Fall 2013

The Contrarian

Our old theoretical models in biology are not working so well lately, says Ana Soto. She is determined to find something better.

By Bruce Morgan

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Ana Soto outside the École Normale Supérieure in Paris. Photograph: Antoine Doyen

Ana Soto does not sound like your average biologist. Instead of talking about reagents and catalysts and her recent findings from a series of carefully controlled experiments conducted in a lab, and leaving it there, this Argentine native with the lush dark bangs crooks her head toward the ceiling tiles in her small, cramped office and says things like “What is the self?” and “How do we know what we know?”

This is different. Soto, a professor within the Department of Integrative Physiology and Pathobiology (IPP), cites Kant, Newton, Darwin, Galileo and Einstein in rapid succession, tossing off each name with an easy sense of familiarity, periodically tapping out points of emphasis on her desk and now and then flashing a wide, disarming, altogether unexpected and innocent smile. Her mind, leaping agilely from realm to realm, moves from the microscopic to the celestial and back again, determined to encompass and comprehend it all. She gives the quick impression of someone who is not easily satisfied.

What’s perturbing her the most these days? Soto’s main complaint is that the linear, deterministic computer models that grew out of our cultural fascination with genetic code, beginning with the discovery of the DNA structure in the early 1950s, are no longer serving us well as explainers and predictors of modern biology. This leaves a yawning void. Although those old models may be flawed, no better alternative theoretical model has yet emerged to make sense of things.

“Right now biologists have trouble interpreting the reams of data they are getting,” Soto says, adding this state of affairs represents a “crisis” in mainstream biology.

Her sense of crisis is not widely shared, she readily concedes. Most biologists who encounter discrepancies or unexpected results in their experiments tend to shrug off the anomalies, she says, happy they will all make sense some day in the future. “So much of what’s taken as knowledge in biology is not because there’s a lot of evidence in its favor; it’s just because people think that way,” Soto asserts. She counts herself among “a small world of people who think there is something we need to do urgently to change that.” First and foremost in this camp, she mentions Carlos Sonnenschein, a colleague within IPP who was her postdoctoral mentor and with whom she has worked in partnership over the past 40 years.

Denis Noble, a retired British professor of cardiovascular physiology at the University of Oxford, is another scientist who proposes a change of perspective. In his 2008 book The Music of Life: Biology Beyond Genes, Noble argues for approaching the human organism as a complex system of interactions in which genes play a subservient role. “He tells us that, based on his experience, something is missing in our current explanations,” Soto says.

Scott Gilbert is a third believer. A developmental biologist and professor at Swarthmore College, he has known Soto for the past 15 years and deeply respects the integrity of her thinking. He offers some perspective on Soto’s notion of a crisis in biology. “Her crisis is a different crisis from what most biologists would talk about,” he explains. While other biologists may identify the crisis in their field in limited terms, such as the meager funding they are getting, or the lack of appreciation of their work among members of the general public, “Ana is saying there is a crisis in the science of biology. She has seen things that can’t be explained in the usual manner.”

Soto and her partners are intent on developing a new way of looking at things—a “theory of organisms”—that covers and explains all the biological bases, including the quirks, deviations and anomalies. “We want to know what happens in the biology of an organism from embryonic development to death,” says Soto, who starts by rejecting the simplicity of the current paradigm. “The idea that the genome is the Tree of Life is not true,” she says.

Carlos Sonnenschein and Soto have been colleagues and collaborators for the  past 40 years.

Carlos Sonnenschein and Soto have been colleagues and collaborators for the
past 40 years.

Charles Darwin represents something of an intellectual model for Soto in the way that his theory of evolution, once found, explained so much of what had formerly been scattered and incomprehensible. Gilbert uses the example of a human arm compared with a bird’s wing. “You could say the arm of a human is like the wing of a bird,” he suggests. “But now, if you have evolutionary theory, it makes perfect sense. Darwin didn’t change the data, but his theory gave the data new meaning. That’s what Ana is looking for.”

