Venture capital flow to women-founded companies has stabilized in the post-pandemic environment. BioSpace looks back at five companies that have nabbed the most over the past two decades.
Biopharmas with women founders have contributed $64.1 billion in venture capital dollars across 3,375 deals since 2008, according to a recent analysis by PitchBook.

2025 has been a particularly good year for female-founded companies across all sectors, with $103.7 billion invested across 2,528 deals so far, according to PitchBook. Zeroing in on biopharma, the capital flow suggests that investment in female-founded companies is stabilizing in the post-pandemic environment. In 2025 so far, female-founded biopharmas have taken in $4.8 billion across 203 deals.

This is a significant drop from the peak in 2021, when $12.7 billion in venture capital was recorded for this category across 412 transactions. Since then, the numbers have declined as the sugar buzz wore off—a trend that is reflected across biopharma, regardless of the gender of the founders.

Much of the cash for women-founded biopharmas has centered in the U.S.’ two key biotech hubs: the Boston-Cambridge area, which saw $24.4 billion in investment across 759 total deals, and San Francisco-Oakland, where 618 deals netted $16.3 billion.

Investment rounds were split equally across early, late and angel rounds. Female-only founded companies took in $7.7 billion in 509 deals, compared to $56.4 billion over 2,866 deals for biopharmas co-founded by women and men.

The largest deal in the 16 years for which PitchBook has data was EQRx, which brought in $570 million in a series B in January 2021. The company, which has since gone out of business, had six founders including Melanie Nallicheri, Susan Hager and Sandra Horning.

Below, BioSpace looks back at the top five rounds since 2008 and where the companies are today.

EQRx

Deal Size: $570 million
Round: B
Founders: Alexis Borisy, Melanie Nallicheri, Robert Forrester, Susan Hager, Peter Bach and Sandra Horning

After a massive fundraising push over three years that raised a total of $1.97 billion, the ending for EQRx was not happy.

The company emerged with a big goal: to develop medicines that were not just innovative, but affordable. EQRx jumped to the markets quickly through a special purpose acquisition company (SPAC) in August 2021, picking up another $1.8 billion in proceeds.

But the lofty goal quickly met with clinical reality. The biotech’s antibody sugemalimab stumbled in the clinic, leaving executives reeling. EQRx pivoted to two other candidates, then ditched the low-cost goal. The staff was slashed in half, and EQRx later sold itself to Revolution Medicines in August 2023, preserving $1 billion in capital for that company. All of EQRx’s assets were terminated and returned to partners.

Neumora

Deal Size: $500 million
Round: A
Founders: Paul Berns, Kristina Burow, Robert Nelsen, Mike Poole, Morgan Sheng and Carol Suh

Believe it or not, a $500 million series A was not enough to earn Neumora the title of largest VC fundraise of 2021. Abogen’s whopping $700 million round nabbed that top slot. But that’s the nature of that year, when investors flocked to the sector buoyed by the hopeful innovation of COVID-19 vaccines that arrived at the end of 2020 to combat the pandemic.

Neumora was the fourth largest VC round of 2021—and that still made waves in the sector. The company emerged with the cash and a partnership with Amgen to develop therapies for neurodegenerative disorders. It has now raised a total of $987 million, including a $250 million IPO in September 2023, according to PitchBook data.

The path has not been a straight line for Neumore, however. In April 2024, the FDA slapped a clinical hold on the biotech’s schizophrenia asset as preclinical safety signals emerged.

But Neumora plowed on, unfortunately revealing a Phase III failure for the kappa opioid receptor (KOR) antagonist navacaprant in major depressive disorder in January this year. With two additional trials expected to readout for the drug this year, Neumora changed things up in March and pushed out the timeline to 2026.

After fielding all these challenges, Neumora is now on the cusp of releasing key Alzheimer’s disease data for NMRA-511. This could be the moment that $500 million seems worthwhile for investors.

Lyell Immunopharma

Deal Size: $493 million
Round: C
Founders: Rick Klausner, Crystal Mackall and Stan Riddell

Lyell Immunopharma was ahead of the pandemic-influenced biotech funding curve with a massive $493 million series C round in March 2020. Since then, the company has continued to battle in the tough cell therapy space, using its influx of cash from various fundraising mechanisms to bring in new approaches to address the modality’s limitations.

Founded by a team of cell therapy experts, Lyell has promised to develop next generation CAR T cell therapies for blood cancer and solid tumors by addressing T cell exhaustion and durability. Riding the wave of biotechs heading for the public markets in 2021, Lyell pulled off a massive $425 million IPO in June. Lyell’s GSK-partnered T cell receptor therapy hit the clinic the next year, but the success was short lived as the Big Pharma walked away from the $250 million three-year partnership months later.

