DR MICHAEL WORMSTONE
PROJECT TITLE: ONGOING FUNDING OF THRT LABORATORY AND ASSOCIATED PHD STUDENTSHIP
PROJECT TIMESCALE: 1st January 2017 to 30 September 2020
The Humane Research Trust Laboratory within the School of Biological Sciences at the University of East Anglia is a centre of excellence in eye research. The support provided by the Trust provides infrastructure, which enables our research strategies to develop and facilitate student education, both at undergraduate and postgraduate level.
The laboratory has a long record of success and innovation; it was therefore important to maintain the standards set by the late Prof George Duncan who was the first Director of the laboratory who sadly passed away in 2007. From that time on, Dr Michael Wormstone has fulfilled this role and the laboratory has continued to thrive under his leadership. The laboratory has greatly advanced knowledge of eye biology and disease resulting in several seminal publications and importantly clinical benefit to patients. Our research is cutting-edge and has lead to a number of major advancements in biomedical research. The basic philosophy is to establish the best model systems to study a particular tissue/organ and in turn elucidate the mechanisms that underpin disease, in doing so we can identify novel therapeutic targets. We strongly believe that human cells and tissue provide the best models for human disease. Our work has improved the well-being of tens of thousands, but a desire and ambition to help many more through our research runs deep and we are working hard to make this happen.
A range of research projects are actively being carried out within the laboratory that aim to improve corneal transplant success, prevent the formation of a fleshy outgrowth across the cornea known as pterygium, improve healthy ageing of the lens to delay cataract formation and improve outcomes for cataract patients. An overview of one line of study is provided below.
How to prevent old bags wrinkling!
Cataract is a clouding of the lens within the eye and affects millions worldwide. At present, the only method available to treat cataract is by surgery. It is estimated that by the year 2020, more than 30 million such operations will be performed annually. The lens can be thought of like a smartie with a soft elastic shell and a protein-rich centre capable of bending light. Cataract generally affects the central part of the lens. In a cataract operation, the surgeon will remove a circular section of the outer shell, which allows them to extract the majority of cells and tissue in the centre of the lens. The product of this procedure is called a capsular bag (Figure 1). An artificial intraocular lens (IOL) can be implanted into the bag, which is required for high quality vision. Initially, outcomes from cataract surgery are superb, but in a significant number of patients a progressive reduction in visual quality often occurs. This problem is known as posterior capsule opacification (PCO) and results from lens cells that survive the rigours of cataract surgery. These cells in time grow across the capsular bag and deform it causing wrinkling of the capsular bag (Figure 1). If these changes take place within your line of vision then sight is reduced. To resolve this problem laser surgery is required to remove the light scattering/wrinkled tissue.
Figure 1: A Diagrammatic representation of a post-surgical capsular bag and PCO development (Wormstone 2009)
Figure 2. A cartoon illustrating the position of a conventional square-edge/closed-bag IOL (top) and an open-bag IOL (bottom) within the capsular bag and how their physical properties could provide a barrier to cell movement. It is also proposed that the open-bag IOL will restrict growth factor levels to cells.
Clinical research shows that a square-edge profile to the IOL inhibits lens epithelial cell movement onto the back of the lens and reduces PCO. However, it has become apparent that this only delays rather than cures the problem. Laser treatments still need to be performed in about 10 – 20 % of patients within 2 years of surgery. Following surgery with implantation of a conventional IOL, the front surface of the lens will typically stick to the back surface of the lens and the IOL (Figure 2). This contact results from cell-cell interactions and release of biological materials, which act like glues fusing the different parts together. This scenario can be described as a closed capsular bag system. Clinical studies suggest that if the capsular bag is kept open, following cataract surgery, with separation of contact between the anterior and posterior capsule, PCO is reduced (Figure 2). Previous work in the laboratory using a human in vitro capsular bag model employed comparative experiments between a traditional closed IOL (Alcon Acrysof) and a novel open bag IOL (Zephyr provided by Anew Optics) and observed better PCO prevention with the open bag IOL design. Our findings, published in IOVS fed into Anew Optics development programme and the first clinical trials for the Zephyr IOL are planned. In addition to showing the benefits of these open-bag IOL designs and aid their development, we elucidated biological mechanisms that govern their success.
