From Molecules to Systems: Towards an Integrated Heuristic for Understanding the Physics of Life

Lead Research Organisation: University of Sheffield
Department Name: Chemistry

Abstract

The last fifty years have seen enormous strides in our understanding of biology at the most basic level, the molecular scale. For example, the structure of DNA has been discovered, and the genetic information encoded in its structure has begun to be worked out. We know that many biological molecules are associated with particular types of behaviour in larger organisms: for example some people have a genetic predisposition to particular diseases. However, understanding the complex links in the chain between a single molecule inside a cell and the behaviour of a person is a very difficult challenge. We can focus in on individual molecules and understand their structures and behaviour in great detail, but every human body contains vast numbers of molecules of many different types, and the challenge is to try to put together the complex systems of interactions between molecules that go on inside each cell; the relationships between cells that lead to the function of tissue; and the way that tissues and organs are integrated into a whole person. When a person discovers they have cancer, for example, there is a strong chance that the disease began with a change in a single molecule; but this will have initiated a staggeringly complex cascade of knock-on chains of cause-and-effect that led to the formation of the disease, and modern epigenetics is also suggesting that a complex chain of cause-and-effect may very well have preceded that initial change. Untangling this web of interactions is an enormous challenge but it is undoubtedly the most important problem facing biology at present.

It is clear that biological systems function on different length scales (molecules/cells/tissues/people) and the challenge is to integrate understanding across the length scales. The ways that biologists think about molecules are very different from the ways that they think about ecosystems, for example, even though a molecular event can trigger a change in an ecosystem. Physics has been addressing the problem of integrating across length scales for many years. At the most extreme, quantum gravity tries to integrate the laws of quantum mechanics (which deals with the smallest building blocks of matter) and general relativity (which describes the behaviour of planets, stars and galaxies). Importantly, physicists have been thinking about detail and also how to integrate across length scales to develop a picture of very large systems. We believe that this gives physicists unique insights that may potentially help biologists to integrate their thinking across the length scales too. The goal of this Network proposal is to stimulate engagement between physicists and biologists to tackle this important challenge together.

The Network will provide a range of activities designed to help physicists and biologists build new partnerships devoted to finding a framework to understand biology across the length scales. Three initial events will focus on key challenges (How do many molecules come together to form a living cell? Can we build synthetic systems that replicate cell behaviour and allow us to understand how the integration from molecules to cells functions? How do many cells work together in tissue, biofilm or other forms?) Following these initial events a series of activities will be developed to provide the means of bringing leading physicists and biologists together to address the important challenges identified.

Our goal will be to provide a framework from within which physicists and biologists can work together to understand biology across the length scales. The rewards for this effort are many, including the development of a better understanding of disease (for example, cancer), ecosystems and the environment, photosynthesis and biological energy harvesting, biotechnology and biofilms. Inevitably this will contribute substantially to the many bioscience-related industries in the UK and to the health and quality of life of its citizens.

Planned Impact

Undoubtedly, the most immediate impact of our Network will be upon academic science. However, the science that we aim to address - the integration of understanding across the length scales - is so fundamental that it underpins a great deal of biology. There are many ways in which a better understanding of the connections between molecular processes and systems behaviour may benefit society. The following are simply a small number of illustrations.
(i) Ecosystems are important in agriculture, and in the conservation of our environment. There is good evidence that molecular phenomena may trigger changes in the behaviour of entire ecosystems. Understanding these complex correlations could be critical in many different ways, from understanding the impact of a xenobiotic compound on the viability of sensitive habitats, to understanding the likely effects of genetically modified organisms in the environment.
(ii) Molecular-level changes are known to be important in many diseases. Cancer provides one illustration. Changes in a single molecule may ultimately lead to a cancerous organ and the death of a person. The potential of physicists to address the kind of cross-length-scale challenges involved in tackling a disease like cancer was recently recognised by the US National Science Foundation, and led to the radical move of establishing an NIH-NSF cancer network specifically to harness the expertise of physicists. While cancer is a disease that has a high public profile, it is not unique and many other diseases pose similar cross-length-scale challenges.
(iii) Biofilms are complex systems of multiple interacting cells. They acquire collective forms of behaviour that are not found in isolated cells. Biofilms are of enormous economic and human significance. For example, the colonisation of urinary catheters by bacterial biofilms costs the NHS many millions of pounds every year and causes suffering to many people who subsequently develop urinary tract infections. From the fouling of ship hulls to the bioremediation of contaminated land, there are many ways in which the development of an understanding that spanned the molecular and systems levels of understanding could have major economic benefit to the UK.
These examples illustrate some of the very many ways that impact could be generated by the new framework for understanding biology across the length scales that our NetworkPlus would aim to establish.

