A study by researchers at the Icahn School of Medicine at Mount Sinai has found that social determinants of health—including environmental conditions, health behaviors, access to resources, and social well-being—can contribute as much as or more than genetic risk in predicting several common diseases. The research, published in The American Journal of Human Genetics, showed that incorporating social, behavioral, and environmental information into disease-risk models improved prediction when incorporated with genetic information for conditions including asthma, chronic kidney disease, coronary heart disease, high cholesterol, breast cancer, and prostate cancer.
“Genes are an important part of the equation, but they do not determine destiny,” said senior author Samira Asgari, PhD, an assistant professor of genetics and genomic sciences at Mount Sinai. “We found that the circumstances of people’s lives—their environments, behaviors, and social experiences—can contribute as much as genetics to predicting disease risk. To truly understand health, we have to look at the whole person, not just their DNA.”
According to the researchers, complex diseases arise through the interaction of genetic predisposition with environmental, behavioral, and social influences, yet these factors are often studied in isolation. Existing genetic models often rely on polygenic risk scores, while epidemiological approaches focus on lifestyle, environmental exposures, or social factors independently. The researchers sought to bridge that gap by integrating both types of data into a single risk prediction framework.
To conduct the study, the team analyzed data from 413,457 participants in the All of Us Research Program, a nationwide research effort in the U.S. supported by the National Institutes of Health. The team combined genetic information, electronic health records, and survey responses, with more than 100 environmental, behavioral, and social variables were evaluated, to create a broad picture of the different factors that may influence health.
Rather than selecting a limited number of known social risk factors in advance for their survey, the researchers used a statistical technique called multiple correspondence analysis, or MCA. The approach converted more than 100 categorical social, environmental, and behavioral measures into low-dimensional representations that helped identify patterns of non-genetic risk.
The choice to use MCA distinguished the study from many previous approaches. Past methods often have depended on selecting a small set of established risk factors or using statistical procedures that prioritize only the strongest predictors. By contrast, MCA identifies patterns across many correlated variables simultaneously, allowing researchers to examine broader social and environmental variables without assuming beforehand which factors have the most influence on health.
The analysis found known contributors to disease risk such as economic status and smoking, but also identified factors that receive less attention in published studies, including loneliness and spirituality. First author Abhijith Biji, a PhD candidate at Icahn School of Medicine, said the data showing associations involving loneliness was particularly notable.
“Some risk factors, such as smoking, have been studied extensively for decades,” Biji said. “What is especially intriguing is that we also observed associations involving factors like loneliness. Understanding how these experiences may become biologically embedded could open new avenues for research and ultimately improve our understanding of disease.”
When the researchers incorporated the MCA-derived measures into prediction models alongside demographic information and polygenic risk scores, predictive performance improved across all six diseases studied. For four of the six diseases, the gains from the MCA-based measures exceeded those attributable to polygenic risk scores.
The findings also suggested that genetic and non-genetic influences generally act independently rather than modifying one another. The researchers found little evidence for broad gene-environment interactions. Instead, inherited genetic risk and social, behavioral, and environmental context appeared to contribute additively to disease risk.
“This additive relationship suggests that interventions targeting social and behavioral factors can reduce disease risk regardless of genetic background, offering hope for broadly applicable public-health strategies,” the researchers wrote.
The researchers noted that the study does not establish causation. Because many survey responses were collected at a single point in time and some exposures may have occurred after disease onset, the findings should be considered as contributions to disease-risk prediction rather than proof that specific factors cause disease.
Building on this work, the team next will seek to integrate social determinants of health with additional biological measures and look mechanisms that may directly connect social experiences to disease. The investigators will also bring in longitudinal data, harmonize survey instruments across cohorts, and integrating other data types to better understand how environmental, behavioral, and social factors influence disease development and interact with biological processes.
“Our goal is to build a more complete understanding of health and disease,” Asgari said. “By combining genetics with social and environmental context, we can move toward risk models that better reflect the realities of people’s lives and help advance more personalized approaches to health.”
Human pluripotent stem cells (hPSCs) have long been viewed as one of regenerative medicine’s most promising raw materials. Now, as more than 100 clinical trials evaluate hPSC-derived therapies for diseases ranging from Parkinson’s disease to heart failure and type 1 diabetes, attention is turning toward a crucial challenge: how to manufacture these cells reliably and economically at industrial scale.
According to Kevin Cyrys and Robert Zweigerdt, PhD, both of Hannover Medical School in Germany, the field has entered a new phase. Rather than simply demonstrating that stem cells can be grown in bioreactors, researchers are increasingly focused on creating robust production platforms that can deliver consistent quality across facilities and patient populations.
