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The theme of my second-annual Breakthroughs of the Year is the long road of progress. My top breakthrough is Casgevy, a gene-editing treatment for sickle-cell anemia. In the 1980s and early 1990s, scientists in Spain and Japan found strange, repeating patterns in the DNA of certain bacteria. Researchers eventually linked these sequences to an immune defense system that they named “clustered regularly interspaced palindromic repeats”—or CRISPR. In the following decades, scientists found clever ways to build on CRISPR to edit genes in plants, animals, and even humans. CRISPR is this year’s top breakthrough not only because of heroic work done in the past 12 months, but also because of a long thread of heroes whose work spans decades.

Sometimes, what looks like a big deal amounts to nothing at all. For several weeks this summer, the internet lost its mind over claims that researchers in South Korea had built a room-temperature superconductor. One viral thread called it “the biggest physics discovery of my lifetime.” The technology could have paved the way to magnificently efficient energy grids and levitating cars. But, alas, it wasn’t real. So, perhaps, this is 2023’s biggest lesson about progress: Time is the ultimate test. The breakthrough of the year took more than three decades to go from discovery to FDA approval, while the “biggest” physics discovery of the year was disproved in about 30 days.

1. CRISPR’s Triumph: A Possible Cure for Sickle-Cell Disease

In December, the FDA approved the world’s first medicine based on CRISPR technology. Developed by Vertex Pharmaceuticals, in Boston, and CRISPR Therapeutics, based in Switzerland, Casgevy is a new treatment for sickle-cell disease, a chronic blood disorder that affects about 100,000 people in the U.S., most of whom are Black.

Sickle-cell disease is caused by a genetic mutation that affects the production of hemoglobin, a protein that carries oxygen in red blood cells. Abnormal hemoglobin makes blood cells hard and shaped like a sickle. When these misshapen cells get clogged together, they block blood flow throughout the body, causing intense pain and, in some cases, deadly anemia.

The Casgevy treatment involves a complex, multipart procedure. Stem cells are collected from a patient’s bone marrow and sent to a lab. Scientists use CRISPR to knock out a gene that represses the production of “fetal hemoglobin,” which most people stop making after birth. (In 1948, scientists discovered that fetal hemoglobin doesn’t “sickle.”) The edited cells are returned to the body via infusion. After weeks or months, the body starts producing fetal hemoglobin, which reduces cell clumping and improves oxygen supply to tissues and organs.

Ideally, CRISPR will offer a one-and-done treatment. In one trial, 28 of 29 patients, who were followed for at least 18 months, were free of severe pain for at least a year. But we don’t have decades’ worth of data yet.

Casgevy is a triumph for CRISPR. But a miracle drug that’s too expensive for its intended population—or too complex to be administered where it is most needed—performs few miracles. More than 70 percent of the world’s sickle-cell patients live in sub-Saharan Africa. The sticker price for Casgevy is about $2 million, which is roughly 2,000 times larger than the GDP per capita of, say, Burkina Faso. The medical infrastructure necessary to go through with the full treatment doesn’t exist in most places. Casgevy is a wondrous invention, but as always, progress is implementation.  

2. GLP-1s: A Diabetes and Weight-Loss Revolution

In the 1990s, a small team of scientists got to know the Gila monster, a thick lizard that can survive on less than one meal a month. When they studied its saliva, they found that it contained a hormone that, in experiments, lowered blood sugar and regulated appetite. A decade later, a synthetic version of this weird lizard spit became the first medicine of its kind approved to treat type 2 diabetes. The medicine was called a “glucagon-like peptide-1 receptor agonist.” Because that’s a mouthful, scientists mostly call these drugs “GLP-1s.”

Today the world is swimming in GLP-1 breakthroughs. These drugs go by many names. Semaglutide is sold by the Danish company Novo Nordisk, under the names Ozempic (approved for type 2 diabetes) or Wegovy (for weight loss). Tirzepatide is sold by Eli Lilly under the names Mounjaro (type 2 diabetes) or Zepbound (weight loss). These medications all mostly work the same way. They mimic gut hormones that stimulate insulin production and signal to the brain that the patient is full. In clinical trials, patients on these medications lose about 15 percent or more of their weight.

The GLP-1 revolution is reshaping medicine and culture “in ways both electrifying and discomfiting,” Science magazine said in an article naming these drugs its Breakthrough of the Year. Half a billion people around the world live with diabetes, and 40 percent of Americans alone are obese. A relatively safe drug that stimulates insulin production and reduces caloric intake could make an enormous difference in lifestyle and culture.

