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Trio Wins Nobel Prize in Medicine for Discoveries on Immune System

One winner is off-the-grid on a backpacking trip, says his friend and colleague

Immunologists Mary E. Brunkow, Fred Ramsdell and Shimon Sakaguchi were awarded the Nobel Prize in Physiology or Medicine for uncovering a process that prevents the immune system from attacking our own tissues, called peripheral immune tolerance. The work unlocked a new field of research and potential therapies.

The trio identified a core feature of how the immune system functions and keeps itself in-check: regulatory T-cells. They prevent other immune cells from harming our own bodies and developing autoimmune conditions including Type 1 diabetes and rheumatoid arthritis. Based on this fundamental knowledge, clinical trials are ongoing to test therapies for autoimmune diseases, cancer and post-organ transplantation.

“Their discoveries have been decisive for our understanding of how the immune system functions and why we do not all develop serious autoimmune diseases,” said Olle Kämpe, chair of the Nobel Committee on Monday.

Brunkow is now based at the Institute for Systems Biology in Seattle, Ramsdell at the San Francisco and Seattle-based Sonoma Biotherapeutics, while Sakaguchi is a distinguished professor at Japan’s Osaka University. The group will share the 11 million Swedish kronor, or roughly $1.1 million, prize.

Ramsdell, as far as anyone is aware, doesn’t know he has won the prize yet; he is backpacking somewhere in Idaho, says Jeff Bluestone, chief executive of Sonoma Biotherapeutics. They last talked when Ramsdell was heading out on the trip in September. Bluestone said he has tried text, email and phone calls that have gone to voicemail.

“He is literally off the grid,” Bluestone said, who has fielded calls and questions all morning. “I seem to have been the default if you couldn’t find Fred.”

The company is developing engineered regulatory T-cells for autoimmune and inflammatory diseases. They are planning on reporting their first set of clinical data on a drug for rheumatoid arthritis at the end of this month.

“The ability to manipulate these cells so that they can become powerful, specific therapeutics is really the promise of the field,” Bluestone said.

Humans are constantly exposed to microbes that could make us sick, and the immune system developed to protect us. As part of this complex system, T-cells have receptors that help the body detect viruses, bacteria or other threats, but some can also attach to and alert against our own tissues, causing damage.

Researchers understood in the 1980s that T-cells mature in the thymus and undergo a test to eliminate cells that would latch on to our own tissues. Yet some can still escape into the bloodstream and become dangerous. Regulatory T-cells can keep these stray, potentially harmful cells in check.

“I first became interested in this field because I wanted to know more about how the immune system works, how your own body attacks itself,” Sakaguchi said at a news conference on Monday. He called the win an honor and a happy surprise.

Sakaguchi made the first key finding while working at the Aichi Cancer Center Research Institute in Nagoya, Japan. His colleagues had discovered that removing the thymus in mice shortly after birth resulted in their immune systems going haywire and the development of autoimmune diseases.

Sakaguchi then isolated mature T-cells from genetically identical mice and injected them into the mice without a thymus, and that appeared to protect them. The results of this trial and others convinced him that the immune system must include some cells that calm it down, and after a decade of work presented the new class of previously unknown immune cells in 1995, called regulatory T-cells.

But many researchers were skeptical of the finding, the committee said.

American duo Brunkow and Ramsdell made a further key discovery in 2001, while working at a biotech company called Celltech Chiroscience in Bothell, Wash., that developed drugs for autoimmune conditions. They were looking at “scurfy” mice; males are unexpectedly born with flaky skin and enlarged spleens and only live for a few weeks, because their organs are attacked by their own immune cells.

Researchers suspected that the mutation causing the condition was somewhere on the X chromosome, because females, which have two X chromosomes, are less affected. The duo mapped a piece of chromosome from a scurfy mouse, a huge undertaking at the time, and planned to look at 20 genes in that area. They found the mutation on the final gene they checked, which they named the Foxp3 gene.

“It was really a molecular slog, to get to that exact mutation,” Brunkow said on Monday. “It was just a very small genetic alteration that results in quite a profound change in the immune system.”

Later, they also discovered that mutations in that human equivalent gene caused a rare autoimmune disease, IPEX, with help from pediatricians around the world who collected samples from affected boys. Two years after that, Sakaguchi and later other researchers were able to prove that the Foxp3 gene controls the development of regulatory T-cells. The T-cells also help the immune system calm down after fighting a foreign invader, so it doesn’t continue on overdrive.