Publications

10 25 50
 
Description Summary of Progress to Date
This network was established to explore the landscape around EPSRC's Grand Challenge for the Physics Programme to "Understand the Physics of Life", and to develop an Agenda for research in this area in the next decade and beyond. Our hypothesis was that there is a schism in biology, between those using reductionist approaches from the bottom up (eg biochemists) and those using systems-level approaches (often computational and mathematical). Reductionist approaches fail to account for the behaviour of whole systems, and systems approaches ignore the molecular basis for biological phenomena. Physicists have a unique capacity to contribute to this challenge because of many years experience of tackling cross-length-scale challenges (eg the search for a grand unified theory of physics, and statistical mechanics). The aim of the network is to integrate understanding from the molecular to the systems scales in biology by bringing together researchers from physics and biology. This enterprise is rich with opportunities for physicists, both experimentally and theoretically.
Network activities
After a Launch meeting, attended by 150 delegates and featuring plenary lectures by Nobel laureate Tim Hunt and the Director of the NSF/NCI Physical Sciences in Oncology Program, Larry Nagahara, we embarked on a Series of Plenary Events. These addresses the themes of The Living Cell, Synthetic Biology and Multicellularity. Each featured series of scientific presentations from eminent UK and international scientists aimed at provoking and spawning discussions (invited speakers were asked to be provocative, to highlight major challenges, and to pose big questions), interspersed with discussion sessions. These discussion sessions, in which attendees were split into groups of approximately ten, had two tasks: to highlight key cross length scale challenges in the general area of the meeting, and then to distil this into ideas for potential future meetings ("focussed workshops") where people could group together to make new connections and collaborations with the aim of meeting the highlighted challenges. The enthusiasm of the participants at these meetings was transparent, and international speakers offered very positive feedback, unprompted. We were delighted to hear that attendees found the experience to be quite unlike that of attending other scientific meetings, and that they were inspired by the experience.
Following each workshop there was a meeting of the steering committee which explored the areas highlighted in the discussion and selected emerging themes that were potential subjects for future workshops. The areas selected were: Forces in Biology, The Physics of Bacterial infection, Information flow in biology, Life in extreme environments, The Physics of Cancer, Morphogenesis and shape formation, Biofilms, and Compartmentalisation. As in the Plenary Events, a heavy emphasis was placed on discussion, with speakers encouraged to address gaps in knowledge and fundamental challenges, and to be provocative. There were extensive networking activities, including discussions, flash presentations and associated "speed-dating" sessions. A goal for these workshops was that everybody who attended should participate. The result was a lively, interactive atmosphere that drew praise from attendees and invited speakers alike.
A Collaboration Fund was established to provide small amounts (up to £5k) of pump-priming funding to support activities designed to build new collaborative partnerships. Strict rules were applied (involvement of a physicist and a biologist was essential, and funding was not given to partners who had worked together previously). A significant number of these was awarded [I've forgotten! Christina should know] and a high fraction originated directly from the Workshops. We hope that substantial research collaborations will follow, and that this will lead to applications to EPSRC, although it is too early to confirm that this will be the case because most of the awards were made during 2015.
We organised a Summer School (in Lancaster) and a Winter School (in Oxford). Each was attended by just over 30 early career researchers. Besides the training aspect of the schools (each of which featured a very intense scientific programme, finishing after 9 pm in the evening on most days), they also provided networking opportunities for the young scientists in attendance. The biological physics community is (with a few exceptions) quite thinly spread and these schools had a vital community-building function. We were also delighted that 50% of the invited speakers at these events and 33% of the attendees were women, a reflection of our commitment to supporting and building a diverse community.
Forward Look
The Network has, with the support and involvement of the biological physics community, prepared a Roadmap, which was launched at the recent Network Summit at The Natural History Museum. The Roadmap is a distillation of many hours of consultation and debate at Network events; we believes it presents an exciting agenda for the next decade and beyond that we believe will have the enthusiastic support of the UK's biological physics community.
Exploitation Route The Network has achieved three things of particular note.
1. It has provided a focus for community building in biological physics. The UK biological physics community is, on the whole, quite widely distributed (with a small number of centres having significant strength in depth). The Network has drawn the community together and given it a much stronger sense of shared identity and purpose.
2. It has delivered a series of Focused Workshops addressing eight major challenges. These have again formed a focus for community building, and they have already facilitated the formation of new collaborative partnerships, in many cases supported by small collaboration awards by the Network - seedcorn funding to help people begin new collaborations.
3. We have drawn up a Roadmap for the future of Biological Physics in the UK. We have sought feedback on the community, via an open meeting at the Natural History Museum, and the final document will shortly be forwarded to EPSRC.
Sectors Chemicals

