Laura Manuelidis

Laura Manuelidis was born Laura Kirchman in Brooklyn, New York to a teacher and an architect.{{cite web |title=Association of Yale Alumni in Medicine Distinguished Alumni Award |url=https://medicine.yale.edu/news-article/association-of-yale-alumni-in-medicine-distinguished-alumni-award/ |website=Yale School of Medicine |date=June 2, 2018}} Manuelidis earned her B.A. from Sarah Lawrence College in 1963, where she studied poetry, and she received her M.D. from Yale Medical School in 1967.

Manuelidis is the head of neuropathology in the surgery department at Yale{{cite web |title=Home > Manuelidis Lab - Surgery - Neuropathology - Yale School of Medicine |url=http://medicine.yale.edu/lab/manuelidis/index.aspx |website=medicine.yale.edu}} and is also a member of the neuroscience and virology faculty. She has been active on numerous government committees, including the Alzheimer's disease advisory panel and the US Food and Drug Administration advisory panel, has been a member of editorial boards, and chair of international meetings. She has also published three books of poetry.

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 spongiform encephalopathy (TSE) diseases including Creutzfeldt–Jakob disease (CJD), kuru and bovine spongiform encephalopathy ("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.{{Citation needed|date=April 2024}} This contrasts with the assertion that the host encoded amyloid forming prion protein, without nucleic acid, is the infectious agent.

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.{{Cite journal |last=Manuelidis |first=L. |date=November 1976 |title=Repeating restriction fragments of human DNA |journal=Nucleic Acids Research |volume=3 |issue=11 |pages=3063–3076 |doi=10.1093/nar/3.11.3063 |issn=0305-1048 |pmid=794832|pmc=343151 }}{{Cite journal |last=Manuelidis |first=L. |date=1978-03-22 |title=Chromosomal localization of complex and simple repeated human DNAs |url=https://pubmed.ncbi.nlm.nih.gov/639625/ |journal=Chromosoma |volume=66 |issue=1 |pages=23–32 |doi=10.1007/BF00285813 |issn=0009-5915 |pmid=639625|s2cid=2061015 }} They were homologous to simian, but not simpler mouse centromere repeats.{{Cite journal |last1=Manuelidis |first1=L. |last2=Wu |first2=J. C. |date=1978-11-02 |title=Homology between human and simian repeated DNA |url=https://pubmed.ncbi.nlm.nih.gov/105293/ |journal=Nature |volume=276 |issue=5683 |pages=92–94 |doi=10.1038/276092a0 |issn=0028-0836 |pmid=105293|bibcode=1978Natur.276...92M |s2cid=4320503 }} 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.{{Cite journal |last1=Manuelidis |first1=L. |last2=Langer-Safer |first2=P. R. |last3=Ward |first3=D. C. |date=November 1982 |title=High-resolution mapping of satellite DNA using biotin-labeled DNA probes |journal=The Journal of Cell Biology |volume=95 |issue=2 Pt 1 |pages=619–625 |doi=10.1083/jcb.95.2.619 |issn=0021-9525 |pmc=2112973 |pmid=6754749}}

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.{{Cite journal |last1=Manuelidis |first1=L. |last2=Biro |first2=P. A. |date=1982-05-25 |title=Genomic representation of the Hind II 1.9 kb repeated DNA |journal=Nucleic Acids Research |volume=10 |issue=10 |pages=3221–3239 |doi=10.1093/nar/10.10.3221 |issn=0305-1048 |pmid=6285293|pmc=320702 }} She found these abundant L1 repeats concentrated in Giemsa dark bands on chromosome arms that contain many tissue-specific genes,{{Cite journal |last1=Manuelidis |first1=L. |last2=Ward |first2=D. C. |date=1984 |title=Chromosomal and nuclear distribution of the HindIII 1.9-kb human DNA repeat segment |url=https://pubmed.ncbi.nlm.nih.gov/6098426/ |journal=Chromosoma |volume=91 |issue=1 |pages=28–38 |doi=10.1007/BF00286482 |issn=0009-5915 |pmid=6098426|s2cid=25178606 }} 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 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.{{Cite journal |last1=Chen |first1=Terence L. |last2=Manuelidis |first2=Laura |date=November 1989 |title=SINEs and LINEs cluster in distinct DNA fragments of Giemsa band size |url=http://dx.doi.org/10.1007/bf00292382 |journal=Chromosoma |volume=98 |issue=5 |pages=309–316 |doi=10.1007/bf00292382 |pmid=2692996 |s2cid=24850090 |issn=0009-5915|url-access=subscription }}