The laureates’ discoveries have paved the way for research looking at forming more or modifying regulatory T-cells to fight autoimmune disease, as well as dismantling the co-opted T-cells that tumors use to hide from the immune system. Sakaguchi said that he wanted to continue researching how to enhance immune responses in cancer and to potentially prevent cancer cells from spreading and metastasizing.

“Suppressing immune responses and simultaneously boosting them when necessary,” he said. “I’d be thrilled if both approaches could be developed at the same time.”

Thomas Perlmann, secretary-general of the Nobel Assembly, said Monday at a news conference that he was able to reach Sakaguchi in his lab and relay the news, but he wasn’t able to get hold of Brunkow or Ramsdell at that point.

“We have their phone numbers, but they are probably on silent mode,” Perlmann said. “I asked them to, if they have a chance, to call me back.”

Brunkow later said that she assumed the call that came in the middle of the night was spam and ignored it. Then, she heard her husband talking with someone in the living room; an Associated Press photographer showed up on their front porch.

“I’m sure it hasn’t quite hit me yet,” she said on a 4:30 a.m. call with Nobelprize.org. “It’s an honor to have been a part of that initial work.”

UK steel industry warns of ‘biggest crisis’ due to new EU tariffs

European Commission set to propose a levy of 50% on steel imports

The UK steel industry is facing its “biggest crisis” in history, the sector’s trade body has warned, as the EU prepares to impose steep tariffs that could be more devastating than those levied by the US.

The European Commission intends to propose tariffs of 50 per cent on steel imports worldwide above a quota set at 2013 levels on Tuesday, according to a document obtained by the Financial Times.

The move threatens to inflict disproportionate damage on the UK steel industry, from which 80 per cent of exports go to Europe. Steel imports squeezed out of the EU could also flood the UK.

Gareth Stace, director-general of industry lobby group UK Steel, warned that the new tariffs “could be terminal for many of our remaining steel companies”, urging ministers to “recognise the urgent need to put in place its own measures to defend against a flood of imports”.

“This is perhaps the biggest crisis the UK steel industry has ever faced. Government must go all out to leverage our trading relationship with the European Union to secure UK country quotas or potentially face disaster,” he said.

The tariffs pile pressure on an industry struggling under the weight of high energy prices, global overcapacity caused by a glut of Chinese steel and the investment needed to decarbonise steel production.

The industry is already grappling with 25 per cent levies imposed by US President Donald Trump after the Labour government failed to secure a promised zero tariff deal.

But a far greater proportion of British steel is sold to Europe than to America. “This risks being Trump on steroids,” said one industry figure. 

The new import taxes represent a fresh blow to a sector already in dire straits with the government forced to step in earlier this year to take control of British Steel from its previous Chinese owner Jingye.

Steel producers are pressing the government to use its long awaited steel strategy, expected this autumn, to reshape the industry’s future, rather than lurching from crisis to crisis.

Under the EU’s proposals, countries will be given specific quotas, as will product categories. The EU industry has also been struggling to compete with cheap imports from China, Turkey, Vietnam and elsewhere.

The EU steel sector announced 18,000 job cuts in 2024, adding to the 90,000 job losses since 2008, industry lobby Eurofer said. 

“There is no other way to ensure the long-term protection of the steel industry,” said one EU official. “If not, we are going to find ourselves without a steel industry.”

Liam Bates, president of long products at Marcegaglia, which has two stainless producing plants in the UK, said the move was no surprise given the pressure from Trump’s tariffs on the EU steel industry.

He added that it would put “huge stress” on its UK business producing rods, which are used in automotive construction and general machinery. 

“Coming immediately after the disappointment of not getting zero free tariffs from the US, we are eagerly anticipating the government’s steel strategy and efforts to make electricity prices competitive,” Bates said.

The UK government has put a brave face on the 25 per cent tariff on British steel sales to the US, which is lower than the 50 per cent applied elsewhere.

But Prime Minister Sir Keir Starmer had previously been hoping for a zero per cent US tariff for a quota of British steel exports.

Even before the imposition of the tariffs, the UK sector was in decline, with domestic crude steel production last year falling to just 4mn tonnes — the lowest total since the Great Depression of the 1930s.

Last year, the EU imported 28mn tonnes of steel, a quarter of the total sold in the bloc. Under the proposed new regime, tariff free quotas would cover 18.3mn tonnes.

The EU measure would replace a 25 per cent tariff that is riddled with exemptions and has failed to stop a surge in imports, and must be renewed after five years.  

It has to be approved by a weighted majority of member states and the European parliament, a process likely to take until early 2026. 

