Sloppy Science Happens More Than You Think
Manipulating DNA through gene editing.
The media loves to tout scientific breakthroughs, and few are as toutable – and in turn, have been as touted – as CRISPR. This method of targeted DNA excision was discovered in bacteria, which use it as an adaptive immune system to combat reinfection with a previously encountered virus.
Shouldn't the editors at a Nature journal know better than to have published an incorrect paper in the first place?
It is cool on so many levels: not only is the basic function fascinating, reminding us that we still have more to discover about even simple organisms that we thought we knew so well, but the ability it grants us to remove and replace any DNA of interest has almost limitless applications in both the lab and the clinic. As if that didn't make it sexy enough, add in a bicoastal, male-female, very public and relatively ugly patent battle, and the CRISPR story is irresistible.
And then last summer, a bombshell dropped. The prestigious journal Nature Methods published a paper in which the authors claimed that CRISPR could cause many unintended mutations, rendering it unfit for clinical use. Havoc duly ensued; stocks in CRISPR-based companies plummeted. Thankfully, the authors of the offending paper were responsible, good scientists; they reassessed, then recanted. Their attention- and headline- grabbing results were wrong, and they admitted as much, leading Nature Methods to formally retract the paper this spring.
How did this happen? Shouldn't the editors at a Nature journal know better than to have published this in the first place?
Alas, high-profile scientific journals publish misleading and downright false results fairly regularly. Some errors are unavoidable – that's how the scientific method works. Hypotheses and conclusions will invariably be overturned as new data becomes available and new technologies are developed that allow for deeper and deeper studies. That's supposed to happen. But that's not what we're talking about here. Nor are we talking about obvious offenses like outright plagiarism. We're talking about mistakes that are avoidable, and that still have serious ramifications.
The cultures of both industry and academia promote research that is poorly designed and even more poorly analyzed.
Two parties are responsible for a scientific publication, and thus two parties bear the blame when things go awry: the scientists who perform and submit the work, and the journals who publish it. Unfortunately, both are incentivized for speedy and flashy publications, and not necessarily for correct publications. It is hardly a surprise, then, that we end up with papers that are speedy and flashy – and not necessarily correct.
"Scientists don't lie and submit falsified data," said Andy Koff, a professor of Molecular Biology at Sloan Kettering Institute, the basic research arm of Memorial Sloan Kettering Cancer Center. Richard Harris, who wrote the book on scientific misconduct running the gamut from unconscious bias and ignorance to more malicious fraudulence, largely concurs (full disclosure: I reviewed the book here). "Scientists want to do good science and want to be recognized as such," he said. But even so, the cultures of both industry and academia promote research that is poorly designed and even more poorly analyzed. In Rigor Mortis: How Sloppy Science Creates Worthless Cures, Crushes Hope, and Wastes Millions, Harris describes how scientists must constantly publish in order to maintain their reputations and positions, to get grants and tenure and students. "They are disincentivized from doing that last extra experiment to prove their results," he said; it could prove too risky if it could cost them a publication.
Ivan Oransky and Adam Marcus founded Retraction Watch, a blog that tracks the retraction of scientific papers, in 2010. Oransky pointed out that blinded peer review – the pride and joy of the scientific publishing enterprise – is a large part of the problem. "Pre-publication peer review is still important, but we can't treat it like the only check on the system. Papers are being reviewed by non-experts, and reviewers are asked to review papers only tangentially related to their field. Moreover, most peer reviewers don't look at the underlying or raw data, even when it is available. How then can they tell if the analysis is flawed or the data is accurate?" he wondered.
Mistaken publications also erode the public's opinion of legitimate science, which is problematic since that opinion isn't especially high to begin with.
Koff agreed that anonymous peer review is valuable, but severely flawed. "Blinded review forces a collective view of importance," he said. "If an article disagrees with the reviewer's worldview, the article gets rejected or forced to adhere to that worldview – even if that means pushing the data someplace it shouldn't necessarily go." We have lost the scientific principle behind review, he thinks, which was to critically analyze a paper. But instead of challenging fundamental assumptions within a paper, reviewers now tend to just ask for more and more supplementary data. And don't get him started on editors. "Editors are supposed to arbitrate between reviewers and writers and they have completely abdicated this responsibility, at every journal. They do not judge, and that's a real failing."
Harris laments the wasted time, effort, and resources that result when erroneous ideas take hold in a field, not to mention lives lost when drug discovery is predicated on basic science findings that end up being wrong. "When no one takes the time, care, and money to reproduce things, science isn't stopping – but it is slowing down," he noted. Mistaken publications also erode the public's opinion of legitimate science, which is problematic since that opinion isn't especially high to begin with.
Scientists and publishers don't only cause the problem, though – they may also provide the solution. Both camps are increasingly recognizing and dealing with the crisis. The self-proclaimed "data thugs" Nick Brown and James Heathers use pretty basic arithmetic to reveal statistical errors in papers. The microbiologist Elisabeth Bik scans the scientific literature for problematic images "in her free time." The psychologist Brian Nosek founded the Center for Open Science, a non-profit organization dedicated to promoting openness, integrity, and reproducibility in scientific research. The Nature family of journals – yes, the one responsible for the latest CRISPR fiasco – has its authors complete a checklist to combat irreproducibility, à la Atul Gawande. And Nature Communications, among other journals, uses transparent peer review, in which authors can opt to have the reviews of their manuscript published anonymously alongside the completed paper. This practice "shows people how the paper evolved," said Koff "and keeps the reviewer and editor accountable. Did the reviewer identify the major problems with the paper? Because there are always major problems with a paper."
