Phillip A. Sharp

Phillip Sharp is among the most consequential molecular biologists of the twentieth century and a Nobel Laureate whose discovery of RNA splicing revolutionized the understanding of gene structure and expression in eukaryotes. His career at MIT, spanning more than five decades, has encompassed seminal discoveries in gene structure, RNA processing, transcription, and the emerging field of RNA-based cancer therapeutics. In 1977, working simultaneously and independently with Richard Roberts at Cold Spring Harbor Laboratory, Sharp demonstrated using electron microscopy and RNA-DNA hybridization that messenger RNA is not a direct copy of genomic DNA — instead, eukaryotic genes are interrupted by non-coding intervening sequences (introns) that are removed from the pre-mRNA transcript by a precise molecular machinery. This discovery of RNA splicing fundamentally changed the understanding of gene organization and gene expression in all eukaryotes. The 1993 Nobel Prize in Physiology or Medicine was awarded jointly to Sharp and Roberts for this discovery. Sharp co-founded Biogen in 1978, one of the first biotechnology companies, and was instrumental in co-founding Alnylam Pharmaceuticals in 2002 — the company that pioneered RNAi therapeutics and brought the first siRNA drug (patisiran) to FDA approval in 2018. His entrepreneurial vision recognized that fundamental RNA biology discoveries could be translated into entirely new classes of medicines. At MIT's Koch Institute, Sharp's laboratory has made seminal contributions to understanding alternative splicing in cancer biology. His group showed that cancer-associated mutations and epigenetic changes disrupt normal splicing programs to generate oncogenic protein isoforms and eliminate tumor suppressor activities. His work on the Mediator complex elucidated how transcriptional regulators communicate with the RNA polymerase II machinery, with important implications for understanding how oncogenic transcription factors hijack gene expression programs. Sharp has been a leading voice on microRNA biology in cancer, contributing to understanding of how the microRNA processing machinery (Drosha, DICER1) is frequently mutated or dysregulated in cancer, and how global microRNA downregulation is a near-universal feature of malignancy. His group studied enhancer RNA (eRNA) production at super-enhancers as a regulatory layer controlling oncogene expression, revealing a new vulnerability that could be targeted therapeutically.

Phillip Sharp 是二十世纪最具影响力的分子生物学家之一，也是诺贝尔奖得主。1977年，他证明了真核生物 mRNA 并非基因组 DNA 的直接拷贝——真核基因被非编码内含子序列打断，需经精确的分子机器从前体 mRNA 中剪除，即 RNA 剪接的发现。这一发现彻底改变了对所有真核生物基因组织和基因表达的理解，与 Richard Roberts 共同获得1993年诺贝尔生理学或医学奖。 Sharp 共同创立了 Biogen（1978年）和 Alnylam 制药公司（2002年）——后者开创了 RNAi 治疗学并将首款 siRNA 药物推向市场。在麻省理工学院科克研究所，他的实验室深入研究了癌症中的异常剪接、microRNA 加工机器的突变，以及超级增强子处增强子RNA（eRNA）调控癌基因表达的新机制。