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.]
By mid-March, Alpha Lee was growing restless. A pioneer of AI-driven drug discovery, Lee leads a team of researchers at the University of Cambridge, but his lab had been closed amidst the government-initiated lockdowns spreading inexorably across Europe.
If the Moonshot proves successful, they hope it could serve as a future benchmark for finding new medicines for chronic diseases.
Having spoken to his collaborators across the globe – many of whom were seeing their own experiments and research projects postponed indefinitely due to the pandemic – he noticed a similar sense of frustration and helplessness in the face of COVID-19.
While there was talk of finding a novel treatment for the virus, Lee was well aware the process was likely to be long and laborious. Traditional methods of drug discovery risked suffering the same fate as the efforts to find a cure for SARS in the early 2000, which took years and were ultimately abandoned long before a drug ever reached the market.
To avoid such an outcome, Lee was convinced that global collaboration was required. Together with a collection of scientists in the UK, US and Israel, he launched the 'COVID Moonshot' – a project which encouraged chemists worldwide to share their ideas for potential drug designs. If the Moonshot proves successful, they hope it could serve as a future benchmark for finding new medicines for chronic diseases.
Solving a Complex Jigsaw
In February, ShanghaiTech University published the first detailed snapshots of the SARS-CoV-2 coronavirus's proteins using a technique called X-ray crystallography. In particular, they revealed a high-resolution profile of the virus's main protease – the part of its structure that enables it to replicate inside a host – and the main drug target. The images were tantalizing.
"We could see all the tiny pieces sitting in the structure like pieces of a jigsaw," said Lee. "All we needed was for someone to come up with the best idea of joining these pieces together with a drug. Then you'd be left with a strong molecule which sits in the protease, and stops it from working, killing the virus in the process."
Normally, ideas for how best to design such a drug would be kept as carefully guarded secrets within individual labs and companies due to their potential value. But as a result, the steady process of trial and error to reach an optimum design can take years to come to fruition.
However, given the scale of the global emergency, Lee felt that the scientific community would be open to collective brainstorming on a mass scale. "Big Pharma usually wouldn't necessarily do this, but time is of the essence here," he said. "It was a case of, 'Let's just rethink every drug discovery stage to see -- ok, how can we go as fast as we can?'"
On March 13, he launched the COVID moonshot, calling for chemists around the globe to come up with the most creative ideas they could think of, on their laptops at home. No design was too weird or wacky to be considered, and crucially nothing would be patented. The entire project would be done on a not-for-profit basis, meaning that any drug that makes it to market will have been created simply for the good of humanity.
It caught fire: Within just two weeks, more than 2,300 potential drug designs had been submitted. By the middle of July, over 10,000 had been received from scientists around the globe.
The Road Toward Clinical Trials
With so many designs to choose from, the team has been attempting to whittle them down to a shortlist of the most promising. Computational drug discovery experts at Diamond and the Weizmann Institute of Science in Rehovot, Israel, have enabled the Moonshot team to develop algorithms for predicting how quick and easy each design would be to make, and to predict how well each proposed drug might bind to the virus in real life.
The latter is an approach known as computational covalent docking and has previously been used in cancer research. "This was becoming more popular even before COVID-19, with several covalent drugs approved by the FDA in recent years," said Nir London, professor of organic chemistry at the Weizmann Institute, and one of the Moonshot team members. "However, all of these were for oncology. A covalent drug against SARS-CoV-2 will certainly highlight covalent drug-discovery as a viable option."
Through this approach, the team have selected 850 compounds to date, which they have manufactured and tested in various preclinical trials already. Fifty of these compounds - which appear to be especially promising when it comes to killing the virus in a test tube – are now being optimized further.
Lee is hoping that at least one of these potential drugs will be shown to be effective in curing animals of COVID-19 within the next six months, a step that would allow the Moonshot team to reach out to potential pharmaceutical partners to test their compounds in humans.
