defined medical challenge, IVF research could be understood as a project with real-life benefits. A healthy baby in the arms of a loving mother or father settles things for most people. Far more difficult to resolve were the questions arising from research on fetal cells collected after abortion procedures and embryonic stem cells derived from fertilized eggs not used by couples involved in IVF. Because the science was linked to abortion it was caught up in the highly-charged debate over the morality of terminating pregnancy. The disruptive protests and occasional violent practices by abortion opponents, who had bombed clinics and killed doctors, were enough to give anyone pause when it came to taking a public stand on embryonic and fetal stem cell research. (Those who actually did this work were careful about security.) A great many doctors and scientists did trek to Washington to testify in favor of continued federal spending on this science and Harvard University took the unusual step of advocating for it as an institution. A panel of medical, religious, scientific, and ethics experts convened by the Reagan administration took the same position in an 18–3 vote. On the other side of the issue stood those who argued on the basis of religious faith and morality. I couldn’t have disagreed more with those who acted on their feelings of awe by trying to ban the use of discarded embryos and fetal tissues in scientific research. In world where sick and injured people endure suffering and loss daily, we have a responsibility to learn all we can about the way we are created, develop, and function so that we can ease at least some of the pain. This is where protecting human dignity lies.
In the 1980s, even more than today, the federal government was the most important funder of the kind of basic science—like Arthur Barclay’s collection of plant samples in the Pacific Northwest—that can seem only vaguely related to something as concrete as a specific drug to treat disease. President Reagan stopped short of seeking an outright ban on all fetal and embryonic stem cell investigations. But he and his successor George H. W. Bush, who were both committed to ending abortion rights, did withhold federal funds from this research. When Congress voted to override the executive ban, which was a sign of how contentious the issue was, Bush used his presidential veto to maintain it.
Scientists who continued their stem cell projects did so with other funds and were careful to use separate facilities and equipment. I still have equipment in my lab bearing the green stickers signifying private funding sources that did not restrict use of the equipment. These awkward arrangements and diminished resources slowed progress. Partisan politics being what it is, Bush’s defeat by Bill Clinton brought a change in 1995. This opening was soon closed by a congressional ban authored by two members of Congress from the Bible Belt, Roger Wicker of Mississippi and Jay W. Dickey Jr. of Arkansas. They attached it as an amendment to an act of Congress that President Clinton felt he needed to sign and thus became law. Also known as the National Rifle Association’s lead supporter in Congress, Dickey’s other main accomplishment prior to entering his new career as a lobbyist was a ban on federal research on gun violence. (After the 2012 mass shooting in Aurora, Colorado, one of fourteen such tragedies that year, Dickey would confess he regretted his work to limit research on gun violence.)
Fortunately, my own work with stem cells was focused not on those derived from fetal or embryonic tissue but on the superstars of the immune system: bone marrow stem cells. As everyone working in this field knew, the valuable stem cel
ls that could produce infection fighters were extremely difficult to identify and isolate from all the material aspirated from a bone marrow donor. At best, conventional techniques produced concentrations of 20 percent stem cells. In my lab, we developed a method that yielded a 75 percent concentration. We did this by taking advantage of the way the immune system worked.
In nature, the body holds its most potent bone marrow stem cells in reserve while others are activated to produce defender cells to fight pathogens and cancers. We used a chemical that would be toxic to those activated ones but not to the cells reserved in the marrow. This last-man-standing approach meant that we could harvest a bounty of the most valuable stem cells, and do so with such high enrichment that we could characterize the molecular features of the cells. We did this with human cells at a time before the mouse models allowing human cell engraftment were fully developed. Instead, we collaborated with a colleague in Nevada who had realized that if cells could be put into an animal before that animal developed immunity, then as the immune system developed, it would fail to recognize the donor’s cells as foreign. The animal would be tolerant of the donor’s cells just as it would its own cells. The trick was to get donor cells into an animal before the first vestiges of its immune system become active. My colleague, Esmail Zanjani, worked with sheep and showed he could use ultrasound-guided injection of the pregnant ewe to successfully implant human cells that would then give rise to human blood as the animal developed. He injected the human cells we had isolated and mature human blood cells of multiple types were present in the lambs after birth. The results demonstrated that we had bona fide human stem cells. The method never took off, perhaps because we published in Science before we had the sheep data, but perhaps also because it did not work in the prevailing model of the day, the mouse. Mice were enthusiastically embraced as the key model as the engineering methods I mentioned were really blossoming. We worked on human cells, which few people did then, and no easy model was available. The mouse has much more activity in its stem cells and so would lose stem cells to the toxin in our activation selection method. No mouse stem cells could survive. The mouse does not always mimic the human and when it doesn’t skepticism emerges. I learned an important lesson and switched almost exclusively to mouse models. We validate in human cells when we can, but I learned that the difficulty of human cell research ran deep.
Working with mice often seems odd when your goal is helping people. Indeed, many things learned in the mouse have not panned out when finally tested in people. But some do and we were lucky enough to be involved in one such experience. We searched for a way to obtain bone marrow cells from blood, to spare patients, donors, and, yes, caregivers from the difficult job of withdrawing them by piercing bone. How did we do this? Well, previous research had established that the body produces “come-to-me” signals that tell cells where they should live. For bone marrow stem cells with a receptor called CXCR4, these signals provided the homing beacon that held them in place inside bones. When we gave mice a chemical that turned off the beacon, the stem cells migrated to the blood. If true in people, it meant that targeting a specific chemical mediator of stem cell location could result in harvesting stem cells from the blood without all the effort, expense, and trauma of going to the operating room.
