Part the First: Who Will Supplant the United States in Scientific Research?<\/strong>\u00a0 Before going any further in answer to The Rev Kev\u2019s suggestion from last week, it is important to note that while the US currently remains the acknowledged leader in scientific research, this is a matter of quantity as much as quality.\u00a0 Other countries are better because support does not depend on success in a grant lottery, but their footprint is smaller.\u00a0 No place is perfect, but there are few American scientists who do not look at Canada and Europe and Australia with some wistfulness.\u00a0 This will eventually include China.<\/p>\n Thus, my unequivocal answer to the Rev is China, which would not have been my choice not so long ago.\u00a0 But then I would never have anticipated the outright attack on American science by the current Administration.\u00a0 When I began working in the laboratory in the 1970s Chinese scientists were not uncommon, but they were from Taiwan mostly, with a few from Hong Kong.\u00a0 The first scientist I ever met from the People\u2019s Republic of China (PRC) was a botanist\/plant biochemist named Mr. Hu.\u00a0 He was \u201crehabilitated\u201d in the late-1970s after being sent to the provinces during the early days of the Cultural Revolution.\u00a0 Our department hosted him for two years, after which he returned to his former academic position at a higher rank.\u00a0 Mao was still dead and the Gang of Four<\/a> were on the way out.<\/p>\n A short twenty years later when I was a research associate, scientists from the PRC were everywhere, not without some friction once in a while.\u00a0 But they are very good scientists, and most of those I knew seem to have remained in the US.\u00a0 However, as support for research has improved in China, many researchers with a connection to the country are returning. \u00a0And the PRC is recruiting.\u00a0 By most measures China is close to the US<\/a> in scientific research in quantity, and I expect they will pass the West in quality soon, despite the blinkered view of American politicians and a few scientists.\u00a0 This would not have crossed any of my colleagues\u2019 minds ten years ago, but there you are.\u00a0 Good science is good science, no matter where it is done.<\/p>\n A short commentary<\/a> in Nature<\/em> (June 9) outlines a likely trajectory.\u00a0 Chinese scientists will stay home and build the institutions required, and leading international scientists other than the convicted liar Charles Lieber<\/a>, formerly of Harvard, will accept research positions in China.\u00a0 Joseph Needham<\/a>, who has been one of my most important teachers in how to be a scientist, would approve<\/a>.\u00a0 It is true that China will struggle due to \u201cconcerns about academic autonomy, institutional transparency and quality of life\u2026(and)\u2026the strength of China\u2019s home-grown research and innovation system will hinge on cultivating a truly open and supportive environment where top talent can remain and thrive.\u201d\u00a0 I expect this to happen sooner rather than later as the current global hegemon leads to a terminal Decline of the West undreamt of by Oswald Spengler.<\/p>\n Absent latter-day Armageddon, China\u2019s home-grown research establishment will surpass all others in the lifetimes of my children.\u00a0 They are a very patient people.\u00a0 We are a very fickle and by definition unserious people.<\/p>\n Part the Second: Follies of American Science, Continued.<\/strong>\u00a0 As China rises, America does something else.\u00a0 Still, as the headline puts it, Senators push back on Trump\u2019s proposed $18 billion NIH budget cut<\/a>, as Jay Bhattacharya offers to \u201cwork with Congress.\u201d<\/p>\n National Institutes of Health Director Jay Bhattacharya faced sharp questions on Tuesday from Republican and Democratic members of a Senate Appropriations subcommittee about the agency\u2019s 2026 budget, with lawmakers struggling to reconcile his stated commitment to biomedical research with recent grant terminations, funding delays, and the Trump administration\u2019s sweeping proposed spending cuts.<\/p>\n<\/blockquote>\n Well, some things are irreconcilable and always will be.\u00a0 Senator Dick Durbin of Illinois noted that Northwestern University (Chicago and Evanston) has had \u201c1,300 awards\u2026terminated or frozen, including $9 million for clinical trials in colon, brain, and childhood cancers\u201d as a result of an $18 billion cut to the NIH budget.