The yen to travel, age 2.
Born in Washington DC 1955
Shipboard journey to England - 1962
Bill,
Steven - US attorney,
Michelle MD - Professor of Medicine at Hopkins,
Lisa MD - Member, Fox Chase Cancer Research Center
A year abroad - age 7
Summer Research at NIH - 1971
Medical & Graduate School - UVA 1976-1982 PhD
work with Bob Wagner on VSV; taught tropical
medicine & ID by Jonathan Ravdin (to whom he
returns to UVA for ID fellowship in 1985
Mary Ann and Bill graduate from
Medical School - 1982
L to R: Bob Wagner (PhD
mentor), Wm Petri Sr., Lionel
Poirier (NIH mentor)
1982-5 Medicine Residency at
CWRU under Chuck Carpenter
At Woods Hole with first 2 grad students from the
lab; L to R Jay Purdy (discoverer of DNA
transformation for E. histolytica and Jim McCoy
(discoverer of the light subunit of the parasite lectin)
2003: Active International Research
• Dhaka Bangladesh - Natural history of
amebiasis, working with Rashidul Haque
• Tblissi Georgia - water-borne outbreak of amebic
liver abscess, working with Nina Trapaidze and
Shota Tsaverna
• New Delhi, India - rRNA transcription in E.
histolytica, working with Sudha Bhattacharya
• Accra, Ghana - amebiasis and HIV, working with
Patrick Ayeh-Kumi
• Ankara Turkey - genetic variation in E.
histolytica, working with Mehment Tanyuksel
In
Bangladesh
with son
David
June 2003
Field Staff in Dhaka
Career-long Colleagues: Barbara Mann, Ph.D.
Career-long Colleagues: Rashidul Haque,
MBBS, PhD
Students, Fellows & Visiting Professors
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Patrick Ayeh-Kumi, M.Phil, Lecturer, University of Ghana Medical School
Lucia Braga, M.D. Professor of Gastroenterology, University of Fortaleza, Brazil
Suman Dhar, Ph.D. Assistant Professor, Jawaharlal Nehru University, New Delhi, India
James Dodson, PhD, Research Assistant Professor, George Mason University
Elizabeth Higgs, MD, Parasitology & International Programs, NIAID
Eric Houpt, M.D. Assistant Professor of Medicine, University of Virginia
Christopher D. Huston, M.D. Assistant Professor of Medicine, University of Vermont
Barbara Mann, Ph.D. Associate Professor of Medicine, University of Virginia
James McCoy, PhD, Research Associate, University of Virginia
Jay Purdy, MD, PhD, Fellow in Infectious Diseases, University of Iowa
Girija Ramakrishnan, Ph.D. Research Assistant Professor, University of Virginia.
Joanna M. Schaenman, MD, PhD, Chief Resident, Internal Medicine, Stanford
Upinder Singh, M.D. Assistant Professor, Department of Medicine, Stanford
Mehmet Tanyuksel, M.D. Professor, Gulhane Military Medical Academy, Turkey.
Randy Vines, PhD, Senior Research Scientist, Virginia Bioinformatics Institute
ASTMH
• 1986: Young Investigator Award
• 1992-2001: Scientific Program Chair - a period
when attendance and abstracts doubled yet
registration fees for students & fellows were
reduced to nominal levels
• 2003 - Proceeds from the amebiasis antigen
detection test donated to ASTMH to fund the
Young Investigator Award (in honor of Bill Sr.)
2001- Final year as ASTMH
Scientific Program Chair
Surrounded by good people: The Petri-Mann Lab Group
Andrew, Danny, Sarah, Bill, Rachel, Mary Ann and David
America in the World:
100 Years of Tropical Medicine
and Hygiene
William A. Petri, Jr., M.D., Ph.D.