Future Implications
If the project does succeed, some believe it could open the door to scientific crowdsourcing as a future means of generating novel medicine ideas for other diseases. Frank von Delft, professor of protein science and structural biology at the University of Oxford's Nuffield Department of Medicine, described it as a new form of 'citizen science.'
"There's a vast resource of expertise and imagination that is simply dying to be tapped into," he said.
Others are slightly more skeptical, pointing out that the uniqueness of the current crisis has meant that many scientists were willing to contribute ideas without expecting any future compensation in return. This meant that it was easy to circumvent the traditional hurdles that prevent large-scale global collaborations from happening – namely how to decide who will profit from the final product and who will hold the intellectual property (IP) rights.
"I think it is too early to judge if this is a viable model for future drug discovery," says London. "I am not sure that without the existential threat we would have seen so many contributions, and so many people and institutions willing to waive compensation and future royalties. Many scientists found themselves at home, frustrated that they don't have a way to contribute to the fight against COVID-19, and this project gave them an opportunity. Plus many can get behind the fact that this project has no associated IP and no one will get rich off of this effort. This breaks down a lot of the typical barriers and red-tape for wider collaboration."
"If a drug would sprout from one of these crowdsourced ideas, it would serve as a very powerful argument to consider this mode of drug discovery further in the future."
However the Moonshot team believes that if they can succeed, it will at the very least send a strong statement to policy makers and the scientific community that greater efforts should be made to make such large-scale collaborations more feasible.
"All across the scientific world, we've seen unprecedented adoption of open-science, collaboration and collegiality during this crisis, perhaps recognizing that only a coordinated global effort could address this global challenge," says London. "If a drug would sprout from one of these crowdsourced ideas, it would serve as a very powerful argument to consider this mode of drug discovery further in the future."
[An earlier version of this article was published on June 8th, 2020 as part of a standalone magazine called GOOD10: The Pandemic Issue. Produced as a partnership among LeapsMag, The Aspen Institute, and GOOD, the magazine is available for free online.]
World’s First “Augmented Reality” Contact Lens Aims to Revolutionize Much More Than Medicine
Imagine a world without screens. Instead of endlessly staring at your computer or craning your neck down to scroll through social media feeds and emails, information simply appears in front of your eyes when you need it and disappears when you don't.
"The vision is super clear...I was reading the poem with my eyes closed."
No more rude interruptions during dinner, no more bumping into people on the street while trying to follow GPS directions — just the information you want, when you need it, projected directly onto your visual field.
While this screenless future sounds like science fiction, it may soon be a reality thanks to the new Silicon Valley startup Mojo Vision, creator of the world's first smart contact lens. With a 14,000 pixel-per-inch display with eye-tracking, image stabilization, and a custom wireless radio, the Mojo smart lens bills itself the "smallest and densest dynamic display ever made." Unlike current augmented reality wearables such as Google Glass or ThirdEye, which project images onto a glass screen, the Mojo smart lens can project images directly onto the retina.
A current prototype displayed at the Consumer Electronics Show earlier this year in Las Vegas includes a tiny screen positioned right above the most sensitive area of the pupil. "[The Mojo lens] is a contact lens that essentially has wireless power and data transmission for a small micro LED projector that is placed over the center of the eye," explains David Hobbs, Director of Product Management at Mojo Vision. "[It] displays critical heads-up information when you need it and fades into the background when you're ready to continue on with your day."
Eventually, Mojo Visions' technology could replace our beloved smart devices but the first generation of the Mojo smart lens will be used to help the 2.2 billion people globally who suffer from vision impairment.
"If you think of the eye as a camera [for the visually impaired], the sensors are not working properly," explains Dr. Ashley Tuan, Vice President of Medical Devices at Mojo Vision and fellow of the American Academy of Optometry. "For this population, our lens can process the image so the contrast can be enhanced, we can make the image larger, magnify it so that low-vision people can see it or we can make it smaller so they can check their environment." In January of this year, the FDA granted Breakthrough Device Designation to Mojo, allowing them to have early and frequent discussions with the FDA about technical, safety and efficacy topics before clinical trials can be done and certification granted.
