China Features reporters Xiong Lei and Wen Chihua recently visited Zongyang County, in East China's Anhui Province, to further dig into the allegations surrounding Harvard's genetic studies in China. Their investigation was conducted in response to a May 30th newsletter by the Harvard School of Public Health (HSPH) that announced the US Office for Human Research Protection (OHRP) had concluded its investigation of the schools' genetic and environmental epidemiological studies in China. The newsletter claimed that two professors from the HSPH went to the research sites in Anhui Province in East China, to carry out a fact-finding inquiry "as thoroughly as possible" and found that "allegations of any harm being done to individual subjects or of fraud in obtaining information consents could not be substantiated." But the following report by Xiong Lei and Wen Chihua tells a different story.

It has been eight years since Zhang Da'niu had a narrow escape from death after having his first and only "physical check-up."

But he remains to this day in the dark about what it was all for.

The 55-year-old farmer in Zongyang County recalls that one morning in 1995 "when the early rice started to grow," a local official asked him to have a physical check-up for free at the township hospital.

"We were told that if there was anything wrong with us, we would be given free medicine," claims Zhou Zhenmei, Zhang's wife. The couple and two of their four sons "left things we were doing and started for the township right away."

Zhang had suffered from asthma for well over 20 years and things went bad for him when, as required, he opened his mouth and tried to say "ah" after allegedly receiving a spray of a "fog-like" agent.

It is claimed no one warned him or his family of any possible risks of inhaling the chemical.

"It was contained in a plastic bottle that looked very much like a mosquito killer sprayer," Zhou says. "Half way into the process of saying 'Ah' he became out of breath and then lost consciousness. He looked as if he was dead."

The doctors, in a panic, gave him an injection and oxygen. None of the doctors were local, as they spoke different dialects, but Zhang and Zhou could not tell where they were from.

Zhang came around hours later after midnight, and he got no further care, it is claimed, although he was still very sick.

Without receiving further medical treatment or taking any sort of medicine, the couple left hospital the following morning and took a wagon back home. Yet Zhang was too weak to sit up and his wife had to support him all the way, holding him by the arm and back, she recalls.

While administering emergency treatment a doctor had promised to mail them some medicine, it is claimed, but it never came.

"He did not ask for our address and I assumed he should know through the official who called us in for the check-up," Zhou says.

Zhang's condition deteriorates during the wet season and he struggles to sleep.

Yet "no one has ever come to us or informed us of the results of the checkup," Zhang claims, nor for what purposes the blood samples taken from his family members would be used for.

Harvard Project Confirmed

Zhang Funian, a village medic in Lianhu Township near the county seat of Zongyang, knew that the check-up, with people selected from across the county, was "for some research project for Harvard University in the United States," although he is unable to name the project.

"We were told to notify villagers with asthmatic symptoms to have a physical check-up in town," recalls the 52-year-old medic. "We were told the check-up would benefit them, and free medical treatment would be offered."

Zhang, who began offering medical service as a barefoot doctor in the village since 1969 after some basic medical training, says he was "not without misgivings about the project as it involved an American institution." But he dismissed his doubts "since it seemed to be authorized."

The medic was ordered to produce a list of a dozen asthmatic patients and their family members in the village, and took them to the county station for epidemic prevention and control "one day in April of 1995." As he was not on the spot, he did not know how the check-up proceeded.

As far as he knows, "none of the farmers was told of the procedures and results of the 'check-up,' or saw a copy of any informed consent forms," Zhang Funian says.

Several papers published since 1995 confirmed that Zongyang, under jurisdiction of Anqing, a medium-sized city in Anhui, was a site for Harvard genetic projects.

One of the projects was on asthma, co-funded by the United States' National Institutes of Health (NIH) and Millennium Pharmaceuticals, a "leading biopharmaceutical company" based in Cambridge, Massachusetts.

Xu Xiping, associate professor of the Harvard School of Public Health (HSPH), was the principal researcher.

Xu published a paper entitled "Familial Aggregation of Pulmonary Function in a Rural Chinese Community" in the American Journal of Respiratory and Critical Care Medicine (pp 1928-1933, Volume 160, Number 6, December 1999), along with his co-authors who included Scott T. Weiss, a professor of environmental health with HSPH and professor of medicine with Harvard Medical School. Weiss is also an associate physician with HMS' Brigham and Women's Hospital (B&WH).

In the paper, they wrote that they had "conducted a large genetic epidemiologic study in Anqing, China, to examine the contributions of environmental and genetic factors to asthma. The survey was conducted between July 1, 1994 and January 26, 1998."

