Bigger, Bedouins, and a blind gazelle – Ireland’s contribution to corneal transplantation

VISICORT is an Irish-led European project, which is carrying out groundbreaking research that will help to improve the outcomes of corneal transplantation. This is not the first time that Ireland has led the field in corneal transplantation. In fact, the first recorded successful experimental corneal allograft was carried out in the early 19th century by Samuel Bigger, an Irish ophthalmic surgeon.

Bigger’s surgical breakthrough took place in unusual circumstances. While travelling in Egypt in 1837, he was captured and held for ransom by a Bedouin tribe. For the intrepid Dr Bigger, a period of captivity in the Egyptian desert was an opportunity for, and not an obstacle to scientific discovery. A footnote to his article ‘An Inquiry into the Possibility of transplanting the Cornea’, published in the Dublin Journal of Medical Science in 1837 laconically reports his success:

The first time Dr Bigger had an opportunity of trying this experiment on one of the inferior animals, occurred in 1835, at a period when he was a prisoner with a Nomadic tribe of Arabs, about twelve or fourteen day’s journey from Grand Cairo. The subject of the operation was a pet gazelle, who had lost one eye from inflammation, and the power of seeing with the other, from a wound of the cornea. The cornea was taken from another animal of the same species, brought in wounded, but not quite dead; adhesion took place, and ten days after the operation the animal gave unequivocal signs of vision, the upper part of the transplanted cornea remaining perfectly transparent.

On his return from Egypt in November 1835, Bigger continued his experiments with rabbits, and continued to refine his approach, adjusting the knife used, the position and number of sutures, and the post-operative treatment of the animals.

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The title of Bigger’s article, as it appeared in the Dublin Journal of Medical Science

Bigger’s work followed on from the research of Johann Dieffenbach (1792–1847), whose disappointing results led him to conclude that keratoplasty was ‘an audacious fantasy’, which would never be achieved. Bigger’s success reinvigorated efforts to successfully carry out corneal transplants into humans. In 1838, Robert Sharp Kissam attempted the transplant of a pig’s cornea into the eye of a young man who was practically blind as a result of a leucomatous cornea. The graft was initially successful, but became opaque after 2 weeks.

Throughout the remainder of the nineteenth century, numerous efforts to achieve a successful corneal allograft in humans continued. These all ended in disappointment, until 7 December 1905 when the Austrian surgeon Eduard Konrad Zirm (1887–1944) performed the first successful penetrating keratoplasty in a human where the graft remained clear. A cornea from an 11-year-old boy who had been blinded by a penetrating scleral injury, was transplanted into the eye of Alois Glogar, a 45-year-old labourer, who had been blinded by severe alkali burns. Zirm’s success proved difficult to replicate – and after reporting the first successful transplant, Zirm himself did not publish any other work on keratoplasty.


4 Eduard Zirm and his patient Alois Glogar

Over the first half of the twentieth century, significant contributions to the development and refinement of keratoplasty techniques were made by a number of prominent ophthalmologists, and an infrastructure for the donation of corneal tissue was established in Europe, the United States, and beyond.

Dramatic technical improvements have been made since Dr Bigger took his scalpel to the Egyptian gazelle. But, in spite of these developments, corneal allograft rejection continues to be the greatest limitation in corneal graft survival. VISICORT’s research addresses this challenge directly, and will provide a clearer understanding of the mechanisms of corneal rejection and new clinical tools and therapies to improve the outcomes of corneal transplantation. Dr Bigger would have approved!

Mark Sweetnam

You can find a more detailed history of corneal transplantation here.

VISICORT research at AVRO

ARVO (1)

VISICORT researchers Jesper Hjortdal, Uwe Pleyer, and Henrik Sejersen at ARVO

VISICORT PI Prof. Jesper Hjortdal presented a poster on VISICORT’s research at the ARVO  (Association for Research in Vision and Ophthalmology)conference which took place in Seattle from April 30th to May 5th. Prof. Hjortdal’s poster was entitled “Adverse Immune signatures and their prevention in corneal transplantation: presentation and update on the VISICORT project” (citation: Hjortdal J. IOVS 2015;57:ARVO E-Abstract 1231).