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.{{Cite journal |last1=Taruscio |first1=D. |last2=Manuelidis |first2=L. |date=December 1991 |title=Integration site preferences of endogenous retroviruses |url=https://pubmed.ncbi.nlm.nih.gov/1790730/ |journal=Chromosoma |volume=101 |issue=3 |pages=141–156 |doi=10.1007/BF00355364 |issn=0009-5915 |pmid=1790730|s2cid=24569226 }} 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.{{Cite journal |last1=Manuelidis |first1=L. |last2=Borden |first2=J.|author-link2=Jonathan Borden |date=1988 |title=Reproducible compartmentalization of individual chromosome domains in human CNS cells revealed by in situ hybridization and three-dimensional reconstruction |url=https://pubmed.ncbi.nlm.nih.gov/3219911/ |journal=Chromosoma |volume=96 |issue=6 |pages=397–410 |doi=10.1007/BF00303033 |issn=0009-5915 |pmid=3219911|s2cid=24792110 }} By charting the movement of the X chromosome in large neurons in epilepsy,{{Cite journal |last1=Borden |first1=J.|author-link1=Jonathan Borden |last2=Manuelidis |first2=L. |date=1988-12-23 |title=Movement of the X chromosome in epilepsy |url=https://pubmed.ncbi.nlm.nih.gov/3201257/ |journal=Science |volume=242 |issue=4886 |pages=1687–1691 |doi=10.1126/science.3201257 |issn=0036-8075 |pmid=3201257|bibcode=1988Sci...242.1687B }} and the movement of centromeres during post-mitotic neuronal development,{{Cite journal |last=Manuelidis |first=L. |date=1985 |title=Indications of centromere movement during interphase and differentiation |url=https://pubmed.ncbi.nlm.nih.gov/3860180/ |journal=Annals of the New York Academy of Sciences |volume=450 |issue=1 |pages=205–221 |doi=10.1111/j.1749-6632.1985.tb21494.x |issn=0077-8923 |pmid=3860180|bibcode=1985NYASA.450..205M |s2cid=38297846 }} 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".{{Cite journal |last=Manuelidis |first=L. |date=1985 |title=Individual interphase chromosome domains revealed by in situ hybridization |url=https://pubmed.ncbi.nlm.nih.gov/3908288/ |journal=Human Genetics |volume=71 |issue=4 |pages=288–293 |doi=10.1007/BF00388453 |issn=0340-6717 |pmid=3908288|s2cid=21509861 }}{{Cite journal |last1=Schardin |first1=M. |last2=Cremer |first2=T.|author-link2=Thomas Cremer |last3=Hager |first3=H. D. |last4=Lang |first4=M. |date=1985 |title=Specific staining of human chromosomes in Chinese hamster x man hybrid cell lines demonstrates interphase chromosome territories |url=https://pubmed.ncbi.nlm.nih.gov/2416668/ |journal=Human Genetics |volume=71 |issue=4 |pages=281–287 |doi=10.1007/BF00388452 |issn=0340-6717 |pmid=2416668|s2cid=9261461 }}

