My Reflections on NF1 – A Segment of My Journey
Meena Upadhyaya, OBE, FRCPath, FLSW, Medical Geneticist and Professor Emerita, Cardiff University
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I joined the Neurofibromatosis Type1 (NF1) research project in 1986; my prior knowledge of NF1 was restricted to two contexts: first, the TV soap opera Dallas, where a relative of Pam was portrayed as having NF1, and second, the Elephant Man considered to have NF1 for many years. As I reflect on that phase of my life, I was in a vulnerable state, grappling with the loss of my husband and the challenges of single parenthood without family support.
Dr. Upadhyaya in Turkey
I got involved with the NF1 project by coincidence. Dr Sue Huson was concluding her MD thesis and preparing to move from Cardiff to London. She had amassed a significant number of NF1 families from Wales and beyond along with their complete clinical details. I utilised DNA from these families for linkage studies to map the disease gene onto a chromosome, and my initial contribution was presenting an exclusion map of NF1 as a poster at the American Society of Human Genetics in 1986 in Washington DC. This poster suggested five chromosomes as the probable location for the NF1 gene. In 1987, I attended the Runnymede meeting in Surrey, London, which was organized by the UK NF support group then called LINK now Nerve Tumours UK. The objective of this meeting was to establish the exclusion map of NF1 conclusively. At this meeting, it was agreed that the probable site for the disease was on chromosomes 17, 5, and 19. Within a few weeks of this meeting, the gene linkage papers were published in Cell and Science. Our research group in Cardiff co-authored the Cell paper. To be honest, at that time, being new to this research area, I had not quite grasped the importance of this discovery.
In 1987, the late Professor Harper, my mentor, asked me to represent him at the NNFF (now CTF) meeting in New York. This was my first time attending such a meeting, and I was quite nervous. However, my talk was well-received, and it gave me the motivation to continue. The meetings back then were small, with only 20-30 people attending, and I had the opportunity to meet many amazing people in the field, including Francis Collins, Bernd Seizinger, Nancy Ratner, Peggy Wallace, David Viskochil, Vic Riccardi, Bruce Korf, David Guttman, and more.
For the next three years, until the identification of the NF1 gene, quarterly meetings were held in New York to share research data among the researchers. At each meeting, we were expected to present new results, which was quite challenging for me as I had to balance work and taking care of my daughter, moreover, my research team was significantly smaller than the American groups. I remember after many of these meetings, Sue Huson and I would write manuscripts in our hotel room as there were tight deadlines for publication of the proceedings of these meetings. In May 1990, I presented a Welsh NF1 patient with a 90Kb deletion mapping to the candidate region for the NF1gene before cloning the gene. This caused a lot of interest and stir among the attendees, and Peter O’Connell, the principal investigator at the Howard Hughes Medical Institute in Salt Lake City, invited me to his lab with my DNA samples. I immediately accepted his offer, but I had to delay my trip by eight weeks due to my daughter’s upcoming exams. As I was boarding the plane on July 6th, I received news that the NF1 gene paper had been published that morning. While I was initially disappointed to have missed out on such a prestigious opportunity, I realized that my daughter’s education was far more important. As parents, we must prioritize our children’s futures and ensure that they receive the best possible education. I stand by my decision, knowing that I made the right choice.
During my historical visit to Salt Lake City, I had the opportunity to learn and acquire new techniques that I was able to implement in Cardiff. I also made many friends including David Viskochil and Richard Cawthorn. On my way back to London, it was a privilege to meet with
Francis Collins, Peggy Wallace and David Gutmann at Michigan. In October 1990, I was invited to the Banbury Centre, a small conference centre located at the Cold Spring Harbor laboratories. This institution is ranked among the leading basic research institutions in molecular biology and genetics. Although I did not realize the significance of this prestigious place at that time, I was privileged to meet some very high-profile scientists and physicians including the famous Nobel prize winner James Watson (the inventor of the structure of DNA), David Cox, and Ellen Solomon.
