Sloppy Science Happens More Than You Think
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."
Fast for Longevity, with Less Hunger, with Dr. Valter Longo
You’ve probably heard about intermittent fasting, where you don’t eat for about 16 hours each day and limit the window where you’re taking in food to the remaining eight hours.
But there’s another type of fasting, called a fasting-mimicking diet, with studies pointing to important benefits. For today’s podcast episode, I chatted with Dr. Valter Longo, a biogerontologist at the University of Southern California, about all kinds of fasting, and particularly the fasting-mimicking diet, which minimizes hunger as much as possible. Going without food for a period of time is an example of good stress: challenges that work at the cellular level to boost health and longevity.
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If you’ve ever spent more than a few minutes looking into fasting, you’ve almost certainly come upon Dr. Longo's name. He is the author of the bestselling book, The Longevity Diet, and the best known researcher of fasting-mimicking diets.
With intermittent fasting, your body might begin to switch up its fuel type. It's usually running on carbs you get from food, which gets turned into glucose, but without food, your liver starts making something called ketones, which are molecules that may benefit the body in a number of ways.
With the fasting-mimicking diet, you go for several days eating only types of food that, in a way, keep themselves secret from your body. So at the level of your cells, the body still thinks that it’s fasting. This is the best of both worlds – you’re not completely starving because you do take in some food, and you’re getting the boosts to health that come with letting a fast run longer than intermittent fasting. In this episode, Dr. Longo talks about the growing number of studies showing why this could be very advantageous for health, as long as you undertake the diet no more than a few times per year.
Dr. Longo is the director of the Longevity Institute at USC’s Leonard Davis School of Gerontology, and the director of the Longevity and Cancer program at the IFOM Institute of Molecular Oncology in Milan. In addition, he's the founder and president of the Create Cures Foundation in L.A., which focuses on nutrition for the prevention and treatment of major chronic illnesses. In 2016, he received the Glenn Award for Research on Aging for the discovery of genes and dietary interventions that regulate aging and prevent diseases. Dr. Longo received his PhD in biochemistry from UCLA and completed his postdoc in the neurobiology of aging and Alzheimer’s at USC.
Show links:
Create Cures Foundation, founded by Dr. Longo: www.createcures.org
Dr. Longo's Facebook: https://www.facebook.com/profvalterlongo/
Dr. Longo's Instagram: https://www.instagram.com/prof_valterlongo/
Dr. Longo's book: The Longevity Diet
The USC Longevity Institute: https://gero.usc.edu/longevity-institute/
Dr. Longo's research on nutrition, longevity and disease: https://pubmed.ncbi.nlm.nih.gov/35487190/
Dr. Longo's research on fasting mimicking diet and cancer: https://pubmed.ncbi.nlm.nih.gov/34707136/
Full list of Dr. Longo's studies: https://pubmed.ncbi.nlm.nih.gov/?term=Longo%2C+Valter%5BAuthor%5D&sort=date
Research on MCT oil and Alzheimer's: https://alz-journals.onlinelibrary.wiley.com/doi/f...
Keto Mojo device for measuring ketones
Silkworms with spider DNA spin silk stronger than Kevlar
Story by Freethink
The study and copying of nature’s models, systems, or elements to address complex human challenges is known as “biomimetics.” Five hundred years ago, an elderly Italian polymath spent months looking at the soaring flight of birds. The result was Leonardo da Vinci’s biomimetic Codex on the Flight of Birds, one of the foundational texts in the science of aerodynamics. It’s the science that elevated the Wright Brothers and has yet to peak.
Today, biomimetics is everywhere. Shark-inspired swimming trunks, gecko-inspired adhesives, and lotus-inspired water-repellents are all taken from observing the natural world. After millions of years of evolution, nature has quite a few tricks up its sleeve. They are tricks we can learn from. And now, thanks to some spider DNA and clever genetic engineering, we have another one to add to the list.
The elusive spider silk
We’ve known for a long time that spider silk is remarkable, in ways that synthetic fibers can’t emulate. Nylon is incredibly strong (it can support a lot of force), and Kevlar is incredibly tough (it can absorb a lot of force). But neither is both strong and tough. In all artificial polymeric fibers, strength and toughness are mutually exclusive, and so we pick the material best for the job and make do.
Spider silk, a natural polymeric fiber, breaks this rule. It is somehow both strong and tough. No surprise, then, that spider silk is a source of much study.The problem, though, is that spiders are incredibly hard to cultivate — let alone farm. If you put them together, they will attack and kill each other until only one or a few survive. If you put 100 spiders in an enclosed space, they will go about an aggressive, arachnocidal Hunger Games. You need to give each its own space and boundaries, and a spider hotel is hard and costly. Silkworms, on the other hand, are peaceful and productive. They’ll hang around all day to make the silk that has been used in textiles for centuries. But silkworm silk is fragile. It has very limited use.
The elusive – and lucrative – trick, then, would be to genetically engineer a silkworm to produce spider-quality silk. So far, efforts have been fruitless. That is, until now.
We can have silkworms creating silk six times as tough as Kevlar and ten times as strong as nylon.
Spider-silkworms
Junpeng Mi and his colleagues working at Donghua University, China, used CRISPR gene-editing technology to recode the silk-creating properties of a silkworm. First, they took genes from Araneus ventricosus, an East Asian orb-weaving spider known for its strong silk. Then they placed these complex genes – genes that involve more than 100 amino acids – into silkworm egg cells. (This description fails to capture how time-consuming, technical, and laborious this was; it’s a procedure that requires hundreds of thousands of microinjections.)
This had all been done before, and this had failed before. Where Mi and his team succeeded was using a concept called “localization.” Localization involves narrowing in on a very specific location in a genome. For this experiment, the team from Donghua University developed a “minimal basic structure model” of silkworm silk, which guided the genetic modifications. They wanted to make sure they had the exactly right transgenic spider silk proteins. Mi said that combining localization with this basic structure model “represents a significant departure from previous research.” And, judging only from the results, he might be right. Their “fibers exhibited impressive tensile strength (1,299 MPa) and toughness (319 MJ/m3), surpassing Kevlar’s toughness 6-fold.”
A world of super-materials
Mi’s research represents the bursting of a barrier. It opens up hugely important avenues for future biomimetic materials. As Mi puts it, “This groundbreaking achievement effectively resolves the scientific, technical, and engineering challenges that have hindered the commercialization of spider silk, positioning it as a viable alternative to commercially synthesized fibers like nylon and contributing to the advancement of ecological civilization.”
Around 60 percent of our clothing is made from synthetic fibers like nylon, polyester, and acrylic. These plastics are useful, but often bad for the environment. They shed into our waterways and sometimes damage wildlife. The production of these fibers is a source of greenhouse gas emissions. Now, we have a “sustainable, eco-friendly high-strength and ultra-tough alternative.” We can have silkworms creating silk six times as tough as Kevlar and ten times as strong as nylon.
We shouldn’t get carried away. This isn’t going to transform the textiles industry overnight. Gene-edited silkworms are still only going to produce a comparatively small amount of silk – even if farmed in the millions. But, as Mi himself concedes, this is only the beginning. If Mi’s localization and structure-model techniques are as remarkable as they seem, then this opens up the door to a great many supermaterials.
Nature continues to inspire. We had the bird, the gecko, and the shark. Now we have the spider-silkworm. What new secrets will we unravel in the future? And in what exciting ways will it change the world?