Researchers Behaving Badly: Known Frauds Are "the Tip of the Iceberg"
Last week, the whistleblowers in the Paolo Macchiarini affair at Sweden's Karolinska Institutet went on the record here to detail the retaliation they suffered for trying to expose a star surgeon's appalling research misconduct.
Scientific fraud of the type committed by Macchiarini is rare, but studies suggest that it's on the rise.
The whistleblowers had discovered that in six published papers, Macchiarini falsified data, lied about the condition of patients and circumvented ethical approvals. As a result, multiple patients suffered and died. But Karolinska turned a blind eye for years.
Scientific fraud of the type committed by Macchiarini is rare, but studies suggest that it's on the rise. Just this week, for example, Retraction Watch and STAT together broke the news that a Harvard Medical School cardiologist and stem cell researcher, Piero Anversa, falsified data in a whopping 31 papers, which now have to be retracted. Anversa had claimed that he could regenerate heart muscle by injecting bone marrow cells into damaged hearts, a result that no one has been able to duplicate.
A 2009 study published in the Public Library of Science (PLOS) found that about two percent of scientists admitted to committing fabrication, falsification or plagiarism in their work. That's a small number, but up to one third of scientists admit to committing "questionable research practices" that fall into a gray area between rigorous accuracy and outright fraud.
These dubious practices may include misrepresentations, research bias, and inaccurate interpretations of data. One common questionable research practice entails formulating a hypothesis after the research is done in order to claim a successful premise. Another highly questionable practice that can shape research is ghost-authoring by representatives of the pharmaceutical industry and other for-profit fields. Still another is gifting co-authorship to unqualified but powerful individuals who can advance one's career. Such practices can unfairly bolster a scientist's reputation and increase the likelihood of getting the work published.
The above percentages represent what scientists admit to doing themselves; when they evaluate the practices of their colleagues, the numbers jump dramatically. In a 2012 study published in the Journal of Research in Medical Sciences, researchers estimated that 14 percent of other scientists commit serious misconduct, while up to 72 percent engage in questionable practices. While these are only estimates, the problem is clearly not one of just a few bad apples.
In the PLOS study, Daniele Fanelli says that increasing evidence suggests the known frauds are "just the 'tip of the iceberg,' and that many cases are never discovered" because fraud is extremely hard to detect.
Essentially everyone wants to be associated with big breakthroughs, and they may overlook scientifically shaky foundations when a major advance is claimed.
In addition, it's likely that most cases of scientific misconduct go unreported because of the high price of whistleblowing. Those in the Macchiarini case showed extraordinary persistence in their multi-year campaign to stop his deadly trachea implants, while suffering serious damage to their careers. Such heroic efforts to unmask fraud are probably rare.
To make matters worse, there are numerous players in the scientific world who may be complicit in either committing misconduct or covering it up. These include not only primary researchers but co-authors, institutional executives, journal editors, and industry leaders. Essentially everyone wants to be associated with big breakthroughs, and they may overlook scientifically shaky foundations when a major advance is claimed.
Another part of the problem is that it's rare for students in science and medicine to receive an education in ethics. And studies have shown that older, more experienced and possibly jaded researchers are more likely to fudge results than their younger, more idealistic colleagues.
So, given the steep price that individuals and institutions pay for scientific misconduct, what compels them to go down that road in the first place? According to the JRMS study, individuals face intense pressures to publish and to attract grant money in order to secure teaching positions at universities. Once they have acquired positions, the pressure is on to keep the grants and publishing credits coming in order to obtain tenure, be appointed to positions on boards, and recruit flocks of graduate students to assist in research. And not to be underestimated is the human ego.
Paolo Macchiarini is an especially vivid example of a scientist seeking not only fortune, but fame. He liberally (and falsely) claimed powerful politicians and celebrities, even the Pope, as patients or admirers. He may be an extreme example, but we live in an age of celebrity scientists who bring huge amounts of grant money and high prestige to the institutions that employ them.
The media plays a significant role in both glorifying stars and unmasking frauds. In the Macchiarini scandal, the media first lifted him up, as in NBC's laudatory documentary, "A Leap of Faith," which painted him as a kind of miracle-worker, and then brought him down, as in the January 2016 documentary, "The Experiments," which chronicled the agonizing death of one of his patients.
