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Human Health

Thanokine Signaling

How cells respond to inputs from dying cells is a rich and untapped source of insights into health and disease. Illustration by Mary Jo Roberts-Braisted

How living cells use dying cells to thrive.

No cell is an island. Our bodies are a complex and continuous series of interactions among trillions of individual living cells. To thrive, cells must process and respond to inputs from surrounding cells, as well as to environmental factors.

Understanding the signals to which a cell responds, and how these responses differ in health and disease, has been an important focus of medical research. The discovery of endocrine and exocrine function, or how cells respond to input from distant cells, has transformed our understanding of pathologies as diverse as diabetes, infertility, and cancer, and how we treat these diseases. The discovery of paracrine function, or how cells respond to input from neighboring cells, has led to new insights and treatments for serious diseases such as Alzheimer’s disease, rheumatoid arthritis, inflammatory bowel disease, and cancer.

Until recently, biologists tended to focus their attention on living cells and their interactions with other living cells. (There’s a reason Lewis Thomas’s 1974 popular science classic was called The Lives of a Cell.) But it turns out that at the scale of our cells, another fundamental, but overlooked, feature of human biology is the interaction of living cells with dying cells.

Generally, life scientists have anthropomorphized the loss of a cell as “cell death.” But the human body is in fact a closely calibrated equilibrium between cell construction and cell disassembly, as billions of cells every day are built through mitosis or retired through myriad distinct mechanisms. When this homeostasis fails and cell disassembly goes awry or begins to outrun cell birth—or the reverse, in the case of cancer—is when trouble starts for the organism as a whole.

Amid these relentless waves of cellular addition and subtraction, which operate as impersonally as a piece of accounting software, scientists are learning that the answer to the question, Did the loss of this particular cell make a difference to tissues? is often yes. That insight may be the start of a new approach to developing medicines that stop disease and keep us in healthy equilibrium longer.

The whole story of cell loss

In the 1970s, researchers discovered a tidy, purposeful, and regulated means by which cells disassembled and removed themselves—a kind of altruistic cellular suicide. A genetically programmed cascade of molecular signals can cause a cell to shrink and fragment into tiny blobs that melt into the background without causing inflammation. Biologists realized that this phenomenon, christened apoptosis, was critical to processes like embryogenesis, when temporary structures such as the webbing between fetal fingers or toes must disappear on schedule. And it turned out to be a completely normal aspect of cellular turnover, involved with the removal of billions of cells in our adult bodies each hour. Conversely, pathologic forms of cell loss were called “necrosis” and associated with violent but simple causes: trauma or infection caused dying cells to rupture and empty their contents, sparking inflammation in nearby tissue and attracting white blood cells called macrophages to engulf the debris and clean up the mess.

But that wasn’t the whole story. In recent years, researchers have discovered more and more forms of programmed cell death, each defined by its own chain of gene expression and protein signaling, and each ending in its own way. Dying cells can release a burst of proteins called cytokines that signal infection, or fill up with watery compartments called vacuoles, or see the oxidation of membrane lipid molecules lead the cell to swell and erupt violently into the surrounding milieu.

If a cell, in response to different toxins or diseases, can die in many different ways, do living cells respond in different ways to the material released by cells undergoing different types of cell death? Wouldn’t it make sense that other cells, in their quest to survive, seek to glean information about the sudden loss of their neighbors?

Over the last two decades researchers have been scrambling to identify and label all the myriad ways cells can perish, but they’ve rarely thought to ask how living cells responded, whether the loss of an individual cell influenced these survivors in useful ways, and whether that effect differed depending on the cause of death. Cell-death researchers were acting like forensic investigators who spend all their time documenting a crime scene but forget to give their findings to police and prosecutors.

“Nature, which is parsimonious, uses the loss of a cell for its own purposes.”

Molecular clues from cell loss

In 2017, Flagship Managing Partner Douglas Cole, MD, and Senior Principal Jason Park, PhD realized that research into cell death had mostly ignored the response of living cells. They asked themselves, How do living cells use information from dying cells? Cole and Park reasoned that nature, which is parsimonious, uses the loss of a cell for its own purposes. They speculated that since tremendous energy goes into generating and assembling the components of a cell, living cells must use the components of dying cells and the information gleaned from the disassembly of other cells in order to thrive.

Flagship Pioneering is now building a startup called Inzen Therapeutics around this singular thesis: that living cells actively use and integrate molecular clues created by dying cells, and that these signals are as differentiated as the mechanisms that can cause cell death in the first place. Inzen scientists believe this interplay between living and dying cells, ThanokineTM Biology, performs important functions in health and disease such as provoking the immune system to attack tumor cells, or activating wound-healing processes, or repairing the pathologic scarring involved in fibrotic diseases. Furthermore, the company is accumulating a wealth of evidence that the way a cell dies has a precise and important impact on how other cells respond.