Some people on GLP-1s report nausea, and some fall out of love with their favorite foods. In rarer cases, the drugs might cause stomach paralysis. But for now, the miraculous effects of these drugs go far beyond diabetes and weight loss. In one trial supported by Novo Nordisk, the drug reduced the incidence of heart attack and stroke by 20 percent. Morgan Stanley survey data found that people on GLP-1s eat less candy, drink less alcohol, and eat 40 percent more vegetables. The medication seems to reduce smoking for smoking addicts, gambling for gambling addicts, and even compulsive nail biting for some. GLP-1s are an exceptional medicine, but they may also prove to be an exceptional tool that helps scientists see more clearly the ways our gut, mind, and willpower work together.

3. GPT and Protein Transformers: What Can’t Large Language Models Do?

In March, OpenAI released GPT-4, the latest and most sophisticated version of the language-model technology that powers ChatGPT. Imagine trying to parse that sentence two years ago—a useful reminder that some things, like large language models, advance at the pace of slowly, slowly, then all at once.

Surveys suggest that most software developers already use AI to accelerate code writing. There is evidence that these tools are raising the productivity of some workers, and surveys suggest that most software developers already use AI to accelerate code writing. These tools also appear to be nibbling away at freelance white-collar work. Famously, OpenAI has claimed that the technology can pass medical-licensing exams and score above the 85th percentile on the LSAT, parts of the SAT, and the uniform bar exam. Still, I am in the camp of believing that this technology is both a sublime accomplishment and basically a toy for most of its users.

One can think of transformers—that’s what the T stands for in GPT—as tools for building a kind of enormous recipe book of language, which AI can consult to cook up meaningful, novel answers to any prompt. If AI can build a cosmic cookbook of linguistic meaning, can it do the same for another corpus of information? For example, could it learn the “language” of how our cells talk to one another?

This spring, a team of researchers announced in Science that they had found a way to use transformer technology to predict protein sequences at the level of individual atoms. This accomplishment builds on AlphaFold, an AI system developed within Alphabet. As several scientists explained to me, the latest breakthrough suggests that we can use language models to quickly spin up the shapes of millions of proteins faster than ever. I’m most impressed by the larger promise: If transformer technology can map both languages and protein structures, it seems like an extraordinary tool for advancing knowledge.

4. Fusion: The Dream Gets a Little Closer

Inside the sun, atoms crash and merge in a process that produces heat and light, making life on this planet possible. Scientists have tried to harness this magic, known as fusion, to produce our own infinite, renewable, and clean energy. The problem: For the longest time, nobody could make it work.

The past 13 months, however, have seen not one but two historic fusion achievements. Last December, 192 lasers at the Lawrence Livermore National Laboratory, in California, blasted a diamond encasing a small amount of frozen hydrogen and created—for less than 100 trillionths of a second—a reaction that produced about three megajoules of energy, or 1.5 times the energy from the lasers. In that moment, scientists said, they achieved the first lab-made fusion reaction to ever create more energy than it took to produce it. Seven months later, they did it again. In July, researchers at the same ignition facility nearly doubled the net amount of energy ever generated by a fusion reaction. Start-ups are racing to keep up with the science labs. The new fusion companies Commonwealth Fusion Systems and Helion are trying to scale this technology.

Will fusion heat your home next year? Fat chance. Next decade? Cross your fingers. Within the lifetime of people reading this article? Conceivably. The naysayers have good reason for skepticism, but these breakthroughs prove that star power on this planet is possible.

5. Malaria and RSV Vaccines: Great News for Kids

Malaria, one of the world’s leading causes of childhood mortality, killed more than 600,000 people in 2022. But with each passing year, we seem to be edging closer to ridding the world of this terrible disease.

Fifteen months ago, the first malaria vaccine, developed by University of Oxford scientists, was found to have up to 80 percent efficacy at preventing infection. It has already been administered to millions of children. But demand still outstrips supply. That’s why it’s so important that in 2023, a second malaria vaccine called R21 was recommended by the World Health Organization, and it appears to be cheaper and easier to manufacture than the first one, and just as effective. The WHO says it expects the addition of R21 to result in sufficient vaccine supply for “all children living in areas where malaria is a public health risk.”

What’s more, in the past year, the FDA approved vaccines against RSV, or respiratory syncytial virus. The American Lung Association estimates that RSV is so common that 97 percent of children catch it before they turn 2, and in a typical year, up to 80,000 children age 5 and younger are hospitalized with RSV along with up to 160,000 older adults. In May, both Pfizer and GSK were granted FDA approval for an RSV vaccine for older adults, and in July, the FDA approved a vaccine to protect infants and toddlers.

