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  • A Genetic Snapshot Could Predict Preterm Birth

    A Genetic Snapshot Could Predict Preterm Birth

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    This article was originally published by Knowable Magazine.

    For expectant parents, pregnancy can be a time filled with joyful anticipation: hearing the beating of a tiny heart, watching the fetus wiggling through the black-and-white blur of an ultrasound, feeling the jostling of a little being in the belly as it swells.

    But for many, pregnancy also comes with serious health issues that can endanger both parent and child. In May, for example, the U.S. Olympic sprinter Tori Bowie died while in labor in her eighth month of pregnancy. Potential factors contributing to her death included complications of preeclampsia, a pregnancy-specific disorder associated with high blood pressure. Preeclampsia occurs in an estimated 4.6 percent of pregnancies globally. Left untreated, it can lead to serious problems such as seizures, coma, and organ damage.

    Preeclampsia and preterm birth are relatively common conditions that can put both the mother and her baby at risk of health issues before and after birth. But doctors don’t have a good way to determine whether an individual will develop one of these complications, says Thomas McElrath, an ob-gyn at Brigham and Women’s Hospital, in Boston. Currently, physicians primarily look to a woman’s prior pregnancies, medical history, and factors such as age and ethnicity to determine her risk. These measures are useful but limited, and may fail to identify problems early enough to enable effective treatment, McElrath says. “They’re not as precise as I think most of us, as clinicians, would really want.”

    That may soon change. Scientists are learning that free-floating bits of genetic material found in a pregnant person’s blood may offer a way to detect complications such as preeclampsia and preterm birth—although some experts caution that it’s too early to determine how useful these tests will be in the clinic. In the meantime, the tests are providing researchers with a new way to unravel the underlying biology of these inscrutable ailments.

    All of us carry bits of our own genetic material—both DNA and its more evanescent cousin, RNA—around in our bloodstreams. During pregnancy, these free-floating fragments, known as cell-free DNA and RNA, are also released from the developing fetus into the mother’s blood, primarily via the placenta. For more than a decade, clinicians have used cell-free DNA from blood to screen the fetus for genetic abnormalities.

    But DNA provides a largely static view of the genetic content within our cells. RNA gives a snapshot of which genes are turned on or off at a specific point in time. Because gene activity varies across cells and over time, researchers realized that they could use RNA to glean a more dynamic view of the changes that occur within the mother’s body during pregnancy. RNA enables scientists to look beyond the fixed genotype to factors that change over the course of pregnancy such as prenatal complications, says Mira Moufarrej, a postdoctoral researcher at Stanford University who co-authored a paper in the 2023 Annual Review of Biomedical Data Science on noninvasive prenatal testing with circulating RNA and DNA.

    Read: The pregnancy risk that doctors won’t mention

    To screen for possible complications, scientists have been looking at cell-free RNA in pregnant women’s blood that originates from both mother and child. Some of the earliest studies of this kind emerged in the early 2000s. In 2003, for example, Dennis Lo, a chemical pathologist at the Chinese University of Hong Kong, and his colleagues reported that in a study of 22 pregnant women, a specific RNA released from the placenta was much more abundant during the third trimester in those who had preeclampsia than in those who did not. Over the years, Lo’s group and others have looked at broader changes in RNA during pregnancy in larger groups of people.

    In a 2018 study, Moufarrej, who was then a doctoral student; her adviser Stephen Quake, a biophysicist at Stanford University; and colleagues reported that cell-free RNA could help determine when labor would occur. The researchers recruited 38 pregnant women in the United States known to be at risk of preterm birth, and then drew a blood sample from each. By comparing cell-free RNA in those who eventually delivered prematurely with that in those who gave birth at full term, they were able to identify a set of RNAs that appeared up to two months prior to labor that could pinpoint about 80 percent of premature births.

    That proof-of-concept investigation spurred the researchers to look further and examine whether cell-free RNA could also predict preeclampsia. Other groups had previously reported RNA-based signatures of preeclampsia—in 2020, for instance, scientists working with the California-based biotech company Illumina reported dozens of RNA transcripts that were unique to a small cohort of pregnant women with the condition. But Moufarrej, Quake, and their colleagues wanted to track RNA changes throughout pregnancy to see whether it might be possible to identify people at risk of preeclampsia during early pregnancy, before symptoms began.