Inzen’s central idea—that living cells depend on input from dying cells—emerged from conversations among Cole, Park, and leaders in the academic research community, including Doug Green at St. Jude Children’s Research Hospital, in Memphis, Tennessee, and Brent Stockwell at Columbia University. Stockwell told Park that everything scientists thought they knew about cell death was wrong. Park remembers, “He got our attention by saying, ‘You guys probably think there are two ways that cells die—on purpose or by accident. There aren’t. There are dozens of ways and we didn’t know how to tell the difference before.’” “We thought: if we didn’t even understand how cells die, there must be other aspects of this fundamentally important biology we haven’t thought about. And the question that kept coming up was, What does this do to the other surrounding cells?”

That sent Park and his fellow researchers into Flagship’s Labs, where they came up with a diabolical list of ways to kill cells—heating, freezing, radiation, UV light, toxic chemicals, and many more—and designed experiments to assess the results. One study disproved the dogma that only macrophages take up the detritus from dead cells. Instead, when the researchers killed fluorescent-tagged cells in tissue cultures, they found bits and pieces turning up in all sorts of adjacent cells—proving the basic concept that living cells readily take in input from dying cells.

Using advances in technologies such as mass spectrometry, the Inzen researchers also showed that the specific kinds of molecules that are created during the disassembly of a cell—including well-known and important signaling proteins such as interleukin-6 (IL-6), tumor necrosis factor (TNF), and transforming growth factor beta (TGF-β)—can differ depending on the insults to the cell. This turned out to be true even in tumor cells, leading to the release of myriad different signals into the tumor microenvironment. The company began to catalog the effects of different sets of Thanokine Signals on surrounding cells, building a library of so-called PhenoMaps™.

New frontiers for drugs

This knowledge could give Inzen a way to design drugs to intervene in the chain of Thanokine Biology—inducing, regulating, blocking, or mimicking the signals, depending on the desired response. To help the body’s immune system destroy tumor cells, for instance, it might be useful to design drugs that not only kill tumor cells but do so in a way that amplifies or simulates immune-activating Thanokine Signals. To prevent liver, lung, or kidney fibrosis, or even scarring after an injury, scientists could try blocking Thanokine activation of fibroblasts and immune cells.

“Every other time biological science has discovered a fundamental new form of communication, it has translated quickly into a very broad range of therapeutic options—neurotransmitters being one example, cytokines being another,” says Inzen’s CEO Volker Herrmann, MD, MBA, a Pfizer veteran. “We think Thanokine Biology has uncovered a new frontier of drug discovery in line with those fertile areas.”

“I still remember vividly my first call with Jason [Park],” says Peter Gough, PhD, who joined Inzen as chief scientific officer in 2019 after many years at pharma giant GSK studying drugs that induced a type of cell death called necroptosis. “He told me about data they’d generated showing that when a cell dies, what it released was dramatically different depending on how it was dying. Even for somebody who had been in the field of cell death for a decade, this was the mind-blowing moment—like thinking the world is flat and seeing for the first time that it’s round.”

Inzen’s findings have been bolstered by work in academic labs. A team led by Andrew Oberst, an immunologist at the University of Washington in Seattle, found in 2019 that it was possible to boost immune-system activation against tumors in mice by injecting cells that were already undergoing necroptosis (and were presumably releasing Thanokine Signals). Oberst’s team saw a similar effect when they engineered tumor cells to express a gene for an enzyme called RIPK3. They speculated that pharmaceutical strategies to boost the immunogenicity of dying tumor cells could make existing cancer therapies, such as immune checkpoint blockade, more effective.

“The implications are tremendous,” says Park. “Think of all the clinical studies where we are combining cytotoxic drugs with a checkpoint inhibitor”— that is, a drug that clears the way for the body’s own T cells to attack tumor cells. “If you just kill a tumor cell, yes, you’re shrinking the tumor, but often it’s only a matter of time until it’s replaced by yet another tumor cell.

We know immune responses are important to long-lasting effects, so what if there are better ways to kill tumors—what if we could use the dying tumor cell itself to control the signals immune cells see in the tumor microenvironment?”

In a 2019 review paper in Cell, Doug Green—who serves on Inzen’s scientific advisory board alongside Brent Stockwell—posed five riddles about cell death, including this one: “If a cell dies in the forest of the body, does it make a sound?” Scientists are now learning that it does, because there’s a medium for this ghostly communication in the form of Thanokine Signals, and because there are always other cells nearby to pick them up.

In this sense, a dead cell has an afterlife, and the larger organism pays close attention to the loss of individual cells and the manner in which it happens.

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