Part the First: Politics and Science. It will be s surprise to no one that autism is somewhere nearby: Inside FDA, career staffers describe how political pressure is influencing their work.
The inquiry came in August and struck scientists at the Food and Drug Administration as highly unusual. The leader of the center that regulates prescription medicines wanted to know what they thought about leucovorin, a generic drug that’s mainly used to alleviate side effects of cancer therapies. He’d seen some promising studies and thought the agency could find a way to approve it as an autism treatment.
From the leucovorin link in the previous paragraph:
The case of leucovorin is simpler to explain: There are several studies that indicate the medicine can improve the performance of people with autism on standardized tests used to measure verbal ability. But these studies are quite small.
One study, published in the European Journal of Pediatrics, followed 80 patients between the ages of 2 and 10 who were randomly assigned to receive either leucovorin or a placebo. Neither their families nor their doctors knew who received the treatment. At the end of 24 weeks, the children who received leucovorin scored 1.2 points higher on a 60-point scale used to measure autism severity than the children who did not.
The result was statistically significant, but smaller studies are prone to false positive results. The normal course for researchers before making a recommendation would be to conduct a much larger randomized controlled trial to verify that the treatment is beneficial. Most such trials include hundreds or thousands of patients, and provide the best evidence of efficacy and safety.
A result that indicates a valid correlation will be statistically significant, by definition. But statistical significance does not imply clinical significance unless the evidence is much stronger than a study with only 80 subjects, a sample that is much too small to make generalizations about something as complex as autism. The work of Bradford Hill and Richard Doll comes to mind. They connected smoking directly to lung cancer during the early days of the British National Health Service by showing that although not everyone who smoked got lung cancer, virtually all the physicians in his sample of more than 41,000 who got lung cancer were smokers. And the more they smoked the more likely their diagnosis, and subsequent death.
Along with the statistics, the dose-response clinched the relationship. The Bradford Hill Criteria for Causation must be ignored when the conclusion precedes the analysis. It took more than forty years, but the “molecular archaeology” of lung cancer and hundreds of other cancers is now well understood. And many cancers are treatable, sometimes curable, because of this (and I personally thank modern clinical and radiation oncology for this).
What is leucovorin anyway? Also called folinic acid, it is similar to methotrexate (MTX), which was one of the first useful cancer chemotherapeutics (1947). MTX inhibits a key enzyme necessary for DNA replication and by doing so will tend to kill cancer cells faster than it kills normal cells. Or that is the idea. Leucovorin can moderate off-target effects of MTX. How leucovorin might lessen symptoms associated with autism remains unknown. Repurposed drugs are often useful, though. Thalidomide is used to treat multiple myeloma, but there was a reason to try. The justification for leucovorin in the treatment of autism is very slim. Back to the primary STAT article, from Dr. Marty Makary, formerly of Johns Hopkins University School of Medicine and now Commissioner Food and Drugs at the Food and Drug Administration (FDA):
“Today, the FDA is filing a federal register notice to change the label on an exciting treatment called prescription leucovorin so that it can be available to children with autism,” he said. “Leucovorin holds promise for hundreds of thousands of kids with autism.” (Here is the tweet.)
Reshma Ramachandran, a health services researcher and clinician at Yale School of Medicine, said the sequence of events is the antithesis of how the FDA is supposed to function.
“What we’re seeing here is, ‘We believe this and we’re going to find the evidence to support that’,” Ramachandran said. “That’s just inherently wrong in terms of how a scientific agency like the FDA operates.”
The disconnect underscores the escalating tension between career scientists and political leaders as Kennedy works through his agenda. STAT interviewed more than 20 current and former agency officials, as well as legal experts, about political influence at the FDA. The conversations offered new insights into the political pressure shaping some of the FDA’s most important actions this year, from tackling autism to revisiting vaccine safety. Most requested anonymity to protect against personal and professional repercussions.
Of course, they requested anonymity. Personal and professional repercussions are the whole point, as is a lack of caution among these politicians and erstwhile scientists. Caution is like taxes, only for the little people, who must do the best they can in a hostile world. None of this is to argue that the FDA, CDC, and NIH are perfect. But at the level of the working scientist in working laboratories, both agencies are essential to public health and biomedical sciences. It was field scientists from CDC who got the head start on AIDS in June 1981, within weeks of the recognition of the disease. Virtually every Nobel Prize for Physiology or Medicine awarded to an American since World War II was supported by NIH.