Urinary tract infections account for more than 8 million trips to the doctor each year.
Few things are more painful than a urinary tract infection (UTI). Common in men and women, these infections account for more than 8 million trips to the doctor each year and can cause an array of uncomfortable symptoms, from a burning feeling during urination to fever, vomiting, and chills. For an unlucky few, UTIs can be chronic—meaning that, despite treatment, they just keep coming back.
But new research, presented at the European Association of Urology (EAU) Congress in Paris this week, brings some hope to people who suffer from UTIs.
Clinicians from the Royal Berkshire Hospital presented the results of a long-term, nine-year clinical trial where 89 men and women who suffered from recurrent UTIs were given an oral vaccine called MV140, designed to prevent the infections. Every day for three months, the participants were given two sprays of the vaccine (flavored to taste like pineapple) and then followed over the course of nine years. Clinicians analyzed medical records and asked the study participants about symptoms to check whether any experienced UTIs or had any adverse reactions from taking the vaccine.
The results showed that across nine years, 48 of the participants (about 54%) remained completely infection-free. On average, the study participants remained infection free for 54.7 months—four and a half years.
“While we need to be pragmatic, this vaccine is a potential breakthrough in preventing UTIs and could offer a safe and effective alternative to conventional treatments,” said Gernot Bonita, Professor of Urology at the Alta Bro Medical Centre for Urology in Switzerland, who is also the EAU Chairman of Guidelines on Urological Infections.
The news comes as a relief not only for people who suffer chronic UTIs, but also to doctors who have seen an uptick in antibiotic-resistant UTIs in the past several years. Because UTIs usually require antibiotics, patients run the risk of developing a resistance to the antibiotics, making infections more difficult to treat. A preventative vaccine could mean less infections, less antibiotics, and less drug resistance overall.
“Many of our participants told us that having the vaccine restored their quality of life,” said Dr. Bob Yang, Consultant Urologist at the Royal Berkshire NHS Foundation Trust, who helped lead the research. “While we’re yet to look at the effect of this vaccine in different patient groups, this follow-up data suggests it could be a game-changer for UTI prevention if it’s offered widely, reducing the need for antibiotic treatments.”
MILESTONE: Doctors have transplanted a pig organ into a human for the first time in history
A surgeon at Massachusetts General Hospital prepares a pig organ for transplant.
Surgeons at Massachusetts General Hospital made history last week when they successfully transplanted a pig kidney into a human patient for the first time ever.
The recipient was a 62-year-old man named Richard Slayman who had been living with end-stage kidney disease caused by diabetes. While Slayman had received a kidney transplant in 2018 from a human donor, his diabetes ultimately caused the kidney to fail less than five years after the transplant. Slayman had undergone dialysis ever since—a procedure that uses an artificial kidney to remove waste products from a person’s blood when the kidneys are unable to—but the dialysis frequently caused blood clots and other complications that landed him in the hospital multiple times.
As a last resort, Slayman’s kidney specialist suggested a transplant using a pig kidney provided by eGenesis, a pharmaceutical company based in Cambridge, Mass. The highly experimental surgery was made possible with the Food and Drug Administration’s “compassionate use” initiative, which allows patients with life-threatening medical conditions access to experimental treatments.
The new frontier of organ donation
Like Slayman, more than 100,000 people are currently on the national organ transplant waiting list, and roughly 17 people die every day waiting for an available organ. To make up for the shortage of human organs, scientists have been experimenting for the past several decades with using organs from animals such as pigs—a new field of medicine known as xenotransplantation. But putting an animal organ into a human body is much more complicated than it might appear, experts say.
“The human immune system reacts incredibly violently to a pig organ, much more so than a human organ,” said Dr. Joren Madsen, director of the Mass General Transplant Center. Even with immunosuppressant drugs that suppress the body’s ability to reject the transplant organ, Madsen said, a human body would reject an animal organ “within minutes.”
So scientists have had to use gene-editing technology to change the animal organs so that they would work inside a human body. The pig kidney in Slayman’s surgery, for instance, had been genetically altered using CRISPR-Cas9 technology to remove harmful pig genes and add human ones. The kidney was also edited to remove pig viruses that could potentially infect a human after transplant.
With CRISPR technology, scientists have been able to prove that interspecies organ transplants are not only possible, but may be able to successfully work long term, too. In the past several years, scientists were able to transplant a pig kidney into a monkey and have the monkey survive for more than two years. More recently, doctors have transplanted pig hearts into human beings—though each recipient of a pig heart only managed to live a couple of months after the transplant. In one of the patients, researchers noted evidence of a pig virus in the man’s heart that had not been identified before the surgery and could be a possible explanation for his heart failure.
So far, so good
Slayman and his medical team ultimately decided to pursue the surgery—and the risk paid off. When the pig organ started producing urine at the end of the four-hour surgery, the entire operating room erupted in applause.
Slayman is currently receiving an infusion of immunosuppressant drugs to prevent the kidney from being rejected, while his doctors monitor the kidney’s function with frequent ultrasounds. Slayman is reported to be “recovering well” at Massachusetts General Hospital and is expected to be discharged within the next several days.