Francis Sellers Collins is an American physician-geneticist, who is the16th Director of the National Institutes of Health (NIH). He was known for identifying several disease genes including cystic fibrosis, Duchenne muscular dystrophy, and Huntington’s disease, as well as carrying out the Human Genome Project and other projects which are significant to biology development, such as the International HapMap Project, which has identified the genetic variations of developing type 2 diabetes.
Collins was born on April 14, 1950, in Virginia. In 1966, at the age of 16 years, he entered the University of Virginia at Charlottesville and received a BS degree in chemistry in 1970. After that, Collins enrolled at Yale University and received a PhD degree in physical chemistry in 1974. In 1974, Collins entered medical school at the University of North Carolina in Chapel Hill. During his last year of medical school, Collins was introduced to the field of human genetics. After receiving his MD degree in 1977, he returned to Yale University School of Medicine as was a fellow in human genetics and pediatrics. At Yale, Collins worked under the direction of Sherman Weissman. In 1984, they published a paper (Collins, F.S., et al. 1984) on the method named chromosome jumping. At that time, in molecular biology, techniques for cloning DNA fragments have contributed in studies of gene sequence and function. For example, the development of cosmid cloning techniques allows generating clones up to 45kb long. Through the techniques of somatic cell genetics and in-situ hybridization, it has been possible to map single-copy genes to particular human chromosomes, and, with techniques of cytogenetics, even to a small region of a particular chromosome. However, the challenge at that time was for larger area, there was a significant gap. The detailed mapping of relatively large areas of the genome, which was an important task in complex genetic loci as the major histocompatibility complex, may occupy more than1000kb of contiguous DNA. While mapping such large regions with the existing technique of “chromosome walking” becomes prohibitively time-consuming. A new method was needed to allow the investigator to take larger steps along the chromosome, preferably with the ability to specify in which direction the step will be taken. That paper presented the principle of such a method and a series of experiments, using a model system, that demonstrate its practicality. Chromosome jumping overcame the distance limitations, by generating a clone many kb away from an initial probe without the need to characterize all of the intervening DNA. The exact distance from the initial probe can be set by the size of the partially digested high molecular weight DNA chosen for construction of the library. Compared to previous method of copying DNA fragments, chromosome walking, chromosome jumping can bypass regions difficult to clone, such as repetitive DNA, which was used in the physical mapping of genomes and enables two ends of a DNA sequence to be cloned more rapid and without the middle section. Potential applications of this approach has been discussed such as mapping of complex genetic loci or moving from a linked gene toward a gene of interest (Collins, F.S., et al. 1987).
In 1984, Collins left Yale to join the staff of the University of Michigan Medical School at Ann Arbor as an assistant professor of internal medicine and human genetics. During his research, he focused on the method “positional cloning” (Collins, F.S. 1992). At that time for disease gene identification, there was one strategy, referred as “functional cloning”, depending on the availability of biological information about the protein product and their function of the responsible gene. Mapping follows cloning. While positional cloning moves in the opposite direction, it is initiated by mapping the responsible gene to its correct location on a chromosome, and function is only determined after the gene is in hand. The scheme for gene identification by positional cloning began with the collection of pedigrees in which the responsible gene is segregating. These families are studied with multiple polymorphic markers until evidence for linkage is identified with one or more of these. Particularly problems can be encountered at this point if the disease is caused by mutations at more than one locus, in which case the analysis of very large families is highly beneficial. There are mathematical methods to predict whether a given set of pedigrees contains sufficient information to give a high likelihood of positive linkage information. Additional fine mapping can then be applied to narrow down the responsible region. Through these techniques and analysis, the candidate region can be defined, and positional cloning is then used to narrow the candidate region until the gene and its mutations are found. Positional cloning is an approach which has merged as a powerful paradigm for the identification of human disease genes. As an important component of modern molecular genetics, it successfully identified the first mutation for Cystic Fibrosis (CF), ΔF508 on the seventh chromosome (Rommens, J.M., et al. 1989; Marx, J.L. 1989), with the collaboration of Lap-Chee Tsui and colleagues at Toronto’s Hospital for Sick Children, who has already identified the locus for the gene and needed to determine the mutation. Positional cloning is an effective method to isolate disease genes in an unbiased manner. It has been used to other genetic discoveries made by Collins and a variety of collaborators, isolating the genes for neurofibromatosis (Fountain, J. W., et al. 1989; Wallace, M.R., et al. 1990), Huntington’s disease (MacDonald, M., et al. 1993), multiple endocrine neoplasia type 1 (Chandrasekharappa, S.C., et al. 1997), Hutchinson–Gilford progeria syndrome (Eriksson, M., et al.2003).
