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What if…

The function of a cell depended not only on input from other living cells, but also on input from cells as they turnover or die?

It turns out…

Cell loss is a critical source of information that living cells use to shape responses in health and disease. Living cells process and respond to inputs from cells that are dying, either as a normal step in the cycle of cell loss or abnormally under disease conditions. This interplay, the domain of ThanokineTM Biology, is a rich and untapped source of insights into how to prevent and treat cancer, immune-inflammatory disorders, fibrotic disorders, and degenerative disease.

Humans are complex multicellular beings. Every cell in the body is surrounded by other cells, and how a cell utilizes information from other cells and its environment is essential to both health and disease.

This paradigm has transformed how we identify and treat a wide variety of diseases. For example, endocrine and exocrine dysfunction, which deals with how cells respond to input from distant cells, is implicated in diabetes, infertility, and cancer. Paracrine dysfunction, which deals with how cells respond to input from neighboring cells, plays a critical role in serious diseases as diverse as Alzheimer’s disease, rheumatoid arthritis, inflammatory bowel disease, and cancer. Cells also respond to inputs from the environment—for example, what individuals consume through diet or are exposed to in the air. These insights have provided the basis for many life-changing drugs and hundreds of billions of dollars of value.

Until recently, scientists mostly focused on signals coming from living cells. But one of the most common and important phenomena that occurs in any given cell’s environment is the loss and replacement of surrounding cells. Hundreds of billions of cells turn over each day. The discovery of ThanokineTM Biology reveals that living cells respond to information released during cell turnover in unexpected ways. It expands our understanding of the pathways that influence the state of living cells and opens new therapeutic opportunities based on one of the most fundamental aspects of health and disease.

Origins

In 2017, Flagship Managing Partner Douglas Cole, MD, and Senior Principal Jason Park, PhD, realized that the research community had largely ignored the question of how living cells respond to cell loss in their environment.

Every day, hundreds of billions of cells die in the human body. In most cases, this occurs as a part of normal development and homeostasis, but aberrant cell loss can be driven by all manner of toxins and pathogens. The macromolecules and organelles that defined those cells required tremendous energy to generate and assemble. Observing that nature is parsimonious—biological systems tend to conserve energy, not waste it—Cole and Park speculated that living cells, in order to thrive, must use the components of other cells undergoing turnover and respond to information gleaned from that process about whether cell loss was occurring due to homeostasis or disease. They launched an exploration that asked, What if living cells depended on information released from dying cells?

The result was a Flagship Labs prototype company, initially called FL47 and later named Inzen Therapeutics, founded to discover and develop drugs based on ThanokineTM Biology. The Flagship Labs exploration was timely. At the time, scientists were reconsidering the very definition of cell death. Historically, “cell death” was largely characterized as a binary phenomenon, either programmed or accidental. The former was understood to be an attribute of normal cell turnover, critical in development and homeostasis, while the latter was associated with pathology. But in early 2018, a committee of over 100 researchers codified a dozen unique, highly regulated mechanisms by which a cell could disassemble and turn over. At the same time, Cole and Park uncovered a handful of reports from other fields showing important biological responses to cell loss occurred, even at a distance, in processes as diverse as tissue fibrosis or regeneration, muscle development, cancer resistance, and stem cell proliferation. What the academic community and others had missed was a bigger, mechanistic framework that linked these two sets of observations: ThanokineTM Biology.

Three factors now made it possible for the Flagship founding team to reimagine cell loss as a form of cell communication and shift the focus to how living cells respond to and make use of information created by the loss of other cells. First was their willingness to challenge dogma: The products of dying cells were generally regarded as either inert detritus to be quietly cleared away by the immune system or else “danger signals” that drove inflammation. Second was the new mechanistic insights: It hadn’t been known that a given cell could turn over in multiple, mechanistically distinct, ways, so it hadn’t been possible to ask whether those different forms of cellular disassembly might lead to different responses from living cells. The third factor was technical: Recent advances in mass spectrometry and machine learning made it possible to discover ThanokineTM signals with scale, speed, and high resolution.

Breakthrough and Advantage

Inzen developed a product platform to interrogate how living cells respond to the information released from dying cells. The platform has three components: It uses a proprietary library with chemical and genetic approaches to induce different forms of cell turnover; it uses advanced mass spectrometry and aspects of machine learning to catalogue and decode ThanokinesTM; and it has unique biological assays that translate new insights into new drug targets. These components are key to generate what Inzen calls PhenoMapsTM, a high-throughput approach to understanding how living cells respond to ThanokineTM signals and enabling the rapid identification of therapeutic targets.

Inzen has discovered that both cell type and turnover mechanisms play a major role in the regulation of ThanokineTM function and dysfunction. These insights are captured in a proprietary database of over 10,000 ThanokinesTM, and enable, for the first time, an understanding of normal versus abnormal signatures across different settings. Inzen has shown that ThanokinesTM influence many cell types and pathways central to important processes such as cancer, fibrosis, immune regulation.

These insights translate rapidly into differentiated therapeutic opportunities. Inzen’s oncology PhenoMapsTM point to new targets and ways to screen for drugs. Most cancer therapeutics, for example, focus either on killing tumor cells or on modulating the tumor microenvironment. Inzen’s insights show that immune cells are highly sensitive to the many ways a given tumor cell can turnover, and its approach identifies drug candidates that not only kill tumor cells but kill them in a way that will drive tumor immunoreactivity through the release of potent immuno-modulatory signals. These drugs represent an unprecedented and holistic approach to addressing the tumor microenvironment, one of the hardest challenges in cancer therapy.

In other cases, the ThanokineTM signals themselves represent drug candidates or targets. Inzen has, for example, shown that a novel, specific ThanokineTM can amplify the activation of stimulator of interferon genes (STING), which plays an important role in innate immunity, through mechanisms never before described. Inzen has also shown that regenerative ThanokinesTM from liver cells in a dish can be captured and administered as a therapeutic to drive liver regeneration in vivo, and that pro-fibrotic ThanokinesTM from liver or lung cells represent potential new targets to stop fibrotic disease in those tissues.

In 2020, researchers around the world have begun publishing similar work in prominent journals examining the products of cell turnover as an important source of signaling inputs to living cells, a strong validation of the work Inzen has been pursuing over the past few years.

Future directions

In the past, the discovery of other broad categories of inputs into living cells — for example, cytokines, hormones, and neurotransmitters — quickly led to the identification of the hallmarks of a range of diseases and these insights translated to transformative medicines across nearly every therapeutic area.

Inzen’s discovery of a fundamental, overlooked category of inputs into living cell opens a vast opportunity to develop new strategies to treat some of the most intractable medical problems in cancer, fibrotic and inflammatory disorders, and degenerative diseases. Inzen imagines a future where it is possible to develop curative cancer drugs that drive immunoreactivity in the tumor microenvironment, eradicating tumors. In addition, targeting ThanokinesTM and associated pathways, Inzen will develop drugs that stop or even resolve fibrosis or stop pathologic inflammation, and therapies that tap into the body’s natural mechanisms for regenerating tissues.

By first expanding the perspective on the inputs that cells respond to in health and disease, and then creating new therapeutic approaches to harness and control the flow of the information encoded in cell turnover, Inzen is opening a vast new frontier of discovery for a broad range of serious diseases.

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