Institutions can also play a crucial role in scientific fraud by putting more emphasis on the number and frequency of papers published than on their quality. The whole course of a scientist's career is profoundly affected by something called the h-index. This is a number based on both the frequency of papers published and how many times the papers are cited by other researchers. Raising one's ranking on the h-index becomes an overriding goal, sometimes eclipsing the kind of patient, time-consuming research that leads to true breakthroughs based on reliable results.
Universities also create a high-pressured environment that encourages scientists to cut corners. They, too, place a heavy emphasis on attracting large monetary grants and accruing fame and prestige. This can lead them, just as it led Karolinska, to protect a star scientist's sloppy or questionable research. According to Dr. Andrew Rosenberg, who is director of the Center for Science and Democracy at the U.S.-based Union of Concerned Scientists, "Karolinska defended its investment in an individual as opposed to the long-term health of the institution. People were dying, and they should have outsourced the investigation from the very beginning."
Having institutions investigate their own practices is a conflict of interest from the get-go, says Rosenberg.
Scientists, universities, and research institutions are also not immune to fads. "Hot" subjects attract grant money and confer prestige, incentivizing scientists to shift their research priorities in a direction that garners more grants. This can mean neglecting the scientist's true area of expertise and interests in favor of a subject that's more likely to attract grant money. In Macchiarini's case, he was allegedly at the forefront of the currently sexy field of regenerative medicine -- a field in which Karolinska was making a huge investment.
The relative scarcity of resources intensifies the already significant pressure on scientists. They may want to publish results rapidly, since they face many competitors for limited grant money, academic positions, students, and influence. The scarcity means that a great many researchers will fail while only a few succeed. Once again, the temptation may be to rush research and to show it in the most positive light possible, even if it means fudging or exaggerating results.
Though the pressures facing scientists are very real, the problem of misconduct is not inevitable.
Intense competition can have a perverse effect on researchers, according to a 2007 study in the journal Science of Engineering and Ethics. Not only does it place undue pressure on scientists to succeed, it frequently leads to the withholding of information from colleagues, which undermines a system in which new discoveries build on the previous work of others. Researchers may feel compelled to withhold their results because of the pressure to be the first to publish. The study's authors propose that more investment in basic research from governments could alleviate some of these competitive pressures.
Scientific journals, although they play a part in publishing flawed science, can't be expected to investigate cases of suspected fraud, says the German science blogger Leonid Schneider. Schneider's writings helped to expose the Macchiarini affair.
"They just basically wait for someone to retract problematic papers," he says.
He also notes that, while American scientists can go to the Office of Research Integrity to report misconduct, whistleblowers in Europe have no external authority to whom they can appeal to investigate cases of fraud.
"They have to go to their employer, who has a vested interest in covering up cases of misconduct," he says.
Science is increasingly international. Major studies can include collaborators from several different countries, and he suggests there should be an international body accessible to all researchers that will investigate suspected fraud.
Ultimately, says Rosenberg, the scientific system must incorporate trust. "You trust co-authors when you write a paper, and peer reviewers at journals trust that scientists at research institutions like Karolinska are acting with integrity."
Without trust, the whole system falls apart. It's the trust of the public, an elusive asset once it has been betrayed, that science depends upon for its very existence. Scientific research is overwhelmingly financed by tax dollars, and the need for the goodwill of the public is more than an abstraction.
The Macchiarini affair raises a profound question of trust and responsibility: Should multiple co-authors be held responsible for a lead author's misconduct?
Karolinska apparently believes so. When the institution at last owned up to the scandal, it vindictively found Karl Henrik-Grinnemo, one of the whistleblowers, guilty of scientific misconduct as well. It also designated two other whistleblowers as "blameworthy" for their roles as co-authors of the papers on which Macchiarini was the lead author.
As a result, the whistleblowers' reputations and employment prospects have become collateral damage. Accusations of research misconduct can be a career killer. Research grants dry up, employment opportunities evaporate, publishing becomes next to impossible, and collaborators vanish into thin air.
Grinnemo contends that co-authors should only be responsible for their discrete contributions, not for the data supplied by others.
"Different aspects of a paper are highly specialized," he says, "and that's why you have multiple authors. You cannot go through every single bit of data because you don't understand all the parts of the article."
This is especially true in multidisciplinary, translational research, where there are sometimes 20 or more authors. "You have to trust co-authors, and if you find something wrong you have to notify all co-authors. But you couldn't go through everything or it would take years to publish an article," says Grinnemo.
Though the pressures facing scientists are very real, the problem of misconduct is not inevitable. Along with increased support from governments and industry, a change in academic culture that emphasizes quality over quantity of published studies could help encourage meritorious research.