Digital/Communication/Information Technologies (including Software)

Electronics

Energy

Environment

Healthcare

Manufacturing

including Industrial Biotechology

Pharmaceuticals and Medical Biotechnology

URL http://www.physicsoflife.org.uk/
 
Description A "road-map for biological physics" was used by EPSRC staff in drawing up a policy for support for the field of biological physics in the future. Subsequently, this led to a number of significant further impacts. In particular, two calls for proposals were issued by UKRI, in 2019 and 2021, leading to funding for a a number of number of large, collaborative grants at the physics-life science interface. These projects are already having substantial on the biological physics community, and are expected to have an enduring impact in the future.
First Year Of Impact 2015
Sector Digital/Communication/Information Technologies (including Software),Healthcare,Pharmaceuticals and Medical Biotechnology,Other
Impact Types Policy & public services

 
Description Impact of Network on development of policy
Geographic Reach National 
Policy Influence Type Implementation circular/rapid advice/letter to e.g. Ministry of Health
 
Description Roadmap for Understanding the Physics of Life
Geographic Reach National 
Policy Influence Type Contribution to a national consultation/review
Impact The Roadmap was prepared to aid EPSRC in the identification of strategic priorities for funding. I am told by EPSRC staff that it was useful during the recent Shaping Capabilities exercise, which led to a "Grow" commitment for biological physics.
URL http://www.physicsoflife.org.uk/roadmap-for-biological-physics.html
 
Description Physics of Life Network 2
Amount £254,064 (GBP)
Funding ID EP/P006639/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 01/2017 
End 01/2020
 
Description Physics of Life Network+ (PoLNet3)
Amount £353,251 (GBP)
Funding ID EP/T022000/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 04/2020 
End 04/2024
 
Description Cancer Sandpit 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Other audiences
Results and Impact A Sandpit event organised in collaboration with CRUK on the theme of understanding the physics of cancer, with the goal of stimulating the submission of new proposals to the CRUK interdisciplinary research grant scheme.
Year(s) Of Engagement Activity 2016
URL http://www.physicsoflife.org.uk
 
Description Closing meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Other audiences
Results and Impact A Final Summit meeting at the Natural History Museum, to launch the Roadmap for Understanding the Physics of Life developed during the life of the network.
Year(s) Of Engagement Activity 2016
URL http://www.physicsoflife.org.uk
 
Description Eight Focussed Workshops 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Other audiences
Results and Impact Eight focussed workshops were organised during our Network, which welcomed participants from all over the UK working in Universities, hospitals, research institutes and industry, on the theme of "understanding the physics of life".
Year(s) Of Engagement Activity 2013,2014,2015,2016
URL http://www.physicsoflife.org.uk
 
Description Launch Meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Other audiences
Results and Impact A launch meeting for our network, with speakers from the UK biological physics community, a Nobel laureate and the leader of the NSF Physical Sciences in Oncology programme.
Year(s) Of Engagement Activity 2013
URL http://www.physicsoflife.org.uk
 
Description Plenary events 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Other audiences
Results and Impact Three Plenary Events were organised to launch our Network, tackling The Living Cell, Synthetic Biology and Multicellular Systems
Year(s) Of Engagement Activity 2013,2014
URL http://www.physicsoflife.org.uk
 
Description Summer/Winter Schools 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Other audiences
Results and Impact A Summer School was run in July 2014, in Lancaster, and a Winter School in January 2016, in Oxford. On each occasion there were 30 attendees and the events were a great success.
Year(s) Of Engagement Activity 2014,2016
URL http://www.physicsoflife.org.uk/summerwinter-schools.html