Super Mario is mathier than you think

Here’s a problem you probably didn’t solve in school: You’re an ambitious young plumber from Brooklyn in a world inhabited by violent human-size mushrooms called Goombas. The love of your life has been kidnapped, so you embark on a quest to rescue her, venturing through stretches of pipe-filled and monster-­ridden terrain where your only means of protection are your powers of jumping and stomping. 

It’s a journey so arduous that no computer—real or hypothetical—is powerful enough to figure out if you can reach her. And according to research published by the MIT Hardness Group, determining whether your quest is possible at all is at least as complicated as decoding the encryption behind financial transactions. But if this problem could talk, the first thing it would say is “Hello, it’s a-me, Mario!”

For the love of the game

Though it does have a YouTube channel, the MIT Hardness Group isn’t an official research group. Instead, it’s a placeholder name for theoretical computer science projects—including several related to Super Mario—from Erik Demaine’s class Algorithmic Lower Bounds: Fun with Hardness Proofs.

Demaine, a professor of computer science, received a MacArthur fellowship (also known as a “genius” grant) for his work in computational geometry on protein folding and origami. But he also researches complexity theory, which focuses on organizing problems into categories based on how much time and memory space it takes for computers to solve them.

He happens to be an avid Super Mario fan as well. “I grew up playing NES [Nintendo Entertainment System] games,” Demaine says. “I poured many hours into playing as a kid, so it’s fun to come back to it these many years later and tie it into my research.”

Erik Demaine
Erik Demaine researches complexity theory, which examines the amount of time and memory that computers need to solve problems. He’s also an avid Super Mario fan.
DONNA COVENEY/MIT

Super Mario takes place on a horizontally scrolling universe of platforms, pipes, and other obstacles. The object of the game is to rescue Princess Peach, the monarch of the Mushroom Kingdom, by racing through this terrain while sidestepping or dueling monsters like Goombas and deadly porcupines called Spinies. The game takes place over several levels; in the original version, each level ends with a flagpole that sends Mario on to the next part of his mission.

Over the last 14 years, Demaine and his collaborators have proved many things about Super Mario, such as that it’s even harder than the infamous traveling-salesman problem (which seeks the most efficient route between many different locations) or the problem of factoring large numbers. But the result that surprised Demaine the most came from four of his students: Hayashi Ani ’21, MEng ’23; Holden Hall ’26; Ricardo Ruiz ’24, MEng ’25; and Naveen Venkat ’23, MEng ’24. For their final project in that 2023 class, the team used a combination of fan-made Super Mario level editors and a platform called Super Mario Maker to create levels so hard that they are undecidable. In other words, it’s impossible to write a computer program that always correctly predicts whether, in those levels, Mario can reach the castle. 

Previously, Demaine had believed that Super Mario belonged in the PSPACE complexity class, which contains problems that are solvable but whose solutions become impractically complex as the problem gets bigger. At the time, he had even said that PSPACE was Mario’s “permanent home.” But the new findings pushed Super Mariointo RE-Complete, the class of undecidable problems. “It’s the hardest complexity class we could imagine for these sorts of games,” Demaine says. 

What computers can’t solve

In 1936, Alan Turing, the father of modern computer science,created a puzzle now known as the Halting Problem to prove it’s not possible to construct a computer that can solve everything.

At the core of the Halting Problem lies a paradox, and it goes like this: Suppose you have a fancy computer, called the Oracle, that looks at any program and correctly determines whether a computer following it will ever come to a stop. For example, if it sees the program “Take 1 and add 3,” the Oracle will say the program halts, but if the program says “Take 1 and add 1 to it until it becomes 0,” the Oracle will say it runs forever. 

Now suppose you have another computer, the Contrarian, and you put the Oracle inside it. When you give the Contrarian a program, it passes it to the Oracle and then does the opposite of whatever the Oracle says the program will do. So if the Oracle assesses the Contrarian’s program and thinks it will halt, the Contrarian will run forever. If the Oracle thinks the program will run forever, the Contrarian will halt. Either way, the Oracle’s assessment is wrong, so the classification problem is undecidable.

