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.]
Would You Eat These Futuristic Foods?
Imagine it's 2050. You wake up and make breakfast: fluffy scrambled eggs that didn't come from a chicken, but that taste identical to the ones you remember eating as a kid. You would never know that the egg protein on your plate, ovalbumin, was developed in an industrial bioreactor using fungi.
"We have this freedom to operate, freedom to engineer way beyond what we have now with livestock or plants."
For lunch, you head to your kitchen's 3D printer and pop in a cartridge, select your preferred texture and flavor, then stand back while your meal is chemically assembled. Afterward, for dessert, you snack on some chocolate that tastes more delicious than the truffles of the past. That's because these cocoa beans were gene-edited to improve their flavor.
2050 is not a random year –it's when the United Nations estimates that the world population will have ballooned to nearly 10 billion people. That's a staggering number of mouths to feed. So, scientists are already working on ways to make new food products that are unlike anything we consume today, but that could offer new, potentially improved nutritional choices and sustainable options for the masses. To whet your appetite, here are three futuristic types of food that are currently in development around the world:
1) Cellular Agriculture
Researchers at VTT Technical Research Centre of Finland, a leading R&D organization in Europe, are on the cutting-edge of developing a whole new ecosystem of food with novel ingredients and novel functionality.
In the high-tech world of cellular agriculture, single-cell organisms can be used in contained environments to produce food ingredients that are identical to traditionally sourced ingredients. For example, whey protein can be developed inside a bioreactor that is functionally the same as the kind in cow's milk.
Ditto for eggs without a chicken – so the world will finally know which came first.
The steel tank bioreactors in VTT´s piloting facility are used to grow larger amounts of plant cells or to brew dairy and egg proteins with microbes.
(VTT)
"We take the gene from a chicken genome, and place that in a microbe, and then the microbe can, with those instructions, make exactly the same protein," explains Lauri Reuter, a Senior Specialist at VTT who holds a doctorate in biotechnology. "It will swim in this bioreactor and kick out the protein, and we get this liquid that can be purified. Then you would cook or bake with it, and the food you would eat tastes and looks like food you would eat right now."
But why settle for what chickens can do? With this technology, it's possible, for example, to modify the ovalbumin protein to decrease its allergenicity.
"This is the power of what we can do with modern tools of genetic engineering," says Christopher Landowski,a Research Team Leader of the Protein Production Team. And the innovative potential doesn't stop there.
"We have this freedom to operate, freedom to engineer way beyond what we have now with livestock or plants," Reuter says. Future foods sourced from cells could include meat analogues, sugar substitutes, dairy substitutes, nutritious veggies that don't taste bitter, personalized nutrition – ingredients designed for individual needs; the list goes on. It could even be used one day to produce food on Mars.
The researchers emphasize the advantages of this method: their living cell factories are efficient – no care of complex animals is required; they can scale up or down in reaction to demand; their environments are contained and don't require antibiotics; and they provide an alternative to using animals.
But the researchers also readily admit that the biggest obstacle is consumer acceptance, which is why they seek to engage with people along the way to alleviate any concerns and to educate them about the technology. Novel foods of this sort have already been eaten in research settings, but it may take another three to five years before the egg and milk proteins hit the market, probably first in the United States before Europe.
Eventually, the researchers anticipate widespread adoption.
Emilia Nordlund, who directs the Food Solutions team, predicts, "Cellular agriculture will revolutionize the food industry as dramatically as the Internet revolutionized many other industries."
Jams made of culture cells of various plants: strawberry, scurvy grass, arctic bramble, tobacco, cloudberry and lingonberry.
(VTT/Lauri Reuter)
2) 3D-printed foods
In South Korea, researchers are developing 3D-printed foods to help solve a problem caused by aging. Elderly people often rely on soft foods which are easier to chew, but aren't always healthy, like Jello and pudding.
With 3D printing, foods of softer textures can be created with the same nutritional value as firmer food, via a processing method that breaks down the food into tiny nutrients by grinding it at a very low temperature with liquid nitrogen.
"The goal is that someone at home can print out food with whatever flavor and texture they want."