VISICORT’s Conor Murphy features in the Medical Independent

VISICORT’s Conor Murphy features in the Medical Independent’s series on cutting-edge Irish healthcare research. Find the article here.


Using tears to source potential biomarkers

Dr Thierry Le Bihan, SynthSys Laboratory, University of Edinburgh

Dr Thierry Le Bihan, SynthSys Laboratory, University of Edinburgh


VISICORT partner Dr Thierry Le Bihan leads the proteomics group at the University of Edinburgh’s SynthSys Laboratory. His team are developing protocols for profiling proteins contained in biological samples from corneal transplant recipients enrolled into VISICORT’s bio-sampling project from five leading European Ophthalmology centres. He comments here on the unique promise (and challenges) of performing proteomic analyses on samples of tears.

Considering all biological fluids as a source of potential markers, tears are quite an attractive option as they are easily obtained by non-invasive methods compared to other types of fluids. Although tears remain a relatively complex and challenging fluid, their analysis is not as difficult as plasma or other fluids which contain a large number of highly abundant proteins. However, one of the obvious difficulties with using tears is related to the amount of fluid sample that can be obtained. There are an increasing number of proteomics studies of tears which have quickly evolved from the generation of list of proteins and method development which were published earlier (De Souza et al., 2007, Genome Biology 2006, 7:R72, doi:10.1186/gb-2006-7-8-r72).

Lei Zhou is one of the most dedicated researchers in the field of tears proteomics and is senior author of the research team that recently published an interesting method to quantify 47 proteins using a high-resolution, multiple reaction monitoring, MS-based assay (Tong et al, 2015, doi: 10.1016/j.jprot.2014.12.002). We have also seen more clinical studies of an ophthalmologic nature being performed of late. Li et al, (2014; Sci rep doi:10.1038/srep05772) published a valuable clinical study of Sjögren syndrome patients with dry eye syndrome.   Other researchers have also begun to explore conditions which are beyond the ophthalmology scope such as Lebrecht et al., (2009; Cancer Genomics Proteomics. 2009 6(3):177-82) which is based on a SELDI approach to identify potential biomarkers for breast cancer in tears. Analysis of tears for proteomics is among the most recent of all bodily fluids. With mass spectrometry instruments becoming more sensitive, and in combination with other “omics” strategies, I am convinced that the use of tears as a source of potential biomarkers will expand significantly in the years to come.

New study reveals how short-lived mesenchymal stem cells re-programme the immune system to prevent corneal transplant rejection

The laboratory of VISICORT researcher Prof. Thomas Ritter has demonstrated that intravenous infusion of mesenchymal stem cells (MSCs) can reduce the rate of rejection of experimental corneal transplants (Treacy et al., Am J Transplant. 2014 Sep;14(9):2023-36) and we are now actively working toward performing a clinical trial of MSCs in human corneal transplant recipients at high risk for rejection. One of the most important research questions regarding MSC therapies in corneal transplantation and other immunological conditions relates to the fact that these cells can exert long-lasting effects on the immune system while persisting in the body for only 1 or 2 days after administration. An important new study from the Department of Ophthalmology at Seoul National University Hospital, South Korea (Ko et al., Proc. Natl. Acad. Sci. USA, 2016 Jan 5;113(1):158-63) has shed new light on this question.

Untitled VISICORT Post-doctoral Researcher, Dr. Paul Lohan who works with Prof. Ritter’s group at the National University of Ireland, Galway comments on the study by Ko et al.:

Regulatory immune cells may be critically important to promote improved survival of an allograft such as a corneal transplant. One such immune cell population is myeloid cells including regulatory monocytes and macrophages. In this paper, Ko and colleagues aimed to investigate whether MSC-educated myeloid cells can induce immune tolerance to allogeneic corneal transplants and to determine the mechanism by which this might occur.