“Human pluripotent stem cells can serve as an unlimited, renewable ‘raw material’ for essentially any therapeutic cell product,” the authors wrote, highlighting the technology’s potential to overcome limitations associated with donor-derived tissues and organs.
The manufacturing challenge is substantial. While some therapies, such as treatments for age-related macular degeneration, require only tens of thousands of cells per dose, others may demand billions of cells for a single patient treatment. Conventional laboratory-scale methods are unlikely to meet such requirements efficiently.
To address this gap, developers are increasingly adopting three-dimensional suspension cultures in bioreactors. Compared with traditional two-dimensional cell culture systems, bioreactors provide tighter control over temperature, oxygen levels, pH, and carbon dioxide while supporting automated, closed-system manufacturing compatible with good manufacturing practice (GMP) standards.
The field has already demonstrated notable progress across multiple therapeutic areas. Researchers have developed scalable processes for producing cardiomyocytes, pancreatic islet cells, hepatocyte-like cells, neural tissues, and immune effectors derived from hPSCs. Some cardiac manufacturing platforms have reported production of billions of cardiomyocytes in liter-scale bioreactors, while immune-cell manufacturing programs have successfully expanded induced pluripotent stem cell-derived natural killer cells in 1–10 L systems while maintaining product quality.
Yet scaling production involves more than increasing cell yields. “Industrial-scale success depends on more than headline totals,” Cyrys and Zweigerdt note, citing the importance of volumetric productivity, production time, reproducibility, and integration of expansion, differentiation, and downstream processing into a coherent GMP-ready workflow.
Looking ahead, Cyrys and Zweigerdt argue that the next generation of stem-cell manufacturing will be defined by data-driven process control. They predict that AI-enabled systems will help move the industry from retrospective quality analysis toward real-time decision support, ultimately improving comparability between batches and strengthening product definitions across manufacturing networks.
Despite ongoing challenges involving cost, quality control, and regulatory compliance, the authors conclude that stem-cell bioprocessing has already crossed an important threshold. Scalable culture systems are no longer the primary obstacle. Instead, the focus has shifted toward engineering reliable industrial processes capable of transforming complex stem-cell biology into reproducible therapeutic products.
BackgroundThe relationship between adverse childhood experiences (ACEs) and personality disorders (PDs) has attracted sustained attention in psychiatry, psychology, and public health. Existing studies have mainly examined epidemiological associations, specific PDs diagnoses, or mechanisms, whereas bibliometric evidence mapping the field’s knowledge structure and thematic evolution remains limited. This study aimed to characterize trends, contributors, collaboration networks, core themes, and frontiers in ACEs–PDs research.MethodsEnglish-language publications on ACEs and PDs were retrieved from Web of Science Core Collection, Scopus, and PubMed from inception to December 31, 2025. After year screening, document-type filtering, and deduplication, 5,084 records were included. Bibliometric analyses were performed using R, VOSviewer, and CiteSpace. The merged dataset was used to examine annual trends, countries/regions, institutions, authors, journals, and keyword co-occurrence, while WoSCC records were used for co-citation analysis, keyword clustering, and burst detection.ResultsACEs–PDs research showed sustained growth, with a marked increase after 2000. The United States occupied a central position in publication output, citation impact, and international collaboration, while the United Kingdom, Germany, Canada, the Netherlands, and Australia also showed strong influence. Harvard University, the University of London, and Ruprecht Karls University Heidelberg were leading institutions; Zanarini M, Fonagy P, Schmahl C, Paris J, and Kleindienst N were key contributors. Influential journals mainly covered psychiatry, personality disorders, child maltreatment, trauma, and developmental psychopathology. Keyword analyses identified childhood adversity, personality disorder, borderline personality disorder, depression, childhood sexual abuse, and post-traumatic stress disorder as core themes. VOSviewer and CiteSpace analyses indicated that hotspots have expanded from childhood abuse, PDs diagnosis, and psychiatric comorbidity to emotion dysregulation, non-suicidal self-injury, social support, functional connectivity, early intervention, and mechanism validation. Highly cited publications revealed a knowledge base centered on childhood abuse/trauma, borderline personality disorder, psychiatric comorbidity, emotion regulation, and neurobiological mechanisms.ConclusionThis study maps development and knowledge structure of ACEs–PDs research. Findings suggest a shift from exposure–outcome association studies toward comorbidity, intermediate phenotypes, neurobiological mechanisms, and clinical translation. Future research should strengthen longitudinal and cross-cultural designs, consider ACE type, timing, duration, and severity, and integrate neuroimaging, inflammatory, epigenetic, and clinical-course phenotypes.