To this end we investigated the effect of growth factors on PCO in relation to open and closed bag devices. Separation of the anterior and posterior capsules significantly reduced growth and fibrotic modifications. Using a cytokine screen, we identified several molecules whose expression levels correlated with growth. Vascular endothelial growth factor (VEGF) was determined as a potentially important regulator of PCO. VEGF was found to be abundant in the capsular bag cultures and inhibition of VEGF signalling reduced lens cell growth and fibrotic modifications in standard culture conditions. Anti-VEGF drugs are in clinical use within the eye and thus the path to their clinical application for PCO prevention will be easier to achieve than for non-FDA approved agents. To build on this base we will pursue two lines of investigation to improve management of posterior capsule opacification and improve outcomes for millions of cataract patients (Figure 3). One method will adopt a physical approach to improve the design of the IOL in order to reduce the impact of biological forces that drive PCO. The second approach will target VEGF. In the latter case we will explore a range of drug delivery approaches to provide the best treatment strategy. We also plan to merge these two strategies, such that anti-VEGF approaches can be used in combination with new IOL designs. Our belief is that this combined strategy will provide the best solution to PCO and improve the lives of millions.
Figure 3. Outline for future developments
- Matthew McDonald, recipient of The Grenville Hawkins Memorial Studentship contributed greatly to this project through the work of his studentship.
- Additional funds were acquired from Fight for Sight to support the work and employ Dr Julie Eldred, a long-time and loyal member of the team.
- Work relating to this project was published in the open access journal Scientific Reports
Eldred JA, McDonald M, Wilkes HS, Spalton DJ, Wormstone IM. Growth factor restriction impedes progression of wound healing following cataract surgery: identification of VEGF as a putative therapeutic target. Scientific Reports, 2016; 6:24453. doi: 10.1038/srep24453.
- Matthew McDonald received the 2016 Student/Trainee Prize in Ophthalmology, known as the Dermot Pierse prize from the Royal society of Medicine
- Work relating to this project has been presented at various meetings throughout the world
NOVEMBER 2015 – INTERIM REPORT
The latest round of funding for the Humane Research Trust Laboratory started on 1st January 2014. We have achieved a great deal in this time. The laboratory has always been viewed as a centre of excellence in eye research and we have continued to maintain this reputation through the current period of funding. We deeply appreciate the generous support of the Humane Research Trust and we are all driven to ensure that we can effectively translate this into meaningful outputs. The current arrangement for the laboratory funding supports a post-doctoral scientist, a PhD student and technical support in addition to laboratory consumables to enable general running of the laboratory. This base has provided stability and an effective working team is firmly in place. This has enabled us to draw in additional grant support from a range of sources. We have also published ten articles and currently have a number under review. The laboratory has also provided a base to support a number of students and several team members have received prizes and awards for their work carried out in the laboratory. In addition, some of the data established by the core team is being used to form the basis of grant applications and has enabled collaborations to take place. The fundamental aims of the current round of funding were to maintain a level of excellence, to further develop our human model systems and broaden the net of interest in our work.
Developing and Refining Human Model Systems
We lead the world with many of our human culture systems and we continue to innovate and refine these models. We are conscious of the need to provide valuable human resources for ocular research in general. With this in mind we are developing a novel tool to immortalise human cells from different parts of the eye. Most cell lines are driven to grow and are often tagged with the label ‘immortal’. This driven state is relevant to rapidly dividing cells, but the natural state of many cells within an organ have limited cell division, such cells include lens epithelial cells, corneal endothelial cells and retinal ganglion cells all of which play a role in ocular health and disease. Our approach is to introduce a molecular system called hTERT into the cells that will establish large populations, but at an appropriate time we will add a trigger that will remove this driving force from the cells and return them to a ‘primary state’ associated with low rates of cell division. This will take some time, but the value of this work will be huge.
