The logic behind cell-to-cell heterogeneity in cellular populations  

We are intrigued by the question of how cell-to-cell variability emerges in a population of genetically identical cells. This phenomenon is widely observed in nature in systems ranging from microbial communities to clonal populations of animal tissue cells.

An example of cell-to-cell variability in a population of human neutrophils from a patient with acute pneumonia. Atypical nuclear segmentation generated a complete modern English alphabet and is a result of accelerated neutrophil maturation (modified from: Morgan AS & Yang DT. Neutrophil alphabet. Blood (2013) 121:3546).

Some of the phenotypic heterogeneity may be caused by the inherent probabilistic nature of biochemical reactions inside a living cell. However, the majority of this variability is not random, but forms quasi-deterministic patterns that are regulated. The reason for this is that cells do not operate in isolation, but create heterogeneous social contexts to which they adapt their phenotypic behaviour.

Our special focus is on how spatial and mechanical constraints within cell populations shape the phenotypic spectrum of constituent cells. To answer this question, we apply a reductionist approach in which isolated single cells are put in conditions precisely mimicking spatiomechanical aspects of their social context in populations. To this end, we work closely with biophysicists and engineers from the labs of Daniel Müller at ETH Zürich (Switzerland) and Matthieu Piel at the Institut Curie (France). By quantifying cellular responses to various boundary conditions and molecularly perturbing them, we wish to discover the mechanisms through which tissue cells can sense their "personal space" and coordinate their cell fate choices with position within their population.

Long-term, we would like to see how these mechanisms contribute to the formation and maintenance of complex tissues in and out of the human body. This goal is motivated by the fact that cell-to-cell heterogeneity can facilitate lineage choice and spatial fate partitioning during the formation and maintenance of complex tissues, because it primes cells to respond to differentiation cues in a differential fashion. Applying the knowledge obtained from studies of cell-to-cell variability to inter-individual heterogeneity will also aid personalized (precision) medicine.

Our local collaborators:

Our research benefits from the Human Induced Pluripotent Stem Cells Initiative (HipSci) hosted by the Centre for Stem Cells & Regenerative Medicine (CSCRM) at King's College London. Sponsored by the Wellcome Trust and the MRC,  HipSci aims at discovering how genetic variation between healthy individuals as well as patients with rare diseases could be harnessed to learn about the specific molecular mechanisms driving inter-individual and cell-to-cell heterogeneity in cellular populations. Our local collaborators from the HipSci Initiative include Dr. Alessandra Vigilante with expertise in bioinformatics & computational biology, working closely with partners at the Wellcome Sanger Institute and the European Bioinformatics Institute of the European Molecular Biology Laboratory (EMBL-EBI), and Dr. Davide Danovi with expertise in cell phenotyping.

Our values and culture:

  • Be ambitious, persistent, and determined.
  • Stay humble and modest. Individuals and teams can do amazing things when they share the credit.
  • Great discoveries lurk everywhere; keep your eyes open.
  • Success begins by choosing important problems, coming to fruition with great ideas and great execution.
  • Stay focused and mindful of our goals with a clear understanding of the path ahead.
  • Value uniqueness, helping people be the best they can be at what they do best.
  • Work hard but have fun and be a little quirky. 

Job opportunities:

Our vision is to solve complex biological problems in cell & tissue research through highly collaborative, international, and multi-disciplinary team science. Therefore, we welcome scholars from all over the world with backgrounds in both the biomedical and physical/computational sciences. If you are interested in opportunities within the Lomakin lab, please e-mail Dr. Alexis Lomakin: alexis.lomakin@kcl.ac.uk