A startup developing treatments for eye diseases has raised $330 million from investors as it readies for late-stage testing.
Ollin Biosciences is about to begin a Phase 3 trial of a treatment for both diabetic macular edema and wet age-related macular degeneration. The conditions affect millions of Americans and can lead to vision loss.
Ahead of the trial, Ollin told STAT it had raised the Series B funding from an assortment of established biotech investors, a pension fund, and even crossover investors — a breed of private investors who will take a stake in a company shortly before it moves over to the stock market. TCGX and ARCH Venture Partners co-led the funding round, which was one of the largest Series B rounds for a biotech company in the last two years.
SAN DIEGO—California’s three life sciences clusters all lost jobs last year, yet the industry remains a major engine of innovation and economic growth, according to a report released by the state’s largest life sciences organization to coincide with the Biotechnology Industry Organization (BIO) International Convention being held here.
BIOCOM California quantified the economic impact of the Golden State’s life sciences industry as generating $394 billion in economic output in 2025—a figure that goes beyond the direct impact of the 406,505 people employed by life sciences employers across the state. The impact figure includes indirect impact (activity generated through suppliers, vendors, and subcontractors supporting the industry) and induced impact (the household spending generated by workers employed in both life-sci organizations and supporting industries).
When indirect and induced impact are accounted for, the life sciences sustain 1,079,365 jobs statewide, the report stated.
However, all three of the state’s top-tier life-sci clusters—the San Francisco Bay Area, San Diego, and the Los Angeles/Orange County region—saw decreases in employment within the industry last year, according to the report.
San Francisco ranks second in the latest edition of GEN’s nationally-quoted A-List of Top 10 U.S. Biopharma Clusters, unchanged from a year ago, while San Diego slid one position to sixth, and LA/Orange County slipped one notch to eighth.
“Continued biotech winter”
“California, like the other states in the country, are still showing the effects of the pandemic and the recovery from that, because it was such a large run up of investment and hiring and building of new space, followed by a pretty significant drop off in 2022, 23,” Tim Scott BIOCOM California’s president and CEO, explained in an interview with GEN conducted at the organization’s booth within the convention’s exhibition floor.
“And then we have the continued biotech winter that’s been caused mostly through the instability at the federal level in terms of policy,” Scott added.
He cited NIH funding cuts, the delay in re-authorizing the Small Business Innovation Research (SBIR) and Small Business Technology Transfer (STTR) seed funding programs, tariffs, and the “most favorite nation” drug pricing framework championed by the Trump administration as a vehicle for lowering drug prices: “All of these things have led the industry and the investors in the industry to pause.”
Most of the life-sci job decline was concentrated in the Bay Area and San Diego regions, which together accounted for 88% of job losses.
The San Francisco Bay Area saw its life-sci workforce slide 2.7% from 2024 to 137,779 jobs last year, driven mainly by decreasing employment in scientific/research tools, biotechnology, and biopharmaceuticals. The San Diego region finished 2025 with 61,866 jobs, a 2.55% decline from the previous year, due primarily to the loss of jobs in the R&D in physical, engineering, and life sciences and electromedical and electrotherapeutic apparatus manufacturing sectors.
Greater Los Angeles, which BIOCOM California defines as Los Angeles, San Bernardino, and Ventura counties, saw its employment base shrink 0.5% year-over-year, to 143,153 last year, with the largest employment decrease coming in drug wholesaler positions. Orange County’s life-sci workforce also dipped by 0.5%, sliding to 57,213 jobs, driven by cuts in scientific/research tools and medical devices and equipment employment—though Orange County also saw increases in biotechnology and research and testing jobs.
“Significant driver”
“In spite of the slight decrease in growth this year, we’re still at about $400 billion in economic output for California in the life sciences. That’s the second largest industry in California,” Scott said. “It’s still a significant driver of economic activity and of innovation.”
Another driver of innovation, NIH funding, stayed flat last year compared to 2024 at $5.23 billion for all of California. But the number of NIH awards statewide fell 8.5% from 9,384 in 2024 to 8,587 in 2025.
Life science manufacturing jobs fell by 2.1% last year to 143,572 jobs, though they still accounted for more than one-third (35.3%) of all of the industry jobs in the state. Across 31 life science industry sub-sectors, 23 recorded job losses, with the largest declines in medical laboratories and R&D within the physical, engineering, and life sciences job category.