\u201d\u00a0 Other Senators chimed in with similar comments and noted the Administration had terminated a 20-year effort to develop an HIV Vaccine<\/a>.\u00a0 I suppose someone at DOGE wonders why this has taken so long, but an effective vaccine against HIV (i.e., a vaccine that prevents the disease and its transmission) will probably come before a similar vaccine against pandemic coronaviruses, emphasis on the plural, especially as humans continue to push into areas that harbor these and other zoonotic pathogens.<\/p>\n The response of Jay Bhattacharya, MD-PhD, about increasing funding for Institutional Development Awards (IDeA) was nothing but nonsensical distraction:<\/p>\n \u201cIn my mind, it\u2019s (IDeA) probably less funded than it ought to be. \u00a0And I actively would love to work with Congress to think of ways that we can make NIH investment in scientific research more geographically dispersed than it currently is,\u201d said Bhattacharya, adding that he believes the concentration of NIH funding among a small number of top universities has led to scientific group think.<\/p>\n<\/blockquote>\n \u201cI actively would love to work,\u201d instead of inactively?\u00a0 Never mind.\u00a0 The IDeA Program is old, and it works as well as it can.\u00a0 My previous institution was eligible for such awards, which \u201cspread the wealth\u201d by setting aside a pot of money for research at institutions in states in the bottom half of NIH research support.\u00a0 This is noble, and it works.\u00a0 But it is also a drop in the bucket.\u00a0 The big states with the big universities and independent research organizations (e.g., Scripps, Salk, Fred Hutchinson) will remain what they are. \u00a0Maybe. \u00a0We can hope.<\/p>\n For a one-stop shop to see where NIH funding to medical schools goes, the Blue Ridge Institute for Medical Research (BRIMR)<\/a> is essential. \u00a0A good place to begin is the Schools of Medicine link on this page<\/a>.\u00a0 It opens an Excel spreadsheet that includes 148 medical schools.\u00a0 That the Top-20 medical schools receive about 50% of the support is not an accident and this does not lead to \u201cscientific group think<\/strong>.\u201d\u00a0 The scientists at the University of Kentucky College of Medicine (55) and the University of Georgia (unranked, but highest ranked university without a medical school that will open in 2026) think exactly like those at UCSF (1), Johns Hopkins (6), and Jay Bhattacharya\u2019s triple alma mater Stanford (7).<\/p>\n One other thing to note here: As shown in the spreadsheet, the overall indirect cost rate (overhead) for this extramural NIH research is 28%<\/strong>.\u00a0 This is a bargain by any reasonable definition.\u00a0 And no, medical schools are not getting rich on indirect costs.\u00a0 These institutions, public and private, provide the built environment and resources necessary for biomedical research, while spreading the wealth beyond Washington DC and environs.\u00a0 This was the vision<\/a> of Vannevar Bush<\/a> (of MIT) eighty years ago, and he was correct.\u00a0 NIH extramural research funding is an incalculable force multiplier of the work done at NIH in Bethesda, Research Triangle Park, and a few other locations.\u00a0 And yes, I am aware that the entire process can be improved.\u00a0 But this is not what the current Secretary of Health and Human Services has in mind.<\/p>\n Part the Third: Can\u2019t Anyone Here Play this Game?<\/strong>\u00a0 Continuing with this thread, The Ol\u2019 Perfesser Casey (\u201cCan\u2019t anyone here play this game?<\/a>\u201c) Stengel comes to mind with this: HHS reverses hundreds of CDC firings<\/a>.<\/p>\n A spokesperson for the Department of Health and Human Services, which oversees the CDC, confirmed that the Atlanta-based agency will bring back more than 450 personnel who were initially fired as part of a department-wide reorganization.<\/p>\n That reorganization, directed in part by the U.S. DOGE Service, has seen the department downsized from approximately 80,000 employees to 60,000, with some of the deepest cuts to the CDC, the National Institutes of Health, and the Food and Drug Administration.<\/p>\n Among the divisions reinstated are the National Center for HIV<\/strong>, Viral Hepatitis<\/strong>, STD<\/strong>, and Tuberculosis Prevention<\/strong>; the National Center for Environmental Health<\/strong>; the Immediate Office of the Director; and the Global Health Center<\/strong>. Those centers include programs that work to keep cruise lines safe from disease, prevent childhood lead poisoning<\/a>, and track and prevent HIV.