The authors administered one million human MSC intravenously to mice 7 and 3 days prior to transplantation of corneas from an unrelated mouse strain. The results showed that MSC-treated transplant recipients had improved rejection-free graft survival compared to non-MSC treated recipients. Additionally, human MSC-treated recipients had less inflammation in the grafts and draining lymph nodes, a more intact corneal endothelium, and less corneal oedema. However, the authors did not attribute these effects to MSCs migrating to the site of transplantation and acting directly on the rejection process as less than 10 MSCs per cornea were detectable. Therefore it appeared likely that the immune modulatory effects of intravenous MSCs take place elsewhere in the body.

The authors found an increased percentage of myeloid cells co-expressing the surface marker combination MHC-II, B220 and CD11b in the lungs of animals treated with human MSCs. To investigate if these cells had the ability to modulate an immune response leading to corneal transplant rejection, B220+ and B220 myeloid cells were isolated from the lungs of human MSC-treated mice. When these isolated lung cells were cultured with stimulated T cells, it was found that B220+ cells significantly suppressed T cell activity, thereby confirming their immune regulatory potential. They next transferred B220+ myeloid cells to mice at the time of a corneal transplant and found that they resulted in a significantly increased rate of rejection-free survival. Furthermore, human MSC administration failed to prevent corneal transplant rejection in mice lacking myeloid cells.

Previous studies have indicated that MSC therapeutic effects are mediated through secretion of soluble molecules. The authors of this study found that expression of a gene known as TSG-6 was increased in the lungs of human MSC-treated corneal transplant recipient mice. The involvement of TSG-6 in generating regulatory myeloid cells was confirmed by the observation that blocking production of TSG-6 in human MSCs prevented the increase of B220+ cells in the lungs of treated mice.

This study provides an explanation for a paradox in the MSC field, i.e. the fact that MSCs only survive a matter of hours or days in the recipient but can have long-lasting effects in immunological diseases. If a similar mechanism occurs in human transplant recipients, then it will represent a powerful new approach to preventing rejection.”

Report on EU MSC2 2015 meeting – Shaping the future of MSC Therapy

ADIPOA-2 researchers participated in the EU-MSC2 meeting in Leiden on the 7th and 8th of September 2015

The two-day meeting brought together researchers from nine EU-funded projects pursuing MSC research. In addition to REDDSTAR, other projects represented at the meeting included ADIPOA-2REDDSTARStellar, RETHRIM, REACH, MERLIN,SCIENCE and NEPHSTROM. After a welcome from Henri Lenferink, Mayor of Leiden, European Commission Project Officer Dr. Charles Kessler highlighted the EU’s continued support to regenerative medicine research, and a Fundamental MSC Biology lecture was delivered by Prof. Dr. Yufang Shi from the Institute of Health Sciences, Shanghai, China. Following on, the nine EU-funded projects were presented.

On the second day of the meeting, interactive panel discussions about key challenges faced when developing MSC therapies, including scientific obstacles, regulatory and ethical issues, technological hurdles and commercialisation barriers ensued. Opportunities for future collaborations and the harmonisation of MSC research in Europe were discussed.

A report of the EU MSC2 meeting is available here.


VISICORT consortium mets at the Aarhus University Hospital

VISICORT Aarhus Group Photo 121110

The VISICORT consortium met at the Aarhus University Hospital, Aarhus, Denmark on the 12–13 November for the project’s third plenary meeting. Teams of researchers from each of the twelve partners involved in the project listened to reports of the work being carried out in each of the project’s workpackages. These included reports of the preclinical experimental work being carried out to model corneal rejection in rats and to access the benefits of mesenchymal stem cells (MSCs) in helping to prevent transplant rejection. The consortium was also updated on the progress in recruiting patients to VISICORT’s clinical studies, and the work that has been carried out to support the complex sample and information management needs of this ambitious project.

