The development of developmental biology
How is it that every human cell contains the blueprint for an entire person? That a single cell, repeatedly dividing and differentiating into trillions, can create the complex organic system that is a human life? Describing the journey of scientific discovery into how that process unfolds, driven by a six-foot-long strand of DNA that is replicated and packed into every cell, is the subject of From One Cell: A Journey into Life’s Origins and the Future of Medicine, by Ben Stanger, M.D.-Ph.D. ’97. As the title suggests, understanding this developmental biology has led to remarkable advances in basic biomedical science and therapies, and (in all likelihood) will lead to certain forms of regenerative medicine in the future.
As Stanger explains, every animal on Earth starts its life as a single cell, a fertilized egg called a zygote. But since every cell contains an identical set of instructions—genes written in the language of DNA—what determines a cell’s fate? How do some cells become heart, others lung, liver, or brain? This question, which he calls “the one cell problem,” has driven the study of embryonic development, led to the discovery of stem cells, and revealed that the same processes that govern growth in organisms can drive disease when they go astray.
Telling stories of the scientists who made key discoveries, stretching back to Aristotle (here, too, the Greeks were two millennia ahead of their time), Stanger guides readers through complex topics like morphogenesis, differentiation, and transcription. It’s a remarkably effective approach. In brief biographies, sometimes described in little more than a page or two, he deftly conveys how confusion gave way to glimmers of understanding, and the chance events that led to revolutionary insights. He describes how naturalism, which relied on deduction based on observation (and was the dominant form of scientific inquiry in the nineteenth century), gave way to experimental biology, the basis for modern, laboratory-based science. One of the leaders of this new approach was Wilhelm Roux, a German physician who “believed that observation alone could never provide a satisfying picture of biology.” In 1888, Roux set out to test in his lab the then-leading model of embryonic development, which held that eggs came with all their parts preassigned, with each bit set to develop into a “designated portion of the future animal.”
In telling the story of how a series of experiments eventually disproved this theory, Stanger contrasts Roux—a methodical and skilled scientist, with the story of 22-year-old Hans Driesch, who in 1889, after earning his Ph.D., stopped in Naples, then a burgeoning center for biomedical research, while on a sort of Grand Tour. Although Driesch came to the city for the science, writes Stanger, the young man “took full advantage of his bachelor’s existence, using Naples as a jumping-off point for trips throughout the Mediterranean, northern Africa, and Asia”—and ended up staying for a decade. Roux, on the other hand, writes Stanger, “had little appetite for the pleasures in which Driesch indulged.” He was “meticulous and adroit at the bench, focused on every detail.” “If the scientific question called for it, Roux eagerly built a new device or invented a new technique. And when it came to performing experiments, Roux’s ability to carry out the most delicate operation was unparalleled….” Driesch, on the other hand, was “clumsy” and “lacked patience and dexterity,” which led him to seek shortcuts. This led Driesch to work with sea urchin eggs for his experiments—principally because they were less likely to die during investigations than the delicate frog eggs Roux favored. By chance, this enabled Driesch to discover something that Roux’s experiment could not.
Both scientists were trying to test the same theory: that the instructions for building an organism were dispersed in a cell, and as it divided to produce daughter cells, only the relevant portion of the developmental instructions for what it should become (what we now know as DNA) would be passed on. On its face, the idea seemed reasonable for explaining why cells developed into different organs and body parts. But was it correct?
Roux reasoned that if it were, then killing one of the two daughter cells derived from the first division of the fertilized egg would lead to a partially formed embryo. He used a needle to dispatch one of the cells, and then watched what happened through a microscope. The remaining cell behaved as predicted, forming only a half embryo. When he performed the same experiment after a second division, killing one of four cells, the remaining three formed three-quarters of an embryo. These results seemed to confirm the theory.
Driesch pursued the same experiment, but with a slightly different protocol. He’d learned from colleagues that with sea urchin eggs he could separate the daughter cells, called blastomeres, simply by shaking them, rather than painstakingly killing one with a thin needle. Having isolated the cells by shaking them apart, he then placed them in petri dishes with fresh seawater, and watched what happened. In Stanger’s telling, Driesch left the dishes overnight, and was astonished the next morning to see complete sea urchin embryos, developing normally, as though nothing had happened: each cell carried the complete instructions for creating a whole organism. But why, then, did Roux’s carefully executed experiment fail?
As Stanger explains, although the cells in Roux’s experiment had been killed, they “were still capable of sending messages from beyond the grave.” The chemical signals that direct early development had persisted even after the cell itself died. “And the message those cells delivered was: ‘I am still here!’ The survivors of Roux’s interventions, believing their siblings still present, and deferring to the signal from their phantom other halves, curtailed their own development to form hemi-embryos instead of complete ones.” Driesch himself never arrived at a satisfactory explanation for his discovery, and within a decade, had abandoned biology for “philosophy, parapsychology, and psychic research.”