Julie Sanderson’s group have also continued to develop their work on the human retina, which has resulted in an extension of the period the organotypic retinal cultures can be maintained, which will increase this model’s value in toxicity testing.
I was also keen to improve our immunohistochemistry potential in the laboratory. Julie Sanderson and her group have employed this technique to great effect on the retina and have produced some beautiful work through this approach. The human lens however is a demanding organ to section even for the most advanced pathologists and I set The Humane Research Trust Student, Simon Ball, the task of getting this right. Simon applied a great deal of effort to this and has now established protocols to produce excellent sections of the lens and he will present some of this work at the annual Association for Research and Vision in Ophthalmology (ARVO) meeting in Seattle next May.
A developing area of research in the laboratory concerns the cornea. We will employ a range of methods to study corneal cell behaviour, which will include human lens cell lines, tissue-derived cells and whole corneal cultures. One of our major ambitions in this area is to optimise corneal storage medium. If this can be improved more donated corneas could be used for transplants.
Engagement and Interaction
An important objective for the current round of funding was to engage more people in our research. We have managed to achieve this through outreach exercises, collaboration with scientists and forming industrial partnerships.
Communicating our findings to the general public, academic peers and company representatives is vital. We pass on our findings to the public in several ways. Through the Trust, newsletters and blogs ensure that supporters can keep up to date with our activities. We have also participated in outreach events in Norwich, for example we contributed to a science day on the senses at Norwich Castle, which was attended by more than 1000 people. These kind of activities are very important as we find many people are fascinated about the science of the eye and how diseases form. It is equally important to communicate our findings and methods to fellow scientists. The best vehicles for this are through publication in journals and presentations at meetings. To this end we have published ten articles since 1st Jan 2014 and delivered twelve oral presentations (ten as invited speakers) and seven posters at national or international meetings. Meetings are particularly important as they allow students to integrate with fellow scientists (young and old) within their field and enable senior scientists to have face-to-face discussions with peers and representatives from industry, which can (and in fact have) lead to collaboration.
Since the start of the current round of funding we have continued to extend our links to other laboratories both within UEA and beyond. I have started to collaborate with scientists at Colorado University. They are now using human lens cell lines, primary human lens cell cultures and human lens tissue explants within their laboratory, while we perform capsular bag experiments. Andrew Smith played a key role in this collaboration and he is joint first author on an article that will be published in Aging Cell, which addresses the role of matrix changes in fibrosis. I feel that this collaboration will continue to develop in the future and lead to more important shared publications and grant applications.
We have teamed up with a health economist, also called Andrew Smith, as in some cases the moral or even scientific argument to develop a line of investigation can fall on deaf ears. We are currently assessing the cost of cataract in drug development per se and reviewing the impact a human lens cell line screening assay could have on the drug development process. A paper has resulted from this collaboration and will be published in Drug Discovery Today.
Julie Sanderson has also established collaborations with colleagues at Cardenal Herrera University in Spain and at the University of Cambridge to investigate neuroprotection of retinal ganglion in relation to glaucoma. These collaborations are again formed because of the human model systems Julie and her team have developed and communication of these tools at meetings.
Locally, I have teamed up with Dr Aram Saeed (School of Pharmacy, UEA) who has expertise in 3D printing and polymer chemistry. We now have a shared PhD student and a technician supported by UEAs proof of concept fund. The purpose of this collaboration is to be able to manufacture intraocular lenses, which are implanted routinely in cataract surgery. This will allow us to modify their design/material, subject them to industry standard quality control and evaluate their impact on posterior capsule opacification using our human capsular bag culture system.