An architectural model of chromosomes as they transit from metaphase to interphase fits the known DNA compaction in diploid cells and allows for rapid transitions and segregation during mitosis, as well as local extensions that accommodate transcription.{{Cite journal |last=Manuelidis |first=L. |date=1990-12-14 |title=A view of interphase chromosomes |url=https://pubmed.ncbi.nlm.nih.gov/2274784/ |journal=Science |volume=250 |issue=4987 |pages=1533–1540 |doi=10.1126/science.2274784 |issn=0036-8075 |pmid=2274784|bibcode=1990Sci...250.1533M |s2cid=41327977 }} Mapping of whole individual chromosomes using high resolution DNA hybridization of chromosome specific libraries developed here{{Cite journal |last1=Lichter |first1=P. |last2=Cremer |first2=T.|author-link2=Thomas Cremer |last3=Borden |first3=J. |last4=Manuelidis |first4=L. |last5=Ward |first5=D. C. |date=November 1988 |title=Delineation of individual human chromosomes in metaphase and interphase cells by in situ suppression hybridization using recombinant DNA libraries |url=https://pubmed.ncbi.nlm.nih.gov/3192212/ |journal=Human Genetics |volume=80 |issue=3 |pages=224–234 |doi=10.1007/BF01790090 |issn=0340-6717 |pmid=3192212|s2cid=17768808 }}{{Cite journal |last1=Cremer |first1=T.|author-link1=Thomas Cremer |last2=Lichter |first2=P. |last3=Borden |first3=J. |last4=Ward |first4=D. C. |last5=Manuelidis |first5=L. |date=November 1988 |title=Detection of chromosome aberrations in metaphase and interphase tumor cells by in situ hybridization using chromosome-specific library probes |url=http://dx.doi.org/10.1007/bf01790091 |journal=Human Genetics |volume=80 |issue=3 |pages=235–246 |doi=10.1007/bf01790091 |pmid=3192213 |s2cid=14660591 |issn=0340-6717}} subsequently were useful for resolving chromosome changes in complex genetic diseases and tumor progression. Finally, the insertion of a huge 11 megabase transgene of the globin exon (lacking introns) was recognized by cells, and silenced by compaction together with transcriptionally inert heterochromatic centromeres in neurons.{{Cite journal |last=Manuelidis |first=L |date=February 1991 |title=Heterochromatic features of an 11-megabase transgene in brain cells. |journal=Proceedings of the National Academy of Sciences |language=en |volume=88 |issue=3 |pages=1049–1053 |doi=10.1073/pnas.88.3.1049 |issn=0027-8424 |pmc=50952 |pmid=1992455|bibcode=1991PNAS...88.1049M |doi-access=free }} This demonstrates that uninterrupted repeats are capable of inducing specific functional and structural changes during interphase. It is likely that this feature operates sequentially during cell differentiation.