    In a study published in 2022, the researchers recruited several dozen mothers at heightened risk of preeclampsia and drew blood from them four times: at or before 12 weeks, in weeks 13 to 20, at or after 23 weeks, and after birth. Afterward, the researchers compared cell-free RNA for women who indeed developed preeclampsia against that of those who did not. The team identified RNAs corresponding to 544 genes whose activity differed in those who developed preeclampsia and those who did not. (The study did not differentiate between maternal and fetal RNA, but because the majority of cell-free RNA in a pregnant person’s blood is their own, Moufarrej says that most of these RNAs are likely maternal in origin.)

    Then, using a computer algorithm, the researchers developed a test based on 18 genes measured prior to 16 weeks of pregnancy that could be used to predict a woman’s risk of developing preeclampsia months later. The test correctly identified all of the women who would later develop preeclampsia—and, equally important, all of the women who the test predicted wouldn’t develop preeclampsia did in fact escape the disease. (About a quarter of the women who were predicted to develop preeclampsia did not get the disease.) The same 18-gene panel also correctly predicted most cases of preeclampsia in two other groups totaling 118 women.

    The team also took a closer look at which tissues the RNA of interest originated from. This included the usual suspects, such as the lining of the blood vessels (also known as the endothelium), which scientists already know is associated with preeclampsia, as well as other, more unexpected sources, such as the nervous and muscular systems. The authors note that, in the future, this information could be used both to understand how preeclampsia affects different parts of the body and to assess which organs are at highest risk of damage in a particular patient.

    According to Quake, studies like these from both his team and others are starting to reveal the diversity of changes throughout the body that contribute to pregnancy complications—and providing evidence for something that clinicians and researchers have long suspected: that both preeclampsia and preterm birth are conditions with a range of underlying causes and outcomes. “There are now strong indications that you should be defining multiple subtypes of preeclampsia and preterm birth with molecular signatures,” says Quake. “That could really transform the way physicians approach the disease.”

    Research teams elsewhere are also looking at other pregnancy complications such as reduced fetal growth, which can cause infants to be at higher risk of problems such as low blood sugar and a reduced ability to fight infections. Some of these tests are now being validated in large studies, while others are still in the early days of development.

    RNA-based tests for both preeclampsia and preterm-birth risk are inching their way toward the clinic. Mirvie, a company co-founded by Quake in South San Francisco, is focused on developing both. Last year, the company published a study of a preterm-birth test with hundreds of pregnant individuals as well as one on a preeclampsia test with samples from more than 1,000 women. Both studies had promising results. The company is now in the middle of an even larger study of the preeclampsia test that will include 10,000 pregnancies, Quake says. (Quake and Moufarrej are both shareholders of Mirvie.)

    Cell-free RNA-based tests for preeclampsia are leading the way, says McElrath, likely because preterm birth has more subtypes and more potential causes—including carrying multiples, chronic health conditions such as diabetes, and preeclampsia—which make it a more complicated issue to address. (McElrath is involved in validating Mirvie’s tests; he serves as a scientific adviser to the company and has a financial stake in it.)

    Read: Childbirth is no fun. But an extremely fast birth can be worse.

    Still, questions about these tests remain. An important next step, says Moufarrej, is determining what’s behind the RNA changes associated with a heightened risk for these pregnancy complications. All of the studies conducted to date have been correlative—linking patterns in RNA with risk—but to provide effective treatment, it will be important to determine the cause of these changes, she adds. Another open question is how important maternal versus fetal RNAs are to determining the risk of pregnancy complications. To date, most studies have not distinguished between these two sources. “This remains an active area of investigation,” McElrath says.

    Erik Sistermans, a human geneticist at Amsterdam UMC, says that although  researchers can learn a lot from cell-free RNA, it’s still too early to judge what the power of these RNA-based tests will be in clinical practice. He notes that he and other researchers are also investigating the possibility of using cell-free DNA to determine the risk of pregnancy complications such as preeclampsia. For example, some groups are looking at chemical modifications to DNA known as epigenetic changes, which occur in response to age, environment, and other factors.

    Yalda Afshar, a maternal- and fetal-medicine physician at UCLA, agrees that it’s still unclear whether these tests will provide benefits not available from existing screening methods such as looking for the presence of risk factors. For these screening tests to truly benefit patients, clinicians will first need to understand the underlying biology of these complications—and have effective treatments to offer patients found to be at risk, she adds. (Afshar is an unpaid consultant for Mirvie.)

