Saturday, 10 June 2017

ARTICLE: Supply, demand, energy, and death

Mitochondrial heterogeneity, metabolic scaling and cell death
J Aryaman, H Hoitzing, JP Burgstaller, IG Johnston, NS Jones
BioEssays e201700001; doi:10.1002/bies.201700001 (2017)
  •  The links between mitochondrial functionality and various aspects of cell physiology remain unclear; we combine recent experimental insights with mathematical modelling to produce quantitative hypotheses linking metabolism, cell proliferation, and mitochondria.
Cells need energy to produce functional machinery, deal with challenges, and continue to grow and divide -- these activities and others are collectively referred to as "cell physiology". Mitochondria are the dominant energy sources in most of our cells, so we'd expect a strong link between how well mitochondria perform and cell physiology. Indeed, when mitochondrial energy production is compromised, deadly diseases can result -- as we've written about before.

The details of this link -- how cells with different mitochondrial populations may differ physiologically -- is not well understood. A recent article shed new light on this link by looking at a measure of mitochondrial functionality in cells of different sizes. They found what we'll call the "mitopeak" -- mitochondrial functionality peaks at intermediate cell sizes, with larger and smaller cells having less functional mitochondria. The subsequent interpretation was that there is an “optimal”, intermediate, size for cells. Above this size, it was suggested that a proposed universal relationship between the energy demands of organisms (from microorganisms to elephants) and their size predicts the reduction in the function of mitochondria. Smaller cells, which result from a large cell having divided, were suggested to have inherited their parent's low mitochondrial functionality. Cells were predicted to “reset” their mitochondrial activity as they initially grow and reach an “optimal” size.

We were interested in the mitopeak, and wondered if scientifically simpler hypotheses could account for it. Using mathematical modelling, our idea was to use the observation that as a cell becomes larger in volume, the size of its mitochondrial population (and hence power supply) increases in concert. We considered that a cell has power demands which also track its volume, as well as demands which are proportional to surface area and power demands which do not depend on cell size at all (such as the energetic cost of replicating the genome at cell division, since the size of a cell's genome does not depend on how big the cell is). Assuming that power supply = demand in a cell, then bigger cells may more easily satisfy e.g. the constant power demands. This is because the number of mitochondria increases with cell volume yet the constant demands remain the same regardless of cell size. In other words, if a cell has more mitochondria as it gets larger, then each mitochondrion has to work less hard to satisfy power demand.

To explain why the smallest cells also have mitochondria which do not appear to work hard, we suggested that some smaller cells could be in the process of dying. If smaller cells are more likely to die, and if dying cells have low mitochondrial functionality (both of these ideas are biologically supported), then, by combining this with the power supply/demand picture above, the observed mitopeak naturally emerges from our mathematical model.

As an alternative model, we also suggested that the mitopeak could come entirely from a nonlinear relationship between cell size and cell death, with mitochondrial functionality as a passive indicator of how healthy a cell is. This indicates the existence of multiple hypotheses which could explain this new dataset.

A recent study has provided new data for the relationship between cell physiology and mitochondrial functionality. We have used mathematical modelling to suggest that a mixture of cellular power demand scaling, as well as cell death, could intuitively account for these new data. However, a nonlinear relationship between cell death and cell size could also account for these data, as well as a nonlinear relationship between mitochondrial functionality and cell size, as proposed by the original authors of the dataset. By integrating such a relationship between cell size and mitochondrial functionality into one of our existing models, we found that this “mitopeak” helps explain a wider set of cell physiological data. Using our model to highlight these competing hypotheses, we suggest future experiments to gather further support for these potential explanations.

Interestingly, we also found that the mitopeak could be an alternative to one aspect of a model we used some time ago to explain a different dataset, looking at the physiological influence of mitochondrial variability. Then, we modelled the activity of mitochondria as a quantity that is inherited identically by each daughter cell from its parent, plus some noise -- noting that this was a guess at the true behaviour because we didn't have the data to make a firm statement. We needed this relationship because observed functionality varied comparatively little between sister cells but substantially across a population. The mitopeak induces this variability without needing random inheritance of functionality, and may thus be the refined picture we've been looking for. These ideas, and suggestions for future strategies to explore the link between mitochondria and cell physiology in more detail, are in our new BioEssays article here. Juvid, Nick, and Iain.

Sunday, 21 May 2017

ARTICLE: A healthy dose of mathematics

Toward Precision Healthcare: Context and Mathematical Challenges
C Colijn, N Jones, IG Johnston, S Yaliraki, M Barahona
Frontiers in Physiology 8 136 (2017)
  • The continuing explosion of available biomedical data will help us tailor and optimise therapies for individual patients; we are designing new maths and statistics to help this process and to include social and other data into an overarching "precision healthcare" approach.
Our research combines tools from maths and statistics with biological data to learn more about the biological world. An exciting, growing, and much-discussed branch of science -- precision medicine -- is a specific instance of this idea. The vision of precision medicine is to use the expanding volume of data that's emerging from medicine and biology to tailor and optimise medical therapies for individual patients, making the therapies as effective as possible. This idea isn't new -- we are well aware, for example, that an individual's blood type dictates which blood transfusions they can successfully receive. But precision medicine is a much bigger picture, potentially taking into account large amounts of genetic, environmental, dietary, and other features to identify the optimal treatment for a disease -- for example, tailoring chemotherapy treatments to match the genetic specifics of a particular cancer case.