The lab of EE Manuelidis and L Manuelidis was the first to serially transmit human Creutzfeldt–Jakob disease (CJD) to guinea pigs and small rodents.{{Cite journal |last1=Manuelidis |first1=E. E. |last2=Kim |first2=J. |last3=Angelo |first3=J. N. |last4=Manuelidis |first4=L. |date=January 1976 |title=Serial propagation of Creutzfeldt-Jakob disease in guinea pigs |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=73 |issue=1 |pages=223–227 |doi=10.1073/pnas.73.1.223 |issn=0027-8424 |pmid=1108016|pmc=335873 |bibcode=1976PNAS...73..223M |doi-access=free }}{{Cite journal |last1=Manuelidis |first1=E E |last2=Gorgacz |first2=E J |last3=Manuelidis |first3=L |date=July 1978 |title=Interspecies transmission of Creutzfeldt-Jakob disease to Syrian hamsters with reference to clinical syndromes and strains of agent. |journal=Proceedings of the National Academy of Sciences |volume=75 |issue=7 |pages=3432–3436 |doi=10.1073/pnas.75.7.3432 |pmid=356055 |pmc=392791 |bibcode=1978PNAS...75.3432M |issn=0027-8424|doi-access=free }}{{Cite journal |last1=MANUELIDIS |first1=ELIAS E. |last2=GORGACZ |first2=EDWARD J. |last3=MANUELIDIS |first3=LAURA |date=February 1978 |title=Transmission of Creutzfeldt–Jakob disease with scrapie-like syndromes to mice |url=http://dx.doi.org/10.1038/271778a0 |journal=Nature |volume=271 |issue=5647 |pages=778–779 |doi=10.1038/271778a0 |pmid=342977 |bibcode=1978Natur.271..778M |s2cid=4201624 |issn=0028-0836|url-access=subscription }} This made it possible to demonstrate fundamental mechanisms of infection, including TSE agent uptake and spread via myeloid cells of the blood,{{Cite journal |last1=Manuelidis |first1=Elias E. |last2=Gorgacs |first2=Edward J. |last3=Manuelidis |first3=Laura |date=1978-06-02 |title=Viremia in Experimental Creutzfeldt-Jakob Disease |url=http://dx.doi.org/10.1126/science.349691 |journal=Science |volume=200 |issue=4345 |pages=1069–1071 |doi=10.1126/science.349691 |pmid=349691 |bibcode=1978Sci...200.1069M |issn=0036-8075|url-access=subscription }}{{Cite journal |last1=Radebold |first1=K. |last2=Chernyak |first2=M. |last3=Martin |first3=D. |last4=Manuelidis |first4=L. |date=2001 |title=Blood borne transit of CJD from brain to gut at early stages of infection |journal=BMC Infectious Diseases |volume=1 |pages=20 |doi=10.1186/1471-2334-1-20 |issn=1471-2334 |pmid=11716790|pmc=59894 |doi-access=free }} a common route for most viruses. A lack of maternal transmission of sporadic CJD (sCJD) in long lived guinea pigs,{{Cite journal |last1=Manuelidis |first1=E. E. |last2=Manuelidis |first2=L. |date=February 1979 |title=Experiments on maternal transmission of Creutzfeldt-Jakob disease in guinea pigs |url=https://pubmed.ncbi.nlm.nih.gov/368815/ |journal=Proceedings of the Society for Experimental Biology and Medicine |volume=160 |issue=2 |pages=233–236 |doi=10.3181/00379727-160-40425 |issn=0037-9727 |pmid=368815|s2cid=26985470 }} contrasts with the proposed germline inheritance of sCJD. As with viruses, different species vary in their susceptibility to specific TSE agent strains. Major agent strain distinctions from scrapie are encoded by different human TSE agents, such as sCJD, kuru of New Guinea,{{Cite journal |last1=Manuelidis |first1=Laura |last2=Chakrabarty |first2=Trisha |last3=Miyazawa |first3=Kohtaro |last4=Nduom |first4=Nana-Aba |last5=Emmerling |first5=Kaitlin |date=2009-08-11 |title=The kuru infectious agent is a unique geographic isolate distinct from Creutzfeldt-Jakob disease and scrapie agents |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=106 |issue=32 |pages=13529–13534 |doi=10.1073/pnas.0905825106 |issn=1091-6490 |pmc=2715327 |pmid=19633190|bibcode=2009PNAS..10613529M |doi-access=free }} bovine-linked vCJD,{{Cite journal |last1=Manuelidis |first1=Laura |last2=Liu |first2=Ying |last3=Mullins |first3=Brian |date=2009-02-01 |title=Strain-specific viral properties of variant Creutzfeldt-Jakob disease (vCJD) are encoded by the agent and not by host prion protein |journal=Journal of Cellular Biochemistry |volume=106 |issue=2 |pages=220–231 |doi=10.1002/jcb.21988 |issn=1097-4644 |pmc=2762821 |pmid=19097123}} and Asiatic CJD. These were discovered and documented though experimental transmissions to normal mice, hamsters and monotypic cell cultures at Yale. Prion protein bands fail to distinguish very different TSE strains in standard mouse brains.