    There are also ethical questions to consider. Screening tests provide only an estimate of risk, not a definitive diagnosis, Sistermans notes. Before these tests are rolled out to the public, it will be crucial to consider how best to communicate test results, and what next steps to take for individuals who are identified as being in a high-risk category, he says. For preeclampsia, low-dose aspirin can help prevent or delay its onset, while the hormone progesterone may help prevent some cases of preterm birth. But every additional test added to a prenatal screen makes decisions more complicated and potentially stressful for pregnant women. “You shouldn’t underestimate the amount of anxiety these kinds of tests may cause,” Sistermans says.

    Still, researchers are optimistic about the future of cell-free RNA-based tests. The tests for preeclampsia are already more accurate than currently available tests for the condition, according to McElrath. And if researchers succeed in predicting other complications, he adds, future patients will benefit not just from additional information about their pregnancies, but also from the opportunity to receive more personalized care. “Once we start to see success in early preeclampsia prediction,” McElrath says, “it will quickly spread out from there.”

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    Diana Kwon

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  • One More COVID Summer?

    One More COVID Summer?

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    Since the pandemic’s earliest days, epidemiologists have been waiting for the coronavirus to finally snap out of its pan-season spree. No more spring waves like the first to hit the United States in 2020, no more mid-year surges like the one that turned Hot Vax Summer on its head. Eventually, or so the hope went, SARS-CoV-2 would adhere to the same calendar that many other airway pathogens stick to, at least in temperate parts of the globe: a heavy winter peak, then a summer on sabbatical.

    But three and a half years into the outbreak, the coronavirus is still stubbornly refusing to take the warmest months off. Some public-health experts are now worried that, after a relatively quiet stretch, the virus is kick-starting yet another summer wave. In the southern and northeastern United States, concentrations of the coronavirus in wastewater have been slowly ticking up for several weeks, with the Midwest and West now following suit; test-positivity rates, emergency-department diagnoses of COVID-19, and COVID hospitalizations are also on the rise. The absolute numbers are still small, and they may stay that way. But these are the clear and early signs of a brewing mid-year wave, says Caitlin Rivers, an epidemiologist at Johns Hopkins University—which would make this the fourth summer in a row with a distinct coronavirus bump.

    Even this far into the pandemic, though, no one can say for certain whether summer waves are a permanent COVID fixture—or if the virus exhibits a predictable seasonal pattern at all. No law of nature dictates that winters must come with respiratory illness, or that summers will not. “We just don’t know very much about what drives the cyclical patterns of respiratory infections,” says Sam Scarpino, an infectious-disease modeler at Northeastern University. Which means there’s still no part of the year when this virus is guaranteed to cut us any slack.

    That many pathogens do wax and wane with the seasons is indisputable. In temperate parts of the world, airborne bugs get a boost in winter, only to be stifled in the heat; polio and other feces-borne pathogens, meanwhile, often rise in summer, along with gonorrhea and some other STIs. But noticing these trends is one thing; truly understanding the triggers is another.

    Read: COVID sure looks seasonal now

    Some diseases lend themselves a bit more easily to explanation: Near the equator, waves of mosquito-borne illness, such as Zika and Chikungunya, tend to be tied to the weather-dependent life cycles of the insects that carry them; in temperate parts of the world, rates of Lyme disease track with the summertime activity of ticks. Flu, too, has pretty strong data to back its preference for wintry months. The virus—which is sheathed in a fragile, fatty layer called an envelope and travels airborne via moist drops—spreads best when it’s cool and dry, conditions that may help keep infectious particles intact and spittle aloft.

    The coronavirus has enough similarities to flu that most experts expect that it will continue to spread in winter too. Both viruses are housed in a sensitive skin; both prefer to move by aerosol. Both are also relatively speedy evolvers that don’t tend to generate long-lasting immunity against infection—factors conducive to repeat waves that hit populations at a fairly stable clip. For those reasons, Anice Lowen, a virologist at Emory University, anticipates that SARS-CoV-2 will continue to show “a clear wintertime seasonality in temperate regions of the world.” Winter is also a time when our bodies can be more susceptible to respiratory bugs: Cold, dry air can interfere with the movement of mucus that shuttles microbes out of the nose and throat; aridity can also make the cells that line those passageways shrivel and die; certain immune defenses might get a bit sleepier, with vitamin D in shorter supply.