The proofs that Super Mario is undecidable rely on a more complex version of this idea. The team’s argument breaks down the video game using a technique called a reduction, in which mathematicians convert a problem they’re trying to solve into a problem they already know something about. “The classic example I remember in a math class is: How do you make a pot of boiling water?” Demaine recalls. “Well, I fill up the pot with water from the sink, and then I put it on the stove, and then it eventually boils. Okay, now I’ll give you a pot of water that’s already filled. How do you make a pot of boiling water? Well, I empty out the pot first and reduce to the previous problem.”

In their particular world of platforms and porcupines, the team broke down their Super Mariolevel into localized parts of Mario’s path called gadgets, which they could use to prove that the level was undecidable.

“A gadget in our sense is anything in your environment that decides whether or not you can go through one pattern [within a level],” explains Jayson Lynch ’12, MEng ’15, PhD ’20, a CSAIL research scientist and head of algorithms at MIT FutureTech. For example, in one gadget Mario might need to jump on a platform to avoid a monster as he makes his way across the screen. As a PhD student mentored by Demaine, Lynch spearheaded the formalization of gadget theory and worked on some of the earlier Super Mario papers but did not study the game’s undecidability.

One of Lynch’s favorite Super Mario gadgets is the door gadget, which works like a door that Mario can open, traverse, and close. The door in question is always either open (when the Spiny is on the right) or closed (when the Spiny is on the left). So if a Spiny is pacing back and forth on the left of the door, Mario has to navigate beneath the moving Spiny and jump up to hit a brick block just as the Spiny reaches it. This bumps the Spiny to the right side, which opens the door and allows Mario to travel across the traverse path and get to the spot where he can close the door. Once there, he must time another jump beneath the pacing Spiny to send it back to the left side of the gadget, closing the door behind him. 

Mario opens the door by bumping the Spiny from the left to the right.
With the Spiny out of the way, Mario can go through the open door and follow the traverse path to the other side. Once there, he’ll be able to bump the Spiny back to the left and close the door.

Since a door is always open or closed, its state can be used to simulate a true or false statement, with open being true and closed being false. Earlier Super Mario papers had strung together multiple door gadgets to simulate a true-or-false problem that complexity researchers already knew to be hard. But to show undecidability, the team used Super Mario level editors to put together another device, called a counter gadget, that tallies the game’s monsters and obstacles. 

If you can build a machine with even just a few of those counters, Demaine says, you can simulate an arbitrary computer—one that could essentially do anything a non-quantum computer could do, given enough time and memory. And with no limit on the number of monsters, such a machine could have infinitely expandable memory, even though the level size stays the same, which he calls “pretty wild.” In other words, any theoretical computer can be built in a Super Mario level. “You could use it to solve anything you can use a computer to do,” says Demaine. “You could have it do your taxes, or compile your code, or run an LLM, or optimize your class schedule.” You might even build Super Mario levels that could excel at sudoku, construct optimal chess strategies, or prove any provable mathematical theorem.

The MIT mathematician Marvin Minsky invented counter machines in 1961 to figure out how simple a computer could be while still being “universal” (as powerful as any other computer, given enough time). These theoretical computers each store two numbers and can change them by adding 1, subtracting 1, or doing something special if a number hits a set value. 

In the counter gadgets the students designed for Super Mario, the numbers reflect how many Goombas the levels contain. A number increases when a pipe spits out a Goomba and decreases when Mario stomps on one. Mario dies if he collides with a Goomba without stomping on it, so he can continue along the path only when the counter is at 0. 

The MIT Hardness group designed this counter gadget in Super Mario Maker 1 to prove undecidability.

Minsky had already proved that counter machines are undecidable because they can run undecidable problems. Since the researchers proved that counter gadgets simulate counter machines, then any level of Super Mario containing a counter gadget will also be unsolvable. “In the future, if someone wants to show a game is undecidable,” explains Holden Hall, one of the students behind the project, “they just have to make one of these gadgets.”

The existence of undecidable problems like the Halting Problem implies that it’s possible to construct an undecidable Super Mario level. Just as the singular undecidable program for the Halting Problem meant thatit’s impossible to figure out if a computer program will run forever, the team’s undecidable level means that it is impossible to determine whether an arbitrary Mario level can be beaten.