But the state’s life-sci manufacturing segment is eventually expected to grow as drug developers either strive to meet growing demand, reshore their production in the United States to avoid tariffs, or both. Gilead Sciences began construction in September 2025 of a new 180,000 square-foot development and manufacturing facility, part of a companywide $32 billion U.S. investment strategy. Two months later, Novartis opened a 10,000-square-foot radioligand therapy (RLT) manufacturing facility for cancer treatments in Carlsbad, CA, the pharma giant’s third U.S.-based RLT site.
While biopharmas and contract manufacturers have announced hundreds of billions of dollars in new projects, projects announced for California remain mostly under construction, so hiring levels have not yet risen to account for the new manufacturing activity, Scott said.
Potential challenges loom
Two more potential challenges loom for California life science companies—one from Washington, the other from Sacramento.
Scott said BIOCOM California is paying attention to federal efforts aimed at further scrutinizing activity between U.S. and Chinese biopharmas.
Earlier this month, Reps. John Moolenaar (R-MI), chairman of the Select Committee on China, and Congresswoman Debbie Dingell (D-MI), introduced the Biotech Investment National Security Act (BINSA). BINSA would amend the Comprehensive Outbound Investment National Security (COINS) Act, enacted last year, by adding pharmaceutical and biological product development to the list of sectors subject to screening of investments by the U.S. government.
The measure would subject U.S. pharmaceutical licensing deals, joint ventures, and equity investments with Chinese covered foreign persons to U.S. Treasury Department review, as well as explicitly cover licensing deals involving technology and intellectual property. BINSA also requires the Secretary of War (formerly Defense) to assess within 60 days whether U.S. capital investment in Chinese biotechnology negatively affects national security and military readiness.
“We’re trying to find the balance between protecting American interests with regard to intellectual property and also competing with China. And we’re balancing that with cooperating with China,” Scott said. “You can imagine a politician in Washington, D.C., wants to really protect our interests. A biotech entrepreneur in California wants to go anywhere in the world to find resources to be able to move their drug toward the clinic.”
In Sacramento, Gov. Gavin Newsom, who leaves office at year’s end when his second term expires, has proposed permanently limiting the amount of business tax credits that a corporation can claim each year. Starting in 2027, corporate taxpayers would be allowed to claim a maximum of either $5 million or 50% of their pre-credit tax liability, whichever is greater. The limit would not affect taxpayers with less than $5 million in credits.
According to California’s Legislative Analyst’s Office (LAO), recent tax collection data shows that fewer than 100 corporate taxpayers in California would be affected. LAO has estimated that the proposal would raise $850 million in 2026–27, since the cap would only apply to part of the fiscal year, and $1.7 billion to $1.8 billion annually between 2027–28 and 2029–30.
However, the R&D credit likely accounts for most of the proposal’s fiscal effect, according to the LAO, since the R&D credit accounts for the overwhelming majority of business credit usage and carry-forward balances. And the roughly 100 affected businesses include many of the largest biopharma giants, Scott said.
“That is a really big tool for engaging pharma and encouraging investment in California. Without the R&D tax credit, companies are less likely to want to invest in California,” Scott asserted. “The R&D tax credit has had a direct effect on driving the growth of the biotech industry in California.”
It’s somewhat surprising that he can choose just one. He’s the person spellers rely on to confirm pronunciations and answer questions about the roots of the words they’re given at the Scripps National Spelling Bee—arguably the world’s most prestigious competition of its kind. The story of how the word earned the top spot on his personal list may well mark the beginning of his unique career path as both a linguist and a Greek Orthodox priest.
In third grade, Sietsema ventured to a garage sale at a friend’s house with 50 cents in his pocket and picked out three books that struck his fancy. Although they were priced at 50 cents each, his friend’s mother said the books he’d chosen were on special and sent him home with all three, including a collection of Edgar Allan Poe stories called Masterpieces of Mystery. Knowing it contained macabre tales like “The Tell-Tale Heart,” his own mother told him he’d need to wait a few years before reading it. Naturally, he started it right away.
As he read “The Unparalleled Adventure of One Hans Pfaall,” Sietsema was baffled by the main character’s description of arriving at the moon in a balloon. Pfaall reported tumbling into a crowd of people who were “eyeing me and my balloon askant, with their arms set a-kimbo.” Sietsema had never encountered the word akimbo (with or without a hyphen) and asked his parents what it meant. They didn’t know, and it wasn’t in the family’s dictionary. The question also stumped his teachers, and the dictionaries in his classroom and the school library were no help either. “For years, I didn’t know what this word meant,” Sietsema says. It stuck in his mind that there was a word out there that he, his parents, and his teachers didn’t know. He thinks it wasn’t till he got to college that he finally found a dictionary with the answer: The moon dwellers in Poe’s story had been standing with their hands on their hips, elbows turned outward.