In their paper, Xu and Weiss claim that a letter explaining the study was sent to each eligible family. Members of 1,161 index families with asthma were recruited from eight counties in Anqing, with Zongyang being the first cited in the list.

Peculiar Published Correction

Rural residents in Zongyang County like Zhang Da'niu and Zhang Funian have had no way of knowing about a US federal investigation that was launched in 1999 into genetic studies performed by Harvard researchers. The investigation continued for three years.

The investigators first questioned whether Xu and his co-authors obtained official or academic approval for their studies.

In a letter in response to questions raised by US government investigators, Xu claimed that the challenged study was "a pilot project" which was "launched by Chinese investigators" with the IRB (institutional review board) approval from "the Anqing Medical Human Subjects Committee in July 1994."

Written in December 1999, Xu addressed the letter to Greg Koski, then director of Human Research Affairs at Partners Health Care System, which owns and operates the Harvard-affiliated B&WH and Massachusetts General Hospital (MGH).

Nearly three years after the investigation started and after Xu and his co-authors published their papers, the journal of Vo 166, 2002, carried a correction note to the editor from Xu Xiping and Scott Weiss, saying that in their 1999 article, "we incorrectly stated" that the ''survey was conducted between July 1, 1994 and January 26, 1998..." Instead, this statement should have read, "Subject enrollment started in February 1995, after obtaining local Chinese IRB approval. Brigham and Women's Hospital IRB approval was received in September 1995."

The same issue of this journal posted similar corrections for a total of seven scientific research articles authored by Xu and Weiss, stating that their respiratory research in China began in February 1995 with approval from a local IRB.

In the letter, Xu told Koski that his institute submitted a Human Subjects application through the B&WH Human Research Committee to conduct the formal study in October 1994, and "this was finally approved in September 1995," so "the formal collaborative study began in October 1995."

But documents acquired from the US Public Health Service through the Freedom of Information Act indicate an earlier involvement of the Harvard institution in the gene hunt.

A copy of "certification of protocol for use of human subjects in research" for the project of Molecular Genetic Epidemiologic Study on Asthma, coded 94-6932-1, carried the signature of Eugene Braunwald, then chairman of the B&WH Department of Medicine, dated "11/15/94."

The protocol describes procedures for an asthma genetics study in Zongyang and Huaining counties of Anqing, including an informed consent document "to be given to every participant" and signed or thumb-printed by him/her before they were enrolled in the study.

An article titled DNA Detectives carried in the Spring 1995 issue of Harvard Public Health Review has a detailed description of Harvard's human genetic projects in China in their initial stage.

It stated that "Xu (Xiping)'s harvest of affected sibling pair blood samples is now being analyzed by hypertension gene hunters at Brigham and Women's Hospital and by asthma gene hunters at Millennium Inc."

In a press release dated July 14, 1995, Millennium Pharmaceuticals announced the "formation of a number of major collaborations that will support the company's comprehensive research programme to identify and characterize genes that play a role in causing asthma and other allergic disorders."

The press release also reported that the first Millennium asthma study "will be completed in collaboration with groups at Anhui Medical University, China, and Channing Laboratory, a joint laboratory of Harvard Medical School and B&WH.

"The clinical aspect of the study, which is centred in Anhui Province, China, is being conducted by Dr Xiping Xu," according to the release. "Collaborating are Drs. Frank Speizer and Scott Weiss, both internationally-recognized epidemiologists with a long term interest in pulmonary disease."

Xu and his colleagues also claimed to have collaborated with what they termed as the "Anqing Medical Human Subjects Committee."

But despite claims by Xu and his co-authors, different statements were given by the local health authorities in Anqing. Concerning the aforementioned "Anqing Medical Human Subjects Committee," an official at Anqing Health Bureau, who identifies himself as "Mr. Chen," says he has "never heard of such a thing."

A senior member identified as Mr. Ding of the Anqing Medical Society also says there has never been such an organization in the city.

Despite the denials, media observers point out that there are Chinese researchers who have been so eager to seek international co-research projects accompanied with funds that they've ignored the ethical issues involved, especially the issues concerning the protection of the rights of the farmers who are the subjects of the projects.

Whatever the explanations, what went on didn't accord with the facts nor was it consistent with the ethical principles the Harvard institutions commit themselves to observing.

Whitewashing?

In their "multiple project assurances" submitted to the US Government to secure research funding, Xu and his co-authors pledged to follow the same principles regarding all research involving humans as subjects, including "to provide a copy of the IRB-approved and signed informed consent document to each subject at the time of consent," and "promptly report to the IRB any injuries or other unanticipated problems involving risks to subjects and others."