Putting the “super” in Super Mario

More than two years after Demaine’s class on hardness proofs, some of his students continue to meet weekly to discuss their Super Marioresearch.

“From the point of view of complexity theory, studying video games is interesting mostly for didactical reasons,” Fabrizio Grandoni, a research professor at the University of Applied Sciences and Arts of Southern Switzerland, told MIT News in 2016. “It’s a simple, natural way to attract students to study this specific topic.”

Hall, who had very little exposure to the ideas of complexity theory before taking Demaine’s class, is a case in point, noting: “I took the class because a bunch of people I knew were taking it. But since I took it, I really enjoyed the class, and so I’ve taken a lot more classes in that realm.”

The applications of the MIT Hardness Group’s work go way beyond stomping on mushrooms and collecting coins. For example, researchers at the University of Texas Rio Grande Valley (including Timothy Gomez, now a PhD student at MIT) have used the gadget theory developed for analyzing games like Super Marioto study the complexity of problems relating to planning robotic motion and modeling chemical reaction networks.

“[Gadget theory] can be used in the negative way to say ‘Oh, well, we should stop searching for algorithms because we know this problem is too hard’—or it can be used in this positive way, because usually, to prove something hard, you’re showing that you can build a computer of a certain type,” Demaine says. 

Though there’s no way of knowing what mark Super Mariowill leave on the future of math and computer science, one thing’s for sure: No matter how many princesses he does or doesn’t save, the legacy of this little plumber is set to extend far beyond video screens. 

STAT+: Want high-quality generic drugs? One expert has ideas on how consumers can trust their supply

For many years, generic drugs have accounted for roughly 90% of the prescriptions doled out to Americans thanks to their lower cost. Yet reliable supplies have been an issue due to inconsistent quality — more than 60% of the generic shortages have been attributed to quality concerns, according to the Food and Drug Administration. Numerous manufacturers, many based in India, have been cited for violating manufacturing protocols that led to product recalls and, sometimes, bans on sending drugs to the U.S.

But Kevin Schulman, a professor and deputy director of the Clinical Excellence Research Center at the Stanford University School of Medicine, believes a solution is within reach. Schulman — who has also worked with an independent lab called Valisure that found impurities in some widely used medicines — argues the FDA should encourage testing by independent, accredited laboratories.

We recently spoke with him about the subject. This is an edited version of our conversation.

Continue to STAT+ to read the full story…

American, British, and Italian Online Information on the Health Risks Associated With Eating Meat: Cross-Sectional Study

Background: The quality of online information regarding the risks associated with meat consumption could play a crucial role in shaping consumers’ behavior. Objective: This study aimed to investigate the quality of Italian, British, and American websites addressing this topic. Methods: A cross-sectional assessment of the top 100 British, Italian, and American web pages on the risks attributable to meat consumption was performed using the JAMA benchmarks tool, evaluating authorship by certified professionals and the inclusion of information on recommended meat consumption, potential meat substitutes, and coverage of issues such as diet sustainability and cancer, cardiovascular, and chronic disease prevention. Websites were then classified according to their stance toward meat consumption (neutral, promoting, or demonizing). Results: American and British websites were classified as high quality in 61% (61/100) and 78.1% (75/96) of cases, respectively, while only 22.3% (21/94) of Italian websites were classified as high quality. Multinomial regression showed that web pages with a demonizing stance toward meat consumption and those authored by certified health professionals were less likely to be Italian than American. Similarly, web pages discussing environmental risks and chronic diseases associated with excessive meat consumption were less likely to be Italian. Compared with American web pages, those promoting meat consumption and those authored by qualified professionals were less likely to be British. Web pages discussing chronic disease risks were also less likely to be British, whereas those mentioning cancer risks were more likely to be British. Conclusions: The widespread prevalence of poor online information quality, especially in certain countries, demands action. Promoting user education in assessing the reliability of websites and involving health professionals in this educational effort may represent viable strategies.
<img src="https://jmir-production.s3.us-east-2.amazonaws.com/thumbs/2bac4d7e6e24532a0dbf79b936f8f403" />

Justice Department announces hundreds of charges in multibillion-dollar health care fraud crackdown

WASHINGTON — The Justice Department on Tuesday announced criminal charges against 455 people as part of a two-week health care fraud crackdown that officials say involved more than $6.5 billion in false claims submitted to insurers.

