Immeasurable Benefits

Science dean Santiago Schnell, who knows firsthand the devastations of rare diseases, marshals mathematics to decode the mysteries of life and the secrets of health.

Author: Jason Kelly ’95

Santiago Schnell grew up on the outskirts of Caracas with the teeming Venezuelan rainforest all around him. Taking walks with an older neighbor as a boy, Schnell absorbed the kaleidoscopic sights and sounds of flourishing life — and kept an eye out for snakes and scorpions.

So much more was happening in those dense woods than what he could see. Schnell’s neighbor, a biologist and textbook publisher, interpreted their shared sensory experience to predict what else they would encounter on their path.

Hear all those birds up in the trees? So many flocking together means a feast of ants must be nearby. A few feet farther on: swarms.

See that tiny speck on the bark? That’s a fast-spreading fungus that will wipe out the surrounding trees. Not long after: gone.

“Experts can see things that nobody else can see between the lines,” Schnell says. “They can make these predictions based on the deep knowledge that they have about nature.”

Identifying and decoding the signals of the natural world seemed to the boy like a superpower. The example motivated him to cultivate that X-ray vision for himself.

His father’s influence helped heighten the resolution of what he would one day be able to see. The elder Schnell, a philosopher and lawyer, had a different kind of insight than their neighbor, a prescience no less influential on his son. In the 1980s, he foresaw the technological revolution — predicting, for example, that a company like Amazon would transform commerce — and he encouraged Schnell to equip himself to be at the vanguard of the coming disruption.

That meant learning advanced mathematics and computer science, the tools to enumerate and interpret the vast swaths of data that would proliferate like rainforest ants. His complementary mentors shaped the kind of science Schnell would pursue. “As a result of having two influential figures in my life,” he says. “[I started] from a very early age to think, ‘You know what, how can I understand the natural world? By using computers and mathematical models.’”

The William K. Warren Foundation Dean of the College of Science since 2021, Schnell has worked for more than two decades to make the life sciences more quantitative. And they have become so.

“The field has absolutely transformed,” says Schnell’s former student Ruth Baker, a University of Oxford professor who specializes in biological mathematics. “I would call it very much a quantitative discipline now.”

Schnell’s research has helped accelerate that transformation. A Notre Dame colleague ranks him among the world’s top five mathematical biologists. Confirmation of that assessment came last year when Schnell received the biennial Arthur T. Winfree Prize, one of the field’s highest honors, for pioneering work on enzyme kinetics and the development of what’s known as the Schnell-Mendoza equation.

Schnell Featured
Photo by Barbara Johnston

Enzymes, he says, “make the chemistry of life a reality,” supporting functions such as digestion, respiration and muscle contraction that we could not survive without. Schnell is part of an international commission to refine the measurement of the biochemical reactions that enzymes facilitate to better understand their efficiency.

“Even though we have been measuring these reactions for over a century, there are still a lot of deficiencies on how the measurements are made,” he says. “They haven’t been standardized.”

For all the progress, he still views the life sciences today as counting on fingers when compared to the mathematical complexity of related fields. Unlike the hard numbers accumulated and analyzed and argued about well past the decimal point in chemistry and physics — “you can go 16 zeros and they’re still fighting over the precision,” Schnell says — life sciences evolved more from observation than calculation. “Very much the same continues today, but with more sophisticated observations,” he says. Biology “hasn’t been born from being an inherently quantitative discipline. And that transformation of making the life sciences inherently quantitative is critical.”

At the risk of oversimplifying his expert opinion: Physicians yet see like his neighbor in the rainforest. Their expertise penetrates much deeper than the untrained eye can, but without full access to the wealth of insight that detailed data could offer to counsel patients with more precision. The numbers derived from, say, bloodwork during a physical exam are blunt instruments. And on the waivers that patients sign before a surgical procedure, he notes, “it always says ‘medicine is not a science,’” which reinforces the traditional subjectivity of the field.

“Most doctors are taking decisions based on symbols and signs that are the result of interactions that they have with the patients and physical observations that they make,” Schnell says. “But measure? Well, there are a few things that can be measured, but not many.”