After significant effort, my research group became the leader in finding NF1 germline mutations despite the presence of multiple NF1 pseudogenes. It culminated in an invitation for me to join the NF1 mutation analysis steering group, which included esteemed leaders like Francis Collins, Jan Friedman, Bruce Korf and Ray White. I had the incredible honour to work alongside such giants in the field. Our team in Cardiff then focused on characterising the NF1 germline and somatic mutational spectrum using DNA and RNA analysis, functional analysis of the mutations, and genotype-phenotype correlation. We also investigated NF1 tumorigenesis, asking two fundamental questions: what causes the development of tumours and why some of the benign tumours become malignant in NF1 patients. Using high-throughput techniques, we identified molecular targets for therapeutic intervention. Our research group identified recurrent somatic mutations in SUZ12 in NF1-associated MPNSTs, which resulted in collaborations with Eric Legius, Karen Cichoswski, and Eric Pasment. These experts focused on cellular, animal models, and molecular aspects of the PRC2 complex, particularly SUZ12 and EED. More recently, we have focused on the molecular genetics of RASopathies and the identification of biomarkers for NF1. Our journey has been challenging, but we remain committed to making a difference in the lives of patients with NF1.
In the nineties, my laboratory was widely recognized as Meena’s International Lab in Cardiff. It gained this nickname because I had a diverse group of scientists and clinicians from various parts of the world working with me. We hosted many researchers from Europe, Brazil, Singapore, China, India and Malaysia, all of whom were interested in NF1 research due to the significant role of neurofibromin in the Ras MAPK pathway and the reputation of the Institute of Medical Genetics in Cardiff. I remember in particular, Sarah who came from Saudi Arabia and was a student at Cardiff University. She applied for a work placement in my lab, and I was pleased to welcome her. However, I wasn’t sure if she complied with the laboratory dress code since she wore a hijab. To ensure that we followed the proper guidelines, I sought advice from Cardiff University and Medical School. To my surprise, there were no specific guidelines for this situation. Sarah proved to be a productive student and integrated well with all the members of my lab. She was later offered a job within my institute, which made me very proud. I remain passionate about promoting equality, diversity, and inclusion, and I believe that Sarah’s success is a testament to the importance of creating a welcoming and inclusive environment for all.
I have been fortunate enough to travel extensively for work, but there’s one particular trip that stands out. I had to give two talks on the same day, on two different continents. I was invited to Kyoto to speak about FSHD, and California to talk about NF1. I could do it because when I flew from Kyoto to San Francisco, I crossed the dateline and gained a day. However, after delivering my second talk, exhaustion had taken over me, and I felt like a zombie. I couldn’t even tell if I was coming or going! I have some fond memories of our annual meetings at Aspen. It was a great venue with opportunities for a range of recreation. On one occasion I remember travelling back from Aspen via Denver to London with Sue Huson and Ros Ferner. We checked in together, with Ros going first, followed by me and then Susan. To my great shock, Ros and Sue were upgraded, while I was not. This incident left me in tears and felt like an example of blatant racism and it incited me to campaign against racism.
I’ve been fortunate enough to organise a few international conferences throughout my career. These include the NF European meeting in Killarney, Ireland, a Rasopathies meeting in Cardiff, and the first international conference on RASopathies in Asia, which took place in Kochi, Kerala, India. The latter was largely sponsored by Astra Zeneca and the Welsh Universities. Despite having one of the world’s largest populations, India remains underserved in terms of clinical genetics services. Therefore, the primary aim of this conference was to bridge this gap and promote better practices and therapies for individuals with neurofibromatoses and RASopathies. The conference featured speakers from almost every corner of the globe and was attended by many people. Since it was such a resounding success, there has been a high demand for another conference. In addition to my charity and community work, my retirement has been productive and challenging, and I have published over 20 NF1 papers since retiring in 2014.
Last year, I was featured in a Pathology in Profile series podcast by the Royal College of Pathologists celebrating its diamond anniversary, I had the privilege of presenting the molecular studies of an interesting NF1 patient with large plexiform neurofibroma which had transitioned to MPNST.
Our NF1 prenatal diagnostic services have always been ahead of the curve, initially utilizing closely linked flanking markers with an error risk of about 5%, even before the gene was cloned. However, we understand that for many couples, prenatal diagnosis is only worthwhile if it can accurately predict the severity of the disease. That’s why we’re committed to providing the most accurate and reliable diagnostic testing available based on genotype-phenotype correlation so that our patients can make informed decisions about their pregnancy with confidence. Revolutionary liquid biopsy combined with sophisticated sequencing technologies has the advantages of being non-invasive, rapid, precise and real-time.