Manuelidis and colleagues were the first to show that prion protein amyloid was derived from a glycosylated 34kd precursor protein using lectins. PrP antibodies and selected lectins bound to the same protein in both normal and CJD and scrapie infected brain fractions.{{Cite journal |last1=Manuelidis |first1=L |last2=Valley |first2=S |last3=Manuelidis |first3=E E |date=June 1985 |title=Specific proteins associated with Creutzfeldt-Jakob disease and scrapie share antigenic and carbohydrate determinants. |journal=Proceedings of the National Academy of Sciences |volume=82 |issue=12 |pages=4263–4267 |doi=10.1073/pnas.82.12.4263 |pmid=2408277 |pmc=397977 |bibcode=1985PNAS...82.4263M |issn=0027-8424|doi-access=free }} Additionally, the correct sugar sequence of PrP was first demonstrated in the Manuelidis lab by sequential deglycosylation and unmasking of sugar residues.{{Cite journal |last1=Sklaviadis |first1=T |last2=Manuelidis |first2=L |last3=Manuelidis |first3=E E |date=August 1986 |title=Characterization of major peptides in Creutzfeldt-Jakob disease and scrapie. |journal=Proceedings of the National Academy of Sciences |volume=83 |issue=16 |pages=6146–6150 |doi=10.1073/pnas.83.16.6146 |pmid=3090551 |pmc=386456 |bibcode=1986PNAS...83.6146S |issn=0027-8424|doi-access=free }} Manuelidis and colleagues also developed monotypic cell cultures infected by many different human and sheep scrapie TSE strains, and developed rapid quantitative assays of infectious titers of 1 million fold or more for each strain.{{Cite journal |last1=Miyazawa |first1=Kohtaro |last2=Emmerling |first2=Kaitlin |last3=Manuelidis |first3=Laura |date=2011 |title=Replication and spread of CJD, kuru and scrapie agents in vivo and in cell culture |journal=Virulence |volume=2 |issue=3 |pages=188–199 |doi=10.4161/viru.2.3.15880 |issn=2150-5608 |pmc=3149681 |pmid=21527829}} As in the brain, misfolded PrP amounts show less than a 5 fold increase and could not even distinguish greater than 100 fold differences in infectivity of cultured agent strains. These culture studies further showed that PrP band patterns are cell-type dependent. Only rare strains show a PrP folding pattern that is distinctive in either brain or in monotypic cells, and a change in PrP bands does not induce any change in strain characteristics.{{Cite journal |last1=Arjona |first1=Alvaro |last2=Simarro |first2=Laura |last3=Islinger |first3=Florian |last4=Nishida |first4=Noriyuki |last5=Manuelidis |first5=Laura |date=2004-05-25 |title=Two Creutzfeldt–Jakob disease agents reproduce prion protein-independent identities in cell cultures |journal=Proceedings of the National Academy of Sciences |volume=101 |issue=23 |pages=8768–8773 |doi=10.1073/pnas.0400158101 |pmid=15161970 |pmc=423270 |bibcode=2004PNAS..101.8768A |issn=0027-8424|doi-access=free }} Moreover, TSE strains modify each other's replication in a virus-like fashion. Experiments in mice, and GT hypothalamic neuronal cells in culture, show both inhibitory and additive infectivity by two different TSE strains: one TSE strain can inhibit replication of a second more virulent strain{{Cite journal |last=Manuelidis |first=L. |date=1998-03-03 |title=Vaccination with an attenuated Creutzfeldt-Jakob disease strain prevents expression of a virulent agent |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=95 |issue=5 |pages=2520–2525 |doi=10.1073/pnas.95.5.2520 |issn=0027-8424 |pmid=9482918|pmc=19398 |bibcode=1998PNAS...95.2520M |doi-access=free }} whereas two different strains can both simultaneously infect cells.{{Cite journal |last1=Nishida |first1=Noriuki |last2=Katamine |first2=Shigeru |last3=Manuelidis |first3=Laura |date=2005-10-21 |title=Reciprocal interference between specific CJD and scrapie agents in neural cell cultures |url=https://pubmed.ncbi.nlm.nih.gov:443/16239476/ |journal=Science |volume=310 |issue=5747 |pages=493–496 |doi=10.1126/science.1118155 |issn=1095-9203 |pmid=16239476|bibcode=2005Sci...310..493N |s2cid=30401756 }}