But beyond that, trust will always play a role when numerous specialists unite to achieve a common goal: the accumulation of knowledge that will promote human health, wealth, and well-being.
[Correction: An earlier version of this story mistakenly credited The New York Times with breaking the news of the Anversa retractions, rather than Retraction Watch and STAT, which jointly published the exclusive on October 14th. The piece in the Times ran on October 15th. We regret the error.]
Scientists Attempt to Make Human Cells Resistant to Coronaviruses and Ebola
Under the electronic microscope, the Ebola particles looked like tiny round bubbles floating inside human cells. Except these Ebola particles couldn't get free from their confinement.
They were trapped inside their bubbles, unable to release their RNA into the human cells to start replicating. These cells stopped the Ebola infection. And they did it on their own, without any medications, albeit in a petri dish of immunologist Adam Lacy-Hulbert. He studies how cells fight infections at the Benaroya Research Institute in Seattle, Washington.
These weren't just any ordinary human cells. They had a specific gene turned on—namely CD74, which typically wouldn't be on. Lacy-Hulbert's team was experimenting with turning various genes on and off to see what made cells fight viral infections better. One particular form of the CD74 gene did the trick. Normally, the Ebola particles would use the cells' own proteases—enzymes that are often called "molecular scissors" because they slice proteins—to cut the bubbles open. But CD74 produced a protein that blocked the scissors from cutting the bubbles, leaving Ebola trapped.
"When that gene turns on, it makes the protein that interferes with Ebola replication," Lacy-Hulbert says. "The protein binds to those molecular scissors and stops them from working." Even better, the protein interfered with coronaviruses too, including SARS-CoV-2, as the team published in the journal Science.
This begs the question: If one can turn on cells' viral resistance in a lab, can this be done in a human body so we that we can better fight Ebola, coronaviruses and other viral scourges?
Recent research indeed shows that our ability to fight viral infections is written in our genes. Genetic variability is at least one reason why some coronavirus-infected people don't develop symptoms while others stay on ventilators for weeks—often due to the aberrant response of their immune system, which went on overdrive to kill the pathogen. But if cells activate certain genes early in the infection, they might successfully stop viruses from replicating before the immune system spirals out of control.
"If my father who is 70 years old tests positive, I would recommend he takes interferon as early as possible."
When we talk about fighting infections, we tend to think in terms of highly specialized immune system cells—B-cells that release antibodies and T-cells that stimulate inflammatory responses, says Lacy-Hulbert. But all other cells in the body have the ability to fight infections too via different means. When cells detect the presence of a pathogen, they release interferons—small protein molecules named so because they set off a genetic chain reaction that interferes with viral replication. These molecules work as alarm signals to other cells around them. The neighboring cells transduce these signals inside themselves and turn on genes responsible for cellular defenses.
"There are at least 300 to 400 genes that are stimulated by type I interferons," says professor Jean-Laurent Casanova at Rockefeller University.
Scientists don't yet know exactly what all of these genes do, but they change the molecular behavior of the cells. "The cells go into a dramatic change and start producing hundreds of proteins that interfere with viral replication on the inside," explains Qian Zhang, a researcher at Casanova's lab. "Some block the proteins the virus needs and some physically tether the virus."
Some cells produce only small amount of interferon, enough to alert their neighbors. Others, such microphages and monocytes, whose jobs are to detect foreign invaders, produce a lot, injecting interferons into the blood to sound the alarm throughout the body. "They are professional cells so their jobs [are] to detect a viral or bacterial infection," Zhang explains.
People with impaired interferon responses are more vulnerable to infections, including influenza and coronaviruses. In two recent studies published in the journal Science, Casanova, Zhang and their colleagues found that patients who lacked a certain type of interferon had more severe Covid-19 symptoms and some died from it. The team ran a genetic comparison of blood samples from patients hospitalized with severe coronavirus cases against those with the asymptomatic infections.
They found that people with severe disease had rare variants in the 13 genes responsible for interferon production. More than three percent of them had a genetic mutation resulting in non-functioning genes. And over ten percent had an autoimmune condition, in which misguided antibodies neutralized their interferons, dampening their bodies' defenses—and these patients were predominantly men. These discoveries help explain why some young and seemingly healthy individuals require life support, while others have mild symptoms or none. The findings also offer ways of stimulating cellular resistance.
