Ushering an era of cellular engineering
Our vision is to help usher an era of cellular engineering, centered around pluripotent stem cells (PSCs).
PSCs can multiply almost indefinitely and become any cell type in the body, which makes them ideal starting material for off-the-shelf cell therapies. But manufacturing those therapies reproducibly, at a scale that makes them broadly accessible, requires that we understand the rules that govern PSC fate: how does a stem cell decide whether to divide, differentiate, or die?
The answer is written in a circuit. Each cell runs a DNA-based processor of roughly 20,000 genes regulating one another through biochemical interactions. Which genes are on defines the state of the processor — the cell’s identity, and how it responds to its microenvironment. Working at the intersection of systems and synthetic biology, we want to know how that processor makes decisions in a single PSC, and how PSCs influence their neighbours.
Towards this vision, we are leading efforts on three main fronts: unlocking the rules that govern PSCs (reverse engineering), enabling robust PSC-derived cell therapies (forward engineering), and building synthetic biology tools to probe PSC fate.
Reverse engineering
the rules that govern PSCsThe molecular mechanisms of cell competition
Your cells are not always good neighbours.
During development, cells coordinate their fates, sensing and responding to the decisions being made around them. But not all of that communication is neighbourly. In cell competition — first described in fruit flies, since found in zebrafish, mice and humans — cells compare themselves against their neighbours, and the losers are killed on contact. It happens in PSCs too: embryonic cells in a dish, sizing each other up.
How mammalian cells run that comparison is still largely unknown, and least understood of all in PSCs. Our active projects are mapping the molecular control points that decide who wins.
Those control points are also a lever. Once competition can be tuned, it becomes an engineering parameter — a way to raise the purity and yield of stem cell manufacturing, and the seed of a new class of cellular therapy.
- Maheden K, Zhang VW & Shakiba N. The field of cell competition comes of age: semantics and technological synergy. Frontiers in Cell and Developmental Biology 10, 891569, 2022.
- Maheden K, Bashth OS & Shakiba N. Evening the playing field: microenvironmental control over stem cell competition during fate programming. Current Opinion in Genetics & Development 70, 66-75, 2021.
What evolutionary game theory reveals about early development
Cells in a multicellular body are supposed to cooperate. Mostly, they do — as single-celled organisms united into animals, they traded competition for collaboration. But natural selection never entirely left the building. After implantation, embryonic cells turn on one another, and roughly a third of the epiblast — the tissue that will become the entire body — is eliminated.
That is an expensive strategy. So why does the embryo pay for it? Is competition a leftover from our unicellular past, or is it doing something useful for the embryo that survives it?
To find out, we treat the embryo as a game board, combining evolutionary game theory with stem cell-derived embryo models to ask what strategy the winning cells are playing — and what the embryo gets in return.
Play the embryo card game- Abou Chakra M, Hislop J, Egilmez I, Alkalai R, Bashth O, Maheden K, Gundagathi A, Ebrahimkhani MR & Shakiba N. The embryo game uncovers hidden cell behaviours. Nature Communications 17, 7506, 2026.
Forward engineering
robust PSC-derived cell therapiesFinding the elite stem cells in a heterogeneous pool
PSCs have two remarkable properties: they can become any cell type in the body, and they can make more of themselves. What they cannot do is agree with each other.
Even PSCs from the same family tree behave differently, and that heterogeneity is a manufacturing challenge (Cell Systems, 2025a). Depending on which cells happen to dominate the pool, the same protocol yields batches of different purity and yield, which puts a ceiling on how predictable and reproducible manufacturing can be.
Turn it around, though, and heterogeneity becomes an opportunity. If individual clones are biased towards particular fates, we can scout for the elite ones — the clones best suited to making a beta cell, a lung cell, or a blood vessel — and build with those (Cell Systems, 2025b).
Doing that requires knowing which cell was which. We have contributed to DNA barcoding technology that tags individual clones, traces their lineages, and allows us to go back and retrieve the winners. Several ongoing projects are using it to identify elite PSCs across differentiation.