<\/p>\n HHS Secretary Robert F. Kennedy Jr. previously said that at least 20% of the department\u2019s cuts were \u201cmistakes\u201d and that it was \u201calways the plan\u201d to reinstate some employees.<\/p>\n<\/blockquote>\n Let me get this straight. \u00a0Needlessly upending the lives of people doing essential scientific work on a whim was just a mistake?\u00a0 Good to know.\u00a0 Come to think of it, they are playing this game exactly as intended, but their intentions are ill-considered in the extreme.<\/p>\n Part the Fourth: And in Other News.<\/strong> RFK Jr. names new members of CDC\u2019s vaccine advisory panel.<\/a>\u00a0 The new members are:<\/p>\n Four of these new members of the panel (down from seventeen, the better to manage outcomes?) were listed in the dedication of RFKJr\u2019s book The Real Anthony Fauci<\/em>: Malone, Kulldorff, Pebsworth, and Meissner.\u00a0 To call this book tendentious in an insult to the word, but its references were not hallucinated by ChatGPT or equivalent.\u00a0 They were chosen and misinterpreted the old-fashioned way, intentionally.\u00a0 Politicians go with people they know, but a few comments about two of the new members may be in order.<\/p>\n Martin Kuldorff<\/strong> is one of three authors of the Great Barrington Declaration<\/a> (Bhattacharya was another author), which was one of the primary sources of the \u201cLet \u2018er rip\u201d approach to COVID-19 so that herd immunity could be reached in a matter of months, while the vulnerable were protected.\u00a0 Not exactly.\u00a0 Herd immunity would most likely require durable immunity to the pathogen, which is not elicited by coronaviruses or vaccines against coronaviruses.\u00a0 Herd immunity (short animation<\/a>) works for measles, as long as more than 90% of the population is vaccinated.\u00a0 Immunity to measles through previous infection or vaccination is very durable.\u00a0 As for protecting the vulnerable, that was left to our imaginations, back when we had no idea of the natural course of SARS-CoV-2 infections.\u00a0 One should never generalize (too much) from his or her own necessarily limited experience, but I have had two very good friends, both very healthy, die of COVID-19 sequelae.\u00a0 Yes, I am still angry about that and will remain so until I join them in the Great Beyond.<\/p>\n Robert Malone<\/a><\/strong> has claimed to be the inventor of mRNA vaccines.\u00a0 As mentioned here before, he was the first author of the first published study<\/a> showing that a foreign mRNA could direct expression of the protein in cultured mouse cells.\u00a0 He later worked on optimizing the procedures for transfecting cultured mammalian cells with foreign mRNAs.\u00a0 Immediately prior to the COVID-19 pandemic, he was coauthor of a few papers on rapid responses to emergent infectious diseases.\u00a0 I read those papers in vain for mention of mRNA.\u00a0 mRNA vaccines were invented by on one in particular and certainly not by Dr. Robert Malone.<\/p>\n For those who can surmount the paywall, more information on the new panel is here<\/a>.\u00a0 STAT\u2019s gloss on Dr. Robert Malone:<\/p>\n Malone has both claimed<\/a> he was one of the inventors of mRNA and denounced the technology, rising to prominence within the anti-vaccine universe and among critics of the Covid response through frequent appearances on podcasts during the pandemic. While Malone did some early research on the technology, he didn\u2019t play a major role.<\/p>\n Malone is a trained physician and researcher. He gained wide attention for questioning the safety of Covid shots and spreading conspiracy theories on Joe Rogan\u2019s podcast in late 2021. He also spoke at rallies and other events in opposition to Covid shots, including alongside Kennedy.<\/p>\n<\/blockquote>\n That about covers it concerning Dr. Robert Malone.\u00a0 Those intrepid souls who so desire can find Dr. Robert Malone and his alter ego Dr. Bret Weinstein all over YouTube<\/a>.<\/p>\n Part the Fifth. Gene Therapy that Works<\/strong>.\u00a0 We discussed gene therapy for hemophilia here in March 2023<\/a>.\u00a0 In a follow-up, this paper from NEJM shows the therapeutic effect endures for at least thirteen years after initial treatment using an adeno-associated vector to deliver the missing Factor IX to patients with Hemophilia B.\u00a0 The paper<\/a> is behind a paywall, so an abstract of the Abstract is included here:<\/p>\n Adeno-associated virus (AAV)\u2013mediated gene therapy has emerged as a promising treatment for hemophilia B<\/strong>. Data on safety and durability from 13 years of follow-up<\/strong> in a cohort of patients who had been successfully treated with scAAV2\/8-LP1-hFIXco gene therapy are now available.