Dealing with these large and diverse datasets will need new mathematical and statistical approaches, built with an ongoing link to clinical practice. At the same time, we're interested in expanding the idea of precision medicine to include the "big data" that's increasingly available about individuals' social and logistic contexts. Social networks can dictate how diseases spread -- and how knowledge and views about therapies, vaccines, and other medically pertinent ideas are transmitted and shaped from person to person. A person's home region determines the genetic structure of local people who may act as donors. We're looking at the idea of "precision healthcare" -- using new maths and statistics to optimise healthcare strategy, not just individual therapies, in the light of large-scale datasets.

One aspect of precision healthcare we'll be exploring is exploring how progressive diseases -- those that involve the accumulation of symptoms over time -- develop in patients, using transition networks like those above to model "disease spaces" and find pathways in those spaces.

We're excited to be part of a new initiative -- the Centre for the Mathematics of Precision Healthcare -- involving six parallel and related research projects that align with this goal. Some of our previous work -- for example, estimating social structures of big UK cities to explore the challenges that genetic diversity poses to gene therapies for mtDNA disease -- already has a precision healthcare feel. In a new review paper (available for free) we discuss this and other examples of past and future work that we hope will contribute to the precision healthcare goal, along with some key ideas and context for the initiative. Iain

Tuesday, 14 February 2017

Conferences 2017

Some conferences with topics intersecting our research interests coming up in 2017:
Registration | Dates | Title | Location | URL

Apr 20/28 | May 21 | FASEB Mitochondrial Biogenesis and Dynamics in Health, Disease and Aging | West Palm Beach, Florida |

Mar 1 / Sep 1 / Oct 19 | 24-26 Oct | Frontiers in Metabolism: From systems physiology to precision medicine | EPFL Lausanne |

Apr 13 | July 21-25 | ISMBC ECCB (European Conference on Computational Biology) | Prague |

Mar 31 | Aug 23-25 | IEEE International Conference on Computational Intelligence in Bioinformatics and Computational Biology | Manchester |

Mar 9 | June 5-7 | Algorithms for Computational Biology | Aveiro, Portugal | 

yet to open | 11 Sep-19 Sep 2017 | EMBO Practical Course: Current Methods in Cell Biology | EMBL Heidelberg |

Aug 10 | 2-4 Nov | EMBO Quantitative Principles in Biology | EMBL Heidelberg |

Feb 14 | 24-26 Apr | Complexis: Complexity, Future Information Systems and Risk | Porto, Portugal |

Apr 10 | Aug 21-24 | ACM-BCB Bioinformatics, Computational Biology, and Health Informatics | Boston, MA |

Feb 8 | Apr 4-7 | Modelling Biological Evolution 2017: Developing Novel Approaches  | Leicester, UK |

Feb 28 | Jun 25-30 | Mathematical Methods and Models in Biosciences (Biomath 2017) | Kruger Park, South Africa |

Feb 10 | Apr 17-21 | Applied Probability @ The Rock | Ayers Rock |

1 May | Jul 24-28 | 39th Conference on Stochastic Processes and their Applications (SPA) | Moscow |

Feb 27 | Jun 12-16 | Mathematical and computational evolutionary biology | Porquerolles Island, France |

Mar 24 | Apr 24-25 | ICPB 2017 : 19th International Conference on Plant Biology | Boston, MA |

Jul 31 | 9-13 Oct | Mitochondria in life, death and disease | Brindisi, Italy |

Jan 31 | Mar 30 - Apr 1 | “Cell Organelles - Origin, Dynamics, Communication” | Mosbach, Germany |

Mar 15 | Jun 11-17 |  FEBS Advanced Course: Functional imaging of cellular signals | Amsterdam |

May 31 | Sep 24-27 | Molecular Basis of Life | Bochum, Germany |

?? | Nov 27 - Dec 1 | IEEE Symposium on Artificial Life(IEEE ALIFE'17) | Hawaii | 

27 Feb | 10 Apr | Developing efficient methodologies for modelling stochastic dynamical systems in biology | Bath, UK |

Some related lists

Sunday, 8 January 2017

Some EEN science news from 2016!

Our paper on mitochondrial gene loss (paper; free preprint; blog article) was, excitingly, Science magazine's #1 favourite news story of 2016! The other stories in the top 10 are all fascinating too -- highly worth a read!

The Science news coverage of the paper is here
and the story appeared in the print journal too 

We were also involved in some news coverage in Nature of some exciting bits of science and policy from outside the group:
Mitochondrial behaviour may dictate whether or not organisms evolve germlines:
Mitochondrial gene therapy approval in the UK:
Potential issues with mitochondrial gene therapies:

Our work on mtDNA dynamics and human population diversity (paper; free preprint; blog article) was included in the latest policy document on UK implementation of mitochondrial gene therapies

And our other bits of work -- particular our work on vaccine confidence (free paper; blog article) -- appeared in various national and international news outlets too, including Scientific American, New Scientist, Le Monde, Daily Mail, Daily Mirror, Fox News and others; for some appearances see