Among those charged is a nurse practitioner accused in Texas of billing Medicaid for medically unnecessary wound-care procedures and using the proceeds for fancy jewelry and luxury cars; a mental health company owner who prosecutors say exploited the homeless by billing for crisis stabilization services they did not need; and a hospice owner alleged to have paid kickbacks to a funeral home employee for information about Medicare beneficiaries.

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Solid Tumor CAR-T Therapy Approved in China, a World First

In a landmark advance for cellular immunotherapy, CARsgen Therapeutics has received regulatory approval in China for satricabtagene autoleucel (satri-cel; CT041), the first CAR-T cell therapy globally approved for the treatment of a solid tumor.

The National Medical Products Administration (NMPA) of China approved satri-cel for Claudin18.2 (CLDN18.2)-positive, HER2-negative advanced gastric or gastroesophageal junction adenocarcinoma (G/GEJA) patients who have progressed after two prior lines of therapy. The decision is a turning point for the CAR-T field, which has improved hematologic malignancies but has struggled to overcome solid tumor biological barriers.

The approval addresses a major unmet need in gastric cancer, the fifth most commonly diagnosed cancer and the fifth leading cause of cancer-related death worldwide, with more than one million new cases and over 750,000 deaths annually. East Asia, particularly China, accounts for 40% of global cases due to risk factors like Helicobacter pylori infection, dietary exposures, and an aging population.

Despite advances in chemotherapy, targeted therapy, and immune checkpoint inhibitors, advanced gastric cancer patients have poor outcomes, especially after multiple treatment lines fail. CAR-T therapy first entered clinical testing for solid tumors in the late 1990s and early 2000s, with pioneering studies targeting ovarian cancer and later neuroblastoma and colorectal cancer, laying the groundwork for today’s next-generation cell therapies.

Satri-cel is an autologous CAR-T therapy that targets CLDN18.2, a stomach-specific tight-junction protein that is highly expressed in gastric and pancreatic cancers but has limited expression in normal tissues. The therapy uses a humanized anti-CLDN18.2 CAR construct that is linked to CD28 and CD3ζ signaling domains, which allows for targeted elimination of tumor cells.

The program’s CARsgen preconditioning strategy boosts CAR-T activity in the immunosuppressive solid tumor microenvironment. Patients receive low-dose nab-paclitaxel to increase CAR-T cell infiltration and antitumor efficacy in addition to cyclophosphamide and fludarabine lymphodepletion.

Clinical evidence supporting approval comes from a randomized confirmatory study published in The Lancet in 2025. In heavily pretreated patients with advanced G/GEJA, satri-cel demonstrated clinically meaningful efficacy and a manageable safety profile compared with available treatment options. The results provide one of the strongest demonstrations to date that CAR-T therapy can generate meaningful clinical benefit in solid tumors.

Importantly, CARsgen is already aggressively pursuing a development strategy beyond late-line gastric cancer. Currently, there are Phase Ib studies in advanced gastric, gastroesophageal junction, and pancreatic cancers, a confirmatory Phase II study in advanced G/GEJA, a Phase Ib study evaluating satri-cel as adjuvant therapy in pancreatic cancer, and investigator-initiated studies evaluating adjuvant and first-line sequential therapy. Satri-cel is being tested in a Phase Ib/II trial for advanced gastric and pancreatic adenocarcinoma outside China, demonstrating its global development goals.

The program has also been the subject of considerable regulatory attention. The FDA has designated satri-cel for CLDN18.2-positive gastric and gastroesophageal junction cancers as an RMAT and Orphan Drug. In Europe, the therapy has been awarded Orphan Medicinal Product designation and PRIME status by the European Medicines Agency. In China, the NMPA designated this product a Breakthrough Therapy for advanced gastric or gastroesophageal junction cancer patients who had failed at least two lines of treatment.

Satri-cel may be the first CAR-T therapy to clear the regulatory finish line in solid tumors, but the competition is heating up. Several companies are developing CLDN18.2-targeted CAR-T, T-cell engager, and antibody programs. AstraZeneca’s zolbetuximab franchise validated CLDN18.2 as a gastric cancer therapeutic target, and Chinese and U.S. biotech companies are developing cell therapy programs to replicate or improve on satri-cel’s results.