The micro-sized food materials are then reconstructed in layers to form what looks like a Lego block. "The cartridges are all textures, some soft and some stiff," explains Jin-Kyu Rhee, associate professor at Ewha Womans University, whose project has been funded for the last three years by the South Korean government. "We are developing a library of food textures, so that people can combine them to simulate a real type of food."
Users could then add powdered versions of various ingredients to create customized food. Flavor, of course, is of prime importance too, so the cartridges have flavors like barbecue to help simulate the experience of eating "real" food.
"The goal is that someone at home can print out food with whatever flavor and texture they want," Rhee says. "They can order their own cartridge and digital recipes to generate their own food, ready to cook with a microwave oven." It could also be used for space travel.
Rhee expects the prototype of the printer to be completed by the end of this year and will then seek out a commercial partner. If all goes well, you might be able to set up your 3D printer next to your coffee pot by 2025.
3) CRISPR-edited foods
You may not know that the cocoa plant is having a tough time out there in nature. It's plagued by fungal disease; on farms, about 30 to 40 percent of the potential cocoa beans are lost every year. For all the chocolate lovers of the world, this means less to go around.
Conventional plant breeding is very slow for trees, so researchers like Mark Guiltinan at Penn State University are devising ways to increase the plants' chances for survival – without moving any genes between species, as in genetically modified organisms (GMOs).
"Because society hasn't really embraced [GMOs] very much, we're trying to develop ways that don't use transgenic plants and speed up breeding," Guiltinan says.
He and his colleagues are using CRISPR-cas9, the precise method of editing DNA, to imbue cocoa plants with immunity to fungal disease.
How does it work? Similar to humans, the plants have an immune system. Part of it functions like brakes, repressing the whole system so it's only working when it needs to.
"Like when you get a fever, your immune system is working full blast, but your body shuts it down when it doesn't need it," he explains. "Plants do exactly the same thing. One idea is if we can reduce or eliminate that brake on the immune system, we could make plants that have a very high immunity."
A CRISPR-edited npr3 mutant cacao plantlet, not too much to see yet, but soon it will become a happy plant in the greenhouse.
(Photo credit: Mark Guiltinan)
The CRISPR-cas9 system allows "a really amazing little protein" to go into the cocoa plant cell, find a specific gene, and shut it off to put the whole immune system into overdrive. This confers the necessary immunity, and though the plant burns through a lot of energy, as if it has a fever all the time, this method would allow for more plants to fend off the fungal attacks every year. Which means more chocolate. It could also greatly reduce the need for pesticides.
"Replacing chemicals with genetics is one part of our goal," Guiltinan says. "And it's totally safe." Another goal of his project is to improve the cocoa beans' quality and flavor profile through gene editing.
Yum. Is your mouth watering yet?
Kira Peikoff was the editor-in-chief of Leaps.org from 2017 to 2021. As a journalist, her work has appeared in The New York Times, Newsweek, Nautilus, Popular Mechanics, The New York Academy of Sciences, and other outlets. She is also the author of four suspense novels that explore controversial issues arising from scientific innovation: Living Proof, No Time to Die, Die Again Tomorrow, and Mother Knows Best. Peikoff holds a B.A. in Journalism from New York University and an M.S. in Bioethics from Columbia University. She lives in New Jersey with her husband and two young sons. Follow her on Twitter @KiraPeikoff.
Got a Virus? Its Name Matters More Than You Think
It's a familiar scenario: You show up at the doctor feeling miserable—sneezing, coughing, lethargic. We've all been there. And we've all been told the same answer: we're suffering from "a virus."
Failing to establish a specific microbial cause undermines the health of individual patients—and potentially the public at large.
Some patients may be satisfied with that diagnosis, others may be frustrated, and still others may demand antibiotic treatment for a bacterial infection that is usually not even present. As an infectious disease doctor who specializes in pandemic preparedness, I detest using the catch-all "virus" diagnosis for a range of symptoms from common colds to life-threatening pneumonias to unexplained fevers. Failing to establish a specific microbial cause undermines the health of individual patients—and potentially the public at large.