    None of that precludes SARS-CoV-2 spread in the heat, even if experts aren’t sure why the virus so easily drives summer waves. Plenty of other microbes manage it: enteroviruses, polio, and more. Even rhinoviruses and adenoviruses, two of the most frequent causes of colds, tend to spread year-round, sometimes showing up in force during the year’s hottest months. (Many scientists presume that has something to do with these viruses’ relatively hardy outer layer, but the reason is undoubtedly more complex than that.) An oft-touted explanation for COVID’s summer waves is that people in certain parts of the country retreat indoors to beat the heat. But that argument alone “is weak,” Lowen told me. In industrialized nations, people spend more than 90 percent of their time indoors.

    That said, an accumulation of many small influences can together create a seasonal tipping point. Summer is a particularly popular time for travel, often to big gatherings. Many months out from winter and its numerous infections and vaccinations, population immunity might also be at a relative low at this time of year, Rivers said. Plus, for all its similarities to the flu, SARS-CoV-2 is its own beast: It has so far affected people more chronically and more severely, and has generated population-sweeping variants at a far faster pace. Those dynamics can all affect when waves manifest.

    And although certain bodily defenses do dip in the cold, data don’t support the idea that immunity is unilaterally stronger in the summer. Micaela Martinez, the director of environmental health at WE ACT for Environmental Justice, in New York, told me the situation is far more complicated than that. For years, she and other researchers have been gathering evidence that suggests that our bodies have distinctly seasonal immunological profiles—with some defensive molecules spiking in the summer and another set in winter. The consequences of those shifts aren’t yet apparent. But some of them could help explain when the coronavirus spreads. By the same token, winter is not a time of disease-ridden doom. Xaquin Castro Dopico, an immunologist at the Karolinska Institute, in Sweden, has found that immune systems in the Northern Hemisphere might be more inflammation-prone in the winter—which, yes, could make certain bouts of illness more severe but could also improve responses to certain vaccinations.

    All of those explanations could apply to COVID’s summer swings—or perhaps none does. “Everybody always wants to have a very simple seasonal answer,” Martinez told me. But one may simply not exist. Even the reasons for the seasonality of polio, a staunch summertime disease prior to its elimination in the U.S., have been “an open question” for many decades, Martinez told me.

    Rivers is hopeful that the coronavirus’s permanent patterns may already be starting to peek through: a wintry heyday, and a smaller maybe-summer hump. “We’re in year four, and we’re seeing the same thing year over year,” she told me. But some experts worry that discussions of COVID-19 seasonality are premature. SARS-CoV-2 is still so fresh to the human population that its patterns could be far from their final form. At an extreme, the patterns researchers observed during the first few years of the pandemic may not prelude the future much at all, because they encapsulate so much change: the initial lack and rapid acquisition of immunity, the virus’s evolution, the ebb and flow of masks, and more. Amid that mishmash of countervailing influences, says Brandon Ogbunu, an infectious-disease modeler at Yale, “you’re going to get some counterintuitive dynamics” that won’t necessarily last long term.

    Read: The next stage of COVID is starting now

    With so much of the world now infected, vaccinated, or both, and COVID mitigations almost entirely gone, the global situation is less in flux now. The virus itself, although still clearly changing at a blistering pace, has not pulled off an Omicron-caliber jump in evolution for more than a year and a half. But no one can yet promise predictability. The cadence of vaccination isn’t yet settled; Scarpino, of Northeastern University, also isn’t ready to dismiss the idea of a viral evolution surprise. Maybe summer waves, to the extent that they’re happening, are a sign that SARS-CoV-2 will remain a microbe for all seasons. Or maybe they’re part of the pandemic’s death rattle—noise in a system that hasn’t yet quieted down.

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    Katherine J. Wu

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  • Does Trump Stand a Real Chance to Repeat 2016?

    Does Trump Stand a Real Chance to Repeat 2016?

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    Stop me if you’ve heard this one before: Well-placed Republican insiders are mobilizing to block Donald Trump from winning the GOP presidential nomination.

    For instance, Trump is conspicuously excluded from the roster of potential 2024 candidates whom the Club for Growth has invited to speak this weekend at a retreat the conservative group is hosting for its biggest donors in Palm Beach, Florida—Trump’s backyard. Likewise, the sprawling network of donors associated with the Koch brothers declared last month that it would work in the 2024 GOP primaries to elect a nominee who “will turn the page on the past several years,” an unmistakable reference to moving beyond Trump. And though they’re still a minority, a steady stream of prominent Republican strategists, donors, and elected officials are openly predicting that the party will lose in 2024 if it nominates Trump again.