President,
American Society of Tropical Medicine and Hygiene
Febrile Illnesses - 18th Century
• Fevers determined more by pulse rate than
temperature
• Intermittent fevers - malaria
• Continued fevers
– With pox - smallpox or varicella
– With petechiae - meningococcemia…
– With jaundice - yellow fever
Philadelphia - 1793
Philadelphia Death Rates: 1690-1990
1793
Philadelphia - 1793
• Early July - 2,000 refugees arrive in
Philadelphia from slave revolt in Santo
Domingo, West Indies
• Early August illness strikes: fever,
headache and abdominal pain rapidly
progressing to death and accompanied by
jaundice, coffee ground emesis &
hemorrhage
Clinical Description
• …after a chilly fit of some duration, a quick tense
pulse-hot skin-pain in the head, back and limbs-flushed
countenance-inflamed eye-moist tongue-oppression
and sense of soreness at the stomach…from 3, 4 or
even 5 days…
• On the febrile symptoms suddenly subsiding, they were
immediately succeeded by a yellow tinge in the opaque
cornea…black vomit…haemorrhages from the nose,
…agitation, deep and distressed sighing, comatose
delirium and finally death.
•
Dr. Wm. Currie, in Mathew Carey, A short history of the malignant fever, lately prevalent in
Philadelphia, 1794.
Burials:August-November 1793
Washington Square,
Philadelphia, 6th & Market
The appearance of most of the grave yards in Philadelphia
is extremely awful. They exhibit a strong likeness of
ploughed fields. Mathew Carey, A short history of the malignant fever,
lately prevalent in Philadelphia, 1794
• A poor man was taken sick on the road at a
village not far from Philadelphia. He lay
calling for water a considerable time in
vain. At length an old woman brought a
pitcher full, and not daring to approach him,
she laid it at a distance desiring him to
crawl to it which he did. After lying there
about forty eight hours, he died; and his
body lay in a state of putrefaction for some
time…
Mathew Carey, A short history of the malignant fever, lately prevalent in
Philadelphia, 1794
• A man and wife, once in affluent
circumstance, were found lying dead in
bed, and between them was their child,
a little infant, who was sucking its
mother’s breasts. How long they had
laid thus, was uncertain.
Mathew Carey, A short history of the malignant fever, lately prevalent in
Philadelphia, 1794
• The scourge of yellow fever has fallen with
extreme severity on some families… of
Godfrey Gebler’s family no less than eleven
were swept off the face of the earth. Dr.
Sproat, his wife, son and daughter--Michael
Hay his wife and three children--David
Flickwir and five of his family-Samuel
Weatherby, wife, and four grown children,
are no more
Mathew Carey, A short history of the malignant fever, lately prevalent in
Philadelphia, 1794
• Of the very large number of persons who
have fallen under this disorder, it is not
improbable that a half or a third have
perished merely for want of necessary care
and attention, owing to the extraordinary
panic
Mathew Carey, A short history of the malignant fever, lately prevalent in
Philadelphia, 1794
• With the poor, the case was, as might be
expected, infinitely worse than with the
rich. Many of these have perished, without
a human being to hand them a drink of
water…
Mathew Carey, A short history of the malignant fever, lately prevalent in
Philadelphia, 1794
Mortality Breakdown -1793
• It has been denied that a person is twice
susceptible of the yellow fever
Mathew Carey, A short history of the malignant fever, lately prevalent in
Philadelphia, 1794
Yellow Fever Deaths & Ambient
Temperatures
120
100
80
60
40
20
8/
7/
17
93
0
Mathew Carey, A
short history of the
malignant fever, lately
prevalent in
Philadelphia, 1794
Yellow Fever Deaths & Ambient
Temperatures
120
100
80
60
40
20
8/
7/
17
93
0
Mathew Carey, A
short history of the
malignant fever, lately
prevalent in
Philadelphia, 1794
Cuban Interior - 1900
Carlos Juan Finlay
(1833 - 1915)
Son of a Scottish doctor and a
Parisienne, born in Cuba but received
early schooling in France
Jefferson Medical College Graduate
Practiced medicine and
ophthalmology in Havana
Became fascinated with the
transmissibility of yellow fever, and
that the agent of disease was in the
air
Finlay in Havana
Aedes aegypti & Carlos Finlay
Finlay hypothesizes that the common
house mosquito transmits Yellow Fever
by directly injecting the blood from an
infected person.