“I credit that puzzle with getting me into dictionaries and being curious about etymology,” he says. It kindled a fascination with words—and an abundance of curiosity—that would shape his life’s trajectory and work.
Growing up in Grand Rapids, Michigan, Sietsema attended a Dutch Reformed Christian school and recalls taking part in only one spelling bee, in second grade. It was in the 1970s, when everyone was hooked on phonics—so he overthought the sounding-it-out implications when asked to spell of. “I spelled it U-V, and of course, I was wrong,” he says.
At the time, he thought he probably wanted to work in the church—when he painted himself as an adult for a class project, he dressed his grown-up self in a cassock. But after taking a class in nuclear chemistry at the local junior college in high school, he decided his backup plan was to become a nuclear engineer. So when he went to the University of Michigan, he enrolled in the school of engineering. While he did well and liked his courses, though, he soon realized he felt called to a career in the church after all.
Sietsema (a.k.a. Father Mark) presides at the 2025 Holy Friday evening service at Holy Trinity Greek Orthodox Church in Lansing, Michigan. As part of that service, he sprinkles the congregation with rose-scented water, which delights the children. “It’s like a one-sided water fight in church,” he says. This service culminates with a procession in which a symbolic tomb is carried around the outside of the church. Everyone who attends takes part and leaves with a flower.
COURTESY OF BRIAN SIETSEMA
Switching to the college of literature, science, and the arts, he chose the studies in religion major, taking advantage of the interdisciplinary freedom it offered to take classes in literature, art, and more. He also tucked in courses that would fulfill seminary prerequisites such as knowledge of the biblical languages, studying ancient Hebrew and ancient Greek as well as modern languages that might come in handy for theological scholarship (Dutch, Swedish, and modern Hebrew).
Being in Ann Arbor gave Sietsema “a different understanding of the wideness of the Christian world,” as he puts it, and he gradually became less sure about which church he wanted to work in. As he neared the end of his fourth year at Michigan, he still needed a few more pre-seminary courses—and it dawned on him that he’d taken an “awful lot” of languages and thoroughly enjoyed them. So he stayed on for a fifth year to study linguistics as well as German, ancient Aramaic, and modern Arabic. One of his professors encouraged him to go to grad school and insisted that he apply to MIT, which was considered the top linguistics program in the country. To his surprise, he got in.
Sietsema calls his four years at MIT a great adventure: “If I could relive them, I would empty out my bank accounts to do so.”
At MIT he worked with Morris Halle, one of the leaders in generative grammar, which Sietsema describes as a working model of the “chemistry” of language—the parts and processes that form the building blocks of verbal communication. Halle and others had developed counting procedures (akin to measured time in music) that help explain stress patterns (that is, which syllables might receive emphasis by varying such things as stress or pitch). Building on that work, Sietsema’s dissertation proposed that the division of words and phrases into metrical units similar to musical measures can be used to predict where high and low tones fall, which he demonstrated in the tonal patterns of four Bantu languages spoken in Tanzania. At the time, research in this area was seen to have implications for creating natural-sounding machine- generated speech.
Sietsema calls Halle “a wonderful mentor,” and the two played well off one another. As he was sweltering in his Central Square apartment while printing the final version of his dissertation, Halle called and asked him to stop by. Knowing that Sietsema read Hebrew, Halle, a Latvian-born Jew who’d learned English as his sixth language, wanted to show him a syllable-counting analysis of the 23rd Psalm he’d just completed; Sietsema answered with his own structural analysis of Psalm 90. “I could tell he was delighted to have this young Gentile boy from Grand Rapids, Michigan, who had the same fascination for biblical Hebrew as he did,” Sietsema says.
Today, he calls his four horizon-expanding years at MIT a great adventure: “If I could relive them, I would empty out my bank accounts to do so.” Beyond embracing the intellectual stimulation of the Institute, he took advantage of Cambridge’s many cultural opportunities and cross-registered at Harvard to study French and Ugaritic. All told, he says, he’s now studied about a dozen languages, including the Latin he took in high school and the modern Greek he would add to his repertoire several years after earning his doctorate. (“I always feel like I’m leaving one out,” he says.)
When Sietsema graduated from MIT in 1989, the job market for linguists was “not great.” As fate would have it, though, Matt Alexander, PhD ’92, his best friend at MIT, had already been hired at the University of Michigan, where a one-year position as a visiting assistant professor of phonology opened up that spring. Alexander recommended Sietsema, who handed in his dissertation and got the job, earning an award for excellence in teaching based on student reviews in his first semester.
