Cell Fate Engineering and Disease Modelling

Almost every cell in our body carries the same genome, yet a neuron, a muscle cell, and a liver cell are fundamentally different. Cell identity is controlled by transcription factors, master switches that turn the right genes on and the wrong ones off. Still, cells can shift between states, a property called cellular plasticity. Plasticity is essential for development and repair, but when it gets out of control, it drives disease.

By deconstructing how one cell type can be converted into another, we discovered a new principle and introduced the concept of “safeguard repressors”: factors that continuously silence the gene programs of other cell types and thereby protect a cell’s identity. In neurons, MYT1L plays this role by blocking many alternative identities, all except the neuronal one. We study what happens when such safeguards fail: in cancer, in neurodevelopmental disorders, and in aging.

The Challenge

Unlocked cell plasticity is a recognized hallmark of cancer. Tumor cells shed their original identity, adopt stem-cell-like features, and switch between states. This plasticity helps them grow and escape treatment. Glioblastoma, the most aggressive brain tumor in adults, and liver cancer, one of the leading causes of cancer death worldwide, are prime examples.

Our Approach

We deconstruct how safeguard repressors keep cells in check and how tumors escape them. We showed that restoring such safeguards can restrain tumor growth and plasticity. Building on this, we pursue a “lock-and-kill” strategy: first lock cancer cells in a stable, vulnerable state, then eliminate them with established therapies such as chemo- and radiotherapy
 

The Challenge

Neurodevelopmental disorders such as autism and intellectual disability affect millions of people and have highly diverse genetic causes. Living brain cells from patients are practically inaccessible, and targeted treatments are largely lacking.

Our Approach

We engineer human neurons and brain organoids from stem cells, including patient-derived and genetically engineered lines, and combine them with genetic mouse models to dissect how risk genes disrupt neuronal identity and function. Using MYT1L syndrome as an example, we showed that losing a neuronal safeguard produces neurons with a “confused” identity and altered activity. Some of these changes could be reversed with an approved drug, even after brain development was complete. Clinical studies still need to test whether this helps patients. We now extend this approach to other risk genes and therapeutic strategies.

The Challenge

Most neurons form before birth and must maintain their identity for a lifetime. With age, the mechanisms that protect cell identity erode, and cells can drift into less functional states. Such identity loss is increasingly linked to aging and to neurodegenerative diseases such as Alzheimer’s. Whether it is a cause or a consequence of aging is unknown.

Our Approach

We ask whether neuronal safeguards such as MYT1L weaken with age, and whether the resulting loss of identity drives neuronal aging. We also explore whether strengthening cell identity could keep aging neurons healthy, an alternative to rejuvenation strategies that temporarily loosen cell identity.