The first half of From One Cell is replete with fascinating stories like these. Often, the discoveries of one scientist led to insights a generation or more later. The false starts, the dead ends, the lags of decades—even centuries—that separate one discovery from the next make compelling reading. Stanger’s deft renderings of the unlikely protagonists, their ideas often rejected, denied, or ignored at first, make the underlying science accessible. The reader’s vicarious experience of these early scientists’ confusion, whether followed by gradual understanding or sudden revelation, works well as a vehicle for explaining the intricacies of modern biomedical science to a general audience.
Stanger has also had a front-row seat to much of the contemporary drama in biomedical research. Now Wise professor of cancer research and professor of medicine and cell and developmental biology at the University of Pennsylvania, he was a postdoctoral fellow in the lab of Harvard stem cell scientist Douglas Melton from 2000 to 2006, a period when politics and ethical considerations made working with human embryonic stem cells a fraught subject.
But he doesn’t dwell on these extra-scientific controversies, focusing instead on how scientific understanding of the “one cell problem” has advanced. Many of those involved have Harvard connections: Robert “Bob” Briggs, Ph.D. ’38, who performed the first nuclear transplantation from one cell to another; Cabot research professor of the natural sciences Matthew Meselson, who played a key role in confirming the existence of messenger RNA—the instructions that tell a cell’s ribosome how to make proteins; Leder professor of genetics Cliff Tabin, who described how external physical tension exerted on cells plays a role in the formation of villi in the intestine; Mario Capecchi, Ph.D. ’67, JF ’68, who created the world’s first knockout mouse, in which a gene is inactivated, or “knocked out” through genetic modification; and Loeb research professor of chemistry and chemical biology Stuart Schreiber, who co-discovered a key epigenetic mechanism (one that passes information about which genes should be turned on and off from one generation to the next) that extends to mammalian cells.
Taken together, the earlier work and the contemporary science described in From One Cell show that there is rarely a straight line to new knowledge—and that large gaps in human understanding remain. For instance, in animals like salamanders, which can regrow limbs after injury, what controls size? Researchers who have transplanted limb buds from a large salamander to a small one, and vice versa, have found that the limbs regenerate with the proportions of the animal from which they came. Other mysteries surround embryonic stem cells. Why, when injected into an early-stage embryo, do they behave normally, but form a tumor when “injected into the flank of an animal”? And why do some cells become cancerous, taking on stem-cell-like capabilities of rapid growth and the ability to migrate (metastasize) to other parts of the body? Much is understood about the environmental factors that can lead to mutations—damage caused by smoke or ultraviolet light, for example—but what makes some cells and not others vulnerable to these insults? Stanger refers to these open questions as “black boxes”: the intriguing, unsolved problems in developmental biology.
Looking to the future, Stanger sees great promise in cell-based therapies, but also suggests the likely limits of what is possible given human biology. For example, the longstanding practice of treating patients with otherwise fatal blood diseases by transplanting healthy stem cells that can reconstitute the blood system (commonly known as a bone marrow transplant, in reference to the origin of the stem cells) could potentially be extended to the treatment of other biological systems, including organs that don’t normally retain stem cells into adulthood. Alternatively, it may be possible, for example, to grow human organs within closely related primate species for transplant into patients—although creating such chimeric animals that are part human does raise ethical issues.
But regrowing limbs, the way salamanders do? That may prove unworkable. Stanger explains that the cells of creatures that can perform such feats of regeneration have a special capacity that is not present in adult human cells: positional awareness. In order to know where to grow, and how much, and what to create, the stem cells involved must be oriented to where exactly in the body they are. Fully-formed human cells have no such map. The kind of human compensatory regeneration that is possible—regrowth of a damaged liver, for example—is qualitatively different.
Why read a book about developmental biology? Stanger makes the case for biological literacy in his closing pages. In a world where it is possible to edit the genes of an unborn child (the first scientist to do so was jailed), a primer is almost a prerequisite for considering the ethics of how such technologies should be used. “The pace of discovery regarding epigenetic regulation and gene editing is moving too fast for even its practitioners to keep up,” he notes, “leaving society at large with few opportunities to weigh the pros and cons.” The problem is not unique to biology. Robert Oppenheimer, speaking to a group of editors and journalists, made the same point about science generally in 1958. Since then, “The challenge of absorbing and sharing science,” Stanger says, “has only gotten worse….”
Whether the real decline in basic-science funding since 1999 is connected to this widening gap, the history of discovery recounted in From One Cell has implications for how science is funded. “The biggest discoveries,” he writes, “ones that changed the course of biology and are in the process of transforming medicine—have been those with no intended application.” Mostly they have been carried out by individuals at “the very beginning of their careers, scientists who are not yet swayed by the assumptions, preconceptions, and presumed limitations that pervade every field”—nor by the directed, “big science” projects that absorb an ever-larger share of research support. “By its very nature, knowledge with the greatest impact begins with a detour…a meandering that defies predictability.”
Managing Editor Jonathan Shaw began writing about stem cell science in 2001 during the controversy over the use of discarded human blastocysts in biomedical research.