Finally, dramatic changes in agent doubling time (weeks to a day) were documented for many TSE strains. TSE agents replicate every 24 hrs in culture, in marked contrast to their very slow and strain specific replication in the brain. This rapid agent replication in culture is likely due to release of agent constraints from the many complex host immune system in animals. These include early microglial responses.{{Cite journal |last1=Manuelidis |first1=Laura |last2=Fritch |first2=William |last3=Xi |first3=You-Gen |date=1997-07-04 |title=Evolution of a Strain of CJD That Induces BSE-Like Plaques |url=http://dx.doi.org/10.1126/science.277.5322.94 |journal=Science |volume=277 |issue=5322 |pages=94–98 |doi=10.1126/science.277.5322.94 |pmid=9204907 |issn=0036-8075|url-access=subscription }}{{Cite journal |last1=Baker |first1=Christopher A. |last2=Martin |first2=Daniel |last3=Manuelidis |first3=Laura |date=November 2002 |title=Microglia from Creutzfeldt-Jakob Disease-Infected Brains Are Infectious and Show Specific mRNA Activation Profiles |url=http://dx.doi.org/10.1128/jvi.76.21.10905-10913.2002 |journal=Journal of Virology |volume=76 |issue=21 |pages=10905–10913 |doi=10.1128/jvi.76.21.10905-10913.2002 |pmid=12368333 |pmc=136595 |issn=0022-538X}}{{Cite journal |last1=Lu |first1=Zhi Yun |last2=Baker |first2=Christopher A. |last3=Manuelidis |first3=Laura |date=2004-10-18 |title=New molecular markers of early and progressive CJD brain infection |url=http://dx.doi.org/10.1002/jcb.20220 |journal=Journal of Cellular Biochemistry |volume=93 |issue=4 |pages=644–652 |doi=10.1002/jcb.20220 |pmid=15660413 |s2cid=9285207 |issn=0730-2312|url-access=subscription }} PrP amyloid itself can also behave as a defensive innate immune response to TSE agent infection, and high levels of PrP amyloid can abolish 99.999% of infectivity.{{Cite journal |last1=Miyazawa |first1=Kohtaro |last2=Kipkorir |first2=Terry |last3=Tittman |first3=Sarah |last4=Manuelidis |first4=Laura |date=2012 |title=Continuous production of prions after infectious particles are eliminated: implications for Alzheimer's disease |journal=PLOS ONE |volume=7 |issue=4 |pages=e35471 |doi=10.1371/journal.pone.0035471 |issn=1932-6203 |pmc=3324552 |pmid=22509412|bibcode=2012PLoSO...735471M |doi-access=free }}{{cite journal |author=Manuelidis L |year=2013 |title=Infectious particles, stress, and induced prion amyloids: a unifying perspective |journal=Virulence |volume=4 |issue=5 |pages=373–83 |doi=10.4161/viru.24838 |pmc=3714129 |pmid=23633671}},

Manueldis has challenged the dominant assertion that host prion protein (PrP), without any nucleic acid, is the causal infectious agent in TSEs. The prion hypothesis was put forth by Stanley B. Prusiner, who won the 1997 Nobel Prize in Physiology or Medicine.{{cite web | url=http://nobelprize.org/nobel_prizes/medicine/laureates/1997/prusiner-autobio.html | title=Stanley B. Prusiner - Autobiography | publisher=NobelPrize.org | access-date=2007-01-02}} In contrast to the amyloid or "infectious form of host PrP", Manuelidis and colleagues showed that infectious CJD 25nm brain particles had a homogeneous viral density and size and separated from most prion protein. Disruption of CJD nucleic acid-protein complexes destroys infectivity.{{Cite journal |last1=Manuelidis |first1=L. |last2=Sklaviadis |first2=T. |last3=Akowitz |first3=A. |last4=Fritch |first4=W. |date=1995-05-23 |title=Viral particles are required for infection in neurodegenerative Creutzfeldt-Jakob disease |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=92 |issue=11 |pages=5124–5128 |doi=10.1073/pnas.92.11.5124 |issn=0027-8424 |pmid=7761460|pmc=41861 |bibcode=1995PNAS...92.5124M |doi-access=free }} Comparable 25 nm particles were also identified within CJD and scrapie infected cell cultures, but not in uninfected controls. As with isolated 25 nm brain particles, cultured cells particles did not bind PrP antibodies.{{cite journal| author=Manuelidis L|author2=Yu ZX |author3=Barquero N |author4=Mullins B |date=February 6, 2007| title=Cells infected with scrapie and Creutzfeldt–Jakob disease agents produce intracellular 25-nm virus-like particles| journal=Proceedings of the National Academy of Sciences| volume=104| issue=6| pages=1965–1970| pmid=17267596| doi = 10.1073/pnas.0610999104| pmc=1794316|bibcode=2007PNAS..104.1965M |doi-access=free }}