<\/p>\n Ten men with severe hemophilia B received a single intravenous infusion<\/strong> of the scAAV2\/8-LP1-hFIXco vector in one of three dose groups (low-dose<\/strong>: 2\u00d71011<\/sup> vector genomes [vg] per kilogram of body weight [in two participants]; intermediate-dose<\/strong>: 6\u00d71011<\/sup> vg per kilogram [in two]; or high-dose<\/strong>: 2\u00d71012<\/sup> vg per kilogram [in six]). Efficacy outcomes included factor IX activity, the annualized bleeding rate, and factor IX concentrate use. Safety assessments included clinical events, liver function, and imaging.<\/p>\n Participants were followed for a median of 13.0 years<\/strong>.\u00a0 Factor IX activity remained stable across the dose cohorts<\/strong>, with mean factor IX levels of 1.7 IU per deciliter in the low-dose group, 2.3 IU per deciliter in the intermediate-dose group, and 4.8 IU per deciliter in the high-dose group. Seven of the 10 participants did not receive prophylaxis. The median annualized bleeding rate decreased from 14.0 episodes to 1.5 episodes<\/strong>, which represented a reduction by a factor of 9.7. Use of factor IX concentrate decreased by a factor of 12.4). A total of 15 vector-related adverse events occurred, primarily transient elevations in aminotransferase levels (indicative of transient mild liver dysfunction). Factor IX inhibitor, thrombosis, or chronic liver injury did not develop in any participant.<\/strong> Two cancers were identified but were deemed by the investigators, together with an expert multidisciplinary team, as being unrelated to the vector. A liver biopsy that was conducted in 1 participant 10 years after the infusion revealed transcriptionally active transgene expression in hepatocytes without fibrosis or dysplasia. \u00a0Levels of neutralizing antibodies to AAV8 remained high throughout follow-up, thus indicating potential barriers to readministration of the vector.<\/strong><\/p>\n<\/blockquote>\n Coagulation factors are synthesized in the liver and secreted into the blood.\u00a0 Thus, infection of the patients\u2019 livers with the AAV vector resulted in stable expression and secretion of Factor IX.\u00a0 This was a one-time treatment, and these patients were not dependent on subsequent infusions of pure Factor IX.\u00a0 However, the AAV8 induced an antibody response, and this means that readministration of the treatment could cause a systemic immune response.<\/p>\n Years ago, scientists got ahead of themselves, and an immune response killed a healthy young volunteer<\/a> in one of the earliest tests of the feasibility of this kind of gene therapy.\u00a0 The current paper shows how biomedical and clinical sciences work together \u2013 incrementally, based on deep knowledge and sound practice.\u00a0 Which leads me to believe the Autism Moon Shot advertised by Secretary Kennedy will have trouble finding the cause(s) of autism spectrum disorder by September.\u00a0 I would also note that the international team of researchers doing this research on gene therapy for hemophilia included Americans supported by NIH.\u00a0 Disease knows no political boundaries, but it seems now that American money can be spent only on American Science.<\/p>\n Part the Sixth.\u00a0 AI and Education<\/strong>. As part of my day job, I have been with trepidation reading the literature on AI in medical education.\u00a0 This is growing at a surprising rate but not as fast as the adoption of various forms of algorithmic intelligence among medical students.\u00a0 Nicholas Carr has written an excellent essay on The Myth of Automated Learning<\/a>, showing that automation is the real threat of AI.<\/p>\n Carr\u2019s take seems exactly right to me. \u00a0\u201cThe real threat AI poses to education isn\u2019t that it encourages cheating. It\u2019s that it discourages learning.<\/strong>\u201d\u00a0 And it does this because AI is fundamentally an automation technology.\u00a0 Computers, even those that talk back, cannot do what human reason does, but they can calculate much faster and thereby produce a reasonable facsimile.<\/p>\n Automation itself can have good or bad effects on a learner\u2019s skills.\u00a0 The worker could (1) improve his skills<\/strong>, (2) see her skills atrophy<\/strong>, or in the worst scenario (3) see his or her skills never develop<\/strong>.