He does not appreciate the need for an
extrinsic incubation period in the
mosquito after it takes an infected blood
meal.
In retrospect, at most only 1 of his 104
experiments from 1881-1898
demonstrates mosquito transmission of
Yellow Fever. Many thought that Finlay
has disproved his hypothesis.
USS Maine entering Havana
Harbor, January 25, 1898
USS Maine - 2/15/98
"Burial of the dead" [1899?]
20,738 cases of
typhoid fever, and
1,500 deaths in the
first 171,000
American soldiers
Yellow fever
outbreaks in
occupation troops
spurs formation of
the Commission
The United States Army
Yellow Fever Commission
(1900 - 1901)
Walter Reed
• Born in Virginia in 1851, MD at age
17 from UVA, then to Bellevue,
official of NY Board of Health
• 1874-1890 in US Army as physician
• Sabbatical at Hopkins with Osler and
trained in bacteriology under Welch
• 1893 Professor of Bacteriology at the
Army Medical School
• Established importance of human to
human transmission of typhoid fever
in Cuba
Jesse William Lazear
(1866 -9/25/ 1900)
• Born to wealthy family in
Baltimore.
• Attended Hopkins, Columbia,
trained in bacteriology in Europe.
• Medical resident & later head of
clinical microbiology Hopkins
• Assigned to Camp Columbia Feb.
1900 as Asst Surgeon, studies
malaria and yellow fever.
• Entomologist, makes Reed aware of
Ross’ work on malaria, meets Finlay
and discusses his hypothesis on
mosquito transmission, and who
gives him mosquito eggs for
experimentation
James Carroll
• Born in Woolwich, England
6/5/1854; served in US Army
starting in 1874 as a private
• Medical School at the U. City of
NY, UMD, & bacteriology with
Wm Welch at Hopkins
• First works with Reed at the
Army Medical School 1893
• Reed’s assistant at the
Bacteriology Labs at Colombian
University
Aristides Agramonte
• Born in Cuba and brought in 1870 to NY
as infant after father killed fighting against
Spain.
• MD from Columbia, bacteriologist with
NY City Health Department
• Assigned to Military Hospital #1 in
Havana as pathologist in charge of the
laboratories
• Cuban scientist who had worked in Reed's
lab at the Columbian University in 1898,
• Thought to be immune to Yellow Fever
from a childhood infection
• An accomplished pathologist who
performed most of the autopsies of
suspected cases of Yellow Fever
George Miller Sternberg (1838-1915)
Member of Chaille Commission to
Havana Cuba in 1879 that met with
Carlos Finlay and concluded the
Yellow Fever was perhaps a living
entity in the atmosphere
Appointed Surgeon General in 1893.
Impressed with Walter Reed’s work
with Welch at Hopkins, appoints him a
Professor at the new Army Medical
School.
1900 he establishes the Yellow Fever
Commission to Cuba
• Military Orders
Establishing the
Yellow Fever
Commission - May 14,
1900
• This was the 4th
Commission to
attempt to deal with
Yellow Fever along
the US coast &
Caribbean
Giuseppe Sanarelli
• Italian bacteriologist who had worked at the
Pasteur Institute
• 1897 working in Brazil & Uruguay he reports the
identification of Bacillus icteroides in 58% of
autopsies of cases of Yellow Fever, but almost
always in association with other bacteria.
• He claims to have reproduced the disease by
injecting formic aldehyde-inactivated broth
cultures into 5 humans (3 of whom died)
Colombia Barracks, Cuba
June 25, 1900 Studies Begin
Hospital Corps, Camp Columbia,
Cuba, September 1900
Lazear’s Impatience with Reed
Dr. Reed had been in the old
discussion over Sanarelli's
bacillus and he still works on
that subject. I am not all
interested in it but want to do
work which may lead to the
discovery of the real organism.
However I am doing as much as,
I can.
Letter fragment from Jesse W.