Manuelidis stated that "Although much work remains to be done, there is a reasonable possibility these are the long sought viral particles that cause transmissible spongiform encephalopathies". She claims that misfolded prion protein probably is not infectious, and that there is no independent confirmation that recombinant PrP can be converted to an infectious form. However, the Prusiner group has published evidence of precisely the kind of conversion that Manueldis claims there is no evidence for.{{Cite journal |last1=Legname |first1=Giuseppe |last2=Baskakov |first2=Ilia V. |last3=Nguyen |first3=Hoang-Oanh B. |last4=Riesner |first4=Detlev |last5=Cohen |first5=Fred E. |last6=DeArmond |first6=Stephen J. |last7=Prusiner |first7=Stanley B. |date=2004-07-30 |title=Synthetic Mammalian Prions |url=https://www.science.org/doi/10.1126/science.1100195 |journal=Science |language=en |volume=305 |issue=5684 |pages=673–676 |doi=10.1126/science.1100195 |pmid=15286374 |bibcode=2004Sci...305..673L |issn=0036-8075|url-access=subscription }} As originally proposed, misfolded PrP amyloid might be an infectious structure or a pathological response protein.{{Cite journal |last1=Merz |first1=P. A. |last2=Somerville |first2=R. A. |last3=Wisniewski |first3=H. M. |last4=Manuelidis |first4=L. |last5=Manuelidis |first5=E. E. |date=Dec 1–7, 1983 |title=Scrapie-associated fibrils in Creutzfeldt-Jakob disease |url=https://pubmed.ncbi.nlm.nih.gov/6358899/ |journal=Nature |volume=306 |issue=5942 |pages=474–476 |doi=10.1038/306474a0 |issn=0028-0836 |pmid=6358899|bibcode=1983Natur.306..474M |s2cid=3075231 }} Later evidence favored the pathological concept, with infectious viral particles binding to and converting receptor PrP to an amyloid form.{{Cite journal |last=Manuelidis |first=Laura |date=2013-07-01 |title=Infectious particles, stress, and induced prion amyloids: a unifying perspective |journal=Virulence |volume=4 |issue=5 |pages=373–383 |doi=10.4161/viru.24838 |issn=2150-5608 |pmc=3714129 |pmid=23633671}} Much additional evidence points to an exogenous source of infectious TSE agents, and the claim that recombinant PrP can be made infectious has not been reproducible.{{Cite journal |last1=Timmes |first1=Andrew G. |last2=Moore |first2=Roger A. |last3=Fischer |first3=Elizabeth R. |last4=Priola |first4=Suzette A. |date=2013 |title=Recombinant prion protein refolded with lipid and RNA has the biochemical hallmarks of a prion but lacks in vivo infectivity |journal=PLOS ONE |volume=8 |issue=7 |pages=e71081 |doi=10.1371/journal.pone.0071081 |issn=1932-6203 |pmc=3728029 |pmid=23936256|bibcode=2013PLoSO...871081T |doi-access=free }}{{Cite journal |last1=Barron |first1=Rona M. |last2=King |first2=Declan |last3=Jeffrey |first3=Martin |last4=McGovern |first4=Gillian |last5=Agarwal |first5=Sonya |last6=Gill |first6=Andrew C. |last7=Piccardo |first7=Pedro |date=October 2016 |title=PrP aggregation can be seeded by pre-formed recombinant PrP amyloid fibrils without the replication of infectious prions |journal=Acta Neuropathologica |volume=132 |issue=4 |pages=611–624 |doi=10.1007/s00401-016-1594-5 |issn=1432-0533 |pmc=5023723 |pmid=27376534}}{{Cite journal |last1=Schmidt |first1=Christian |last2=Fizet |first2=Jeremie |last3=Properzi |first3=Francesca |last4=Batchelor |first4=Mark |last5=Sandberg |first5=Malin K. |last6=Edgeworth |first6=Julie A. |last7=Afran |first7=Louise |last8=Ho |first8=Sammy |last9=Badhan |first9=Anjna |last10=Klier |first10=Steffi |last11=Linehan |first11=Jacqueline M. |last12=Brandner |first12=Sebastian |last13=Hosszu |first13=Laszlo L. P. |last14=Tattum |first14=M. Howard |last15=Jat |first15=Parmjit |date=December 2015 |title=A systematic investigation of production of synthetic prions from recombinant prion protein |journal=Open Biology |volume=5 |issue=12 |pages=150165 |doi=10.1098/rsob.150165 |issn=2046-2441 |pmc=4703057 |pmid=26631378}} In fact, one can remove all detectable forms of PrP from infectious brain particles, yet these particles retain high infectivity.