As Schnell sees it, medicine is at the beginning of a multigenerational effort to understand the mathematics that reveal the continuum between health and disease, even between life and death. A person might be well one day — or one minute — and ill the next. The apparent suddenness of that change does not reflect the pace of progression in the body. Revealing the imperceptible mechanisms of how cells go from being healthy to sick, and what genetic and environmental factors hasten or impede that process, would be a biomedical revolution.

Think of it as setting up an impaired-driving checkpoint for the body. Once a drunken driver veers into traffic or off the road, he says, even if lives can be saved, the victims face a greater risk of permanent debilitation. But precise measurements could allow more conditions to be identified before they’ve reached that point of no return, as with cancer that goes undiagnosed until it has spread beyond the point of less-invasive interventions.

“Stage two, stage three, it might be curable, but it comes at a high cost to the patient; the patient is never going to be the same,” Schnell says. “How do we avoid a disease expressed to the point that it’s a disaster? That’s the whole goal academically: Precise measurements allow you to prevent the disease state that is irreversible.”

Progress in genetics offers another example of how much ground remains to be tilled in the life sciences. Many people today know the genes they carry and their related chances for certain conditions, for instance. That knowledge only goes so far. The presence of this or that gene might represent a risk, but current methods can’t measure to what degree that gene is being expressed, if at all, in any given individual. A true accounting of the probability of disease lies in that still-opaque space. What can be accurately determined now, Schnell says, is “a correlation, but it’s a correlation that is based on observations, not on actual measurements.”

Those Rs in correlation roll off his tongue in a resonant accent that requires — and rewards — careful listening. Close attention to his words helps a layperson parse the complexities of Schnell’s scientific ideas, which he translates with accessible examples like the drunken driver or the use of everyday objects around his office.

Befitting his status as researcher and dean, Schnell, 52, a husband and father of a college-age son and daughter, looks like he could have been developed in a lab to academia’s precise specifications. Wearing tortoiseshell glasses and bowties, he conveys the cinematic sartorial ideal of an esteemed professor, as if his emphasis on precise measurements extends to the kind of tailoring suited to the popular notion of his chosen profession.

If Schnell has a mathematician’s mind, he also has a philosopher’s heart and a theologian’s soul. He distributes a motto for the college on bookmarks: Spes in caelis, pes in terris. Hope in heaven, feet on earth.

Appearances belie the medical difficulties that have been a fact of his own life. “I’m completely screwed up from a health point of view,” he says.

Aggressive therapies to alleviate serious allergies and immune deficiencies led to a cancer diagnosis when Schnell was 15. An experimental treatment cured the cancer — and the experience impressed upon him the lifesaving power of science and medicine — but he continued to experience gastrointestinal issues that were common in his extended family. He dealt with severe Crohn’s disease and colitis, requiring the eventual removal of his large intestine and colon. Breathing problems have dogged him for years as well, and he now sleeps with a respirator.

All that despite being his mother’s “miracle child,” born after two lost pregnancies. A younger sister and brother came along without health issues. Nobody knew why the misfortune of multiple miscarriages and stillbirths befell his mother and other relatives through the years. There were unexplained crib deaths, too, and some other surviving children experienced gastrointestinal and respiratory complications.

It wasn’t until Schnell was well established as a scholar at Oxford, where he earned his doctorate, that his academic mission took on a personal dimension. His sister called one day to tell him her newborn was very sick. Like their mother, she had lost pregnancies and now agonized over the suffering infant.

Doctors had pinpointed a cause: a rare condition called Haddad syndrome that compromises the heart, lungs and gastrointestinal system. Afflicted babies often die in their sleep within days of birth, before a diagnosis, leaving the impression of the mysterious sudden infant death syndrome. Naming the problem offered a through line to trace the family history, but that offered no solace for the acute crisis facing this newest child.

They held out little hope that the baby boy, facing multiple surgeries and requiring expensive medical care and equipment, would ever leave the hospital. Schnell’s sister sought his advice about whether, given such a dire prognosis, she should remove her own miracle child from life support. He knew she never would.

The real purpose of her phone call was to plead with Schnell, the young research scientist of such promise, to enlighten her about what could be done to spare the family the impossible choice of death or a life of tethered medical dependence. Not much, he told her. For rare diseases, the financial incentives for companies and foundations and governments to fund the development of potential treatments or medications didn’t pencil out. She issued a challenge: “If you’re so gifted with all these things in academic medicine and measurements, why you don’t spend a significant amount of your time studying rare diseases?”