6. Killer AI: Artificial Intelligence at War

In the nightmares of AI doomers, our greatest achievements in software will one day rise against us and cause mass death. Maybe they’re wrong. But by any reasonable analysis, the 2020s have already been a breakout decade for AI that kills. Unlike other breakthroughs on this list, this one presents obvious and immediate moral problems.

In the world’s most high-profile conflict, Israel has reportedly accelerated its bombing campaign against Gaza with the use of an AI target-creation platform called Habsora, or “the Gospel.” According to reporting in The Guardian and +972, an Israeli magazine, the Israel Defense Forces use Habsora to produce dozens of targeting recommendations every day based on amassed intelligence that can identify the private homes of individuals suspected of working with Hamas or Islamic Jihad. (The IDF has also independently acknowledged its use of AI to generate bombing targets.)

Israel’s retaliation against Hamas for the October 7 attack has involved one of the heaviest air-bombing campaigns in history. Military analysts told the Financial Times that the seven-week destruction of northern Gaza has approached the damage caused by the Allies’ years-long bombing of German cities in World War II. Clearly, Israel’s AI-assisted bombing campaign shows us another side of the idea that AI is an accelerant.

Meanwhile, the war in Ukraine is perhaps the first major conflict in world history to become a war of drone engineering. (One could also make the case that this designation should go to Azerbaijan's drone-heavy military campaign in the Armenian territory of Nagorno-Karabakh.) Initially, Ukraine depended on a drone called the Bayraktar TB2, made in Turkey, to attack Russian tanks and trucks. Aerial footage of the drone attacks produced viral video-game-like images of exploded convoys. As Wired UK reported, a pop song was written to honor the Bayraktar, and a lemur in the Kyiv Zoo was named after it. But Russia has responded by using jamming technology that is taking out 10,000 drones a month. Ukraine is now struggling to manufacture and buy enough drones to make up the difference, while Russia is using kamikaze drones to destroy Ukrainian infrastructure.

7. Fervo and Hydrogen: Making Use of a Hot Planet

If the energy industry is, in many respects, the search for more heat, one tantalizing solution is to take advantage of our hot subterranean planet. Traditional geothermal plants drill into underground springs and hot-water reservoirs, whose heat powers turbines. But in much of the world, these reservoirs are too deep to access. When we drill, we hit hard rock.

Last year’s version of this list mentioned Quaise, an experimental start-up that tries to vaporize granite with a highly concentrated beam of radio-frequency power. This year, we’re celebrating Fervo, which is part of a crop of so-called enhanced geothermal systems. Fervo uses fracking techniques developed by the oil-and-gas industry to break into hot underground rock. Then Fervo injects cold water into the rock fissures, creating a kind of artificial hot spring. In November, Fervo announced that its Nevada enhanced-geothermal project is operational and sending carbon-free electricity to Google data centers.

That’s not the end of this year’s advancement in underground heat. Eleven years ago, engineers in Mali happened upon a deposit of hydrogen gas. When it was hooked up to a generator, it produced electricity for the local town and only water as exhaust. In 2023, enough governments and start-ups accelerated their search for natural hydrogen-gas deposits that Science magazine named hydrogen-gas exploration one of its breakthroughs of the year. (This is different from the “natural gas” you’ve already heard of, which is a fossil fuel.) One U.S.-government study estimated that the Earth could hold 1 trillion tons of hydrogen, enough to provide thousands of years of fuel and fertilizer.

8. Engineered Skin Bacteria: What If Face Paint Cured Cancer?

In last year’s breakthroughs essay, I told you about a liquid solution that revived the organs of dead pigs. This year, in the category of “Wait, what?,” we bring you the news that face paint cures cancer. Well, sort of face paint. And more like “fight” cancer than cure. Also, just in mice. But still!

Let’s back up. Some common skin bacteria can trigger our immune system to produce T cells, which seek and destroy diseases in the body. This spring, scientists announced that they had engineered an ordinary skin bacterium to carry bits of tumor material. When they rubbed this concoction on the head of mice in a lab, the animals produced T cells inside the body that sought out distant tumor cells and attacked them. So yeah, basically, face paint that fights cancer.

Many vaccines already use modified viruses, such as adenovirus, as delivery trucks to drive disease-fighting therapies into the body. The ability to deliver cancer therapies (or even vaccines) through the skin represents an amazing possibility, especially in a world where people are afraid of needles. It’s thrilling to think that the future of medicine, whether vaccines or cancer treatments, could be as low-fuss as a set of skin creams.