{{Cite journal |last1=Kipkorir |first1=Terry |last2=Tittman |first2=Sarah |last3=Botsios |first3=Sotirios |last4=Manuelidis |first4=Laura |date=November 2014 |title=Highly infectious CJD particles lack prion protein but contain many viral-linked peptides by LC-MS/MS |journal=Journal of Cellular Biochemistry |volume=115 |issue=11 |pages=2012–2021 |doi=10.1002/jcb.24873 |issn=1097-4644 |pmc=7166504 |pmid=24933657}} Thus, PrP may not be an integral or required component of the infectious particle.{{cite journal | last1=Kipkorir |first1=T |last2=Colangelo |first2=CM |last3=Manuelidis |first3=Laura | pmid = 25930988 | doi=10.1002/pmic.201500059 | volume=15 | title=Proteomic analysis of host brain components that bind to infectious particles in Creutzfeldt-Jakob disease | year=2015 | journal=Proteomics | pages=2983–98 | issue=17 | pmc=4601564 }} On the other hand, all high infectivity scrapie and CJD fractions contain nucleic acids when analyzed using modern amplification strategies.{{Cite journal |last=Manuelidis |first=Laura |date=April 2011 |title=Nuclease resistant circular DNAs copurify with infectivity in scrapie and CJD |url=https://pubmed.ncbi.nlm.nih.gov/21165784/ |journal=Journal of Neurovirology |volume=17 |issue=2 |pages=131–145 |doi=10.1007/s13365-010-0007-0 |issn=1538-2443 |pmid=21165784|s2cid=18457762 }} When these nucleic acids are destroyed with nucleases that have no effect on PrP, 99.8% of the infectious titer is abolished.{{cite journal |author=Botsios Sotirios, Manuelidis Laura |year=2016 |title=CJD and Scrapie Require Agent-Associated Nucleic Acids for Infection |journal=J. Cell. Biochem. |volume=9999 |issue=8 |pages=1–12 |doi=10.1002/jcb.25495 |pmid=26773845 |s2cid=26685867}} Novel circular SPHINX DNAs from the microbiome of 1.8kb and 2.4kb have been identified in isolated infectious particles, but their role in infection and/or disease is not yet clear because they are also present at much lower levels in non-infectious preparations. Only a few infectious particle nucleic acid sequences have been analyzed to date. Nevertheless, host innate immune responses, including a remarkably strong interferon response to infection,{{Cite journal |last1=Aguilar |first1=Gerard |last2=Pagano |first2=Nathan |last3=Manuelidis |first3=Laura |date=2022 |title=Reduced Expression of Prion Protein With Increased Interferon-β Fail to Limit Creutzfeldt-Jakob Disease Agent Replication in Differentiating Neuronal Cells |journal=Frontiers in Physiology |volume=13 |pages=837662 |doi=10.3389/fphys.2022.837662 |issn=1664-042X |pmc=8895124 |pmid=35250638|doi-access=free }} further demonstrate TSE agents are recognized as foreign infectious invaders. Misfolded PrP does not elicit this effect.

• Frank Bastian
• Stanley Prusiner
• Prion
• Slow virus
• Virino
• Spiroplasma

• http://medicine.yale.edu/lab/manuelidis/index.aspx

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{{DEFAULTSORT:Manuelidis, Laura}}

Category:Sarah Lawrence College alumni

Category:American women biochemists

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Category:American pathologists

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Category:Prion researchers