Lazear to Mabel H. Lazear,
July 15, 1900
Reed, Caroll & Agromonte & Lazear disprove
B. icteroides as cause of Yellow Fever
Proceedings 28th Annual Meeting of the American Public
Health Association, Indianapolis IN, October 22-26, 1900
Henry Rose Carter
(1852 - 1925)
UVA graduate in engineering. Injury in Civil
War prevents him from continuing as an
engineer. Entered Marine Hospital Service
Curious about why yellow fever could
appear on a ship that had been at sea for 2
weeks with no sickness on board.
Studies the incubation period in the
Mississippi towns of Orwood and Taylor
Extrinsic Incubation Period
Interval between infecting and secondary cases of Yellow Fever from the Records of the
Yellow Fever at Orwood and Taylor, Miss. 1898. New Orleans Medical & Surgical Journal,
May 1900, H.R. Carter
An intermediate host?
• H. Durham and W. Myers from the Liverpool
School visit Finlay and the YF Commission in
Cuba in mid-July 1900.
• They make the connection between the 2 week
period of extrinsic incubation identified by Carter
and Finlay’s hypothesis that mosquitoes are the
vector
• “Some means of transmission by the aid of an
intermediate host-a town-loving host for this
town-loving disease--is to some extent more
plausible than might be anticipated”
• Durham & Myers, BMJ 2 (9/8/1900):656b
Reed Proposes Human
Experimentation
Letter from Walter Reed to George Miller Sternberg, July 24, 1900
There is plenty of material in Havana, with
every probability of its rapid increase- our
last case here died on Monday -- we will
therefore expect to transfer our field of work
to Military Hospital No. 1- Lazaer, Carroll
and Agramonte are all deeply interested in
the problem, Personally, I feel that only can
experimentation on human beings serve to
clear the field for further effective work -with one or two points cleared up, we could
then work to so much better advantage.
Carroll: Self-Experimentation by
the Yellow Fever Board
“The final determination to investigate the mosquito theory
was arrived at during an informal meeting of the Board (Dr.
Agramonte being absent) at Columbia Barracks on the
evening before Dr. Reed's departure for the United States
early in August 1900. … The proposal to submit
ourselves to inoculation was made by myself, twice,
before it was brought up by Dr. Reed, for the first time, at
the meeting above mentioned, where it was finally
decided upon by actual vote”.
•
(Letter from
James Carroll to Robert M. O'Reilly, August 29, 1906)
Carroll: Why did Reed depart Cuba?
• “On the evening of the 3rd of August, Reed,
Lazear and I agreed to be bitten. On the
following morning Reed sailed for the
United States, without a word of
explanation so far as I knew” (letter from
Caroll to Dr. Wm Kelly, 6/23/1906)
• Summoned back to Washington to complete
the report of the Typhoid Fever
Commission?
Reed’s Remorse in the US
I have been so ashamed of myself for
being here in a safe country, while my
associates have been coming down
with yellow Jack
The General has suggested that I do not
return, but somehow I feel that, as the
Senior member of a Bd- investigating
yellow Fever, my place is in Cuba, as
long as the work goes onI shall, of course, take every precaution
that I can against contracting the
disease, and I certainly shall not, with
the facts that we now have allow a
"loaded" mosquito to bite me! That
would be fool-hardy in the extreme(Reed to Keane, 9/25/1900)
Carroll letter to his wife - 10/3/1900
Lazear on Carroll
•Dr. Carroll is not a very entertaining person. He is a bacteriologist
pure and simple. To me bacteriology is interesting only in its
relation to medicine. He is interested in germs for their own sake,
and has a very narrow horizon. Still good work may come out of it
all. Carroll would amuse you very much. He is very tall and thin.
Wears spectacles, bald headed, has a light red mustache, projecting
ears and a rather dull expression. Letter fragment from Jesse W.
Lazear to Mabel H. Lazear, July 15, 1900
Agramonte, Lazear, Carroll
Carroll’s Infection
• Lazear experiments on himself and 8 volunteers none become ill as mosquitoes have not undergone
extrinsic incubation period
• 8/27/1900 Lazear places a mosquito on Carroll’s
arm that had fed 12 days earlier on Yellow Fever
patient. 8/29 Carroll develops symptoms.
