Laura Manuelidis is a physician and neuropathologist at Yale University.
Career
Manuelidis earned her B.A. degree from Sarah Lawrence College, where she studied poetry, and her M.D. is from Yale Medical School. She is head of the section of Neuropathology in the department of Surgery at Yale and is also a member of the Neuroscience and Virology faculty. She has been active on numerous government committees including the Advisory Panel on Alzheimer's disease and US FDA advisory panel, has been a member of editorial boards, and chair of international meetings. She has also published 3 books of poetry.
Achievements
Manuelidis has made major contributions in two areas: A) the discovery of large chromosomal DNA repeats and the elucidation of their role in the organization and structure of chromosomes in metaphase and interphase nuclei; B) the experimental investigation of the infectious agents that cause human Transmissible Encephalopathy (TSE) diseases including Creutzfeldt–Jakob disease (CJD), kuru and BSE ("mad cow disease"). Transmission to small animals and cells in culture exposed basic biologic and molecular agent facts most consistent with an exponentially replicating ~25 nm viral particle that contains an essential but unknown nucleic acid for infection. This contrasts with the assertion that the host encoded amyloid forming prion protein, without nucleic acid, is the infectious agent.
Chromosome Sequence and Structure
Early in her career, Manuelidis discovered major unknown DNA sequence motifs, and demonstrated their megabase organization in metaphase chromosomes and interphase nuclei. Using restriction enzymes on whole human DNA and extracting specific gel bands, an approach no one had used previously for whole mammalian genomes, she discovered human complex repeated (α satellite) DNA sequences and localized them in centromeres. They were homologous to simian, but not simpler mouse centromere repeats. These late replicating sequences, that contain few if any genes, define all human chromosome centromeres as shown by the development of high resolution in-situ hybridization. As in other mammalian cells, centromeres are critical for proper segregation of chromosomes between two new daughter cells during mitosis, and the discovery and localization of these satellite sequences have facilitated diagnosis of trisomy and chromosomal aberrations in genetic diseases and tumors. Manuelidis also discovered, isolated, and sequenced the human long interspersed L1 repeats (LINES) and showed they contained a transcriptional open reading frame. She found these abundant L1 repeats concentrated in Giemsa dark bands on chromosome arms that contain many tissue-specific genes whereas ALU short repeats concentrate in light bands with the majority of housekeeping genes. L1 repeats are conserved in evolution and show 70% homology to mouse L1 repeats. After retroviral HIV was sequenced, others deduced that L1 repeats were retroviral. It thus became clear that these ancient large retroviral invaders entered the genome and were symbiotically transfigured, or pathologically tamed, during evolution to attain a structural, and possibly functional role in megabase chromosome band domains.The enormous sizes of L1 and Alu rich domains were also demonstrated by pulse-field electrophoresis. Additional endogenous retroviral DNAs, such as those that produce retroviral intracisternal A particles (IAP) in rodents, as well as less numerous human endogenous retroviral repeats, are also integrated in specific chromosome locations. This further undermines the assumption repeated DNAs are parasitic "junk".
Manuelidis also opened up the field of 3-dimensional chromosome structure in the interphase nucleus of differentiated cells by combining optical serial sections and high resolution in-situ hybridization of specific DNA sequences. These studies dramatically transfigured the picture of interphase nuclei. Previously, interphase compartments were viewed as ill-defined dense heterochromatic blobs beside unorganized euchromatic chromatin spaghetti with no cohesive 3-D structure. In differentiated neurons very distinct patterns of individual centromere positions were demonstrated for each neuronal subtype. These positions are conserved in evolution even though centromeric DNA repeats are species-specific. By charting the movement of the X chromosome in large neurons in epilepsy, and the movement of centromeres during post-mitotic neuronal development, dynamic changes of large chromosome were illuminated. High-resolution mapping of whole individual human chromosomes in mouse and hamster-hybrid human cells further showed each chromosome was compact and occupied its own individual space or "territory".