Nationality

American

Alma mater

Harvard University, MIT, Yale University

Known for

Ribosome profiling Protein folding

Awards

• Protein Society Irving Sigal Young Investigator Award (2004)

• Raymond and Beverly Sackler International Prize (2008)

• National Academy of Sciences Award for Scientific Discovery (2015)

Scientific career

Fields

Biochemistry Biophysics

Institutions

MIT

UCSF

HHMI

Doctoral advisor

Peter Kim

Other academic advisors

Arthur Horwich

Jonathan S. Weissman is the Landon T. Clay Professor of Biology at the Massachusetts Institute of Technology, a member of the Whitehead Institute, and a Howard Hughes Medical Institute Investigator. From 1996 to 2020, he was a faculty member in the department of Cellular Molecular Pharmacology at the University of California, San Francisco.

Education[edit]

He earned his B.A. in Physics from Harvard College (1988) and his Ph.D. in Physics (1993) from MIT working with Peter Kim. There, he started his studies on protein folding examining Bovine pancreatic trypsin inhibitor (BPTI).^[1]

He was a postdoctoral fellow at Yale University (1993-1996), where he worked with Arthur Horwich studying the mechanism of GroEL.^[2][3]

Career[edit]

Weissman's research team studies how cells ensure that proteins fold into their correct shape, as well as the role of protein misfolding in disease and normal physiology. The team also develops experimental and analytical approaches for exploring the organizational principles of biological systems and globally monitoring protein translation through ribosome profiling. A broad goal of his work is to bridge large-scale approaches and in depth mechanistic investigations to reveal the information encoded within genomes.^[4][5][6]

Weissman has been a member of the National Academy of Sciences since 2009.

References[edit]

• ^ Hoffman, M (Sep 20, 1991). "Straightening out the protein folding puzzle". Science. 253 (5026): 1357–8. Bibcode:1991Sci...253.1357H. doi:10.1126/science.1896845. PMID 1896845. S2CID 38632703.

• ^ Weissman, JS; Hohl, CM; Kovalenko, O; Kashi, Y; Chen, S; Braig, K; Saibil, HR; Fenton, WA; Horwich, AL (Nov 17, 1995). "Mechanism of GroEL action: productive release of polypeptide from a sequestered position under GroES". Cell. 83 (4): 577–87. doi:10.1016/0092-8674(95)90098-5. PMID 7585961. S2CID 17839893.

• ^ Weissman, Jonathan S.; O'Shea, Erin K. (1 January 2009). "2004 Irving Sigal Young Investigator Award". Protein Science. 13 (12): 3333–3335. doi:10.1110/ps.041134604. PMC 2287319. PMID 15557272.

• ^ "New Technique Focuses on Transcription". HHMI. 20 January 2011. Retrieved 14 February 2013.

• ^ Ingolia, Nicholas T.; Lareau, Liana F.; Weissman, Jonathan S. (1 November 2011). "Ribosome Profiling of Mouse Embryonic Stem Cells Reveals the Complexity and Dynamics of Mammalian Proteomes". Cell. 147 (4): 789–802. doi:10.1016/j.cell.2011.10.002. PMC 3225288. PMID 22056041.

• ^ "Jonathan S. Weissman". HHMI. Retrieved 14 February 2013.

External links[edit]

• UCSF Academic Bio

• His Howard Hughes Medical Institute bio

• Weissman Lab website

In late August and early September 1999,

New York City and surrounding areas experienced

an outbreak of human encephalitis

consistent with an arboviral etiology. Serological

evidence from this outbreak implicated

a flavivirus as the etiologic agent. Concur-

rent with this human encephalitis outbreak, a

viral encephalitis of unknown etiology was

discovered in American crows (Corvus

brachyrhynchos) and fish crows (Corvus ossifragus)

dying in the same geographic area.

Deaths were also observed among several

exotic avian species, including a Chilean flamingo

(Phoenicopterus chilensis) at the

Bronx Zoo. Necropsy samples from these

birds were submitted to the National Veterinary

Services Laboratories, U.S. Department

of Agriculture, and were inoculated into embryonated

chicken eggs for virus isolation.

Flavivirus-like particles (diameter 40 nm)

were observed by electron microscopy in the

allantoic fluid 4 days after inoculation. The

isolates were forwarded to the Centers for

Disease Control and Prevention (CDC) for

identification.

