My Reflections on NF1
Meena Upadhyaya, OBE, FRCPath, FLSW, Medical Geneticist and Professor Emerita, Cardiff University
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I joined the Neurofibromatosis Type1 (NF1) 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 for many years (wrongly, it now appears) to have had NF1. 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 in a foreign country 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. This poster suggested five possible chromosomes (out of 22), one of which would be 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 and now Nerve Tumours UK. The objective of this meeting was to establish conclusively the exclusion map of NF1. At this meeting, it was agreed that the remaining possible sites for the disease included chromosomes 17, 5, or 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 who had more confidence in me and my research activities than I ever did, asked me to represent him at the National Neurofibromatosis Foundation (NNFF, now the Children’s Tumor Foundation CTF) meeting in New York. This was my first time attending such a meeting, and I was hugely nervous. However, my talk was well-received, and this 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, Ray White, Peggy Wallace, Nancy Ratner, David Viskochil, Vic Riccardi, Bruce Korf, David Gutmann, 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. 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. I remember in 1989; I received an invitation to speak at the American Society of Human Genetics in a plenary session organised by Francis Collins. I was a bundle of nerves, and my hands and legs were shaking as I ascended to the podium and my tongue was tied while I stood there for nearly 60 seconds without a word. In May 1990, I presented a Welsh NF1 patient with a 90Kb deletion mapping to the candidate region for the NF1 gene on chromosome 17. This was before cloning of the gene and it caused a lot of interest and quite a stir among the attendees. Peter O’Connell, the principal investigator at the Howard Hughes Medical Institute in Salt Lake City, invited me to visit his lab, along with my DNA samples. I immediately accepted his offer, but I had to delay my trip by ten weeks due to my daughter’s upcoming exams. As I was boarding the plane on July 6th, I received news that the NF1 gene papers had been published that morning. While I was initially disappointed to have missed out on such a landmark publication, 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 visit to Salt Lake City, I had the opportunity to learn and acquire new techniques including SSCP that I was then able to implement back 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 to give a talk, it is 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 (one of the discoverers of the structure of DNA), David Cox, Jim Gusella, Louis Kunkel, Eric Lander, David Houseman, Karen Stephens and Ellen Solomon.
Lamplighting Ceremony
After significant effort, my research group became the leader in finding NF1 germline mutations in the nineties 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 spectra 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 Pasmant. These experts focused on cellular, animal models, and molecular aspects of the PRC2 complex, particularly SUZ12 and EED, and our findings were published in Nature. 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 Wales. 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 Sahar who came from Saudi Arabia and was a student at Cardiff University. She applied for a work placement on NF1 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 great surprise, there were no specific guidelines for this scenario. Sahar 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 Sahar’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, 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 recreational activities. I vividly remember a particular trip when I was travelling back from Aspen to London via Denver with my friends 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 shock. It felt like a clear example of blatant racism that should be eliminated.
I’ve had the opportunity to organise several international conferences throughout my career. These include the NF European meeting in Killarney, Ireland, an international 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, the Welsh Universities and CTF. Despite having one of the world’s largest populations, India remains underserved in terms of clinical genetics services for NF. 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 2015.
Last year, I presented molecular studies of an interesting NF1 patient with a large plexiform neurofibroma that had transitioned to MPNST. This case was featured in a ‘Pathology in Profile’ series podcast by the Royal College of Pathologists, celebrating its diamond anniversary. I am pleased that it has received a large number of likes.
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 advantage 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 school teacher, 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 socialise 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 when 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. I have dealt with many patients with complex molecular findings.
Collaboration has been a crucial factor in my professional development. Genetic conditions are mostly rare, families affected by many of them, including NF1, exist globally, and international collaborations help to speed up research and strengthen its 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 and Jim Gusella to map the NF1 gene and contributed to the cloning of the NF1 gene through collaborations with Francis Collins, Peggy Wallace and David Viskochil. Furthermore, we demonstrated that new small NF1 germline lesions 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, Ab Guha, Pierre Wolkenstein and others. Our work on genotype-phenotype correlation also benefited from our interactions with several Europeans including Eric Pasmant, Pierre Wolkenstein, Ludwin Messiaen and other American researchers. I have also led several international collaborations on NF1 tumorigenesis with Victor Mautner, Jan Dumanski, 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 grateful to have received the European Theodor Schwann Award, an OBE from King Charles, and a national Saint David Award for my contributions to medical genetics, particularly in the field of NF1. I had the privilege of playing 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 in 1990 and have aided with the organisation of many European meetings.
It was a proud moment to represent Wales and Nerve Tumours UK at the recent coronation ceremony of King Charles at Westminister Abbey, London. 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 and women were underrepresented but I have watched as the field has grown exponentially to over 300 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 Professor Sir 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 also thank my dear friend late Ludwine Messiaen for her outstanding work in the field of molecular diagnosis of NF and it was an honour to collaborate with her. 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 through my NF1 research 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. 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. Over the past 40 years, NF1 researchers have made remarkable strides, transitioning from the assembly of NF1 families to the groundbreaking development of effective treatments.