• However Carroll travels off post to Havana before
developing Yellow Fever, so that when he
develops Yellow Fever it is not conclusive that it
was from the mosquito. He recovers by 9/7/1900.
Dean’s Infection
• Private William Dean (“xy”) offers to
volunteer.
• Dean is infected with same mosquito that
bit Carroll on the day Carroll becomes ill.
Dean suffers mild attack of yellow fever
and recovers.
Lazear on Track of Real Germ
I rather think I am on the track of the real germ, but nothing must
be said as yet, not same a hint I have not mentioned it to a soul.
Columbia Barracks, Sept. 8 1900 Letter from Dr. Jesse Lazear to
his wife.
Lazear’s Infection with
Yellow Fever
• September 13, 1900 Lazear allows himself to be
bitten again.
• September 18, 1900 he develops fever
• September 22 black vomit
• September 25 dies.
• Carroll writes that “I will never forget the
expression of alarm in his eyes when I last saw
him alive on the 3rd or 4th day of his illness”
9/19/00 - Fever Curve for
Jesse W. Lazear
Letter from Walter Reed to Emilie
Lawrence Reed, October 6, 1900
• Dr Lazear contracted the disease at the yellow fever
[Hospital in Havana] by letting an infected mosquito bite
him- He saw the insect on his hand & deliberately let it get
its fill of blood in order to test our theory- Five days later
he had his chill, followed by high fever- His case was a
very severe one from the beginning, his death occurring on
the 6th day there after- He was a splendid, brave fellow & I
lament his loss more than words can tell; but his death was
not in vain- His name will live in the history of those who
have benefited humanity
Telegram from Jefferson Randolph Kean
to Mabel H. Lazear, September 26, 1900
Letter from Mabel Houston Lazear to
James Carroll, November 10, 1900
anxious to know more about these
circumstances as to how Dr
Lazear contracted yellow fever
In a note from General Wood
yesterday he writes that Dr Lazear
allowed a mosquito to bite him
that had just bitten a yellow fever
patience.
Is it possible Gen. Wood could be
mistaken - much as I know Dr
Lazear loved his work I can
hardly think he could have
allowed his enthusiasm to carry
him so far.
Jesse William Lazear (1866 September 25, 1900)
The Washington Observer, September 29, 1900
• Disprove bacillus icteroides
• Mosquito identified as Culex
fasciatus by Howard of USDA
• Successful transmission requires
extrinsic incubation of
approximately 12 days. Both
Dean & Carroll bitten by same
mosquito (12 & 16 days after it
had fed on a Yellow Fever pt.)
• Problems with Carroll’s potential
acquisition of infection from
autopsy or from Havana
detailed.
• Dean’s case is more convincing
as he had not traveled outside of
Columbia Barracks for 16 days
prior to inoculation. Same
mosquito as had bitten Carroll 4
• “give our attention to the theory of the propagation
of yellow fever by means of the mosquito, -a
theory first advanced and ingeniously discussed by
Dr. Carlos J. Finlay of Havana, in 1881…”
• Other observations…confirmed Carter’s
conclusions, thus pointing as it seemed to us the
presence of an intermediate host, such as the
mosquito, which having taken the parasite into its
stomach…was able after a certain interval to
reconvey the infecting agent to other
individuals…”
• Drs. Durham and Myers, to whom we had the
pleasure of submitting Carter’s observations, have
been equally impressed by their importance”
Sternberg: Need for Additional
Human Experimentation
I am glad to know that you are in a fair way to
carry on additional inoculation
experiments…The profession generally will
not be disposed to accept the experiments
already published as definitely settling the
question as to the role of the mosquito in the
transmission of the disease.