Donald Trump says US truck imports to face 25% tariff from November 1

Announcement comes on eve of talks in Washington with Canadian Prime Minister Mark Carney

President Donald Trump has warned that medium and heavy trucks imported to the US will face a 25 per cent tariff starting on November 1, in a new move to overhaul supply chains in the global car industry.

Trump announced the step in a Truth Social post on Monday, on the eve of a visit to the White House by Mark Carney, the prime minister of Canada, which would be heavily affected by any new tariffs on US truck imports.

The president had said in late September that he would be imposing 25 per cent tariffs on some truck imports this month but failed to implement them, raising questions about his commitment to the policy. His statement on Monday suggests he is determined to press ahead.

“Beginning November 1st, 2025, all Medium and Heavy Duty Trucks coming into the United States from other Countries will be Tariffed at the Rate of 25%,” Trump posted.

Since Trump returned to the White House for his second term he has slapped levies on a wide range of automobile and auto parts imports from around the world, in a bid to spur more domestic production.

The White House has not offered any details on the truck tariffs, including whether vehicle parts would be affected and whether imports from Canada and Mexico would be exempt if they are compliant with the domestic content rules in the existing free trade agreement between the North American neighbours.

The announcement on the eve of the White House meeting between Trump and Carney could overshadow their talks on Tuesday. Canada, which has strong economic ties to the US, has been trying to avoid an escalation in the trade war with its southern neighbour.

“Hopefully the PM is able to get progress on some tariff relief. It would be a welcome step in the right direction,” said Goldy Hyder, president of the Business Council of Canada.

Flavio Volpe, president of Canada’s Automotive Parts Manufacturers’​ Association said his group would “need to wait and see the paperwork via the registry or an Executive Order”.

“It’s unclear whether this policy-by-social post intends an exemption for US content like on light vehicles or a USMCA [the North American trade deal] exemption for major components like engines,” Volpe said. “The OEMs are fighting for both,” he said, referring to the big carmakers.

The 112-year-old marque that burns cash like an AI startup

A profit warning today from Aston Martin-Lagonda is as good an excuse as any to run the numbers on one of the London market’s most ridiculous companies. Here’s a chart:

Based on group free cash flow, each Aston Martin sold wholesale since 2014 has cost the company more than £45,000 on average. Assuming 62,000 Aston Martins delivered between 2014 and the end of the current year, that adds up to a £2.8bn customer subsidy.

The subsidy’s been funded by new equity (nearly £2bn raised since IPO) and debt (more than £400mn of net issuance, meaning year-end net debt will be £1.3bn or nearly eight times Ebitda). It’s been a very expensive vanity project for Lawrence Stroll, whose consortium rescued Aston Martin from probable bankruptcy in 2020.

The shares are down 96 per cent from the IPO (which raised no new money!), but that only tells half the story. There’s been an effective equity-to-debt swap since Stroll took control:

And there’s more to come. JPMorgan, Aston Martin’s joint house broker, forecasts £360mn of cash burn in 2025 and a further £230mn in the first half of 2026.

Seasonality is one of the many peculiar things about Aston Martin, with the company making the bulk of its sales in the second half. That means cash burn should ease by the end of 2026.

Still, to keep the lights on in the meantime, Aston Martin may need to raise another £200mn, JPM says. It expects a cash call on similar terms to the previous two, which were done at a £2.3bn enterprise value.

Another thing lacking, in addition to profit and cash flow, is a break-even target. Today’s profit warning came with a small cut to capex and a pledge to reduce sales and administration costs, but no guidance more specific than 2026 should be better than 2025.

With a very concentrated ownership base and no big debt refinancings due before 2029, a route to profitability may be less of a concern to Aston Martin’s bosses than to independent shareholders.

Peter Thiel tells investors that scale will determine success in the AI race.

Peter Thiel’s Founders Fund is doubling down on its biggest artificial intelligence bets, embracing a concentrated strategy as rivals spread their bets across a wide swath of startups.

Among them are OpenAI, data center builder Crusoe and General Matter, a nuclear fuel startup the firm has incubated, Founders Fund said at its recent annual general meeting for investors. In contrast, other venture firms have poured money across the AI landscape, often backing multiple companies competing in the same markets.

Founders Fund’s decision to invest more in its biggest AI companies is notable because Thiel has warned of a bubble and Founders Fund has recently been relatively cautious about investing in generative AI startups. The firm first put money into OpenAI in early 2023 but didn’t invest as heavily in other model developers and app companies as peers.

