From micron to metre: crossing scales in the human body

In early November, an international team of scientists assembled in Hinxton Hall on the Wellcome Genome Campus for the second meeting of the CIFAR Macmillan Multiscale Human (MHU) research programme. They had come together to share their perspectives on a complex, dynamic and ‘multiscale’ system: the human body

The human body works at many scales: molecular dynamics of proteins and DNA happen at the nanometre, cell behaviours like division or migration can occur at the micrometre, and tissues and organs function from milimetres to metres. These scales do not work in isolation. Changes at the molecular level can alter cell behaviour, tissue architecture and organ function; in the other direction, changes in the environment can impact the body to cause molecular changes.

But we are still very much in the dark about how functions transfer between these spatial scales, at both short and long time periods. This is a profound gap in our understanding of how the body works. It also hinders prediction of causal relationships, for instance how genetic changes lead to changes in bodily function as manifested by patients in the clinic.

The Multiscale Human (MHU) programme was established to tackle this challenge. Launched in April 2023 following a highly competitive global call from CIFAR, a research organisation that convenes the brightest minds to tackle the most critical challenges facing society today, the MHU is co-directed by Gary Bader (University of Toronto), Katy Börner (Indiana University) and Sarah Teichmann (Wellcome Sanger Institute).

The sixteen MHU Fellows have a breadth of expertise spanning genomics, cell and developmental biology, neuroscience, medicine, mathematical modelling, engineering, data science, artificial intelligence and more. Each of these disciplines provides a different way to investigate human biology, but they are traditionally kept separate in their own academic silos. The MHU aims to break these silos and synergise interdisciplinary advances, and will meet twice a year for an initial term of five years to achieve this.

“It's turning into one of my favourite meetings, mainly because I meet people I don’t usually see in my own field’s conferences. It’s a fun challenge to learn to speak each other’s languages, and I’m also incredibly excited by the opportunity for sustained interaction over a number of years that is uniquely provided by CIFAR.”

Sid Goyal,
MHU Fellow, University of Toronto

To help the MHU develop their ideas and plans, three experienced scientific leaders who sit on the MHU Advisory Council also attended the November meeting, with Kay Davies bringing perspectives from genetics/drug discovery, Pavel Kabat earth sciences, and Hiroaki Kitano systems biology/robotics.

“We learned a lot from Kay, Pavel and Hiroaki about how to organise our programme to ensure it flourishes. But just as valuable were their insights from their own research – to take one example, Pavel’s experience in developing complex climate models helped us think differently about how we want to model the body. Similarly, our fantastic roster of guest speakers from multiple disciplines gave new perspectives on our main challenges and aims.”

Sarah Teichmann,
Wellcome Sanger Institute, MHU Co-Director 

Building on initiatives like the Human Cell Atlas and HuBMAP, the MHU team has two initial aims:

• first to discover new ways to map the body at all scales from organ to molecule,
• and then to use these maps to build computational models, which can be used to understand the system and predict the cross-scale effects of perturbations.

Making multiscale maps and models of the body fundamentally relies on correlating and integrating biological data from different scales and collected using different methods. Guest speakers Lucy Collinson from the Francis Crick Institute and Maria Brbić  from the Swiss Federal Institute of Technology, Lausanne provided perspectives on the challenges of integrating imaging and genomics data respectively. This sparked extended discussions on how to best harness the potential – and avoid the pitfalls – of machine learning, increasingly used for data analysis and integration. Guest perspectives on machine learning in image analysis from Sebastian Ahnert, University of Cambridge and Alan Turing Institute, and large-scale predictions of the outcomes of protein variants from Joshua Pan, Google DeepMind, provided valuable case studies for the team.

One of the MHU programme’s aims is to make multiscale maps of the body that anyone in the world can use. To help understand how they might do this, guest speaker Ed Parsons, Google, gave a fascinating history of the development of Google Maps, which typically has a billion active users at any one time. Parsons argued that a key choice for any map maker is which data to include, and, just as importantly, which data to leave out. This is as relevant for cartography of the world as it is for the body, and depends critically on the message the map is trying to convey and the purpose a map is trying to serve. The exciting cross-fertilisation between geography and biology epitomised the powerful potential of crossing disciplines that is a cornerstone of CIFAR.

The second MHU meeting brought a fantastic array of boundary-pushing science to the beautiful surroundings of the Wellcome Genome Campus. The MHU programme will meet again next Spring, and in the meantime CIFAR funding will start to support intra-MHU lab visits and pilot projects. The first cross-discipline collaboration between MHU Fellows launched in November: a Kaggle competition to segment the vasculature of the human kidney from 3D Hierarchical Phase-Contrast Tomography (HiP-CT) data.