Today the basic method of moving stem cells from the bone marrow to the blood is used by most bone marrow transplant centers, which takes almost all the pain out of the harvesting procedure. It involves an older medicine, the cytokine G-CSF, and a method to target the molecule we had worked on. But as luck would have it, the company that made the compound we used to prove our science didn’t move forward to commercialize it. This is common in corporate medicine, where executives must make bets on future products without being certain of the odds. Another company wound up producing a different agent used for the procedure. It was an agent they had already tested in humans for another purpose (ironically, AIDS). They quickly showed it too moved stem cells into the blood. While the business windfall went elsewhere, we had the reward of knowing we had added something to the science that provided benefit to patients.
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Big scientific endeavors can seem amorphous and are therefore vulnerable to misunderstanding. The $3 billion Human Genome Project (HGP), which was launched in 1989 by the National Institutes of Health, was typical. Some proponents stressed how it would yield progress against specific diseases, like Alzheimer’s, cystic fibrosis, and cancer, which would make it relevant to every person on earth. However, this suggestion risked raising expectations too high. A more realistic view would note that genomic research would aid the overall science of molecular biology and perhaps associate specific genes with diseases. This would be painstaking work, and therapies based on it would lie many years—if not decades—in the future.
The genome sought by the HGP team would not be a complete and exact blueprint for a species. They were hoping to collect something more like a raw listing of the set of gene pairs stored in the nucleus of a cell. The pairs are made up of the nucleic acids adenine and thymine or cytosine and guanine. These AT or CG combinations instruct the development and activities of cells, organs, and—ultimately—human individuals. They are found inside the nuclei of cells in the twisted-ladder structure that James Watson and Francis Crick dubbed the double helix. Human nuclei contain 3.1 billion base pairs. Were they to be untangled and stretched out, the DNA from a single cell would produce a six-foot-long string.
The term genome was coined in 1920, and the first complete identification of a simple one, for a virus, was accomplished in 1976. The federal Human Genome Project became possible with the development of machines—DNA sequencers—that automated a labor-intensive process. However, the early sequencers were expensive—$200,000 in 2017 dollars—and would only report a string of six hundred base pairs with each run. These strings were similar to the list of words in a dictionary. And just as a page in a dictionary doesn’t provide you with the sentences and paragraphs to make a story, a piece of a genome cannot tell you how, for example, something as specialized as a liver cell or a skin cell is created or performs its functions.
The government-backed genome project progressed slowly until it got a jolt from a competing team headed by scientist and entrepreneur Craig Venter. In 1998, Venter announced that his group, working at a new company called Celera, would use a new generation of sequencing machines and the data being generated by the HGP scientists to race ahead of them. His commercial goals included the patenting of genes and the production of a genome that could be sold to researchers at companies, universities, and institutes. Venter was extremely flamboyant, as scientists go. He sailed a big yacht that flew a ballooning spinnaker sail that featured a picture of himself in a wizard’s hat. At one public event where he was set to speak, he walked onstage accompanied by sequined Broadway dancers.
Venter was so brash that he proposed to reach his goal while spending a fraction of what the taxpayers were investing in the Human Genome Project, and this made politicians in Washington impatient with the government’s effort. His backing from corporate funders also raised concerns about how the results of his research might be used. Who would receive the benefits if the genome, or parts of it, could be patented with an eye toward profit? Would therapies derived from this science be so expensive that only the very rich could receive them? Shouldn’t the general public expect to share in the gains if government research provided the foundational work for Venter’s group? These concerns became more acute when Celera filed preliminary patents on 6,500 gene fragments that its scientists had identified. This move was particularly alarming to politicians in foreign countries where scientists had joined the genome project initiated by the U.S. government. This was a particular interest for British prime minister Tony Blair, who wanted the raw data of the genome to be freely available to all.
Although the iconoclastic Venter might say that a privately backed effort would be more creative, nimble, and driven to succeed, I would argue t
hat only the federal government could have organized and initiated the great genome hunt. It was the biological version of Project Apollo, which the National Aeronautics and Space Administration (NASA) organized to put the first human beings on the surface of the moon. Accomplished in just eight years, Apollo did science, engineering, and manufacturing on a scale that no private group could match. If you are skeptical about this, consider that the first manned private spaceflight, which relied on technology developed under NASA, wouldn’t be made until 2004, which was thirty-five years after the first lunar landing.
Of course, I’m not arguing that the competition Venter’s group provided wasn’t helpful. Scientists are no less ego-driven than anyone else. A few, like John Gurdon, may be so idealistic or self-effacing that they resist attention, but most of us are competitive sorts, and we enjoy getting credit for our work. Prestigious prizes, including the Nobel, are awarded in part to motivate scientists, and very few would decline to attend a reception at the White House or an invitation to provide the keynote speech at a major conference. But most of us understand that in the grand scheme of things, we are minor players and that progress depends on eventually sharing information and research results.
For a brief period, the competition between the genome teams overwhelmed the usual cordiality we expect in science. Venter, whose style departed from the norm, took much of the early blame for this state of affairs, but he had partners in the dance of dysfunction. The HGP’s top leader, Francis Collins, believed he was doing work as important as the Apollo moonshot program and the splitting of the atom. This feeling and a sense of public ownership over the work, by many accounts, led him to resent Venter as an interloper—but he sought to accommodate him. In 2000, the two groups reached an agreement that resulted in a tie at the finish line. In 2001, on February 12—which was Charles Darwin’s birthday—two reports were published with similar data. As often happens, The New York Times broke the news a day early, announcing to the world that the global consortium put together by the government and the Celera Genomic team led by Craig Venter had reached the goal. Their most startling finding was the fact that humans possessed far fewer genes than science suspected. Instead of one hundred thousand or more, the number would eventually be estimated at about nineteen thousand.