Luckily, the Tufts biologist has been given some time to explore a few of these questions. Soto has been selected as one of four Blaise Pascal Chairs at the École Normale Supérieure in Paris, beginning this fall. She will be in residence on a part-time basis over the next two years, commuting back and forth to Boston and maintaining her full teaching and research life at Tufts for the duration of her honorary designation.

She will be working in partnership with Sonnenschein; Giuseppe Longo, a mathematics professor at the École and an adjunct professor at Tufts; plus a selection of other scholars from Paris and Toulouse. In her role as Pascal Chair, Soto will be hosting seminars of invited guests, conducting research and giving frequent talks of her own.

Since its inception, in 1996, the Pascal Chair has been occupied by an array of distinguished thinkers divided between the sciences and the humanities. Previous laureates include a smattering of Nobel Prize winners. Last year’s occupant of the biology chair, Elizabeth Blackburn, was a recipient of the 2009 Nobel Prize in Physiology or Medicine.

The École itself, while perhaps little known among members of the general public, dates from the 1790s, when it was created in the hopeful aftermath of the French Revolution, and is generally ranked among the most elite institutions of higher learning in the world. Its compact main home is a small, leafy enclave wedged in next to the Sorbonne on the Left Bank, right at the heart of French intellectualism.

Pascal, for whom the chair is named, was one of the intellectual giants of 17th-century France. A scientist, mathematician and philosopher, he was born in a French provincial town. His father, who educated him at home, forbade Pascal to study mathematics, fearing this would distract him from the classics. One day Dad discovered his son scratching triangular shapes on the floor of his room; Pascal had deduced basic principles of geometry through his own reasoning power. As a teenager, the boy built a wooden calculating device to help his father, a tax collector, on his daily rounds that today is considered one of the first computers. The year was approximately 1650.

In later life Pascal got interested in philosophy and began jotting down his thoughts for a volume of observations that eventually became his Pensées. In a random sample (“All men’s miseries derive from not being able to sit in a quiet room alone”), you can detect the Gallic shrug, still much in evidence in cafes, classrooms and public squares throughout France.

Pascal’s native land has been enchanting people for a long time now. Besotted writers, brainy artists and philosophers have been going to Paris forever, each determined in his or her own way to redraw the map of human perception. What are the chances that Soto will succeed in her quest? “She’s picked a grand goal, to revolutionize biology,” Swarthmore’s Gilbert answers slowly. “If she can pull it off, well . . .” His voice bears a mix of skepticism and wonder.

The Big Picture

Ana Soto grew up in a middle-class family on the outskirts of Buenos Aires, Argentina. She earned an M.D. at the University of Buenos Aires in 1970 and practiced briefly as an emergency room physician before migrating to Tufts Medical School as a cancer researcher in 1973. Medical practice didn’t quite ring her chime. “I could be a doctor, but I’m interested in ideas, so I became an academic,” she says matter-of-factly. Despite her considerable prominence as a biologist, Soto never pursued an advanced degree in the field.

Her personal interests have led her in many directions, including the research sectors of developmental biology, oncology, physiology and toxicology. (“That’s an unusual combination,” Gilbert points out.) A glance at Soto’s CV leaves the impression of a restless seeker who’s traveled far and wide to absorb, distill and dispense ideas. In recent decades she has been a visiting professor in Spain, Norway, France and the United Kingdom, often repeatedly and at different schools within the same country. She clearly likes to get around.

Ana Soto may be going to Paris, but it’s not to sip wine in a fashionable cafe or watch boats glide along the Seine at dusk. She is going there to turn the world of biology upside down.

If anything, all this global exposure has reinforced a central, ever-more-fixed conviction of Soto’s—that the computer modeling still so much in vogue does not work as well as it should in biology. “The problem with the computer is that it’s totally deterministic,” she begins. “If DNA works like a computer, the way we used to believe back in 1960, information will go down to RNA and proteins with extreme precision—one gene, one mRNA, one protein—all determined with total certainty. But mRNA is edited, and thus a piece of DNA, say a gene, does not correspond to a unique RNA. Due to splicing, one gene could be transcribed into several mRNAs. ”

There’s instability there. Soto points out that philosophers were the first to notice just how the deterministic models in biology were flawed.

