I was born the seventh of nine children in Kuantan, a small town in Malaya (now Malaysia), but grew up in various towns in Malaysia. My father was a public servant and was frequently transferred. My mother, who did not finish school, greatly valued education. She was a hard worker and the single most important role model in my life; she instilled in me strong work ethics that were pivotal to shaping my career. I loved learning, and was particularly drawn to biology, leading me to medicine at the University of Malaya in Kuala Lumpur, Malaysia, where I obtained my MB, BS in 1975.
Personal reasons brought me to the UK, where I completed my postgraduate training and became board certified in internal medicine and hematology. My research career took a significant leap forward in 1982 when I joined the MRC Molecular Haematology Unit at the Weatherall Institute of Molecular Medicine. Through my project with the late Sir David Weatherall, my passion for the hemoglobin field began. Sir David challenged me to investigate why some patients with -thalassemia are so mild and transfusion-independent unlike the majority, starting me on a life-long career in genotype-phenotype correlation studies. Rising to his challenge, I started collecting blood samples from patients with unusually mild -thalassemia, together with their family members, which often involved extensive travels across the UK.
As it turned out, most of the thalassemia intermedia patients had an innate ability to produce fetal hemoglobin (HbF), and the family studies indicated that the gene(s) was/were inherited independently of the -globin gene (the gene responsible for -thalassemia). I should note that independent segregation of the high HbF gene(s) had been shown by several other groups years before me.
I felt compelled to unravel the genetic architecture and the gene(s) underlying this common variation of HbF production in adults which had a complex inheritance pattern. One of the first families I studied grew to 270 members spanning seven generations and involved a field trip to Malawi, Africa. At this critical time of my research, I was fortunate to meet Mark Lathrop, a Canadian Biostatistician who was then in Oxford and who introduced me to Florence Demenais, another Biostatistician. Together, we located the first transacting gene (quantitative trait locus (QTL)) on chromosome 6q modifying HbF in this family that was not on the-globin complex. However, this chromosome 6q QTL could not explain the high HbF levels in the other families which were too small for traditional genetic linkage association studies. At this roadblock, I had to first convince myself and the sceptics that it was worthwhile chasing after the other gene(s). But we were able to jumpstart the research again when I heard of Tim Spector (then director of the Twin Research Unit in Guy’s and St Thomas’ Hospital, London) who was actively recruiting twins for various studies. I overcame my own doubts by first doing traditional twin studies, comparing the similarity of HbF levels in identical twins vs non-identical twins. Those findings convinced me that there was indeed a huge genetic component to the level of HbF that was worth pursuing.
In 2000, I moved to King’s College London. I returned to my first calling as a physician, taking over the care of patients with sickle cell disease (SCD), another inherited disorder of -hemoglobin but with different patient demographics and disease manifestation than -thalassemia. The common feature in both these single gene disorders is the remarkable variation in disease severity; they shared similar genetic modifying factors, one of which is the innate ability to produce HbF which resuscitated the challenge for me to locate the other QTLs for HbF. Expanding our twin collection to over 5000 individuals, I collaborated with Mark Lathrop, applying the first genome-wide association study (GWAS) to identify key loci controlling HbF production in adults. The GWAS not only ‘rediscovered’ the 6q QTL but also discovered BCL11A, which was until then, known as an oncogene involved in leukemogenesis, and its relevance to HbF and erythropoiesis, unsuspected. We published our findings in 2007, which were replicated a year later by another group in a Sardinian population. The seminal finding that the BCL11A gene is a key suppressor of HbF has enabled the development of treatments that increase HbF by suppressing BCL11A expression. I am honored to share the Shaw Prize with Stu Orkin, who has done so much to reveal the workings of BCL11A.
In March 2015, I relocated to the NIH/NHLBI in the US where I continue to focus on SCD. While discovery of the BCL11A gene remains the most hard-won and personally important to me, my current goal is to find more drugs for treating SCD, as genetic therapy will not be accessible any time soon for most of the 8 million people affected.
12 November 2024 Hong Kong