Shortly after his one-year gig at Michigan ended, he returned to Massachusetts and landed a job as pronunciation editor at Merriam-Webster in Springfield. Although the work was very different from the theoretical linguistics he’d focused on in grad school, “as the guy who had studied a whole bunch of language back in undergrad, it was kind of coming home to old-school philology,” he says. His main job was to ensure that pronunciations—which can change—were up to date. Fluoride, for example, shifted from floo-o-ride in the early 1900s to flor-ide in the second half of the century.
At Merriam-Webster, he made the call on which pronunciations would go into the 10th edition of Merriam-Webster’s Collegiate Dictionary—and in what order of preference. The dictionary, he explains, takes a descriptivist approach that reflects common word usage, so he kept a radio and a TV on in the background as he worked. He’d listen for interesting pronunciations and record them on index cards, noting how each such word was said, who said it, where the person was from, and what the context was. These went into Merriam-Webster’s “huge files” of index cards containing citations of words in actual usage.
Sietsema also had a hand in identifying new words and usages that appeared in the 10th edition, which was initially released in 1993—and he was responsible for the inclusion of definitions for interjectional uses of like. He recognized three informal uses: to introduce a quotation (“So she was like, ‘Let’s go eat’”); to give an approximation (“There were like 10 people in line”); and to emphasize (“He was, like, gorgeous”) or convey something apologetically or vaguely (“I need to, like, borrow some money”). While not a fan of such usages, he recognized them as real linguistic phenomena that had earned a place in the dictionary.
During his tenure as pronunciation editor, he introduced the use of the International Phonetic Alphabet (a standard phonetic notation for all languages) into Merriam-Webster publications long before it became widely used in American mass-market dictionaries. He also oversaw the recording of pronunciations for digital versions of the dictionary and flew out to a San Diego recording studio to supervise the voice actors. When the actors refused to record certain words that offended them, Sietsema had to step into the breach and do it himself. If you go to www.merriam-webster.com and search for a choice two-part expletive the actor Samuel L. Jackson is famous for delivering, it will be his voice that you hear when you click on the icon of the speaker—offering a decidedly less memorable rendition.
Working at Merriam-Webster gave Sietsema access to what he describes as its “fantastic library of old books on every subject imaginable.” He seized the opportunity to delve into historical questions about the development of Christianity—something he’d been curious about. It struck him that Orthodox Christianity was the most original form of the faith that was still around. Having met Katherine Chapekis, a young linguist raised in the Greek Orthodox tradition, during his year teaching in Ann Arbor also nudged him in the direction of Orthodoxy. In 1991, he converted and they married, and she began working at Merriam-Webster the following year as a definer and researcher who tracked down first usages of English words.
After 15 years of answering etymological queries, when the bee was expanded in 2018 Sietsema began serving as a pronouncer for some of the earlier rounds as well.
AP PHOTO/CAROLYN KASTER
At the Greek Orthodox church in Springfield, Sietsema’s facility for languages proved useful when he served as a volunteer chanter, helping the priest lead services in Greek. “I do a good job with the liturgical Greek because I have the phonological knowledge to know how to make my mouth do the things that it needs to do to sound like authentic Greek speech as opposed to an American just rattling off Greek letters,” he says.
He began taking evening classes in Byzantine chant, and before long the bishop was encouraging him to attend seminary. Merriam-Webster allowed him to work four 10-hour days so he could commute to Brookline to study at the Holy Cross Greek Orthodox School of Theology. And after four years, he earned a master of divinity degree.
Sietsema fully intended to go back to being a lexicographer, perhaps eventually getting ordained so he could serve as a substitute priest on weekends. But he’d made what he jokingly calls “a terrible mistake” at the seminary: He’d embraced his studies so enthusiastically that he became the valedictorian and had to give the commencement speech. The archbishop of America—the head of the Greek Orthodox church in the US—came up from New York to attend the ceremony, and he happened to be in need of a deacon who could also serve as a speechwriter. “A few weeks later, I got a call from the archdiocese saying ‘We want you to be ordained, and we want you to come to New York, and we want you to write for the archbishop,’” Sietsema recalls.
In short order, he and his wife moved to the Upper East Side of Manhattan so he could begin his new post as Father Mark (he used his middle name because Orthodox priests must be ordained with a saint’s name, and there are no Orthodox Saint Brians). As deacon to the archbishop and then to his successor, he wrote their speeches and encyclicals on top of many other duties—including chauffeuring them through New York City traffic—and traveled with them around the country and to Greece, meeting President Clinton, ambassadors, members of Congress, Elie Wiesel, and South Africa’s Anglican Archbishop Desmond Tutu along the way. But after two years, as the father of a newborn, he was eager to move on from a job that required putting in as many as 14 hours six or seven days a week. So in 2000, he returned to Michigan to become pastor of the Holy Trinity Greek Orthodox Church in Lansing.