A number of students have had the pleasure of working in The Humane Research Laboratory. Support for our undergraduate students is an integral part of the laboratory’s support. Since 1st January 2014 we have supported 19 undergraduate final year project students in the laboratory. Our project students become lab members for the duration of their project and can contribute greatly to our research. In some cases students contribute to published works. Indeed Kamal Manzar, a former project student is a co-author on a recently published article in IOVS, while another, Helen Wilkes is a co-author on a submission to Scientific Reports that is currently under review.
With respect to postgraduate studentships we have a number of students who have worked in the laboratory over the past couple of years. Two of these, Simon Ball and Matthew McDonald are/were supported by the Trust. Both have been successful. Simon, as I described earlier, has greatly advanced our immunohistochemistry capabilities in the lens and has developed new assays to increase our knowledge of DNA repair in the eye. He is an author on one published paper and has another under review. Matthew, who was the recipient of the Grenville Hawkins Memorial Studentship, again enjoyed a very successful time with his work on vascular endothelial growth factor (VEGF) in the lens. Matthew’s work was rewarded with the Association of Physician’s award and is co-author on a submission currently under review. He also completed his year of study with a distinction. Both Simon and Matthew will be attending the ARVO in May 2016, which will add greatly to their education.
Prizes and Awards
The excellence of the research carried out in the Humane Research Trust laboratory has been recognised by a number of prizes and awards to team members. These are listed below.
Most recent is the invitation to Dr Michael Wormstone to become a Silver Fellow in the ARVO Fellows Class of 2016. On behalf of everyone at the Trust, many congratulations on the honour of receiving this invitation. The citation speaks volumes of your contribution, dedication and successes in your chosen field of vision and ophthalmology research, and is a tribute to both you and the university.
- British Toxicology Society (BTS) Travel award to Annual Congress (Phillip Wright).
- BTS ‘Best Poster’ prize at the Annual Congress (Phillip Wright).
- 2015 ARVO Travel Award (Phillip Wright).
- National Foundation for Eye Research (NFER) Young Investigator Travel Award to attend ICL 2015 (Andrew Smith).
- Association of Physicians Award (Matt McDonald).
- ARVO annual meeting programming committee – Physiology/Pharmacology Section. Chair 2014 (Julie Sanderson).
- Invited to become an Editorial Board Member of IOVS (Michael Wormstone).
- Made a Fellow of the Association for Research in Vision and Ophthalmology (Michael Wormstone)
- NFER Cataract Research Award (Michael Wormstone).
I feel the structure currently in place has worked extremely well and has established a stable core within the laboratory. This has provided flexibility in how we approach specific projects and has set a firm foundation for new publications and grant applications.
I believe we have utilised the generous support provided by The Humane Research Trust to great effect and we continue to be a centre of excellence. We have further developed our research platform, generated multiple outputs and broadened our connections. We remain determined to further develop our ideas with the ultimate aim of benefitting the millions of individuals worldwide affected by eye disorders.
JAN 2015 – DR WORMSTONE COLLECTS A MUCH DESERVED AWARD
I wanted to let you know some good news. I have been named the recipient of the National Foundation for Eye Research (NFER) Cataract Research Award and will receive this at the big eye meeting (ARVO) in Denver this May. The prize is an international award based on career performance and contribution to the field. I am obviously pleased personally to win the award, but it very much reflects the efforts of the whole team and places into context the international reputation of the lab and the significant contributions our work is making to the field.
“I am delighted to see that you are the recipient of the NFER Cataract Research Award. It is a great reflection on you and your team, the School and its laboratory and the University. Congratulations to you all.”
Les Rhoades – Chairman
DECEMBER 2014 – LATEST NEWS
Today was the announcement of the national Research Excellence Framework results. UEA has fared well. The University has prepared several web pages relating to the REF and have used our work as a case study/research highlight. The link to the relevant webpage ishttps://www.uea.ac.uk/research/ref/research-stories/improving-success-rates-for-cataractsand I thought this would be of interest to the Trust’s supporters.