Schnell took her admonishment to heart and, while continuing his groundbreaking work on enzymes, initiated collaborations to heed his sister’s appeal. Her son died at age 10, but Schnell, whose own children do not suffer from the condition, has persisted in studying overlooked “orphan diseases” and advocating for patients.

The philosophy he adopted is “the other way around on how academic medicine works,” which tends to focus on conditions that afflict many but may not be life-threatening, Schnell says. Instead, in a research career that includes published work on 10 rare diseases, he strives to identify the characteristics of extreme, fatal illnesses to understand health. “People run away from rare diseases, but I discovered, if it kills you, it has to be important.”

He wants to learn what goes wrong to illuminate what’s right in normal developmental processes. To work backwards from identifying the breakdowns that cause, for example, rare epilepsies in children for insight into healthy brain development.

“What are the things that are broken, that don’t make you healthy anymore?” he says. “I’m studying the weakest link. If you are able to identify the weakest link that kills you, then you have the secret of health and the mystery of life.”

Expanding the scope of his research to include rare diseases may, in retrospect, have been a first step toward Notre Dame, where the College of Science prioritizes such efforts, a component of a mission to support the underserved. Stints at Indiana University and the University of Michigan — where he contributed to endocrinologist Peter Arvan’s trailblazing work on a rare form of juvenile diabetes — preceded Schnell’s hiring as dean.

Here he has extended a hand beyond the laboratories and lecture halls into the realms of faith and ideas, drawing on the devout Catholicism that also called him here. If Schnell has a mathematician’s mind, he also has a philosopher’s heart and a theologian’s soul. He distributes a motto for the college on bookmarks: Spes in caelis, pes in terris. Hope in heaven, feet on earth.

Schnell brings the ineffable and the tangible, heaven and earth, into dialogue with fervent, unbounded curiosity. “He’s amazing in terms of his energy, I don’t know where he gets it from,” says Baker, the Oxford mathematician. “And he just loves talking about a million different types of things.”

Science, in his capacious mind, contributes only certain pieces toward the completion of life’s holistic mosaic. He broadens the impact of his work in collaborations with others who think not in terms of big data and mathematical precision, but about the immeasurable elements of the human experience.

“As a leader, Santiago is actually showing us how to simultaneously be excellent at our individual research fields and, at the same time, move away from compartmentalization of these disciplines,” says Notre Dame philosopher of science Nicholas Teh. “In a way that’s not just small talk or social, but in a way that actually flows from our research.”

Consider: organs. The heart and lungs, the kidneys, the liver. The life-giving components of the body. That’s a scientist’s purview, on the surface, but the topic opens a “what is . . . ” question with philosophical and theological dimensions.

“What is an organ?” says Teh, a collaborator with Schnell, theologian John Cavadini and others on an upcoming conference series that begins with that question. “The broader philosophical question is, ‘How is an organ understood in terms of a certain kind of functionality related to the functionality of the human person as a whole?’”

Schnell relishes the “what is . . . ” question and its “how is . . .” corollaries. Such prompts inspire thinking that transcends dictionary definitions and disciplinary boundaries.

“I understand the notion of organs, but I cannot fully define it, and I want to understand how it works and what makes something complete,” Schnell says, equating organs to rooms in a home or components of a computer chip or religious rites, distinct but functionally interconnected and dependent elements. “When you think, for example, from the theological point of view, the sacraments are considered the organs of the Church. So, how the Church is alive, because you have the sacraments of the Church all together. There is a universal question: How the sacraments arise. Why they are so complementary to each other. What makes them to be the unity of the Church as organs, the same way that the heart, the lung, the stomach and the brain are the organs of the human body?”

A single perspective would be insufficient to address those questions. Schnell holds up a Kleenex box. Viewed from a certain angle, it’s a flat square. Turned slightly, additional dimensions become evident. From another direction the tissues tucked inside are visible. But it takes all points of view to perceive the whole.

Understanding human life, the nature of the earth, the origins and expanse of the universe and beyond, requires expertise coalesced from every which way. As Schnell puts it, “The only way we can have our feet on the earth while having our heads in the heavens is by having that unity of knowledge.”

The benefits of that pursuit, the mathematical biologist believes, don’t even need a back-of-the-envelope estimate to justify. They are incalculable.

Jason Kelly is an associate editor of this magazine.