Thiel used the 20-year-old firm’s annual general meeting last month to lay out its plan to concentrate its investments in a handful of AI companies. Speaking to the firm’s hundreds of limited partners and Silicon Valley luminaries in a video presentation, Founders Fund partners outlined plans to stand behind a single company operating at each level of the AI business, according to notes prepared by an attendee and people familiar with the meeting.

One of them is OpenAI. The company’s CEO, Sam Altman, took the stage with Thiel to promote their shared view that the winners in AI will be companies that can get to enormous scale the fastest. That strategy justifies Founders Fund’s recent roughly $1 billion investment in OpenAI at a $300 billion valuation when including more than $40 billion in new capital, one of the biggest investments in the firm’s history.

The OpenAI investment fits with the longtime strategy of Founders Fund, led by Thiel and a handful of other partners, to concentrate funds into a small number of its favorite companies, such as defense contractor Anduril. It has profited from big early bets on companies including Airbnb and Palantir and has developed a reputation for going against the grain, making an investment in SpaceX when others were not eager to put money behind rocket launches.

Founders Fund said its $671 million total investment in SpaceX beginning in 2008 has turned into a $20.3 billion position when including its current holdings and the shares it’s sold, a more than 30 times gain for the funds.

Altman and Thiel have a long history. Thiel invested in Altman’s venture fund, Hydrazine Capital, more than a decade ago, and OpenAI listed Thiel as one of its initial donors when it began in 2015.

Speaking at the meeting, Altman said OpenAI would continue to use its billions in capital to fund advanced chips and data centers, while ramping up hiring to generate more business. The company is now valued at $500 billion, based on an employee share sale this week.

Altman said that makes OpenAI the most valuable company per employee in the world, and it could go public in the next couple of years if the conditions are right. An OpenAI spokesperson said he wasn’t at the event, so he couldn’t comment on what Altman said.

Founders Fund’s rivals such as Andreessen Horowitz and Lightspeed Venture Partners have spread their bets widely across several AI model makers and application startups. The divide in how venture capitalists approach AI could determine which investment firms and AI companies emerge stronger from the current funding boom. The dot-com frenzy led to a shakeout in the venture capital industry after many funds had big losses.

Founders Fund made an early foray into AI in 2011 with an investment in DeepMind before the startup’s sale to Google. As other investors have begun piling into AI startups and driving up prices, Founders Fund has applied extra scrutiny to potential AI investments, said one person familiar with the firm’s approach.

Thiel has publicly compared the current state of AI to the dot-com boom. “The rough analogy is that AI in 2024 is like the internet in 1999,” he said on a podcast last year. “On a business level, it’s very, very treacherous.”

Founders Fund’s AI strategy aligns with Thiel’s long-held belief that the best investments are in companies with the potential to create monopolies instead of competing in existing markets. It’s also planning to make a smaller number of investments from its growth-stage funds, which are funding its biggest AI bets.

The firm told investors at the meeting that it plans to back about 10 companies in its most recent $4.6 billion growth-stage fund. That compares to 15 companies in its second growth fund and 31 companies in its first growth fund, both of which were smaller in size.

The first $1.7 billion growth fund raised in 2020 had a 10% net of fees internal rate of return through the first quarter this year, while the second $3.4 billion growth fund raised in 2022 had a 24% IRR through the same cutoff date, said one person familiar with the returns.

Founders Fund said AI coding startup Cognition, one of its biggest bets, is on track to beat its target of generating roughly $200 million in annual recurring revenue by the end of the year from its Devin software tool. The firm recently led a $400 million round of funding valuing Cognition at $10.2 billion, including the new cash, after first investing early last year.

Founders Fund also said at the meeting it plans to invest in a new round of funding for data center builder Crusoe at a $10 billion valuation. The firm invested $240 million in the company last year. Crusoe last month completed the first phase of its Abilene, Texas, data center campus for Oracle, which is supplying OpenAI with cloud computing.

General Matter, a startup building U.S.-based uranium enrichment facilities, is another example of how Founders Fund is concentrating its AI bets. The firm incubated General Matter, co-founded by Founders Fund partner Scott Nolan, and led its first two funding rounds, giving Founders Fund a 27.5% stake, it said at the meeting.

Founders Fund thinks General Matter will become a critical supplier of uranium to companies building small nuclear reactors to power AI data centers. The company is aiming to begin operations at a planned uranium enrichment facility in Paducah, Ky., by the end of the decade.

One area Founders Fund is shying away from is AI chips, which Nvidia dominates. Of the five categories of AI companies the firm laid out at the meeting, chips was the only one where it hasn’t yet made any major bets.

Founders Fund also hasn’t backed any of OpenAI’s major competitors in AI model development, like Anthropic or xAI.