9. Loyal Drugs: Life-Extension Meds for Dogs

Longevity science is having a moment. Bloomberg Businessweek recently devoted an issue to the “tech titans, venture capitalists, crypto enthusiasts and AI researchers [who] have turned longevity research into something between the hottest science and a tragic comedy.” There must be a trillion (I’m rounding up) podcast episodes about how metformin, statins, and other drugs can extend our life. But where is the hard evidence that we are getting any closer to figuring out how to help our loved ones live longer?

Look to the dogs. Large breeds, such as Great Danes and rottweilers, generally die younger than small dogs. A new drug made by the biotech company Loyal tries to extend their life span by targeting a hormone called “insulin-like growth factor-1,” or IGF-1. Some scientists believe that high levels of the chemical speed up aging in big dogs. By reducing IGF-1, Loyal hopes to curb aging-related increases in insulin. In November, the company announced that it had met a specific FDA requirement for future fast-tracked authorization of drugs that could extend the life span of big dogs. “The data you provided are sufficient to show that there is a reasonable expectation of effectiveness,” an official at the FDA wrote the company in a letter provided to The New York Times.

Loyal’s drug is not available to pet owners yet—and might not be for several years. But the FDA’s support nonetheless marks a historic acknowledgment of the promise of life-span-extension medicine.

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American legislators demand scenarios for war termination that neither Ukraine nor the Biden administration can provide, because critics of Ukraine aid are asking the wrong questions.

First, here are three new stories from The Atlantic:

The most consequential act of sabotage in modern times The new face of the “Great Replacement” Why this math professor objects to diversity statements

Survival Is the Only Strategy

In my previous career, when I was teaching strategy and national-security affairs to U.S. military officers, we used historical case studies to analyze the decisions—some good, some disastrous—made by leaders in the United States and other nations. The specter of Vietnam and the still-painful wounds of Afghanistan and Iraq played a large role in the curriculum.

These open-ended conflicts in Asia and the Middle East convinced generations of American strategists that planning in every war, no matter how the conflict began, should include an “exit strategy.” I was required to teach this concept, but I have always vehemently disagreed with it, and I wish I could ban the term itself from the strategic lexicon. Exit strategies are the kind of thing that appeal to American hubris: Only very powerful countries, captured by the delusion that planning and firepower grant near-complete control of events, can afford to think about how to “exit” a war before it’s even been won.

For data-driven Americans who have internalized the middle-management tropes of business schools, the concept is pure catnip. Tell us what you need, how long this will last, and explain our return on investment—as if war were just another spreadsheet exercise. (“Return on investment” is another sensible business concept that too many in the defense community have clumsily tried to apply to national-security strategies.)

None of this is to say that nations should merely plunge ahead with military action on a whim. Especially for relatively small operations, “How will we know when we’re done?” is a crucial question. Sometimes the answer is clear, such as in the 1983 U.S. invasion of Grenada, when the goals were to rescue American citizens, depose a Marxist-Leninist regime, flush Cuban forces from the country, and hand the government over to new leaders. All of these objectives were achieved after combat operations that lasted approximately four days, with 19 Americans killed in action.

Only days earlier in 1983, however, the inability to answer the question of “Why are we here and when should we leave?” led to disaster in Lebanon. American military personnel, sent with unclear goals into a chaotic situation, ended up sitting around in a camp at the Beirut airport. A suicide bomber drove into the base and killed 220 Marines, 18 sailors, and three soldiers. The operation was such a mess that it has been taught as a case study at the Naval War College for years.

In an all-out war, when the stakes are much higher, questions about exit strategies become nonsensical, even inane. Imagine an American telling Winston Churchill during the Battle of Britain: “Prime Minister, if we’re going to send aid, we really need to know your exit strategy here.” Imagine calling Golda Meir in 1973, as Israel was reeling under a surprise attack by Egypt and Syria, and waffling about how we’d have to get back to her unless she could be just a smidge clearer on how the conflict might end.

That’s essentially what many critics of aid to Ukraine—especially in the Republican Party—are asking of President Joe Biden and Ukrainian President Volodymyr Zelensky.

I will leave aside the obvious bad faith involved in many of the GOP complaints about Ukraine. Some Republican legislators oppose aid purely to give Biden a public black eye. Others, as I wrote recently, are sucking up to the extreme wing of their own party, including more than a few who actually admire Russian President Vladimir Putin as some sort of white-Christian champion.