A New Frontier in the Making
The idea of making human cells genetically resistant to infections—and possibly other stressors like cancer or aging—has been considered before. It is the concept behind the Genome Project-write or GP-write project, which aims to create "ultra-safe" versions of human cells that resist a variety of pathogens by way of "recoding" or rewriting the cells' genes.
To build proteins, cells use combinations of three DNA bases called codons to represent amino acids—the proteins' building blocks. But biologists find that many of the codons are redundant so if they were removed from all genes, the human cells would still make all their proteins. However, the viruses, whose genes would still include these eliminated redundant codons, would no longer successfully be able to replicate inside human cells.
In 2016, the GP-Write team successfully reduced the number of Escherichia coli's codons from 64 to 57. Recoding genes in all human cells would be harder, but some recoded cells may be transplanted into the body, says Harvard Medical School geneticist George Church, the GP-Write core founding member.
"You can recode a subset of the body, such as all of your blood," he says. "You can also grow an organ inside a recoded pig and transplant it."
Church adds that these methods are still in stages that are too early to help us with this pandemic.
LeapsMag exclusively interviewed Church in 2019 about his latest progress with DNA recoding:
The Push for Clinical Trials
In the meantime, interferons may prove an easier medicine. Lacy-Hulbert thinks that interferon gamma might play a role in activating the CD74 gene, which gums up the molecular scissors. There also may be other ways to activate that gene. "So we are now thinking, can we develop a drug that mimics that actual activity?" he says.
Some interferons are already manufactured and used for treating certain diseases, including multiple sclerosis. Theoretically, nothing prevents doctors from prescribing interferons to Covid patients, but it must be done in the early stages of infection—to stimulate genes that trigger cellular defenses before the virus invades too many cells and before the immune systems mobilizes its big guns.
"If my father who is 70 years old tests positive, I would recommend he takes interferon as early as possible," says Zhang. But to make it a mainstream practice, doctors need clear prescription guidelines. "What would really help doctors make these decisions is clinical trials," says Casanova, so that such guidelines can be established. "We are now starting to push for clinical trials," he adds.
Lina Zeldovich has written about science, medicine and technology for Popular Science, Smithsonian, National Geographic, Scientific American, Reader’s Digest, the New York Times and other major national and international publications. A Columbia J-School alumna, she has won several awards for her stories, including the ASJA Crisis Coverage Award for Covid reporting, and has been a contributing editor at Nautilus Magazine. In 2021, Zeldovich released her first book, The Other Dark Matter, published by the University of Chicago Press, about the science and business of turning waste into wealth and health. You can find her on http://linazeldovich.com/ and @linazeldovich.
Thousands of Vaccine Volunteers Got a Dummy Shot. Should They Get the Real Deal Now?
The highly anticipated rollout of a COVID-19 vaccine poses ethical considerations: When will trial volunteers who got a placebo be vaccinated? And how will this affect the data in those trials?
It's an issue that vaccine manufacturers and study investigators are wrestling with as the Food and Drug Administration is expected to grant emergency use authorization this weekend to a vaccine developed by Pfizer and the German company BioNTech. Another vaccine, produced by Moderna, is nearing approval in the United States.
The most vulnerable—health care workers and nursing home residents—are deemed eligible to receive the initial limited supply in accordance with priority recommendations from the Centers for Disease Control and Prevention (CDC).
With health care workers constituting an estimated 20 percent of trial participants, this question also comes to the fore: "Is it now ethically imperative that we offer them the vaccine, those who have had placebo?" says William Schaffner, an infectious diseases physician at Vanderbilt University and an adviser to the CDC's immunization practices committee.
When a "gold-standard" measure becomes available, participants in the placebo group "would ordinarily be notified" of the strong public health recommendation to opt for immunization, says Johan Bester, interim assistant dean for biomedical science education and director of bioethics at the University of Nevada, Las Vegas School of Medicine.
"If a treatment or prevention exists that we know works, it is unethical to withhold it from people who would benefit from it just to answer a research question." This moral principle poses a quandary for ethicists and physicians alike, as they ponder possible paths to proceed with vaccination amid ongoing trials. Rigorous trials are double-blinded—neither the participants nor the investigators know who received the actual vaccine and who got a dummy injection.
"The intent of these trials is to follow these folks for up to two years," says Marci Drees, infection prevention officer and hospital epidemiologist for ChristianaCare in Wilmington, Delaware. At a minimum, she adds, researchers would prefer to monitor participants for six months.
"You can still follow safety over a long-term period of time without actually continuing to have a placebo group for comparison."