But Zhang Da'niu and his wife Zhou Zhenmei, both illiterate, said they have never seen or heard of any "informed consent agreement," nor have they signed or left their fingerprints on any document as such.

They said they have never been told that their blood samples were to be used in an American human genetic research project operated by a foreign university called "Harvard."

Zhang Da'niu collapsed and remained unconscious for at least eight hours after inhaling chemicals for the Harvard asthma genetics study. His case has never been reported, let alone "promptly."

Under standing rules of the US Public Health Service, materials and samples for research shall be obtained only after the human subject volunteer receives a "full and complete disclosure of risks associated with the applicable procedures and benefits derived."

But neither Zhang Da'niu the farmer nor Zhang Funian, the village medic in Zongyang County, could recall they were ever told of anything about the required informed consent.

Asthma is only one of more than a dozen projects drawing the Harvard research team to sample Chinese farmers' blood for genetic screening to find hereditary links to diseases ranging from asthma to hypertension, obesity, diabetes and osteoporosis.

Several of them were funded by Millennium before the NIH grants were awarded. All this has been unknown to the Chinese who received the so-called "check-up." None of them has benefited in any way from their participation, not even from the "medical advice" Xu Xiping claimed to offer in his grant application.

After the Harvard projects were challenged for their ethical problems, the US Government began to make investigations on these projects in 1999.

But midway through the federal investigation, the very person who assumed the helm of the agency that conducted the investigations, the Office for Human Research Protections (OHRP), was Greg Koski, former Director of the Human Research Affairs overseeing human subjects research projects at the Harvard teaching hospitals B&WH and MGH.

According to investigation records released through the Freedom of Information Act, Koski personally directed the internal investigation of the asthma study for the Harvard-affiliated B&WH in December 1999 and reported to the federal investigators that he found no need for further corrective actions for Xu Xiping's asthma genetics study in China.

And not long before the federal investigations of the B&WH were concluded, he left his post as the first director of OHRP in November 2002 to return to Harvard.

The investigations did find "the breadth and seriousness of violations" of ethical principles in the Harvard Anhui projects.

Moreover, the inquiries were made to the Harvard researchers and their collaborators only.

And the federal investigators largely relied on responses from Xu Xiping and his Harvard colleagues for any challenges. None of the staff from the OHRP came to any sites in China for a field study.

The US government investigation relied on field trips made by Harvard faculty members. The latest of such trips was made by Troyen Brennan, head of the HSPH's IRB, who is a leading physician at B&WH in addition to his teaching and administrative responsibilities at HSPH.

But does Brennan speak Chinese? Did he communicate directly with the Chinese farmers involved in the research in their mother tongue? If not, who served as his interpreter? Who arranged his visits and interviews in China? Which sites did he go to? How did he confirm that the consent forms were signed by the research subjects?

These questions were put to the physician and his lawyer by e-mail.

However, all replies were passed on by Robin Herman, HSPH's communications director.

No answers came from Brennan, and Herman cites nothing more than an official statement her school released after OHRP concluded its inquiries to the Harvard projects on May 30 of this year, which doesn't address any of the above questions.

The OHRP conclusion came in a letter dated May 2, 2003, which "acknowledges" all of the "corrective actions" taken by Harvard have never been made known to the Chinese farmers and claimed "there should be no need for further involvement of the OHRP in this matter."

Despite Zhang Da'niu and his countrymen's testimony concerning their ignorance of the Harvard projects, the HSPH statement claims that (the Chinese) "participants gave voluntary, informed consent."

And despite Zhang Da'niu's collapse, HSPS Dean Barry R. Bloom is quoted as saying, "Harvard seeks to ensure the highest level of protection of human subjects in all its work" and "no individual participant had been harmed and no wilful violations of human subjects procedures took place."

Harvard President Lawrence Summers admitted at Beijing University in May 2002 that the Harvard genetic projects in China took place in a "badly wrong" manner.

Yet a year later, he claimed to be "gratified" to learn that "the inquiry revealed no substantive harm done in our study, and that all procedural concerns raised have been fully addressed."

All this, again, is unknown to Anhui farmers like Zhang Da'niu and his wife Zhou Meizhen. Zhang Da'niu still looks forward to receiving the medicine he was promised, while many questions linger on in the mind of the village medic Zhang Funian.

"I know no reply to that," he says. "I wish I had studied at Harvard to know the answer."

(China Daily September 25, 2003)