    David Frum: Trump’s running, and Republicans have only themselves to blame

    If all of this sounds like an echo of the 2016 Republican primary race, that’s because it is. Both the Club for Growth and the Koch network opposed Trump’s nomination then too. Big donors almost entirely shunned him, hardly any elected officials endorsed him until after he had already secured the nomination, and party leaders such as Senator Lindsey Graham warned that “if we nominate Trump, we will get destroyed … and we will deserve it.”

    None of this stopped Trump from winning the nomination, and, except for the relatively small band of Never Trump conservative activists, all of that internal Republican opposition evaporated after he won the White House.

    Whether this institutional opposition to Trump will prove more effective and durable now is an open question. Republicans resistant to Trump are cautiously optimistic that this time will be different. That’s partly because of signs that Florida Governor Ron DeSantis might unify the party’s anti-Trump forces more effectively than any of his rivals did in 2016. But it’s also because those who oppose Trump are mobilizing earlier than they did in the 2016 race.

    “The thing about 2015 is that Trump had the initiative; he surprised everyone,” says the conservative strategist Bill Kristol, who became one of Trump’s leading GOP critics. “The establishment was always on the back foot trying to react to him, and the candidates were diffuse, so there was never a coming together. Here, at least in theory, you have big institutions mobilizing against him early, and they are ready from the beginning.”

    Yet even with those undeniable shifts in the landscape, many Republicans remain dubious that opposition from party leaders and big donors will have much impact on Trump’s fate in 2024.

    Almost everyone in the GOP agrees that Trump faces political challenges now that he didn’t then—in particular, more widespread concerns among Republican voters about whether he can win a general election. But some believe that, if anything, more overt opposition to Trump from the party elite will help him convince his die-hard supporters that he alone is fighting for them. “Trump is such a unique political figure that, in some ways, you could argue that having all these institutional forces mobilize against him makes him stronger,” Craig Robinson, the former political director for the Republican Party in Iowa, told me.

    Trump’s camp is ready to make those sort of arguments against the groups and party leaders that oppose him. Hogan Gidley, Trump’s former White House deputy press secretary, says it is “naive” to assume that the party establishment could really unite behind a single alternative, as many of Trump’s critics hope. But, he adds, “if in fact there is a coalescing this time,” Trump and his allies are prepared to argue that it represents a continuation of “a concerted effort by the establishment to try to take down someone they couldn’t control.”

    Given how quickly top Republicans bent the knee to Trump after he was elected, it may be hard to remember that in 2016, he was more distant from his party’s leadership than any candidate who had won either side’s presidential nomination since the Democratic outsiders George McGovern in 1972 and Jimmy Carter in 1976. The McGovern and Carter victories were the direct products of the rule changes that Democrats instituted after their bitter nomination fight in 1968 to shift power for selecting the presidential nominee from party bosses, elected officials, and other insiders at their quadrennial national convention to voters through primaries and caucuses. Republicans quickly followed suit.

    Over time, though, political scientists began to perceive a striking pattern in which the new system took on more characteristics of the old one. Although the reformed rules ostensibly empowered voters to select the nominees during the marathon of primaries and caucuses, in fact, the winners were usually those around whom party insiders coalesced during what became known as “the invisible primary.” That phrase referred to the rolling courtship of donors, other elected officials, and party interest groups that the contenders slogged through for a year or more before the first voters cast a ballot in Iowa and New Hampshire.

    The “invisible primary” didn’t always have a clear winner, but when it did, that candidate almost always won the nomination—as demonstrated by the Democrats Walter Mondale in 1984, Bill Clinton in 1992, Al Gore in 2000, and Hillary Clinton in 2016, and by the Republicans George H. W. Bush in 1988, Bob Dole in 1996, George W. Bush in 2000, John McCain in 2008, and Mitt Romney in 2012. The race between Hillary Clinton and Barack Obama in 2008 probably stood as the premier example of a contest in which the invisible primary ended in a standoff.