The public at large has certainly not gotten the news. Gilbert observes that people seem to love the idea of a biological determinism built into our DNA and driving us forward on our respective personal paths. “We have really latched on to the concept that the genes are what define you,” he says. Gilbert cites examples from a series of American automotive ad campaigns that he says he has shown his college classes to illustrate the premise.

A recent ad for a more compact version of the Hummer carries the tagline “Same DNA, smaller chromosomes” (which means nothing biologically, Gilbert notes) to indicate the vehicle contains the same essence as the larger version, just in a tidier package. Another ad, for the Jeep Compass, highlights the virtue of the vehicle by saying simply, “It’s in the genes.” A third ad, this time for the Kia Sportage, claims that the newest version of the compact SUV has been “genetically modified.” The message is so prevalent in our culture that we scarcely notice it any more.

Both Soto and Gilbert observe that recent findings of unpredictability in genetic development tend to support their outsider’s questioning attitude. Soto cites “bursts of gene expression” that indicate deviation from a straight-line model. “We are finding that environment can direct gene expression,” Gilbert elaborates. “In many cases, bacteria are telling the genes of our body what to do.”

Emerging research in this area, including the U.S. government’s $173 million Human Microbiome Project, hints at the sheer complexity of these interactions, where the collective genes of the microbiome are said to outnumber human genes by more than a hundred to one.

“We’ve use the old model for 50 years now, but if the old model is not working, well, you have to drop it,” Soto remarks, her dark eyes flashing. “We can continue crunching the numbers, but this will not translate into a better understanding of biological organization. It’s not technology that’s going to solve the problem. It’s going to require our thinking in a different way.” Over the past decade, she says, there has been a growing recognition of this need.

The crux of the problem is complexity. How do you handle complexity within a field like biology as the old, simple models seemingly lose their relevance? “These models have served us well, but not on every scale,” says Soto. In physics, which she cites in counterpoint, there are several theories applied to phenomena occurring at different scales. Physicists aim at unifying these theories, not reducing them to a single iteration. “Every electron is identical,” Soto remarks.

Physics has an advantage that way. In biology, Soto says, the presumptions shift. Every cell division results in two (slightly) different cells. “In biology, variation is central,” is how Soto puts it. In their experiments, biologists are removing variables “that are inherent to biology,” she continues. “But in the big picture, this is not a problem of experiments. This is a problem of ideas.”

Outliers and Pioneers

You’ve got to admire anyone who stands apart from the mainstream, holds fast to certain principles and moves on from there. Soto has a long history of being iconoclastic in her scientific work, proceeding to the theoretical plane only after reviewing the evidence in front of her eyes.

A prime example would be the findings outlined in her 1999 book The Society of Cells, coauthored with Sonnenschein, in which the authors proposed a bold new theory of cancer. “The somatic mutation theory of carcinogenesis has been the dominant force driving cancer research during the 20th century,” Soto begins in describing her research interests on her current CV. “This theory places carcinogenesis at the cellular and subcellular hierarchical levels of biological complexity. Its basic premises are: (1) cancer is a defect of the control of cell proliferation and (2) the default state of metazoan cells is quiescence.”

In the next line Soto takes a swing of her bat and drives the ball deep into left field. “Those two premises,” she writes, “are contradicted by evidence.” In their book, after examining all the evidence, Sonnenschein and Soto proposed a new theory of carcinogenesis. “We got persuaded,” Soto tells me in her office, “that cancer is a problem of tissues, not of individual cells.”

Most biologists who encounter  discrepancies in their experiments tend to shrug off the anomalies, Soto says, happy they will all make sense some day in the future.