Continuing on, Lyell reported mixed Phase I data for the CAR T therapy LYL797 in solid tumors in June 2024. The results revealed strong response rates across patients, but a death and high rates of cytokine release syndrome marred the readout. The asset was discontinued in October 2024, just as Lyell bought ImmPACT Bio for $30 million in cash plus shares.

The heart of that deal was an autologous dual-targeting CD19/CD20 CAR T, now known as rondecabtagene autoleucel (ronde-cel). Lyell began a pair of pivotal trials for the candidate this year, including a head-to-head test pitting ronde-cel against approved CD19 CAR T cell therapies, including Bristol Myers Squibb’s Breyanzi or Gilead’s Yescarta.

Lyell also followed the biopharma trend and picked up a new CAR T cell candidate from China’s Innovative Cellular Therapeutics.

Laronde

Deal Size: $440 million
Round: B
Founders: Avak Kahvejian, Noubar Afeyan, Nicholas Plugis, Erica Weinstein, Sophie Boer

This Flagship Pioneering–backed startup vowed to champion a new form of RNA medicines called Endless RNA upon launch in 2021. The company rode the success of Moderna—the star of Flagship’s portfolio—to a $440 million series B months after the public debut in July 2021.

But the journey was short lived. In June 2023, STAT published an expose on data integrity issues at the biotech. The company could not replicate the preclinical data that had underpinned the massive raise. Laronde cut two programs and many employees were forced to resign, including CEO Pablo Cagnoni.

Flagship folded the embattled biotech into another of its portfolio companies, Senda Biosciences, to form Sail Biomedicines in October 2023. That biotech is continuing the eRNA mission but has yet to enter the clinic.

BioNTech

Deal Size: $425 million
Round: N/A
Founders: Ugur Sahin, Özlem Türeci and Christoph Huber

BioNTech’s story has been told over and over—the Pfizer-partnered pandemic savior developed one of the two COVID-19 vaccines that helped bring the world back from the crisis. This generated billions in revenue and has helped fuel the biotech’s next phase.

But step back to January 2019, when the German mRNA company raised a remarkable $425 million, and you’ll see that BioNTech always had big ambitions. This later-stage round involved just two pharma entities: Pfizer Ventures with $333.5 million in cash and Sanofi with $91.5 million, according to Pitchbook data.

The company followed that year with a more traditional series B in July that totaled $325 million. These fundraises primed the biotech to enter the first year of the pandemic fully charged and ready for some R&D.

While the TrumpRx deals only cover Lilly and Novo for now, the agreements are good for any cardiometabolic biotechs waiting in the wings, according to a new 2026 preview report from PitchBook.
New drug pricing plans for Novo Nordisk and Eli Lilly’s GLP-1 obesity treatments have cleared the runway for new entrants, with the regulatory bumps and grooves for insurance coverage smoothed out to open up a new patient population and bring in ever more investors, according to a new report from PitchBook.

In its annual exit report, the analysis firm said the addition of the approved GLP-1 drugs to Medicare and Medicaid with Most Favored Nation pricing expands the addressable market for the therapies by 7 to 15 million people. It also charts a new course for patients after they faced insurance denials for treatment.

While the TrumpRx deals only cover Lilly and Novo for now, the agreements are good for any biotechs waiting in the wings, PitchBook said.

“Expanded CMS coverage strengthens the case for broader GLP-1 label indications and reinforces long-term cardiometabolic franchise strategies,” the firm said. “Later entrants are positioned to benefit from a clearer regulatory pathway for obesity pharmacotherapy and a larger patient and prescriber base, which may accelerate adoption curves for differentiated products.”

With that said, PitchBook noted that Lilly and Novo are even more entrenched as the market incumbents with the deals in hand and manufacturing logistics already resolved. Any newcomers will still have to face those hurdles.

Nevertheless, the metabolic space will head into 2026 buoyed by exciting M&A developments, too. Specifically, the Pfizer-Novo bidding war to buy Metsera, which ultimately ended with Pfizer’s $10 billion takeover. While this week-long drama underscored the “escalating strategic urgency in this space,” PitchBook notes that there are 120 assets in development across 60 companies, and therefore plenty of potential deals to be made.

“As competition for late-stage assets intensifies, acquirers may move upstream, targeting earlier-stage, higher-risk platforms that offer novel biology or delivery modalities,” PitchBook wrote.

Appetite for Risk Rises

Overall, venture capital activity in biopharma bottomed out in the second quarter, but it seems to have returned in the third, PitchBook reported. This should continue into 2026, with additional rate cuts expected in the new year that could increase investors’ appetite for risk, the firm wrote.

Besides obesity, hungry Big Pharmas have been buying into CAR T cell therapy, antibody-drug conjugates and small molecules.

Thanks to the rise in larger deals—Cidara Therapeutics, Verona Pharma and Avidity Biosciences being recent examples—exit values have risen, even as deal counts remain muted. PitchBook named three companies with exit potential for 2026: the obesity-focused Verdiva Bio, Kailera Therapeutics and genetic medicine biotech ReCode Therapeutics.