“The World Series can be a four-game sweep and the Super Bowl can be a blowout, but the National Spelling Bee always comes down to one last word.”
Not long after settling into parish life, Sietsema got an unexpected call from the Scripps Spelling Bee. His wife had served on the event’s word panel from 1997 to 2000, and he had traveled with her to one of the members’ off-site gatherings in 1998. He’d tagged along to dinner one night, and they were pleased to meet the person who was responsible for pronunciations in the bee’s official dictionary. But now, just a few weeks before the 2003 event, there was a crisis: The longtime pronouncer had suddenly died. The veteran associate pronouncer would step into his role and take on the job of giving spellers their words, but a new associate pronouncer would be needed to answer spellers’ questions about word roots, monitor pronunciations, and be prepared to serve as the pronouncer if needed. Could he do it? Honored to be asked, Sietsema got the okay from his bishop and said yes.
Little did he know it would become a permanent gig. After 15 years of answering root-word queries, when the bee expanded in 2018 he began serving as a pronouncer for some of the earlier rounds as well—though never for the finals. Now he’s the head of a team of associate pronouncers. “It’s just wonderful to see these young people blossom right in front of you, asking their questions and analyzing the word on the spot and figuring out how it all goes together,” he says. He dismisses the idea that the kids have photographic memories, saying they’re “really just good little word detectives.”
As a member of the bee’s word panel, Sietsema attends multiple daylong meetings to create and fine-tune each year’s list by mining the 500,000 or so words in Merriam-Webster’s unabridged dictionary. “For an introductory round, you want something that’s an interesting word, a useful word, but something that’s gettable,” he says. “For the later rounds, you really want to find something that’s going to challenge the speller. And it’s nice to have a word that’s analyzable.” “Rooty” words—those with obvious roots—are ideal.
The advent of unabridged online dictionaries has streamlined how students prepare for the bee, which once required wading through the dictionary manually to compile word lists. Today, it’s easy to generate lists of words derived from a particular language to study their roots, for example. Meanwhile, the competition has become increasingly fierce, and once-verboten terms like geographical names are considered fair game. For some of the words in the hardest rounds, “it looks like you’re just taking a spoonful of alphabet soup,” he says. “And that’s for the spellers who really, really are committed to learning just about every word they can in the dictionary.”
When it gets down to the last spellers in the final round, there’s an electric feeling in the room. “It’s always a close competition,” he says. “The World Series can be a four-game sweep and the Super Bowl can be a blowout, but the National Spelling Bee always comes down to one last word, and that’s what makes it exciting each and every time.”
The philosopher Friedrich Nietzsche famously wrote that a characteristic of theologians is their “unfitness for philology,” meaning they can’t be trusted to interpret texts with objective accuracy. He also maintained that a sense of restraint characterizes a good linguist. Sietsema says he’s right on both counts. When linguists analyze texts, “we know what we don’t know, and that’s important because you don’t find meaning where it’s not in the original,” he says. He thinks the well-trained linguist has a mission to the world of theology: to help clarify what is an appropriate interpretation of a sacred text and what is going too far.
He’s put his unique blend of skills into practice. In the early days of the covid pandemic, for instance, a Greek Orthodox scholar defended the practice of continuing to use a single spoon to administer communion. The scholar argued that holy things cannot cause harm and that abandoning them for fear of an earthly disease was far more dangerous than the disease itself, citing a passage from a homily of an archbishop of Constantinople in the fourth century CE saying “nothing is worse than to relegate spiritual things to human reasoning.” Sietsema responded with a thoughtful defense of reason, pointing out that the scholar’s argument relied on a mistranslation of logismoi, which he explained refers not to the faculty of reason but to negative mental habits, such as flawed reckonings, intrusive thoughts, or vain rationalizations. He countered that the church very much values reason and advocated “the exercise of good sense, good science, and compassion,” arguing that “those who pit faith against the faculty of reason end up losing one or the other or both.”
Sietsema’s time at MIT, he says, taught him to pay attention not only to what’s in data sets but also to what’s not there that could be. “That particular muscle gets used in both linguistic analysis and lexicography, as well as in pastoral care,” he says. “When you’re listening to people pour out their hearts, it’s important to notice what they’re saying and what they’re not saying.”