Finally, I am also reminded of a field of medicine that for the last forty years has been searching for their holy grail, because they have known it must exist for over a hundred years. The amyloid hypothesis of Alzheimer’s disease (AD) might not be a dead end, but that is a reasonable conclusion.
Part the Second: Just Because You Stop Looking Does Not Mean the Problem has Gone Away. We rely on STAT once again today, because it is a good source, with only a modicum of cheerleading for Biomedicine (the union of Big Medicine and Big Pharma). In this case, CDC team running top survey on health and nutrition is laid off. And as the tagline says, “NHANES has collected data on eating patterns, diabetes, and other common diseases for decades.” The CDC staff responsible for publishing the Morbidity and Mortality Weekly Report was recalled after being fired; I doubt the same with be true for the National Health and Nutrition Examination Survey”
NHANES is the principal source of information measuring the health and nutritional status of people living in the community, according to the National Library of Medicine. It’s known for combining rigorous data measurements with answers to questionnaires.
Based in Hyattsville, Md., the statistics center has for 60 years provided information on common diseases and behaviors based on nationally representative surveys. Those surveys are conducted by contractors who measure the health and nutrition of Americans via questionnaires that are followed by health exams and lab tests. The number of people terminated across NCHS’s four divisions (data analysis, informatics, operations, and planning) adds up to about 100, including all eight who had remained in the planning branch after earlier cuts on Feb. 14 and April 1 that also spurred retirements.
“Anything related to any emerging outbreaks are also going to be compromised,” Denys Lau, formerly the director of a division that tracks the nation’s health care provision and utilization, told STAT. He is now editor-in chief of the American Journal of Public Health.
Lau is puzzled by the lost ability to track concerns health secretary Robert F. Kennedy Jr. has prioritized, such as obesity, nutrition, oral health, and environmental exposure to chemicals.
Like Lau, Tom Frieden, president and CEO of the global health organization Resolve to Save Lives and former CDC director, also views the administration’s stated goals and actions as inconsistent. “NHANES helped identify Americans’ dangerous overconsumption of ultra-processed foods, an issue Secretary Kennedy himself has repeatedly cited as a major health threat.”
Inconsistent? Probably not. The goal of the Current Administration seems to be to confirm various and sundry preconceived notions about health and wellbeing (not “wellness”). Needless to say, this is not science as it has been practiced, until the day before yesterday, since the time of Paracelsus, who was the father of toxicology because alchemy could be very dangerous. NHANES was one important counterweight to Big Food and Big Ag. And no, Big Food/Big Ag will not win the war, but their defeat will take time and consistent effort.
Part the Third: Completion of Yet Another Hat Trick. I have no doubt the current Director of the National Institutes of Health can explain this: They advised federal health agencies on the ethics and impact of scientific research. They’re no longer wanted:
For two years, a panel of scientific experts, clinicians, and patient advocates had been hammering out ways to increase community engagement in National Institutes of Health-funded science. When they presented their road map to the NIH Director Jay Bhattacharya last week, he praised it for addressing a top priority: rebuilding public trust in clinical research. Which made it all the more confusing to the assembled panelists that this meeting would be their last.
The advisory committee, NExTRAC, was established in 2019 to take over the work of a storied panel, the Recombinant DNA Advisory Committee, or RAC. Starting in the mid-’70s, as the first genetic engineering technologies were being developed, RAC oversaw the rollout of synthetic insulin and the earliest days of gene therapy’s rocky entrance into clinical testing, laying much of the groundwork for its modern-day success. Newer biosafety and ethical quagmires, like CRISPR gene drives and novel uses of personal health data, have been the purview of NExTRAC over the past five years. But in May, members received emails from Bhattacharya notifying them that the committee was being sunset as part of an effort to make the NIH run more efficiently.