Commenting on the meeting, VISICORT coordinator Prof. Matthew Griffin (NUIG) said: “It was clear from our meeting in Aarhus that the VISICORT project is now in full swing. We are fortunate to have recruited an exceptional group of front line researchers who are working together across all partner sites to optimise and streamline biological sampling and transport procedures, maximise subject enrolment to our clinical studies, perform and interpret key pre-clinical experiments, and lay the groundwork for advanced immunological profiling and system-level analysis of corneal transplant rejection. The VISICORT consortium has established and integrated two unique assets that serve as a foundation for the next stages of the project: a purpose-designed clinical database of new and established corneal transplant recipients from five leading medical centres developed for us by PathXL, Belfast, Northern Ireland and a centralised bio-repository of samples from these same study subjects at the site of VISICORT partner Biostór Ireland Ltd. In addition, the combined clinical, scientific and technological expertise of the consortium is being harnessed to effectively translate our pre-clinical observations into the first clinical trial protocol for mesenchymal stems cells in corneal transplant recipients at high risk for rejection. We face an exciting time over the next six months with laboratory and clinical studies beginning to yield novel data and insights into the immune responses that determine the success or failure of the most common tissue transplant”.

Prof. Jesper Østergaard Hjortdal (Aarhus University), who hosted the meeting comments: ‘It was a great pleasure to welcome the VISICORT team to Aarhus University Hospital. In addition to progress reports from each workpackage, three workshops were organised in the fields of clinical studies, sample collection, preparation and logging, and bioinformatics. The meeting was held in a very constructive atmosphere, and all indications suggest that the VISICORT project will have a very successful outcome.”

The corneal transplant team at the Department of Ophthalmology at Aarhus University Hospital is the largest in the Nordic countries, and performs around 300 corneal transplantations annually. In addition, the Danish Cornea Bank, which is based at the hospital? distributes more than 400 cornea grafts per year. Corneal transplantations are only performed at two hospitals in Denmark, and the hospital in Aarhus serves more than half of the Danish population (close to 3 million citizens). 


Winning essay writers visit REMEDI

The Regenerative Medicine Institute (REMEDI) at NUI Galway was delighted to host a visit by winning essay writers from St Nathy’s College,  Ballaghdereen, Co. Roscommon. Each of the winning students had written an essay on the topic of stem cell, outlining the history of their discovery, and their potential to revolutionise the treatment of a range of medical conditions. The winning students – Michael Raleigh (1st), Tom Murray (2nd), Mohammad Hamid (3rd), and Annie Quinlan (3rd) – and John Guilfoyle, their teacher, were treated to a tour of REMEDI’s facilities. The competition was initiated by Oonagh Redmond, a teacher at St Nathy’s, and was organised by members of the ADIPOA-2 team. Prizes were sponsored by ADIPOA-2, VISICORT, and REDDSTAR.

VISICORT brochure available for download

VISICORT z-fold brochure draft-p1

VISICORT has produced a new brochure to promote the project, and to explain its aims, objectives, and approach to a general audience. Copies of the brochure can be downloaded here.

Italian Study of Corneal Transplantation  (Y. O’Donoghue, Orbsen Therapeutics)

A recently published study in Transplantation Proceedings presents changing trends in corneal transplantation (CT) from Italy.  The Corneal Transplant Epidemiological Study (CORTES) presents seven years of data, 2002 to 2008, from a prospective study which included over 13,000 CT.  In general, trends were driven by changing clinical practise and mirrored similar trends observed in Western countries over the same period.   The study demonstrated the marked transformation in surgical approach to CT from Penetrating Keratoplasty to Endothelial Keratoplasty in recent years.  Of particular relevance to VISICORT is the 20% increase observed in re-grafts over the period; regraft was the second highest indication for corneal transplant over the study period.  Regrafts are considered as high-risk transplants and VISICORT’s immunomodulatory stem cell therapy aims to provide novel treatment for high-risk transplant recipients.