For now, Dr. Tuan is one of the few people who has actually worn the Mojo lens. "I put the contact lens on my eye. It was very comfortable like any contact lenses I've worn before," she describes. "The vision is super clear and then when I put on the accessories, suddenly I see Yoda in front of me and I see my vital signs. And then I have my colleague that prepared a beautiful poem that I loved when I was young [and] I was reading the poem with my eyes closed."
At the moment, there are several electronic glasses on the market like Acesight and Nueyes Pro that provide similar solutions for those suffering from visual impairment, but they are large, cumbersome, and highly visible. Mojo lens would be a discreet, more comfortable alternative that offers users more freedom of movement and independence.
"In the case of augmented-reality contact lenses, there could be an opportunity to improve the lives of people with low vision," says Dr. Thomas Steinemann, spokesperson for the American Academy of Ophthalmology and professor of ophthalmology at MetroHealth Medical Center in Cleveland. "There are existing tools for people currently living with low vision—such as digital apps, magnifiers, etc.— but something wearable could provide more flexibility and significantly more aid in day-to-day tasks."
As one of the first examples of "invisible computing," the potential applications of Mojo lens in the medical field are endless.
According to Dr. Tuan, the visually impaired often suffer from depression due to their lack of mobility and 70 percent of them are underemployed. "We hope that they can use this device to gain their mobility so they can get that social aspect back in their lives and then, eventually, employment," she explains. "That is our first and most important goal."
But helping those with low visual capabilities is only Mojo lens' first possible medical application; augmented reality is already being used in medicine and is poised to revolutionize the field in the coming decades. For example, Accuvein, a device that uses lasers to provide real-time images of veins, is widely used by nurses and doctors to help with the insertion of needles for IVs and blood tests.
According to the National Center for Biotechnology Information, augmentation of reality has been used in surgery for many years with surgeons using devices such as Google Glass to overlay critical information about their patients into their visual field. Using software like the Holographic Navigation Platform by Scopsis, surgeons can see a mixed-reality overlay that can "show you complicated tumor boundaries, assist with implant placements and guide you along anatomical pathways," its developers say.
However, according to Dr. Tuan, augmented reality headsets have drawbacks in the surgical setting. "The advantage of [Mojo lens] is you don't need to worry about sweating or that the headset or glasses will slide down to your nose," she explains "Also, our lens is designed so that it will understand your intent, so when you don't want the image overlay it will disappear, it will not block your visual field, and when you need it, it will come back at the right time."
As one of the first examples of "invisible computing," the potential applications of Mojo lens in the medical field are endless. Possibilities include live translation of sign language for deaf people; helping those with autism to read emotions; and improving doctors' bedside manner by allowing them to fully engage with patients without relying on a computer.
"[By] monitoring those blood vessels we can [track] chronic disease progression: high blood pressure, diabetes, and Alzheimer's."
Furthermore, the lens could be used to monitor health issues. "We have image sensors in the lens right now that point to the world but we can have a camera pointing inside of your eye to your retina," says Dr. Tuan, "[By] monitoring those blood vessels we can [track] chronic disease progression: high blood pressure, diabetes, and Alzheimer's."
For the moment, the future medical applications of the Mojo lens are still theoretical, but the team is confident they can eventually become a reality after going through the proper regulatory review. The company is still in the process of design, prototype and testing of the lens, so they don't know exactly when it will be available for use, but they anticipate shipping the first available products in the next couple of years. Once it does go to market, it will be available by prescription only for those with visual impairments, but the team's goal is to bring it to broader consumer markets pending regulatory clearance.
"We see that right now there's a unique opportunity here for Mojo lens and invisible computing to help to shape what the next decade of technology development looks like," explains David Hobbs. "We can use [the Mojo lens] to better serve us as opposed to us serving technology better."