    The pattern of primary voters eventually choosing the candidate who had first secured the most support from elected officials, interest groups, and donors became so reliable that the political scientist Marty Cohen and his three colleagues could flatly declare, per the title of their 2008 book, The Party Decides. “The reformers of the 1970s tried to wrest the presidential nomination away from insiders and to bestow it on rank-and-file partisans,” they wrote, “but the people who are regularly active in party politics have regained much of the control that was lost.”

    Trump’s march to the 2016 GOP nomination represents the most explicit recent exception to the “party decides” theory. Trump amassed almost none of the assets that usually boost nominees. During the 2016 primaries, Jeb Bush, Ted Cruz, and Marco Rubio all outraised him. Those rivals also won far more endorsements than Trump did; only Senator Jeff Sessions of Alabama and three governors endorsed Trump at any point in the primaries. And to describe Trump’s ground-level political organizations in the early states as skeletal would be to overstate the meat on their bones.

    Trump in 2016 overcame these limitations with forceful and flamboyant performances at Republican debates, arena-size rallies in the key states, and, above all, a wave of unprecedented national-media coverage in which he appealed to white voters’ anxieties over racial and cultural change more openly than any national candidate in either party had since George Wallace. “Trump was able to run a national media campaign to win the nomination, and that is something that we just didn’t expect to be a successful path,” Cohen, a political scientist at James Madison University, told me this week.

    Cohen, like many others, believes that one principal reason Trump survived such widespread resistance from party leaders is that those opposed to him never united behind a single alternative, splintering instead among Cruz, Rubio, Bush, and former Ohio Governor John Kasich. “I think that when the party is able to coalesce on an acceptable candidate, they still have a pretty good chance at getting them nominated,” Cohen said. “The question that’s pressing is how difficult is it now to solidify around one particular candidate?”

    That exact question is looming again for the Republicans skeptical of Trump. Many in the party believe the ceiling on Trump’s potential support is lower now than it was in the 2016 primaries—particularly among college-educated Republican voters, who mostly voted against him even then. But Trump’s solid hold on about one-third of GOP voters could still allow him to win if no one consolidates the remainder of the party.

    To many of Trump’s GOP skeptics, the biggest difference from 2016 is the possibility that DeSantis might unify the party’s anti-Trump forces more thoroughly than anyone did then. “I think you are going to see a lot of folks coalesce around DeSantis this summer after he runs around the track and does his formal announcement,” predicts the GOP strategist Scott Reed, who served as Dole’s campaign manager in 1996.

    DeSantis is certainly generating enormous interest: A retreat he convened in Florida last weekend drew a procession of elected officials, conservative activists, and donors. And all of the Republican strategists I spoke with in recent days expect donors to be much more conscious than they were in 2016 of concentrating their dollars on a few candidates to reduce the chances that Trump can again divide and conquer a large and unwieldy field. DeSantis will likely be lavishly funded, but that calculation could make it difficult for many others contemplating the race to raise enough money to truly compete.

    However, many of those strategists also remain unconvinced that the party’s Trump skeptics will move en masse to the DeSantis side until they see more evidence that he can handle the rigors of a national campaign—and of running against Trump. Mike Murphy, a GOP strategist who helped direct the super PAC supporting Jeb Bush in 2016, told me that though “the donor mentality is going to be a lot different … it’s not going to be binary: ‘We’re all going to be for DeSantis, and nobody else can raise any money.’”

    Read: The coming Republican amnesia

    In fact, several GOP strategists I spoke with predicted that with DeSantis and Trump both defining themselves primarily as pugnacious culture warriors, there might be room in the top tier for a third candidate who offers a less polarizing and more optimistic message. And one name came up repeatedly as a possibility for that role: South Carolina Senator Tim Scott, the sole Black Republican in the chamber. “I think he could come here and do very well,” Robinson, the former Iowa GOP political director, said.

    What’s clear already is that, for groups, donors, and candidates alike, opposing Trump won’t be for the fainthearted. Without identifying specific targets, Gidley, for instance, says Trump’s allies are prepared to argue that big donors organizing against him are doing so to protect business interests in China. “That’s going to be a massive point that was not talked about in 2016 that will most assuredly be exposed in 2024,” says Gidley, now an official at the America First Policy Institute, which was founded by former Trump aides.