George Miller Sternberg to Walter Reed, November 17, 1900
Informed Consent - 11/26/1900
The undersigned, Antonio Benino being more than
twenty-five years of age, native of Cerceda, in the
province of Corima, the son of Manuel Benino and
Josefa Castro here states by these presents, being in
the enjoyment and exercise of his own very free will,
that he consents to submit himself to experiments for
the purpose of determining the methods of transmission of yellow fever, …
The undersigned understands perfectly well that in
case of the development of yellow fever in him, that he
endangers his life to a certain extent but it being
entirely impossible for him to avoid the infection
during his stay in this island, he prefers to take the
chance of contracting it intentionally in the belief that
he will receive from the said Commission the greatest
care and the most skillful medical service.
Letter from Walter Reed to Emilie
Lawrence Reed, November 27, 1900
• I am having two small houses constructed- I don't
know whether I have told you this already -- one for
mosquito-bitten patients, and the other for testing the
clothing infection theory -- but I don't want to try the
latter until I have succeeded or failed with the
former. Another week, I hope, will enable us to tell
what mosquitoes can do, as we now have some
insects that bit yellow fever cases 10 days ago todayIf we can get them to live 8 or 10 days more, I
believe we can reproduce the disease promptly-
Camp Lazear Mosquito Building 2
Walter Reed to Emilie Lawrence Reed, [December 25 or 26], 1900
Camp Lazear
• Camp Lazear was built on the rolling fields of the
Finca San Jose, on the farm of Dr. Ignacio Rojas, who
leased the land to the Americans.
Camp Lazear - Completed
11/20/1900
Letter from William Crawford Gorgas to
Henry Rose Carter, December 13, 1900
Reed and his Board are making most
extensive experiments in the
line of Finlay's mosquito theory, and
in the line of Reed’s preliminary
report. Evidence seems to point very
strongly to the mosquito being
the transmitter of the disease. There
was so much evidence against
it that I was not at all impressed with
the few cases reported in his
original article but his experiments
since, have about convinced me.
Celebration of the Proof of Mosquito
Transmission - 12/22/00
•
VOLUNTEERS 1900-1901
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1 James Carroll Aug 312 xy Sept 53 Jesse W. Lazear Sept 18
4 John R. Kissinger Dec 8
Antonio Benino Dec 13
5 Spanish Immigrant Oct. 26
6 Becente Presedo Dec 12
7 Niconar Fernandez Dec 13
8 John J. Moran Dec 25
9 Jose Martinez Fernandez Jan 3
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Blood inoculations - 1901
10 Warren G. Jerunegan Jan 8
11 William Olsen Jan 11
Wallace Forbes Jan. 24
12 William tamming Jan. 24
13 John H. Andrus Oct 26 Jan 28
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•
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•
•
•
Mosquito inoculations I
14 Levi E. Folk Oct. 28 Jan 23
15 Clyde L. West Oct. 27 Feb 3
James Hildebrand
16 James L. Hanberry Oct 26 Feb 9
17 Char. G. Sontagg Oct. 28 Feb 10
•
•
•
•
•
•
•
•
Carrolls Experiments 1901
Pablo Ruis Castillo Sept. 19
18 P. R. C.- Spaniard -} Mosquito
19 Jacinto Mendez Alvarez Spaniard} Mosquito Oct 13
20 Manuel Gutierrez Moran Spaniard} blood injection Oct 21
21 P. Hamann 23 Bol } blood injection Oct 19
22 A.W. Covington} CA} blood injection
23 John R. Bullard} blood injection Oct 23
Hospital Corps - Camp
Columbia, September 1900
Sontag (M)
West (M)
Andrus (B)
Jermerlan (B)
Kissinger (M)
Truby
Cook (F)
F = fomites
M = Mosquito
B = Blood
Letter from Walter Reed to Emilie
Lawrence Reed, December 31, 1900
• 11:50 P. M. Dec. 31st 1900- Only 10 minutes of the old
Century remain, lovie, dear. Here I have been sitting reading
that most wonderful book- La Roche on Yellow fever -written in 1853- Forty-seven years later it has been permitted
to me & my assistants to lift the impenetrable veil that has
surrounded the causation of this dreadful pest of humanity
and to put it on a rational & scientific basis- I thank God that
this has been accomplished during the latter days of the old
century- May its cure be wrought out in the early days of the
new century!