\u00a0 When I had students in the laboratory, they could use shortcuts in the form of automation or reagent kits only after they learned the old-fashioned way manually.\u00a0 If I say so myself, students in other labs lagged in their development of skills and thus scientific intuition when in their day-to-day operations they were encouraged to use shortcuts and automation in the name of a faux efficiency that improved apparent productivity in the guise of more publications.\u00a0 Automation in the lab can be a great thing, but only after everyone involved knows precisely what goes on inside the machine or algorithm.\u00a0 And more importantly, what does not:<\/p>\n Which scenario plays out hinges on the level of mastery a person brings to the job. If a worker has already mastered the activity being automated, the machine can become an aid to further skill development.<\/strong> \u00a0It takes over a routine but time-consuming task, allowing the person to tackle and master harder challenges. \u00a0In the hands of an experienced mathematician, for instance, a slide rule or a calculator becomes an intelligence amplifier (same with automation of routine<\/strong> lab chores).<\/p>\n If, however, the maintenance of the skill in question requires frequent practice \u2014 as is the case with most manual skills and many skills requiring a combination of manual and mental dexterity \u2014 then automation can threaten the talent of even a master practitioner.<\/strong> \u00a0We see this in aviation<\/a> (and I would here add medicine and scientific research). \u00a0When skilled pilots become so dependent on autopilot systems that they rarely practice manual flying, they suffer what researchers term \u201cskill fade.\u201d They lose situational awareness, and their reactions slow. They get rusty.<\/p>\n Automation is most pernicious in the third scenario: when a machine takes command of a job before the person using the machine has gained any direct experience doing the work. Without experience, without practice, talent is stillborn.<\/strong> \u00a0That was the story of the \u201cdeskilling\u201d phenomenon of the early Industrial Revolution. \u00a0Skilled craftsmen were replaced by unskilled machine operators. \u00a0The work sped up, but the only skill the machine operators developed was the skill of operating the machine, which in most cases was hardly any skill at all. \u00a0Take away the machine, and the work stops.<\/p>\n<\/blockquote>\n To bring this back to medicine and medical education, could the judicious use of AI improve a physician\u2019s craft?\u00a0 I think it could, but only if the Aristotelian final cause of the AI app is something other than making money for its vendor.\u00a0 Will the use of AI interfere with the practice of being a physician in his or her medical practice?\u00a0 Perhaps.\u00a0 Will AI interfere with a medical student learning the art, craft, and science of medicine?\u00a0 Undoubtedly.\u00a0 Will this lead to catastrophe?\u00a0 Yes, when healing hands never have the chance to develop properly.<\/p>\n Carr notes that \u201cAI too often produces\u2026the illusion of learning<\/strong>.\u201d\u00a0 I have watched medical students use an extract from the standard textbook of pharmacology (now in its fourteenth edition<\/a>) as a prompt to convert information on chemotherapy drugs into a pdf of pristine columns of names, mechanisms, and specific uses.\u00a0 Done and dusted in seconds.\u00a0 All well and good.\u00a0 Efficient, yes, but effective?\u00a0 Not in my experience.\u00a0 What I fear is that AI really is the \u201cmagic fairy dust\u201d that (too many) medical students view as a substitute for the grueling work and total immersion in what makes their calling possible. \u00a0As Han Solo put it in a galaxy a long time ago and far, far away, \u201cI have a bad feeling about this.\u201d<\/p>\n More to come after wrestling with his serpent.\u00a0 But I have found hope in several of our most accomplished students who just finished their first year of medical school. \u00a0They have told me, to a person, they can be no help to me in my investigation because they study the old-fashioned way.\u00a0 That is, they use the syllabus and reading guide as their prompts and actually read and study the 12-to-15 standard medical textbooks they must know deep in their bones to develop the foundation to become the good physician.\u00a0 Wonders never cease but they seem to be increasingly rare.<\/p>\n See you next week.\u00a0 Suggestions still welcome!<\/p>\n\n
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