For those who are unfamiliar with the Recombinant DNA Advisory Committee, this was one of the first times biomedical scientists thought before they jumped on the next big thing. The Asilomar Conference was called by Paul Berg and other scientists of his stature to discuss the advisability of placing what might be called a cancer gene in the genome of a bacterium that inhabits the human gut. As an aside, Paul Berg had probably the greatest reply to the phone call congratulating him for winning the Nobel Prize, if I remember correctly after forty-five years he asked, “For what?” The issue of recombinant DNA (gene cloning) seems quaint now, but it was not in 1975. The work of RAC was essential in establishing safety guidelines for recombinant DNA research, as was the work of NExTRAC.
Now it’s unclear how, or if, the NIH will foster open conversations around scientific and ethical issues involving novel biotechnologies. The loss of NExTRAC is part of a pattern of shedding scientific expertise and patient perspectives in the name of slimming down the federal government. Since January, President Trump’s administration has terminated nearly four dozen committees that provide advice to various agencies within the Department of Health and Human Services, according to a federal database.
Some of the terminations have been previously reported by STAT and other outlets, including the elimination of committees that worked to improve hospital infection control and reduce systemic barriers to health care for poor, marginalized, and rural Americans, made recommendations for studying long Covid and advised on emerging ethical issues in human health research and programs that screen newborns for genetic conditions. For others, like NExTRAC and groups that have advised on Alzheimer’s research and how the NIH conducts grant reviews, the impacts of the terminations are only now coming into view.
At the final meeting of NExTRAC, on Sept. 29, Bhattacharya said that the decision “does not represent a diminished commitment by me to seek advice in challenging the status quo,” and that public discussions of these issues would take place via “alternative avenues.” The committee’s closing bit of business was voting to endorse the recommendations of its public engagement working group.
A large part of Bhattacharya’s status quo was that Covid would be a minor nuisance if only we let everyone get infected. The recent review panels I have served on have included lay members of the community. They have been a revelation to most of my colleagues, as they often ask the obvious questions that the experts in the room never even considered. So, at one level this is perfectly understandable from the perspective of the Current Administration. But for the rest of us, Quis custodiet ipsos custodes? If no one is looking over the guards’ shoulders, they will do as they will, everywhere, which is the point.
Again, NIH could be exasperating to those of us who depend on it for our scientific careers. It was never perfect, but the results of Vannevar Bush’s vision surpassed even his imagination. Now? If research is to be funded by those with an interest in the outcomes, said outcomes are foreordained and the “results” will not by much different from from those papers in which image manipulation has become a professional sport, albeit played by amateurs so far (scary thought). This is not a difficult concept. And the MMR combination vaccine still does not cause autism. Nor does acetaminophen.
Part the Fourth: Coral Catastrophe. As the saying goes, this has been “preyin’ on my mind” as ocean temperatures have reached new heights: Coral die-off marks Earth’s first climate ‘tipping point’:
Surging temperatures worldwide have pushed coral reef ecosystems into a state of widespread decline, marking the first time the planet has reached a climate ‘tipping point’, researchers announced today.
They also say that without rapid action to curb greenhouse-gas emissions, other systems on Earth will also soon reach planetary tipping points, thresholds for profound changes that cannot be rolled back.
“We can no longer talk about tipping points as a future risk,” says Steve Smith, a social scientist at the University of Exeter, UK, and a lead author on a report released today about how close Earth is to reaching roughly 20 planetary tipping points. “This is our new reality.”
Led by Smith and other scientists at the University of Exeter, the report assesses the risk of breaching tipping points such as ice-sheet collapse, rising seas and dieback of the Amazon rainforest. It also discusses progress towards various positive tipping points focused on social and economic change, such as the adoption of clean energy.
The group’s first such assessment, released less than two years ago, raised alarms but did not officially declare that any climate tipping points had been reached. In the past few years, however, global temperatures have surged, sparking concerns among some scientists that global warming is accelerating and could lead to even more widespread impacts in the coming decades than the changes that have already been recorded.
The impact on coral reefs has been particularly severe in the past two years , pushing these ecosystems to their tipping point, the researchers say. The warming waters have caused corals across the globe to bleach, a process that occurs when the organisms expel the symbiotic algae that provide them with nutrients, oxygen and vibrant colours. The fourth global bleaching event in the past few decades began in January 2023, and researchers estimate that it has affected more than 84% of the planet’s coral ecosystems.