Other objections appear to be more grounded, but in the end make little sense. What does it mean, for example, to say that aid to Ukraine needs more “oversight”? The United States—in a policy I think wise—has placed limits on how American weapons can be used, but the Ukrainians are not going to be able to account for every shell and missile. Even the hyper-bureaucratized U.S. military doesn’t do that in the heat of battle, because war never works that way. In a note widely attributed to Britain’s Duke of Wellington (the man who would eventually defeat Napoleon), the famed general bristled at penny-pinching from his superiors back home while he was fighting on the Iberian Peninsula. “We are at war with France, a fact which may come as a bit of a surprise to you gentlemen in Whitehall,” he wrote in 1812.

This brings me to my present purpose, which is to request elucidation of my instructions from His Majesty’s Government so that I may better understand why I am dragging an army over these barren plains. I construe that perforce it must be one of two alternative duties, as given below. I shall pursue either one with the best of my ability, but I cannot do both: 1.To train an army of uniformed British clerks in Spain for the benefit of the accountants and copy-boys in London or perchance. 2. To see to it that the forces of Napoleon are driven out of Spain.

More than two centuries later, Republicans such as Senator J. D. Vance of Ohio seem to think it’s clever to haul off zingers about Ukrainian officials buying bigger yachts while America sends aid. (Senator Thom Tillis, Vance’s Republican colleague from North Carolina, described Vance’s accusation directly and fragrantly: “Total and unmitigated bullshit.”) But if we’re really going to obsess about return on investment, aid to Ukraine might count as one of the most devastatingly efficient and effective defense expenditures of American treasure in the history of the republic.

The U.S. intelligence community, in a newly declassified report to Congress, estimates that Russia has lost 87 percent of the total number of active-duty ground troops that it had prior to launching its invasion of Ukraine—and note that this does not mean “men sent into battle” but nearly nine-tenths of its entire army—and two-thirds of its preinvasion inventory of tanks.

The United States has so far provided military aid to Ukraine that amounts to roughly a tenth of its total annual defense budget. In return, one of America’s most dangerous enemies has sacrificed almost all of its existing soldiers and the bulk of its armor. The courage of the Ukrainian people and the valor of their armed forces have accomplished all of this without a single American soldier being ordered into battle. And yet Republicans want to depict this astonishing achievement as a budgetary strain that makes America less safe.

Despite the clear impact of American aid, critics continue to ask: How does it all end? For Ukraine, the only exit strategy is survival, just as it was for Britain in 1940 or Israel in 1973. The Ukrainians will keep fighting, because the alternative is the enslavement and butchery of the Ukrainian people, and the end of Ukraine as a nation. The Russians are the people who need an exit strategy. But as long as some in the GOP keep giving Putin the hope that he can outlast the West—and as long as Russian parents keep handing Putin their sons to burn on the pyre of his ego and delusions—this war will go on.

The Kremlin will stay the course. So should we, for as long as it takes to ensure the survival of Ukraine and the security of Europe, the United States, and the world.

Related:

Will America abandon Ukraine? Why the GOP doesn’t really want a deal on Ukraine and the border

Today’s News

In an effort led by Republican lawmakers, the House voted to officially launch an impeachment inquiry into the Biden family’s business dealings. Hunter Biden refused to appear for a closed-door deposition in the Republican-led impeachment inquiry into his father, but offered to testify publicly instead. The Supreme Court agreed to take up a case regarding the availability of the abortion pill mifepristone, which can be acquired by mail.

Dispatches

Work in Progress: Anxiety is content now, Derek Thompson writes. The way we commonly discuss mental-health issues—especially on the internet—isn’t helping us.

Explore all of our newsletters here.

Evening Read

Illustration by Paul Spella. Sources: Hulton Archive / Getty; Gamma-Keystone / Getty.

The Rise and Fall of the ‘IBM Way’

By Deborah Cohen

IBM is one of the oldest technology companies in the world, with a raft of innovations to its credit, including mainframe computing, computer-programming languages, and AI-powered tools. But ask an ordinary person under the age of 40 what exactly IBM does (or did), and the responses will be vague at best. “Something to do with computers, right?” was the best the Gen Zers I queried could come up with. If a Millennial knows anything about IBM, it’s Watson, the company’s prototype AI system that prevailed on Jeopardy in 2011 …

Today, as we hurtle toward a future in which AI threatens to obliterate the individual both as employee and creator, much of the IBM story reads like a tale from a faraway world. The company’s technological accomplishments are still recognizable as the forerunners of the digital era, yet its culture of social responsibility—a focus on employees rather than shareholders, restraint in executive compensation, and investment in anti-poverty programs—proved a dead end. A mashup of progressivism and paternalism, communalism and cutthroat competition, the once ballyhooed “IBM Way” was, for better and worse, inextricably intertwined with the family at the top.

Read the full article.

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Katherine Hu contributed to this newsletter.

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