For cancer specialists and cell therapy specialists, satri-cel’s approval is not just a new treatment option but a proof-of-concept that engineered cellular therapies can successfully address the challenges of solid tumors. Whether this breakthrough can be applied to other tumor types remains to be seen, but the field has crossed a milestone that has eluded oncology for decades.

The post Solid Tumor CAR-T Therapy Approved in China, a World First appeared first on Inside Precision Medicine.

The impacts of a justice-focused body image program for early adolescents

To address gaps in universal, diversity-focused eating disorders prevention with early adolescents, our team co-created an evidence-informed body image intervention through a community-engaged, participatory research process. The Body Justice intervention and associated research were co-created by a team of middle school students and staff and undergraduate students and faculty in the Pacific Northwest United States. The intervention includes eight brief lessons (six hours total) with culturally-tailored content rooted in cognitive dissonance and media literacy (e.g., cultural appearance ideals, diversity representation within media, food culture). The intervention was delivered with 7th grade students over three years (N = 333; 49% students of color; 53% cisgender boys, 36% cisgender girls, 12% gender diverse; 27% sexually diverse) using college student leaders (near peers) and middle school student co-leaders. Student satisfaction immediately after the intervention was moderate overall and higher for students of color, sexually diverse students, and cisgender girls and gender diverse students compared to their peers with majority identities. Across the sample, there was a significant reduction in unhealthy weight control behaviors from baseline to two-month follow-up with similar improvement among subgroups except for students of color, who had smaller reductions over time compared to their white peers. Across the sample, there was a significant reduction in internalized appearance norms from pre to post-intervention and through follow-up. These reductions were similar across gender, but the change was significant only for white students and straight students. There was no overall improvement in perceived appearance pressure from social media over time, but subgroup analyses revealed that students of color experienced improvement over time unlike other subgroups. In general, subgroup analyses should be interpreted cautiously due to concerns about adequate power. These results suggest that the Body Justice curriculum was delivered effectively and was well-liked by middle school students with marginalized identities. While aspects of the intervention were beneficial (e.g., a reduction in unhealthy weight control behaviors over time), findings suggest potentially differential results across identity subgroups. This has implications for collaborative school-based research, body image and eating disorders prevention, and community-engaged methods to foster equity.

Opinion: Ending birthright citizenship could be a public health disaster

Sometime before the end of June, the Supreme Court is expected to deliver its opinion in Trump v. Barbara, the case challenging President Trump’s executive order seeking to end birthright citizenship in the United States. At stake is the long-standing interpretation of the Citizenship Clause of the 14th Amendment, which for more than a century has been understood and affirmed to mean that any child born in the United States, regardless of their parents’ citizenship status, is a U.S. citizen (with a remarkably narrow exception carved out for the children of diplomats).

Ending the guarantee of birthright citizenship would dramatically increase the size of the undocumented population in the U.S. and could invite a future executive to nullify the citizenship of countless American-born children of immigrants. It would also have stark consequences at the intersection of bioethics and public health.

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STAT+: A sweeping new AI to detect heart conditions is coming to OpenEvidence

Doctors using OpenEvidence will soon be able to upload an image of an electrocardiogram to get an algorithmic prediction of whether a patient has structural heart disease. 

Called EchoNext, the artificial intelligence model was developed by researchers at New York-Presbyterian Hospital and Columbia University and is being commercialized by a spinout called Pathway Labs. The company this month received a sweeping Food and Drug Administration clearance for the technology that can sniff out six forms of structural heart disease — including conditions where blood doesn’t flow properly through the organ owing to blocked or leaky valves and where the chambers of the heart don’t pump blood as well as they should — from EKG. 

In addition to marketing it to hospitals, Pathway will take the novel step of licensing the technology to OpenEvidence, a medical evidence search engine that’s used by hundreds of thousands of clinicians.