During his time as a deacon at the Archdiocese in New York City, Sietsema stands alongside Archbishop Iakovos, the head of the Greek Orthodox church in the US, at a water blessing service attended by former President George H.W. Bush.
COURTESY OF BRIAN SIETSEMA
As both a priest and a linguist, he’s called on to notice and remember. Attention to detail matters whether he’s gearing up for the celebration of Pascha, or Easter, at Holy Trinity or preparing for the National Spelling Bee, which he calls “the holy week of spelling.”
This spring, before heading to Washington for his 24th National Spelling Bee in May, Sietsema reflected on what words he might add to his list of favorites. A top candidate was one given to Evelyn Blacklock, a speller in his first bee as associate pronouncer in 2003: clepsydra, meaning an old-style water clock. “She didn’t know it, but through a series of questions to me about the Greek roots of the word—from kleptein (to steal) and hydōr (water)—she was able to divine the English spelling,” he recalls. “It was so satisfying to watch this feat of word sleuthing happen in real time, and it gave me a good insight into the importance of my role at the bee.”
It seems unlikely, however, that akimbo will ever lose top billing on his list. It’s easy to imagine Sietsema facing the future with his own hands on hips, elbows out, embracing linguistics, theology, and scientific reason as he shares his joy for life and the words we use to describe it.
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.
Background: Functional impairments associated with mental health conditions are on the rise. Predicting functional outcomes may improve the targeting of preventive interventions. While prognostic models have primarily focused on psychosis, early recognition services require a transdiagnostic approach. Objective: This study aimed to predict global functioning within a 2-year follow-up using baseline clinical and structural magnetic resonance imaging (MRI) data in a population-based sample of young, help-seeking individuals presenting with affective and anxiety symptoms as well as attention-deficit hyperactivity disorder. Methods: We classified 357 help-seeking individuals aged 18‐35 years recruited from 9 sites as “impaired” (Global Assessment of Functioning [GAF] ≤60; n=228) or “nonimpaired” (GAF>60; n=129) at year 1 and/or year 2 follow-up. GAF classification group status at follow-up was predicted using linear support vector machine (SVM), decision tree, and large language model (LLM) Llama-3 using clinical assessments and/or structural MRI. Leave-one-site-out (SVM) or external sample (LLM) was used for validation. Results: SVM achieved balanced accuracy of 69.2% using clinical features only. Items related to baseline occupational functioning, interpersonal relationships, cognitive functioning, psychotic and affective symptoms, as well as the presence of anxiety disorder, were most predictive. The decision tree further reduced the feature set to 5 predictive items, achieving balanced accuracy of 76.6%. Although amygdala and hippocampal subregions achieved balanced accuracy of 57.1%, structural MRI did not improve the overall prediction. Llama-3 performed comparably well to SVM (balanced accuracy of 72.6%). Conclusions: Machine learning demonstrated good performance in predicting global functioning. Interestingly, the out-of-the-box LLM performed comparably well without being trained or fine-tuned, highlighting the potential of leveraging free-text data for mental health prognosis.
BackgroundParoxysmal sympathetic hyperactivity (PSH) is a devastating complication of traumatic brain injury (TBI), characterized by the simultaneous onset of various manifestations due to sympathetic overactivity. Paradoxical bradycardia, an uncommon manifestation of PSH, is poorly characterized, and there is limited evidence regarding its clinical features, pathophysiological mechanisms and targeted management.Case presentationA 25-years-old male sustained severe traumatic brain injury in a nighttime motorcycle collision with a parked vehicle and underwent multiple neurosurgical procedures. He developed typical PSH on day 48 post injury, with a Paroxysmal Sympathetic Hyperactivity Assessment Measure (PSH-AM) score of 27. On the 92nd day post-injury, the patient developed persistent resting bradycardia (40–66 beats/min) after cranioplasty, while a reduced maximum heart rate (140–159 beats/min) was noted during PSH episodes. He subsequently experienced an acute PSH episode with severe bradycardia (38–43 beats/min, PSH-AM score of 20). After excluding common predisposing factors, intravenous isoproterenol (initial dose 4 μg/min, titrated to 2 μg/min) was administered in combination with anti-PSH medication regimen, and the patient’s clinical symptoms were relieved. The patient was discharged in a stable condition and had no further episodes of bradycardia at the 3-months follow-up.ConclusionParadoxical bradycardia represents an atypical clinical phenotype of post-TBI PSH, likely mediated by an atypical Cushing reflex secondary to fluctuating intracranial pressure elevations during PSH exacerbations. Clinically, for TBI patients with unexplained bradycardia, potential primary causes should be actively explored, with particular attention to monitoring dynamic changes in intracranial pressure.