I found it incredibly fulfilling to provide reassurance to patients and families suffering from NF1 that we were making every effort to find a treatment for their disease. To achieve this, we organized an annual meeting for NF1 Welsh families for nearly two decades, where we shared the latest scientific developments related to the disease. During the meeting, a panel of experts, including clinical and molecular geneticists, a schoolteacher, a GP, a psychologist, a patient representative and a genetic counsellor were available to answer any questions that attendees may have had. The meeting concluded with a high tea, where everyone could socialize and connect with other families affected by NF1. I am extremely grateful to Sheila and Clive Owen from Port Talbot for raising more than £50K for my research. Another kind lady donated all the cash gifts she had received for her 70th birthday, and a very kind grandmother with an NF1 granddaughter donated £30 per month from her pension for my research for nearly 15 years. Another patient very generously donated her neurofibromas for our research. I cannot thank them enough. I was deeply touched when a Welsh NF1 patient with MPNST donated his body for my research before he died.
I am honoured to serve as a trustee and medical advisor for Nerve Tumours UK, providing support and advice to Welsh NF1 families and healthcare professionals. Additionally, I have had the privilege of sharing my research data and interacting with patients and their families at various international meetings. My knowledge of complex molecular findings allows me to provide valuable guidance.
Collaboration has been a crucial factor in my professional development, particularly in the field of genetic conditions. Given the rarity of these conditions, families with genetic disorders exist globally, and collaborations help strengthen our findings. I have had the pleasure of working with a range of collaborators, both nationally and internationally. In the 1980s, we collaborated with Bernd Seizinger to map the NF1 gene and contributed to the cloning of the NF1 gene through collaborations with Francis Collins and David Viskochil. Furthermore, we demonstrated that new NF1 germline mutations were of paternal origin in collaboration with Bruce Ponder, and played a vital role in defining the NF1 germline and somatic mutational spectrum through collaboration with Victor Mautner, Eric Legius, Martino Ruggieri, Susan Huson, Gareth Evans,Ros Ferner and more. Our work on genotype-phenotype correlation also benefited from our interactions with several Europeans including Eric Pasmant, Pierre Wolkenstein, Ludwin Messiaen and American researchers. I have also led several international collaborations on NF1 tumorigenesis with Victor Mautner, Jan Dumansky, Ab Guha, Vic Riccardi, and many European researchers. These interactions with able and diverse minds have had a significant impact on my productivity and beyond.
I faced many challenges due to my gender and culture. Despite this, I am proud to have received the European Theodor Schwann Award, OBE, and a national Saint David Award for my contributions to medical genetics, particularly in the field of NF1. I played a major role in creating the European NF Theodor Schwann Award, which recognises the contributions of scientists and clinicians at each European meeting. I have also been actively involved in the European NF Group since its inception and have aided the organisation of many European meetings.
I am proud to have been a part of the NF1 research community since 1986. At that time, there were only a handful of researchers studying NF1, but I have watched as the field has grown exponentially to over 500 researchers today. NF1 has taken centre stage in cancer biology, and I feel honoured to have contributed to its development. I owe a debt of gratitude to the Late Sir Professor Peter Harper and Sue Huson for introducing me to the NF1 project and supporting me in the early stages of my career. I would also like to acknowledge Vic Riccardi for his insightful and inspiring discussions at various conferences. I am grateful to the many scientists and clinicians who contributed to my two books on NF1 despite their busy schedules. Finally, I extend my heartfelt appreciation to the members of my lab and colleagues who have supported me throughout my career.
The future for NF remains promising. The first FDA-approved drug for NF1, Selumetinib, a MEK inhibitor has proven to be a game-changer for NF1 patients with inoperable plexiform neurofibromas. While MEK inhibitor treatment alone may not be able to completely eradicate neurofibromas, it is possible that combination treatment using MEK inhibitors together with drugs that target other pathways could be more effective. Also, the tyrosine kinase inhibitor cabozantinib was recently shown to be effective in a phase 2 clinical trial for inoperable plexiform neurofibromas reducing tumour volume and pain. The advancement of animal models that closely mimic human pathology and the use of NF1 patient-derived induced pluripotent stem cells (iPSC) will continue to enhance our understanding of the role of neurofibromin and the pathways it governs. These models will help identify new biomarkers and also provide an avenue for developing personalized cell models of NF1. As we gather more information on the correlation between NF1 genotype and phenotype, we will gain insight into the future progression and severity of the disease. Exploring the molecular interactions between Schwann cells and their tumour microenvironment will open new avenues to develop more effective treatments. With the help of high-throughput screening and small molecule libraries, we can expand the range of targeted agents that can be used to treat NF1. Genome-guided therapeutics such as gene editing may offer new options for precision medicine for NF1 patients. Significant collaborations between academia, hospitals, governing bodies and pharmaceutical industries will provide great opportunities for the future of NF1 treatment.