Corals are among the oldest multicellular organisms on Earth. Their biology is remarkable. Bleaching occurs under environmental stress, in this case warm water, as the coral (Subphylum Anthozoa) expel their symbiont photosynthetic dinoflagellates (not algae) in response to the stress. Under normal conditions, the zooxanthellae live happily inside the coral polyp (including hard and soft corals and jellyfish). The coral provides carbon dioxide, and zooxanthellae produce food for the coral by photosynthesis. Win, win, and a healthy, colorful one at that.
Several widespread bleaching events have occurred over the past twenty years. In most cases the corals recovered, because bleached corals are not necessarily dead. They are very ill, however. One of these days, recovery will not happen and what was once a thriving ecosystem will become a vast underwater desert. But as great Newt Gingrich put it back in the day, “So what, extinction happens all the time” (paraphrase). Yes, Newt, this is true. But what we humans did to the dodo and the passenger pigeon does not have to be repeated in the current Sixth Great Extinction, which is entirely due to human cupidity and stupidity by all reasonable scientific explanations.
Part the Fifth: The Nervous Breakdown of the Professional Managerial Class Continues. As explained by Corey Robin in Mamdani’s New Birth of Freedom. Perhaps, but the firm of Clinton Obama Biden Pelosi Cuomo Jeffries & Schumer LLC will not go down without another fight, which could be their last. They could win, although it is difficult to see Hakim Jeffries winning anything except his own re-election in Brooklyn:
Reading this New York Times report on Eric Adams’ dropping out of the race—where Adams is described, with no sense of irony, as “politically moderate” and is quoted as warning against Mamdani’s desire to “destroy the very system we built together over generations” while Cuomo is quoted as saying, “We are facing an existential threat in an extreme radicalism that threatens the existence of this city as we know it.”
Zohran Mamdani is running now against Andrew Cuomo, a corrupt sexual harasser, who has been aided from the start by Donald Trump. Donald Trump is a corrupt sexual harasser who never met a law he didn’t want to break. Through pressure from Trump and Billy Ackman and a combination of real estate developers, financiers, pro-Israel forces, Cuomo is now being helped by the stepping down of Eric Adams, another corrupt politician whose bacon was saved only when Trump forced lower-tier federal prosecutors to drop the government’s corruption case against Adams in return for Adams’ helping Trump pursue his illegal and unconstitutional plan to deport immigrants.
Notice what Zohran, already blessed with so many political gifts, has going for him here. Not only is he completely untainted by corruption. He’s never broken the law. He’s as clean as a whistle.
There was a time when that wouldn’t have been remarkable. We’ve reached a moment in our political development when it is. What’s more, that steadfast legality and sense of lawfulness belongs to a democratic socialist, a critic of Israel, a man who wants to freeze the rent, make buses free and fast, childcare universal, and life in New York affordable.
We shall see. But the way to make America great again is to stabilize the rent, subsidize mass transit and make it universal in large urban environments, make childcare and healthcare universal, support all public schools as the best systems are currently funded, and make every city, town, and village affordable for everyone. What will become of Billy Ackman, Donald Trump, and their gaggle of wannabe trillionaires? They will still be rich, even in a one-person, one-vote society instead of our one dollar-one vote Inferno (Gustave Doré jpg) that Dante would have had difficulty describing. Oh, and the people? Yes, Mr. Ackman, they will still go to work, but in occupations, even vocations, that provide for human flourishing instead of dead-end, soul-destroying jobs that do not keep them afloat, much less rising with the tide among the yachts large and small. Imagine that!
Part the Sixth: Update on the New ICE Age. Here is an example from the real, local world in ICE raid leaves ripple effects across Coastal Georgia communities. Whether the State of Georgia and its taxpayers will get the better of this deal in the end is uncertain, which is true for all such development agreements. A similar large patch of farmland east of Atlanta prepared for Rivian years ago has finally seen a few shovels dirtied ceremoniously. Whatever the motivation for the ICE raid west of Savannah, there is also little doubt Hyundai had an agreement, tacit or otherwise, with the federal government that Koreans would be coming and going at this mega-site until the various interconnected components were up and running.