Confirming a specific diagnosis to determine which virus is behind those nasty symptoms is not just an academic exercise. The benefits are plentiful. Patients can forego antibiotic treatment, possibly benefit from antiviral treatment, understand their illness, and be given a prognosis. Additionally, if hospitalized, patients with certain viral infections require specific types of precautions so as not to spread the virus within the hospital.
Another largely undervalued benefit of such an approach is that it allows experts to begin assembling an arsenal of tools that might stave off a global health catastrophe. With severe pandemics, such as the 1918 influenza pandemic that killed 50 to 100 million people, it can be challenging to predict which of the myriad microbial species (bacteria, viruses, fungi, parasites, prions) will be the most likely cause. Many different approaches to prediction exist, but there is a general lack of rigorous analysis about what it takes for any microorganism to reach the pantheon of pandemic pathogens. My colleagues and I at the Johns Hopkins Center for Health Security recently developed a new framework to understand the characteristics of pandemic pathogens.
One of our major conclusions is that the most likely pandemic pathogen will be viral and spread through respiratory means. Viruses rise to the top of the list because, when compared to other types of infectious agents, they have several features that confer pandemic potential: they mutate a lot, the speed of infection is rapid, and there are no broad-spectrum antivirals akin to broad-spectrum antibacterial agents. Contagion through breathing, coughing, and sneezing is likely because it is much more difficult for standard public health measures to extinguish respiratory spread agents compared to other routes of transmission like food, body fluids, or mosquitoes.
With this information, physicians and scientists can begin taking actions to prevent spread of the infection by developing vaccines, testing antiviral compounds, and making diagnostic tests for concerning viruses.
Many of the viral families that could pose a pandemic threat are very common causes of upper respiratory infections like influenza, the common cold, and bronchitis. These viruses cause a wide range of illnesses from mild coughs to serious pneumonias. Indeed, the 2009 H1N1 influenza pandemic virus was discovered in San Diego in a child with very mild illness in whom viral diagnostic testing was pursued. This event highlights the fact that such diseases are not only found in exotic locations in the developing world, but could appear anywhere.
Understanding the patterns of respiratory virus infections -- how frequent they are, which strains are predominating, changes in severity of disease, expanding geographic range -- may provide a glimpse into the first forays of a new human virus or an alert to changing behavior from a well-known virus. With this information, physicians and scientists can begin taking actions to prevent spread of the infection by developing vaccines, testing antiviral compounds, and making diagnostic tests for concerning viruses. Additionally, alerts to healthcare providers will provide greater situational awareness of the patterns of infection.
So, the next time you are given a wastebasket diagnosis of "viral syndrome," push your doctor a little harder. In 2018, we have countless diagnostic tests for viral infections available, many at the point-of-care, that too few physicians use. Not only will you be more satisfied with a real diagnosis, you may be spared an unnecessary course of antibiotics. You can also rest assured that having a name for your virus will help epidemiologists doing a very important job. While we have not yet technologically achieved the famed Tricorder of Star Trek fame that diagnoses everything with a sweep of the hand, using the tools we do have could be one of the keys to detecting the next pandemic virus early enough to intervene.
Dr. Adalja is focused on emerging infectious disease, pandemic preparedness, and biosecurity. He has served on US government panels tasked with developing guidelines for the treatment of plague, botulism, and anthrax in mass casualty settings and the system of care for infectious disease emergencies, and as an external advisor to the New York City Health and Hospital Emergency Management Highly Infectious Disease training program, as well as on a FEMA working group on nuclear disaster recovery. Dr. Adalja is an Associate Editor of the journal Health Security. He was a coeditor of the volume Global Catastrophic Biological Risks, a contributing author for the Handbook of Bioterrorism and Disaster Medicine, the Emergency Medicine CorePendium, Clinical Microbiology Made Ridiculously Simple, UpToDate's section on biological terrorism, and a NATO volume on bioterrorism. He has also published in such journals as the New England Journal of Medicine, the Journal of Infectious Diseases, Clinical Infectious Diseases, Emerging Infectious Diseases, and the Annals of Emergency Medicine. He is a board-certified physician in internal medicine, emergency medicine, infectious diseases, and critical care medicine. Follow him on Twitter: @AmeshAA