Continue to STAT+ to read the full story…

Breast and Cervical Cancer Stigma in Rwanda

Conditions: Breast Cancer; Cervical Cancer

Interventions: Behavioral: Behavioral: RISE Intervention; Behavioral: Behavioral: CHW Educational Intervention

Sponsors: Dana-Farber Cancer Institute; Dana-Farber/Harvard Cancer Center (DF/HCC) Boston, MA; American Association for Cancer Research; Breast Cancer Research Foundation

Not yet recruiting

Gene Therapy Restores Brain Function and Behavior in Fragile X Syndrome

A University of California, Riverside-led research team has developed a gene therapy that restored production of a missing brain protein, corrected abnormalities in brain circuitry, and improved behavior in a mouse model of Fragile X syndrome (FXS). The study, published in the journal Molecular Therapy Nucleic Acids, tested an adeno-associated virus (AAV)-based therapy carrying a normal human version of the FMR1 gene to produce the Fragile X messenger ribonucleoprotein (FMRP) and found that early treatment normalized several measures of brain activity while improving social behavior, exploratory behavior, and cognitive flexibility.

“In a typical brain, FMRP acts like a brake or a volume control,” said senior author Iryna Ethell, PhD, a professor of biomedical sciences at the UC Riverside School of Medicine. “Without it, neural circuits become overactive and less efficient, which contributes to many of the developmental and behavioral challenges associated with FXS.”

FXS is the most common single-gene cause of autism spectrum disorder. According to the researchers, the disorder typically manifests from expansion of CGG repeats in the 5′ untranslated region of FMR1. The mutation causes methylation and silencing of the gene, leading to a major reduction or complete loss of FMRP, an RNA-binding protein that regulates numerous messenger RNAs involved in synapse formation, maturation, and function. Loss of the protein can lead to abnormal synaptic activity and increased cortical hyperexcitability.

FXS can produce sensory hypersensitivity, seizures, anxiety, intellectual disability, developmental delays, repetitive behaviors, and social communication difficulty. Current treatments for this syndrome don’t seek to cure it, rather they are aimed at managing the associated symptoms of anxiety, hyperactivity, irritability, aggression, depression, and seizures.

The therapy developed by the research team was designed to replace missing FMRP rather than repair the original mutation. To do this, the researchers used an AAV9 viral vector to deliver human FMR1 isoform 7, one of the most abundant forms of the protein found in the brain. The therapy was tested in newborn mice lacking FMRP via intracerebroventricular injections at either a low or high doses.

The work built on earlier research that explored the potential of AAV-mediated restoration of FMRP in rodent models. These prior studies used a range of viral serotypes, promoters, delivery routes, and FMRP isoforms and showed they could partially or completely correct specific biochemical, physiological, and behavioral abnormalities. The researchers noted that studies involving mouse and rat FMRP homologs had shown that restoring the protein could improve a range of Fragile X-related deficits.

The current study showed that high-dose treatment produced the strongest positive effects in the mouse models. Electroencephalography showed normalization of baseline gamma power, improvements in responses to sound, reduced background neural activity, and improved habituation to repeated auditory stimuli. The therapy also restored abnormal patterns of brain-wave coupling that have been associated with Fragile X-related dysfunction.

Behavioral testing showed that these improvements persisted into adulthood. Mice receiving the higher dose displayed normalized exploratory behavior, improved social preference, and better performance in probabilistic reversal learning, a measure of cognitive flexibility that requires adapting when previously rewarded behaviors stop producing rewards.

“Fragile X mice tend to persist with an old solution even after the rules change,” Ethell said. “After treatment, they became much better at adapting, performing similarly to mice with normal FMR1 function.”

The researchers noted that their work showed the importance of delivering at therapy for FXS early in its development. They said that widespread distribution of the potential new gene therapy throughout the brain was necessary to achieve a therapeutic benefit. There was a clear relationship between the proportion of neurons expressing the therapeutic gene and the degree of functional recovery, which indicated that restoring FMRP in a sufficient number of cortical cells is critical for correcting any behavioral deficits.

While a promising step, the investigators said that the work was a preclinical study and that future research will now focus on developing delivery methods that can of have broad distribution across the human brain. The team also believes their approach could have broader applications.

“Beyond FXS, the findings may provide a roadmap for treating other genetic neurodevelopmental disorders caused by the loss of a single critical protein,” Ethell said. “Our study shows it may be possible to restore function across complex brain networks by replacing a missing gene. That gives us reason to be optimistic about the future of genetic medicine.”

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