Richard M. Myers: “I have high hopes for the combination therapy being successful”
DocTIS is an EU-funded international collaboration bringing together leading biomedical institutions from Spain, Sweden, Italy, Germany, the UK, and the US. Through precision-focused, systems biology approaches, its mission is to improve treatment efficacy for six major immune-mediated inflammatory diseases (IMIDs): Crohn’s disease, ulcerative colitis, rheumatoid arthritis, systemic lupus erythematosus, psoriasis, and psoriatic arthritis.
By generating and analysing large-scale omics data from well-characterised patient cohorts (integrating clinical, molecular, and computational insights) DocTIS aims to identify drug combinations that surpass existing monotherapies in efficacy, safety, and durability. Now in its final phase, the project is transitioning from data generation and preclinical validation into clinical trials in Spain and the UK, with the goal of confirming its innovative therapeutic strategies in patient care.
Among the distinguished partners in this consortium, the HudsonAlpha Institute for Biotechnology plays a pivotal role in the Molecular Data Generation from IMID Biobank Patients work package.
The HudsonAlpha Institute for Biotechnology investigates the human genome to understand how allelic variation, gene expression changes, and epigenetics influence human traits, behaviours, and diseases. Using state-of-the-art, high-throughput genomic methods—including DNA sequencing, genotyping, chromatin immunoprecipitation, RNA expression profiling, transcriptional promoter activity measurement, and DNA methylation mapping—paired with advanced computational and statistical analysis, HudsonAlpha identifies and characterises the functional elements of the genome and how they work together in both healthy and pathological conditions. Their research spans brain disorders, amyotrophic lateral sclerosis (ALS), developmental disorders, autoimmune diseases, and more, and has supported over 5,000 research projects worldwide.
Within DocTIS, HudsonAlpha contributes to three interconnected tasks. In bulk genomic data generation, the institute conducts deep RNA-seq analyses on patient blood samples collected at multiple time points, creating detailed transcriptome profiles that are integrated with other molecular datasets to study disease mechanisms, treatment effects, and drug responses. In methylation data generation, the team performs genome-wide DNA methylation profiling of 384 blood samples to identify differentially methylated regions. In genotyping, HudsonAlpha sequences 192 individuals at 2.5 million genomic sites using a single pre-treatment sample per patient, leveraging the stability of genomic DNA over time.
We speak with Richard M. Myers, Ph. D, Chief Scientific Officer of the HudsonAlpha Institute for Biotechnology, to explore how this cutting-edge genomic infrastructure is driving the DocTIS mission forward.
Hi, Richard! Please, tell us about yourself.
Hi! I am Chief Scientific Officer, Faculty Investigator and former President of the HudsonAlpha Institute for Biotechnology, which is a non-profit research and teaching institute in Huntsville, Alabama, U.S.A. I did my undergraduate and Ph.D. degrees in Biochemistry (B.S. at University of Alabama and Ph.D. from University of California at Berkeley) and then did a postdoctoral fellowship with Tom Maniatis at Harvard University. My first faculty position was at the University of California at San Francisco, and after that I was at Stanford University School of Medicine, where I was Chair of Genetics and Director of the Stanford Human Genome Center. There, I directed one of the major U.S. genome centers where we, with the Joint Genome Institute in California, contributed more than 10% of the data for the public Human Genome Project. In 2008, I left Stanford to build HudsonAlpha, and I continue to do research and help in leading the institute.
What initially drew you to the DocTIS project?
I have been collaborating with Dr. Sara Marsal at the Vall d’Hebron University Hospital in Barcelona for more than 20 years, working to understand Immune Mediated Inflammatory Diseases. Sara had already begun collaborations around the entire country of Spain to build a remarkable biobank of patients and control individuals for six (now 8) IMIDs, and I was fortunate to be able to provide genomic and genetic expertise to delve into these disorders.
What role does your organization play in the DocTIS project?
My laboratory has collaborated with the DocTIS consortium since it began. Our expertise is in human genetics and genomics, emphasizing not only genetic variation and its contribution to disease, but also how our genomes are read and interpreted on cellular, tissue and organismal levels. This means we study regulation of gene expression, which includes understanding transcriptional control, cis- and trans-acting components of transcription and epigenetics. For the DocTIS project, we performed transcriptome analyses, genotyping and epigenetic analyses on the patient cohort that is the basis of this study. We have greatly enjoyed the camaraderie and collaborations with the talented group of DocTIS researchers, located in multiple countries.
What is the key innovation you are contributing to?
Years ago, we helped to develop methods for measuring messenger RNA (and other RNA) levels, as well as DNA methylation profiles, on a genome-wide scale, and we applied these to the DocTIS cohort. Our data were combined with data generated by other researchers in the consortium, helping to build an integrated and very large dataset that helped in choosing the disease and combination drug approaches used in the study. These data will also be used to analyse the clinical outcomes of the trial.
Regarding your initial expectations, how has the project developed?
It wasn’t particularly surprising, but it was wonderful to see this large group of researchers work closely together on a common goal, which is to develop and test a unique new way of treating disease. I have been involved in many large-scale collaborations and consortia, and this group has been such a positive and highly skilled team to work with.
What has been the biggest challenge for you and your team?
At the beginning of the collaboration, it took a little while for the team to coalesce, but once some kinks were worked out, it has sailed extremely smoothly. We are geographically dispersed, and while the in-person meetings were very important, virtual communication and sharing really helped.
What results from the DocTIS project have been most satisfying for you?
The fact that a new paradigm was developed by this group and is now in clinical trials is extremely satisfying and exciting. This is a major success, as it is hard to get all the pieces and ideas together to make a trial happen. I and all our colleagues are especially excited to have a very strong possibility of helping patients and families.
The clinical trials have started, what are your expectations?
Drug development is always incredibly difficult, and many attempts fail. However, I am more optimistic about this trial succeeding because the logic behind the choice of the two already-approved drugs is very strong, safety profiles of each of them are strong (so it seems less likely that adverse events will occur), and the trial design by real experts is so sound.
How do you think DocTIS could help improve the quality of life for IMID patients in Europe?
Because IMIDs are lifelong diseases and the existing drugs work for only a portion of patients with a disease, this new regime of combination therapy seems likely to be effective for a significant number of patients. Effective means that they have fewer flares and can make the disease have much less impact on their day-to-day lives.
What key learnings do you take from the DocTIS collaboration?
I learned a lot more about clinical trials than I had known before. It was really helpful to see the care and thought that need to go into designing an effective trial.
Is there anything about your team you would like to highlight?
I have a wonderful laboratory of deeply experienced and dedicated researchers, and many of them contributed in various ways to our DocTIS work. I particularly want to mention Dr. Ivan Rodriguez, a senior scientist who led much of the effort in my lab.
What are your hopes for the future of DocTIS and IMID therapies?
I am very happy with the progress that was made in this project, and I have high hopes for the combination therapy being successful. I think the logical next step will be to apply the same combination to additional IMIDs.
As DocTIS enters its final stage, it highlights the power of collaboration across countries and disciplines. Led by the Vall d’Hebron Research Institute (VHIR), the consortium unites Cardiff University, the University of Verona, Charité – Universitätsmedizin Berlin, the Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), the National Center for Genomic Analysis (CNAG), IMIDomics Inc., HudsonAlpha Institute for Biotechnology, and Zabala Innovation. Each partner brings unique expertise, whether in patient care, clinical trials, genomic research, large-scale data analysis, or project coordination, all working toward the same goal: developing safer and more effective combination therapies for people living with IMIDs.