The complete nucleotide sequence of one

of these viral isolates (WN-NY99, from the

dead Chilean flamingo) has now been determined.

The viral genomic RNA was amplified

and copied into overlapping DNA fragments

of ;2 to 3 kb by means of the reverse

transcription polymerase chain reaction (RTPCR)

(1). Both strands of the purified DNAs

were sequenced with the use of primers

spaced about 400 bases apart along the entire

genome. The complete 11,029-nucleotide

genomic sequence of WN-NY99 has been

submitted to GenBank (accession number

AF196835). The deduced amino acid sequence

of the coding region of WN-NY99

(genomic positions 97 to 10,395) is shown in

Fig. 1. The WN-NY99 virus genome exhibited

standard flavivirus genomic organization,

the same overall genomic organization

as was described for the WN-Nigeria and

Kunjin (KUN) viruses (2). A short 59 noncoding

region of 96 nucleotides is followed

by an ATG initiation codon at position 97 and

a single open reading frame of 10,302 nucleotides

coding for three structural proteins—

capsid, premembrane ( prM), and envelope

(E)—and five nonstructural proteins (NS1,

NS2a/NS2b, NS3, NS4a/NS4b, and NS5).

The coding region of WN-NY99 is followed

by a 39 noncoding region of 631 nucleotides.

To identify the New York virus antigenically,

we performed indirect immunofluorescence

antibody tests using a panel of welldefined

monoclonal antibodies (mAbs) to

map various isolates from birds and mosquitoes.

The mAb end-point titers with the North

American isolates were compared to titers

derived with other representatives of the Japanese

encephalitis (JE) virus serocomplex of

flaviviruses (Table 1). These mAbs, which

are specific for the E-glycoprotein, can distinguish

WN virus from KUN virus and can

also distinguish either of these viruses from

other members of the JE virus serocomplex.

Viruses were grown in Vero cells, spotted

onto 12-well slides, air-dried, and fixed with

acetone before staining. All viruses reacted

similarly with the broad flavivirus-reactive,

positive-control mAb 4G2 (3, 4). None of

these viruses reacted with the negative-control

antibody, which is specific for the E1

glycoprotein of eastern equine encephalitis

(EEE), an unrelated alphavirus (5). All WN

isolates, including those from North America,

reacted specifically with the WN virus–specific

mAb H5.46, but not with the KUN

virus–specific mAb 10A1 (four- to eightfold

titer differences) (6–8). Similarly, only KUN

virus reacted with mAb 10A1, but not with

mAb H5.46. No KUN or WN viruses reacted

with either the St. Louis encephalitis (SLE)

virus–specific mAb 6B5A-2 or the Murray

Valley encephalitis (MVE) virus–specific

mAb 4B6C-2 (9, 10). These results type the

North American isolates as WN virus and not

as KUN, SLE, or MVE viruses.

WN virus belongs to the family Flaviviridae,

genus Flavivirus, and is a member of the

JE virus serocomplex, which also includes

JE, SLE, MVE, and KUN viruses, among

others (11). Flaviviruses are plus-sense, single-

stranded RNA viruses with a genome of

;11,000 nucleotides (2). Recently published

sequence and phylogenetic data suggest that,

within this serocomplex, KUN viruses appear

to be a subtype of WN virus rather than a

separate viral species (12). Although flaviviruses

are closely related to each other antigenically

and cross-react in serological tests

with polyclonal antisera, most have a rather

distinctive geographic distribution. Those of

the JE serocomplex are maintained in a natural

transmission cycle involving mosquito

vectors and bird reservoir hosts. Humans and

horses are usually incidental hosts.

To determine more precisely the relationships

between the WN-NY99 virus and other

related virus strains, we performed a phylogenetic

analysis on an informative region of

the E-glycoprotein gene (genome positions

1402 to 1656) (12, 13). Aligned nucleic acid

sequence data from 33 WN viruses, seven

KUN viruses, and one JE virus were analyzed

with the use of algorithms for parsimony

(PAUP), distance (MEGA; Fig. 2), and maximum

likelihood (fastDNAml) (14–17). The

phylogenetic trees generated by these analyses

had the same overall topology as that

previously observed, insofar as all WN and

KUN viruses are separated into two major

lineages (12, 13). Viruses in lineage 1 are

primarily of West African, Middle Eastern,

Eastern European, and Australian origin. Lineage

2 consists exclusively of viruses from

the African continent that have apparently not

been involved in human or equine outbreaks,

but rather are maintained in enzootic cycles.