    Even against such threats, the conditions seem to be in place for the GOP institutions skeptical of Trump to move back toward the “party decides” model in 2024. Jennifer Horn, the former Republican state party chair in New Hampshire and a leading Trump critic, told me that it’s likely the institutional resistance to him this time “will be stronger and more organized” than it was in 2016. Doubts about Trump’s electability, she added, could resonate with more GOP primary voters than opponents’ 2016 arguments against his morality or fealty to conservative principles did. “His biggest vulnerability in a primary is whether or not he can win a general election,” she said.

    But Horn cautions that such internal resistance could melt away again after a few primaries if it looks like Trump is on track to win the nomination. “If we get into the primaries and Trump is winning, it will all go to the side, just as in 2016,” Horn predicted. “We saw the degree to which the party and the donors and everyone else completely sold their soul and became all Trump, all the time. If he becomes the guy again, he’s going to be everybody’s guy.”

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    Ronald Brownstein

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  • A World Without Chuck Grassley in the Senate?

    A World Without Chuck Grassley in the Senate?

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    The long-serving Senator Chuck Grassley is, for lack of a comparison closer to home, Iowa’s Queen Elizabeth II. This is partly a matter of sheer longevity. At 89, the senator is older than John Deere’s first self-propelled combine, which appeared in 1947. He was 26 when Buddy Holly, Ritchie Valens, and the Big Bopper died in a plane crash in 1959. The year Kevin Costner filmed Field of Dreams in Dyersville, 1988, Grassley was 55.

    Age aside, Grassley is simply a part of Iowa’s political furniture—many voters in the state have never known a time without him. When I was born, in 1993, he’d been the state’s senior senator for 12 years; he has held elected office—first in the state House, then in the U.S. House and Senate—since my father was 4 years old. For many Iowans, the day when Grassley would not be their senator has been scarcely imaginable.

    Until now, maybe. Every six years, Iowa Democrats have inched closer to unseating the seven-term Republican senator. This time, they seem closer than ever: A recent poll showed Grassley leading 64-year-old Mike Franken only narrowly, suggesting that this will be Grassley’s toughest reelection fight in four decades.

    Read: What does Chuck Grassley fear?

    Twelve years ago, he defeated Roxanne Conlin by 31 points. In 2016, he beat Patty Judge by 24. This year’s race against Franken didn’t seem particularly newsworthy until earlier this month, when Selzer & Company, Iowa’s most respected polling firm, released results from a survey showing that Grassley was leading Franken by a mere three percentage points. “It says to me that Franken is running a competent campaign and has a shot to defeat the seemingly invincible Chuck Grassley—previously perceived to be invincible,” J. Ann Selzer, the president of Selzer & Company, told the Des Moines Register.

    The poll is only a snapshot in time, and it could certainly prove wrong. But it’s reasonable to assume, given other polling since then, that Franken is closer to unseating Grassley than any challenger before him. The most obvious reason for this is that Iowans may finally be noticing how old their senator is—a veritable crinoid in the creek bed of Iowa politics. Although Grassley seems healthy—he runs several miles each morning and kicks off campaign events by doing push-ups onstage—more than 60 percent of the Selzer poll’s respondents said his age was a real concern. “There are a lot of voters between 75 and 85 who think, I wouldn’t want to be in the United States Senate right now. I wouldn’t want to have that life; why does he?” Jeff Link, an Iowa Democratic strategist, told me.

    Read: The president’s cognitive decline

    For the first time in the history of this particular poll, more Iowan respondents disapprove of Grassley’s job performance than approve of it. Pair that dissatisfaction with the fact that Franken is a strong candidate. A retired Navy vice admiral from deep-red northwest Iowa, the Democrat could provide a nonthreatening alternative for the independents and Republicans who are reluctant to give Grassley another term. Franken “is energetic, very smart—almost loquacious—but he knows what he’s talking about,” David Oman, a state Republican strategist and a former co-chair of the Iowa GOP, told me. Despite that positive assessment, the recent emergence of an assault allegation from a former campaign manager might cool Democrats’ enthusiasm. (Franken has denied the allegation, and police have closed the case, calling it “unfounded.”)

    Undergirding all of these factors is the plain reality that Iowa, like the rest of the country, is becoming more partisan and more polarized. For 30 years, Iowans sent both Grassley and a Democrat, Tom Harkin, who retired in 2014, to the Senate at every chance, no matter which party was in the White House or who was occupying the governor’s mansion. The consensus among Iowans was that such a balance was ideal. But the days of winning big by being part of that balance are over.