But in the midst of a pandemic, that may not be feasible. Prolonged exposure to the highly contagious and lethal virus could have dire consequences.
To avoid compromising the integrity of the blinded data, "there are some potentially creative solutions," Drees says. For instance, trial participants could receive the opposite of what they initially got, whether it was the vaccine or the placebo.
One factor in this decision-making process depends on when a particular trial is slated to conclude. If that time is approaching, the risk of waiting would be lower than if the trial is only halfway in progress, says Eric Lofgren, an epidemiologist at Washington State University who has studied the impact of COVID-19 in jails and at in-person sporting events.
Sometimes a study concludes earlier than the projected completion date. "All clinical trials have a data and safety monitoring board that reviews the interim results," Lofgren says. The board may halt a trial after finding evidence of harm, or when a treatment or vaccine has proven to be "sufficiently good," rendering it unethical to deprive the placebo group of its benefits.
The initial months of a trial are most crucial for assessing a vaccine's safety. Differences between the trial groups would be illuminating if fewer individuals who got the active vaccine contracted the virus and developed symptoms when compared to the placebo recipients. After that point, in vaccine-administered participants, "you can still follow safety over a long-term period of time without actually continuing to have a placebo group for comparison," says Dial Hewlett Jr., medical director for disease control at the Westchester County Department of Health in New York.
Even outside of a trial, safety is paramount and any severe side effects that occur will be closely monitored and investigated through national reporting networks. For example, regulators in the U.K. are investigating several rare but serious allergic reactions to the Pfizer vaccine given on Tuesday. The FDA has asked Pfizer to track allergic reactions in its safety monitoring plan, and some experts are proposing that Pfizer conduct a separate study of the vaccine on people with a history of severe allergies.
As the FDA eventually grants authorization to multiple vaccines, more participants are likely to leave trials and opt to be vaccinated. It is important that enough participants choose to stay in ongoing trials, says Nicole Hassoun, professor of philosophy at the State University of New York at Binghamton, where she directs the Global Health Impact program to extend medical access to the poor.
She's hopeful that younger participants and individuals without underlying medical conditions will make that determination. But the departure of too many participants at high risk for the virus would make it more difficult to evaluate the vaccine's safety and efficacy in those populations, Hassoun says, while acknowledging, "We can't have the best of both worlds."
Once a safe and effective vaccine is approved in the United States, "it would not be ethically appropriate to do placebo trials to test new vaccines."
One solution would entail allowing health care workers to exit a trial after a vaccine is approved, even though this would result in "a conundrum when the next group of people are brought forward to get the vaccine—whether they're people age 65 and older or they're essential workers, or whoever they are," says Vanderbilt physician Schaffner, who is a former board member of the Infectious Diseases Society of America. "All of a sudden, you'll have an erosion of the volunteers who are in the trial."
For now, one way or another, experts agree that current and subsequent trials should proceed. There is a compelling reason to identify additional vaccines with potentially greater effectiveness but with fewer side effects or less complex delivery methods that don't require storage at extremely low temperatures.
"Continuing with existing vaccine trials and starting others remains important," says Nir Eyal, professor and director of Rutgers University's Center for Population-Level Bioethics in New Brunswick, New Jersey. "We still need to tell how much proven vaccines block infections and how long their duration lasts. And populations around the world need vaccines that are easier to store and deliver, or simply cheaper."
But once a safe and effective vaccine is approved in the United States, "it would not be ethically appropriate to do placebo trials to test new vaccines," says bioethicist Bester at the University of Nevada, Las Vegas School of Medicine. "One possibility if a new vaccine emerges, is to test it against existing vaccines."
In a letter sent to trial volunteers in November, Pfizer and BioNTech committed to establishing "a process that would allow interested participants in the placebo group who meet the eligibility criteria for early access in their country to 'cross-over' to the vaccine group." The trial plans to continue monitoring all subjects regardless of whether people in the placebo group cross over, Pfizer said in a presentation to the FDA today. After Pfizer has collected six months of safety data, in April 2021, it plans to ask the FDA for full approval of the vaccine.
In the meantime, the company pledged to update volunteers as they obtain more input from regulatory authorities. "Thank you again for making a difference by being a part of this study," they wrote. "It is only through the efforts of volunteers like you that reaching this important milestone and developing a potential vaccine against COVID-19 is possible."
CORRECTION: An earlier version of this article mistakenly stated that the FDA would be granting emergency "approval" to the Pfizer/BioNTech vaccine, rather than "emergency use authorization." We regret the error.