Within lineage 1, the KUN viruses and

the Indian WN viruses both appear as

monophyletic sister clades to the European

and African WN viruses. The WN-NY99

virus is found within lineage 1 and is most

closely related to WN viruses that have

recently been isolated from North Africa,

Romania, Kenya, Italy, and the Middle

East. Of particular note is the close relationship

between the WN-NY99 virus and a

WN virus isolated from the brain of a dead

goose in Israel in 1998. Phylogenetic analysis

of a portion of the gene encoding the

NS5 protein and of the 39 noncoding region

(830 bases) of 12 WN and KUN viruses

also generates trees with nearly identical

topology, with WN-NY99 demonstrating

the closest relationship with lineage 1 WN

viruses (18). Flavivirus sequences amplified

from brain specimens from fatal hu-

man cases occurring in the New York City

outbreak have been analyzed by comparing

genomic sequences from the nonstructural

protein genes to single strains of KUN

and WN viruses (19). Briese et al. concluded

that the agent responsible for the New

York City area outbreak was most closely

related to KUN virus, and accordingly

called the outbreak virus Kunjin/West Nile–

like. The phylogenetic tree in Fig. 2 compares

40 WN and KUN viruses and is more representative

of the phylogeny among WN viruses.

To investigate these relationships further,

we derived additional sequence data from the

structural gene region of the genome ( positions

549 to 1826 in the genes encoding the

prM and E proteins) from selected isolates

obtained during the 1999 epidemic and compared

them to other WN strains within lineage

1 for which sequence data from this

region were available. Table 2 displays the

percent identity among these viruses. The

high degree of sequence similarity (.99.8%)

among the various strains circulating

throughout New York City and surrounding

counties and states indicates that a single WN

strain was introduced and circulated during

the U.S. WN virus outbreak. The identical

genomic sequences identified from human

brain specimens also confirm the association

of this WN-NY99 virus with human disease.

The small number of nucleotide substitutions

observed among the strains analyzed is indicative

of viral microevolution occurring during

the outbreak.

A high degree of similarity between all of

the U.S. WN viruses and the WN virus isolated

in Israel in 1998 (.99.8%) was observed.

Within these 1278 nucleotides (genome positions

549 to 1826), only two nucleotide differences

occurred between WN-NY99 and WNIsrael

1998. Although this high degree of homology

was unexpected, it could not have resulted

from cross-contamination of U.S. viruses

with the Israeli virus; the sequencing of the

WN-Israel 1998 virus was performed independently

at the Pasteur Institute, whereas the isolation

and sequencing of New York isolates

was carried out independently at CDC. For

comparison, analysis of this same region of

WN-NY99 with another virus within the same

lineage (Romania 1996, mosquito isolate) revealed

37 nucleotide differences (96.9% identity).

The cumulative data support the hypothesis

that the epidemic and epizootic observed in

the late summer of 1999 in the northeastern

United States ( primarily New York, New Jersey,

and Connecticut) are attributable to a WN

virus that has been circulating in the Mediterranean

region since 1998. It is noteworthy that

the WN-Israel 1998 virus was associated with

increased pathogenicity for birds, a property

also observed in the U.S. outbreak and previously

observed only experimentally (20). The

absence of reported human cases during this

Israeli epizootic may be due to background

human immunity to the WN virus in Israel.

The northeastern U.S. outbreak is the first

documented incidence of the WN virus in the

Western Hemisphere. This virus has a widespread

distribution in Africa, West Asia, and

the Middle East, occasionally causing epidemics

in Europe that are thought to be initiated by

viruses introduced by migrant birds (21). The

current epidemic of WN virus in New York

City is unprecedented and underscores the ease

with which pathogens can move among the

population centers of the world. It is not yet

known how the virus was introduced, nor how

long it has been in the United States. The extent

of its geographic distribution remains a mystery,

as does the long-term impact it may have

on human and animal health. The WN virus

could have entered the Western Hemisphere

through a number of mechanisms, including

travel by infected humans, importation of illegal

birds or other domestic pets, or unintentional

introduction of virus-infected ticks or mosquitoes.

Additional surveillance as well as field

and laboratory studies are in progress to help

address these questions. Because it cannot be

predicted whether the WN virus will reappear

in the year 2000 transmission season, all components

of the public health system must be

prepared with rapid surveillance and clinical

detection systems in place.