Francis Collins has been recognized for his achievements by being elected as director of the National Center for Human Genome Research in 1993, which became National Human Genome Research Institute (NHGRI) in 1997. As director, he led the Human Genome Project. The Human Genome Project (HGP) was the world’s largest collaborative biological
Project in order to determine the sequence of nucleotide base pairs that make up human DNA, and of identifying and mapping all of the genes of the human genome from both a physical and a functional standpoint, which the working draft of the genome was announced in 2000 and the papers describing it were initially published in February 2001. Followed work finishing the reference version of the human genome sequence was published by 2003. The Human Genome Project was declared complete in April 2003. Although this was reported to cover 99% of the euchromatic human genome with 99.99% accuracy, a major quality assessment of the human genome sequence indicating over 92% of sampling exceeded 99.99% accuracy which was within the intended goal (Schmutz, J., et al., 2004). Further analyses and papers on the HGP continue to occur.
Another major activity at NHGRI during his tenure as director was the International HapMap project, which was to develop a haplotype map (HapMap) of the human genome. HapMap is used to describe the common patterns of human genetic variation, finding genetic variants affecting health, disease and responses to drugs and environmental factors. It generates a catalog of human genetic variations, which is called single-nucleotide polymorphisms (SNPs). Collins lab at NHGRI is focusing on identifying and understanding the genetic variations that influence the risk of developing type 2 diabetes (T2D). T2D makes up about 90% of cases of diabetes, which is a long-term metabolic disorder and has increased the rate of patients recently. In 2015 there were approximately 392 million people diagnosed. Many genes are involved in T2D, with each being a small contributor to an increased probability of becoming a patient. Using genome-wide association study (Scott, L.J., et al. 2007), Collins lab genotyped 1161 Finnish T2D cases and 1174 Finnish normal glucose-tolerant (NGT) controls with >315,000 single-nucleotide polymorphisms (SNPs) and imputed genotypes for an additional >2 million autosomal SNPs. They identify T2D-associated variants in an intergenic region of chromosome 11p12, contribute to the identification of T2D-associated variants near the genes IGF2BP2 and CDKAL1 and the region of CDKN2A and CDKN2B, and confirm that variants near TCF7L2, SLC30A8, HHEX, FTO, PPARG, and KCNJ11 are associated with T2D risk. This brings the number of T2D loci now confidently identified to at least 10. Latest study (Mahajan, A., et al. 2018) shows an extension for T2D-risk variants and enriches discovery of lower-frequency risk alleles.
Collins was nominated as director of the National Institutes of Health (NIH) by President Barack Obama on July 8, 2009. He has contributed to the establishing of recent NIH related and NIH-led projects. For example, the National Center for Advancing Translational Sciences (NCATS) in 2011, which is to catalyze the generation of innovative methods and technologies that will enhance the development, testing, and implementation of diagnostics and therapeutics across a wide range of diseases and conditions (Collins, F. S. 2011), the Brain Research through Advancing Innovative Neurotechnologies (BRAIN) in 2013, which is intended to support the development and application of innovative technologies that can create a dynamic understanding of brain function, and Precision Medicine Initiative (PMI) in 2015, now known as All of Us, which aims to gather data from one million or more people living in the United States to accelerate research and improve health by taking into account individual differences in lifestyle, environment, and biology, researchers will uncover paths toward delivering precision medicine, to make advances in tailoring medical care to the individual.