The yen to travel age 2 Born in

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 Ph. D 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 (Ph. D 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 Mc. Coy (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 - r. RNA 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, Ph. D

Students, Fellows & Visiting Professors • • • • 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, Ph. D, 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 Mc. Coy, Ph. D, Research Associate, University of Virginia Jay Purdy, MD, Ph. D, Fellow in Infectious Diseases, University of Iowa Girija Ramakrishnan, Ph. D. Research Assistant Professor, University of Virginia. Joanna M. Schaenman, MD, Ph. D, 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, Ph. D, 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 - 18 th 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, 6 th & 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

Mathew Carey, A short history of the malignant fever, lately prevalent in Philadelphia, 1794

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 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 4 th 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 28 th 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 townloving disease--is to some extent more plausible than might be anticipated” • Durham & Myers, BMJ 2 (9/8/1900): 656 b

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 3 rd 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 on- I 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 3 rd or 4 th 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 6 th 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 days previously.

• “give our attention to 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 today- If 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 • • • 1 James Carroll Aug 31 - 2 xy Sept 5 - 3 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 • • • 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 • • • 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. 31 st 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!