Gilbert helps explain how the pair proceeded. “Ana and Carlos start by saying there are three or four things we are assuming in the way we approach cancer, and then showing how those assumptions are wrong,” he relates. “The standard thinking about cancer says that cancer occurs when cells proliferate. But, as they point out, cells want to divide naturally. The standard thinking says cancer cells show motility. But non-motility of cells is what’s abnormal. The standard thinking says that cancer cells are cells that have ‘gone bad.’ But what often occurs is a complex set of interactions out of which a bad environment forms. This poor environment can allow neighboring cells, with their inherent potentials for proliferation and migration, to become tumors.”

Given her book’s unexpected viewpoint, how was The Society of Cells received by the scientific community? “Well, we got reviews there and there,” Soto answers a bit hesitantly, naming a few professional journals. “One review said our book had already become an underground classic.” With that last statement, pride suffuses her face for a moment and is gone. Soto is not a prideful person by any means, but she is anchored by an inner core of steady belief in herself that drives her forward through the crosswinds.

There are plenty of those to go around. Soto and Sonnenschein have advanced their careers side by side according to their own best instincts, ignoring the general popularity of their views and letting the results of their experiments fall where they will. “We may be outliers in some ways,” Soto admits, unfazed by the term, “but on the other hand, with endocrine disruption, we are also pioneers.”

Soto and Sonnenschein have been investigating endocrine disruptors, compounds that interfere with the normal cascade of chemical signals in the body, for more than 20 years now. A study of theirs published in Endocrinology in 2006 showed that even minute levels of a chemical long thought to be safe, the plastics component called bisphenol-A (BPA), could significantly affect the growth of several organs when exposure occurs during fetal development. Once the subjects reach adulthood, they tend to show decreased fertility, certain altered behaviors, obesity and an increased predisposition to mammary cancer.

The additive is widely used in baby bottles, eyeglass lenses, cell phones, water bottles, CDs and DVDs and household appliances, as well as in industrial resins and epoxies. An earlier study had revealed that BPA can be found in 95 percent of Americans’ bodies.

By exposing fetal mice to BPA, Soto and Sonnenschein determined that very small doses of the chemical—of the same magnitude that people routinely encounter—were responsible for significant morphological changes in the mice’s mammary glands, which later showed an increased propensity to mammary cancer. These findings effectively upended the conventional wisdom that the amount of BPA in the environment occurred at levels too low to affect human health. The two collaborators are now ranked among the world’s top experts on endocrine disruption.

Mixing Things Up

Soto may be going to Paris, but it’s not to sip wine in a fashionable café or watch long, tapered boats glide along the Seine at dusk. She is going there to turn the world of biology upside down. As Gilbert puts it succinctly, “We have a language of reductionism, and that language is not sufficient to give us a three-dimensional organism. We need a language of complexity.”

The prevailing mode of thinking about biology these days is “bottom up,” according to Gilbert. In effect, we know about the genes and their influence on the cells that create organisms. Our thinking moves from small to large. “What Ana and a few others are working on is the other direction, from the organism back down to the genes,” Gilbert suggests.

Viewed historically, Soto’s search is occurring within a tradition of inquiry called “holism,” says the Swarthmore biologist, who has taught the history of science at his college for decades. “This is the idea that the whole precedes the parts, which goes back to Kant and is counterintuitive. In this way of thinking, the identity of every part is determined by the whole. That is to say, parts can have multiple meanings, and what they’re meaning becomes fixed by the whole.”

An example that Gilbert has deployed for dramatic effect more than once in the classroom uses the beguiling newspaper headline “Prostitutes Appeal to the Pope.” Is this a revelation of hidden personal desire or something more officious and bland concerning a group of workers’ united plea to be recognized by the papacy in some way? Context determines everything.

In Paris, Soto plans to mix things up fearlessly in her hunt for big answers by including a physicist, a mathematician, two philosophers and two biologists (i.e., Sonnenschein and her) on her investigative team. “That will give us the chance to think about things from different perspectives,” she relates matter-of-factly, as though she were planning a dinner party among friends. Her scope is long term, spread out over many years. Naturally, it will take everyone a while to get fully settled in the new milieu. “Then,” she says, “we will see if all this theoretical talk has any bearing on the concept of metamorphosis.”

 

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Bruce Morgan is the editor of this magazine.

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