- Movasat H, Giacopino E, Shahdoost A, Dorri Nokoorani Y, Abrbekouh AH, Tahamtani Y & Shakiba N. A systems view of cellular heterogeneity: unlocking the “wheel of fate”. Cell Systems 16, 101300, 2025.
- Dorri Nokoorani Y, Movasat H, Giacopino E, Shahdoost A, Lipsitz Y & Shakiba N. Harnessing heterogeneity for the rational design of cell manufacturing. Cell Systems 16, 101458, 2025.
- Ishiguro S, Ishida K, Sakata RC, Ichiraku M, Takimoto R, Yogo R, Kijima Y, Mori H, Tanaka M, King S, Tarumoto S, Tsujimura T, Bashth O, Masuyama N, Adel A, Toyoshima H, Seki M, Oh JH, Archambault AS, Nishida K, Kondo A, Kuhara S, Aburatani H, Klein Geltink RI, Yamamoto T, Shakiba N, Takashima Y & Yachie N. A multi-kingdom genetic barcoding system for precise clone isolation. Nature Biotechnology 44, 616-629, 2026.
Combatting cancer-like variants in PSC culture
Grow PSCs long enough and some of them start to cheat.
Mutations and karyotypic abnormalities accumulate in culture as cells divide. Any variant with a growth advantage does exactly what evolution predicts: it takes over the flask and pushes out the normal cells. Many of these variants carry changes in cancer-associated genes, making them unsafe to transplant. With PSC-derived therapies moving into clinical trials, demand for high-quality batches is climbing — and so is the cost of a bad one (Cell Stem Cell, 2025).
We are building the countermeasures: technologies that detect and remove variants, culture strategies that curb their growth in 2D and 3D, and evidence-based practices for PSC bioprocessing.
- Benvenisty N, Draper JS, Gokhale PJ, Healy L, Hewitt Z, Hursh D, Hodgson A, Ludwig TE, Mah N, McClelland SE, Mennecozzi M, Merkle FT, Mountford JC, Pera M, Prigione A, Rodriguez TA, Rossi A, Rouhani FJ, Saeb-Parsy K, Selfa Aspiroz L, Shakiba N, Spits C, Tonge PD & Barbaric I. A call to action for deciphering genetic variants in human pluripotent stem cells for cell therapy. Cell Stem Cell 32, 508-512, 2025.
Predictive computational models of PSC fate
We would like to fly the experiment before we run it.
Getting there means closing the loop between experiment and theory: experiments train the simulator, the simulator proposes the perturbations worth testing, and the results feed back in. Through collaborations spanning computational and synthetic biology, we are building predictive models of PSC growth and differentiation — working toward a virtual cell you can engineer.
- Abou Chakra M & Shakiba N. Virtual twins and the future of human developmental biology. npj Systems Biology and Applications, 2026.
- Heydari T, Bashth O, Fernandes J, Sabbineni B, Aguilar-Hidalgo D, Chen J, Shakiba N, Edelstein-Keshet L & Zandstra PW. Predicting and controlling collective fate in multicellular systems. bioRxiv (preprint), 2025.
Technologies to probe PSC fate
Synthetic biology tool development
We have ongoing projects that build new synthetic biology tools that allow us to track PSC fate, mapping cell state to future fate in multicellular systems. We are also developing tools to track the social history of cells in multicellular systems.
- Ishiguro S, Ishida K, Sakata RC, Ichiraku M, Takimoto R, Yogo R, Kijima Y, Mori H, Tanaka M, King S, Tarumoto S, Tsujimura T, Bashth O, Masuyama N, Adel A, Toyoshima H, Seki M, Oh JH, Archambault AS, Nishida K, Kondo A, Kuhara S, Aburatani H, Klein Geltink RI, Yamamoto T, Shakiba N, Takashima Y & Yachie N. A multi-kingdom genetic barcoding system for precise clone isolation. Nature Biotechnology 44, 616-629, 2026.