    Grassley has changed, too. Back then, he was viewed as a kind of farmers-first independent, interested chiefly in restraining federal spending, whistleblower protections, and promoting free trade. Democrats liked him—and often voted for him. In 1991, Grassley was one of just two Republicans to vote against the Gulf War. “That made him seem above partisanship,” David Yepsen, a former reporter for the Des Moines Register, told me. Grassley’s image, among Iowans, was of a man who operated above the partisan fray.

    Read: What everyone’s missing about Iowa

    That gloss began to wear off in 2009. At first, Grassley seemed a willing negotiating partner on President Barack Obama’s plans for health-care reform; he worked for months on a bipartisan bill. But he hadn’t bargained for how unpopular the Affordable Care Act would be with his party’s base. During a tour of central Iowa that summer, Grassley was mobbed by Republicans and Tea Partiers who rejected the plan. He buckled under the pressure, abandoned the talks, and ultimately voted against the final bill. “He’d never been treated that way by his own party. It changed him,” Yepsen said. “It made him mindful that there’s a new kind of conservative out there, a new generation coming on—the populists.” And he responded accordingly.

    In the ensuing years, Grassley came to recognize that there were fewer and fewer points to be earned by working across the aisle. In 2016, as the chair of the Judiciary Committee, he was party to the Senate’s refusal to give Obama’s Supreme Court nominee Merrick Garland a hearing, and along with Republican leadership, he held open more than 100 seats on the federal bench during the final months of the Obama administration for Donald Trump to fill. “You can’t underestimate Democrats in Iowa watching his leadership in the Judiciary Committee putting all these conservatives on the Court, and seeing them now do their thing on the Dobbs decision,” Yepsen said. “Conservatives love it. But it makes him much more of a partisan.”

    Whether Grassley would support the candidacy of Donald Trump was initially an open question. The womanizing, scandal-plagued Republican presidential nominee seemed, after all, to be the Iowa senator’s bizarro opposite. Yet Grassley, like most others in the GOP, fell in line. He has stuck by Trump through vulgar comments and allegations. In 2019, Grassley—an actual author of the 1989 Whistleblower Protection Act—defended Trump’s firing of the whistleblower and impeachment witness Alexander Vindman. Lately, Grassley has broken from his party only a handful of times, including to gently push back on some of Trump’s “America First” protectionist trade policies and to support the 2021 bipartisan infrastructure bill. The senator seems altogether untroubled by Trump’s effort to discredit the 2020 election, and continues to appear alongside him at rallies.

    “The way that [Grassley] didn’t stand up for much of anything is emblematic of the Republican Party in the years of Trump,” Bill Kristol, the editor at large of The Bulwark, told me. “People you thought would be independent just ended up going along.”

    Nowadays, the way Iowans view Grassley simply reflects their politics, not some old-timey desire for balance and comity. Democrats see him as an utter disappointment—a caricature of the man they may once have disagreed with but at least respected. Some Republicans are pleased with the careful line he’s walked, embracing Trump while hanging on to moderates. For other Republicans, Grassley is not nearly MAGA enough. This year, for the first time in his Senate career, Grassley faced a primary challenger. Jim Carlin, a state senator who has criticized Grassley for voting to certify the results of the 2020 election, earned 26 percent of the primary vote.

    Given this transformation in how Iowans regard Grassley, defeat at the hands of a Democrat is more plausible than it’s ever been. More plausible, but still not likely. The Selzer poll may have given Franken a jolt of momentum, including a burst of Hail Mary fundraising, but the state is reddening and the gap in party registration is wide and growing: The Iowa GOP has roughly 88,000 more registered voters this year than the Iowa Democratic Party, according to the Iowa secretary of state’s office. In 2020, that advantage was only about 20,000. This gap, combined with the historical precedent of higher Republican turnout in off-year elections, seems likely to add up to a Grassley victory. The numbers are “hugely problematic,” Jeff Link, the Democratic strategist, said—even for a three-star admiral.

    A world without Chuck Grassley in power is one in which most Iowans have never actually lived. That may be why “Faith in adversity” has recently become the unofficial motto of the state’s Democrats. This year, they even decided to put it on a sign. Orange placards dapple grassy lawns throughout Iowa, each bearing a message of hopeful conviction—We believe Michael Franken will defeat Chuck Grassley, the signs say—as though they can speak such a mammoth upset into existence.

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    Elaine Godfrey

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