Saving sight by turning back our “biological clocks”
Telomeres are structures made from DNA sequences and proteins found at the ends of chromosomes. The play a crucial role in a crucial role in cell fate and aging.
In young humans, telomeres are approximately 8,000-10,000 nucleotides long. Telomeres have three major purposes;
- Protection: they protect the end of chromosomes by forming a cap. Without telomeres, chromosomes are at higher risk of damage.
- Replication: every time a cell replicates the chromosome shortens. However, telomeres ensure that the essential part of the chromosome and important genes, do not shorten. However, with every cell replication the telomere shortens. Without telomeres, important DNA would be lost at 50-70 times the normal rate.
- Organisation: Telomeres assist chromosomes to be organised in cells.
When telomeres shorten to a critical length, the cell stops dividing and dies. The ‘critical length’ triggers the cell to die by a process known as ‘apoptosis’ or programmed cell death. Telomere length is a highly heritable trait, i.e., people inherit a strong predisposition from their parents to either somewhat shorter or longer telomeres than average. Once established at birth, the relative length of someone’s telomeres tracks fairly consistently throughout the life course. Other factors associated with having shorter than average telomeres include being of an older age, male sex, and caucasians.
Having shorter telomeres is associated with aging, mortality, and some age-related diseases. For example, people in the general population with shorter than average telomeres have, on average, about two and a half years lower life expectancy than people with longer than average telomeres. People who inherit extremely short telomeres due to rare mutations in specific genes suffer premature aging syndromes (“telomeropathies”), accompanied by life-changing damage to various organs and decades of reduced life expectancy.
Telomerase is an enzyme that adds nucleotides to telomeres to lengthen the telomere. Its discovery resulted in a Nobel Prize in 2009 which galvanised the scientific world. Since then, there has been significant research to understand the impact of shortening telomeres. Research has also been undertaken to identify diseases which are associated with shortening telomeres. The ultimate aim is to identify variables that can preserve telomere length and treatments that may result in lengthening telomeres. The key scientific findings regarding telomeres to date include:
- Mice models lacking the enzyme telomerase were found to show signs of premature aging.
- Telomere length is a good predictor of lifespan.
- Factors such as smoking and obesity shorten telomere length.
- Cancer cells contain active telomerase to enable them to become ‘immortal’ and continue to divide in an uncontrolled fashion.
- Telomeres and telomerase present a number of potential targets for the design of new cancer therapies.
Telomere biology has been identified to be significant in the following conditions:
- Aging
- Cancers
- Chronic kidney disease
- Chronic obstructive lung disease
- Diabetes
- Ischaemic heart disease
There is intense interest in developing medicines that can restore (and/or halt the shortening of) telomere length more appreciably through more powerful cellular rejuvenation. Researchers are trying to find a simple and safe way to manipulate telomerase, preserve telomeres, and create cures for telomere diseases.
A key approach is which complements longer-term strategies that aim to develop entirely new medicines – is to rapidly “repurpose” existing medicines that are shown to have telomere restoration and cellular rejuvenation properties, i.e., to redeploy to save and restore sight with drugs currently used for other purposes.
“Our team will be among the very first systematic users worldwide of this valuable data resource for the study of telomeres and age-related eye conditions.”
What is our novel approach?
We will conduct highly cost-effective studies of the role of telomeres in age-related eye conditions by taking advantage of innovative “big data” analytical techniques and a revolutionary large-scale research survey set up with separate funding to study other common diseases. With a team of inter-disciplinary clinicians, data scientists, and biologists, we will conduct a series of complementary and inter-locking computational, wet-lab and clinical investigations around the theme of telomeres in age-related eye conditions.
The aims of this three year project are to explore the relationship between telomere length and major causes of blindness using cutting-edge computational polygenic methods to analyse UK biobank in collaboration with the University of Cambridge to explore conditions such as; age-related macular degeneration, glaucoma, cataract and diabetic eye disease.
Vision Research Foundation has already provided research support to access the UK Biobank – one of the largest Big Databases in the world. The UK Biobank has already been used to make significant scientific discoveries. New technologies are accelerating the use of big data. In the past few years, researchers have developed new technologies to collect and process information at an unprecedented scale, with data-base size measured in petabytes or exabytes. With the advent of cloud-based storage and advanced modelling, complex analyses can be performed rapidly. Research in Big data, such as this project has the potential to enhance research and medical education as well as disrupt conventional approaches to healthcare.
The impact of this work could be profound for the prevention and treatment of age-related eye conditions, especially as age-related eye conditions are the leading causes of blindness in NZ and globally.
Dr William Schierding, PhD
William came to New Zealand in 2012 after beginning his career in the United States, where he earned his Masters Degree in Genetic Epidemiology and then worked as a Programmer Analyst at the McDonnell Genome Institute at Washington University in St. Louis. In New Zealand, William completed his PhD at the University of Auckland (Liggins Institute), where he was focused on the functional consequences of the 3-D structure of genome organization. William is currently working as a Senior Research Fellow at the Liggins Institute.
William’s research focus is on the intersection of genetic and epigenetic research with modern “big data” approaches (machine learning to determine the significance of molecular risk factors). He is currently studying the harmonisation of polygenic risk scores, epigenetic status, and clinical measurements in predictive computational models for better disease prediction (focusing on EEG and MRI imaging phenotypes, glaucoma, and various cancer types).
This work has led to several successful collaborations within Australia, the UK, USA, and Finland. Qualifications: PhD, Bioinformatics Areas of expertise: Machine Learning, Neural Networks, and Risk Prediction genome sequencing and mutation detection GWAS RNA sequencing DNA methylation Hi-C spatial genomics Research topics available for aspiring students: Big Data, Bioinformatics Cancer Glaucoma Epigenetics
