MRC Transition Support CDA Yanlan Mao

As we develop, how do our tissues and organs know when to stop growing when they reach the correct size and shape? How do they then maintain this correct size and shape throughout the rest of adulthood? If they are damaged by injury, how do they heal themselves again to restore their size and shape? Mis-regulation of these processes can lead to overgrowth diseases such as cancer and keloidal scars. Can we understand these processes from a new perspective in order to design new therapies for wound healing and growth related diseases?

These are the questions I have been answering with my CDA fellowship over the last 5 years. In particular, I have focused on the role of mechanical forces in these processes. There is increasing evidence that mechanical forces can have a huge impact on the growth of cells. For example, astronauts in space start to lose their bone mass, because there is no mechanical tension from gravity to stimulate bone formation. Despite the large amount of evidence around us that a tissue's mechanical environment is very important for its growth, little work has been done to investigate this at the tissue level.

One key finding from my CDA research has been in revealing a new way in which tissues buffer the constant fluctuation of forces that they experience in order to maintain their correct tissue shape. We showed that actin and myosin, important proteins in the body that provide cells and tissue with their structure, align themselves in a new direction when they experience external stretching forces. This strengthens the tissue, and prevents any cuts in the tissue from ripping throughout, much like the strengthened fabric of a parachute. Another finding from the CDA has been the discovery of a new mechanism to heal wounds. Normally cells in a tissue stick together tightly, to maintain the structure of the tissue. However, after injury, cells start to move relative to each other, and 'flow' into the hole at the injured site. We call this process increased tissue fluidity, much like how the molecules in a fluid flow past each other. We show that by increasing the fluidity of a tissue, i.e. the ease in which cells can move past each other, we can increase the rate of wound healing.

The above 2 projects have recently been published in high impact journals, but there are many other projects that have suffered delays in their progress. This is mainly because I have taken 2 periods of maternity leave during my CDA, and I have just returned to work from my 2nd leave. During my last maternity leave, I tried to ensure the continuity of my lab's research, but inevitably, momentum has been reduced, and progress slower, as I simultaneously attend to the needs of a newborn. It would thus be physically and mentally impossible to apply for a Senior Fellowship now. It would result in an application that is less competitive than if I could have an extra 18 months to prepare my application and produce key preliminary data to strengthen my Senior Fellowship application.

I need to focus on publishing the remaining papers from my CDA, some of which provide critical data for Senior Fellowships. As my maternity extension on my CDA did not extend staff and consumable costs, I am currently running out of funds to support my staff, who are needed to finish and publish the remaining papers in the most efficient way. Due to the slow turn around of grant applications, without some immediate transition support, I would lose all my current lab members, which would have a massive detrimental effect on the lab that I have worked so hard to build, and I would lose even more momentum, which would further reduce my chances of successfully obtaining a Senior Fellowship. I believe 18 months is sufficient for me to publish the remaining key papers, gather enough preliminary data for the Senior Fellowship, and most importantly, regain my momentum and creativity, to write a Senior Fellowship that I am confident will be successful.

My CDA has investigated the role of mechanical forces in tissue growth, morphogenesis, and wound healing. I have made a number of key discoveries during my CDA, including the function of actomyosin in buffering mechanical forces to maintain tissue shape, and the role of tissue fluidity in wound healing. These have been published in high impact journals. However, the bulk of my CDA research is yet to be published. Several of these are critical for future grants, such as a Senior Fellowship, as they provide essential evidence to show that I can lead and manage an interdisciplinary research team and conduct research and publish at the highest international level, key criteria for Senior Fellows. The progress of these manuscripts has been hindered mostly by my 2nd period of maternity leave, which has taken place in the last 8 months. Inevitably my research momentum was reduced during these last 8 months as I simultaneously attend to a newborn. It would thus be physically and mentally impossible to apply for a Senior Fellowship, which would start by the end of my CDA in May 2020. I need additional time to regain my research momentum and give me sufficient time for the creative processes necessary to successfully apply for a Senior Fellowship. Due to the slow turn around of grant applications, without some immediate transition support, I would lose all my current lab members, which would have a massive detrimental effect on the lab that I have worked so hard to build, and I would lose even more momentum, which would further reduce my chances of successfully obtaining a Senior Fellowship. The aim of this Transition Support is therefore for me to regain research momentum, retain key current research staff, publish the remaining papers from my CDA in the most efficient and timely manner, and gather enough preliminary data to successfully obtain a Senior Fellowship.

The main beneficiaries are likely to be scientists working in related fields (see Academic Beneficiaries). However, this work will also benefit a wider audience:

Student training

A large number of undergraduate and graduate students will benefit from their involvement in this interdisciplinary systems level research through summer projects, rotation projects, and MRes programmes. I will be actively involved in various PhD programmes at UCL, and hopefully students will gain an understanding and appreciation of the way productive interdisciplinary collaborations work. Their training in science, presentation and time management skills, will benefit them in multiple future careers, academic or non-academic.

General Public

Through our various public engagement events, aimed at school children and adults, we will inform the public of our research, which will hopefully inspire future generations to study science, but also help the public understand the benefits of fundamental interdisciplinary research, and how it can improve human health.

Long term clinical impact

Apart from the immediate scientific beneficiaries, my vision is to apply the knowledge gained from this research to design novel physical therapies for tissue repair and regeneration, tissue engineering and cancer treatment. I aim to work with clinicians, material scientists and engineers to design the optimal tools and biomaterials to improve our treatment of these tissue defects. This has the potential to benefit lifelong national and international human health.

Commercial exploitations

The tissue stretcher that I have developed allows any tissue that can be explanted ex vivo, to be stretched or compressed, and live imaged at the same time - it can be easily modified to fit embryos, neurons, skin grafts, etc. I would like to commercialise this device so that it can be used by a wider range of clinical and non clinical scientists interested in applying forces to their tissue of interest. We have already started to explore some options with UCL Business.

Medical companies

Commercial companies interested in wound healing and anti-scarring/fibrosis therapies could use the mechanical measurement data around wounds to design strategies to counteract the over-growth triggered by the mechanical changes around the wound. Data towards understanding how wounds sense when to stop healing will be critical for medical companies to treat scars and fibrosis