On the policy front, PitchBook noted that the initial TrumpRx agreements have helped alleviate some concerns, but that 2026 will see the direct-to-consumer option open to patients for the first time.

“Despite headline price reductions, it remains uncertain whether the TrumpRx model will meaningfully lower patient out-of-pocket cost, although the benefit to pharma companies is clear as they avoid the potential for heavy import tariffs,” PitchBook said. “At a high level, the TrumpRx initiative underscores a growing push to bypass pharmacy benefit managers and improve price transparency.”

U.K.-based pharmas will not face tariffs as long as Donald Trump is president, according to the agreement.

The U.S. and U.K. have reached a trade deal that will see the latter country pay 25% more for new medicines, which in turn has exempted pharma companies headquartered there from tariffs on imports into the U.S.

The deal, the details of which had previously been proposed, is the latest in President Donald Trump’s Most Favored Nation push to equalize drug pricing between the U.S. and other developed nations where medicines are currently much cheaper. The Office of the U.S. Trade Representative announced the finalized agreement on Monday.

The U.K.’s National Health Service will increase the net price paid for new medicines by 25% under the agreement. The nation will also no longer demand portfolio-wide concessions to make up for expensive new medicines under the Voluntary Scheme for Branded Medicines Pricing, Access and Growth or other rebate schemes.

In return, the U.S. will exempt U.K.-based pharma companies from tariffs for the remainder of Trump’s term as president. The U.S. has also promised to “work to ensure that U.K. citizens have access to the latest pharmaceutical breakthroughs” although no further details were provided.

Earlier in the year, the U.S. struck a trade deal with the European Union that involved a 15% tariff on pharmaceutical imports but didn’t touch on drug pricing.

Following Novo Nordisk’s price cuts for its own GLP-1 medicines, Eli Lilly is offering discounts for the obesity drug purchased through LillyDirect. Both pharmas recently struck a deal with the White House for cheaper prices via the yet-to-be-launched TrumpRx.
Eli Lilly is once again cutting the price of its blockbuster obesity drug Zepbound, adding another log to the GLP-1 pricing fire.

The new price is for Zepbound single-dose vials purchased through Lilly’s direct-to-consumer (DTC) platform LillyDirect, according to the company’s announcement Monday. The change brings the cost of a one-month supply of the drug’s lowest dose (2.5 mg)—recommended only as a starter dose—from $349 to $299, while the 5-mg dose goes from $499 per month to $399. All other doses—7.5, 10, 12.5 and 15 mg—will go from $499 to $449 per month.

The move follows obesity rival Novo Nordisk’s Nov. 17 announcement that it will offer patients a self-pay option, providing access to its own GLP1 drugs Wegovy and Ozempic for $199 per month.

Writing to investors Monday morning, BMO Capital Markets analysts wrote that “although Lilly is reducing the prices for cash pay Zepbound, we still see the product priced at a premium to Novo’s cash pay Wegovy.”

The pricing games come after both Lilly and Novo struck deals with the U.S. federal government to offer their GLP-1 medicines at a discount through Medicare and through a DTC platform called TrumpRx, which has not yet launched.

Novo’s drugs—Ozempic for diabetes and Wegovy for obesity—had their prices cut from $1,000 and $1,350 per month, respectively, to $350 per month when purchased through TrumpRx, while Lilly’s drugs Zepbound and orfoglipron will be available at an “average of $346.”

Separately, the Centers for Medicare and Medicaid Services (CMS) last week announced the latest round of Inflation Reduction Act price negotiations, which will bring the cost of Novo’s Ozempic and Wegovy down 71% from list price starting on Jan. 1, 2027.

Analysts at BMO Capital Markets, writing to investors when the pricing negotiations were announced, said, “We reiterate that the important comparison remains the difference between the product’s newly discounted price and the product’s ultimate net price, including rebates,” instead of focusing on list prices.

San Francisco-based 5AM Venture Management reduced its stake in Centessa Pharmaceuticals (NASDAQ:CNTA) by 150,000 shares in the third quarter, according to a November 14 SEC filing.

What Happened

According to a filing published with the Securities and Exchange Commission on November 14, 5AM Venture Management disclosed a reduction in its Centessa Pharmaceuticals position. The fund reported holding 680,945 shares, down by 150,000 shares from the previous quarter. Despite the sale, the overall position value still increased given the stock’s sharp rise last quarter of more than 80%. The revised stake was valued at approximately $16.5 million as of September 30, representing approximately 6.1% of the fund’s approximately $273 million in reportable assets.

What Else to Know

Top five holdings after the update:

• NASDAQ:SKYE: $38 million (13.9% of AUM)
• NASDAQ:TRDA: $24.7 million (9.0% of AUM)
• NASDAQ:PHVS: $19.9 million (7.3% of AUM)
• NASDAQ:CAMP: $17.6 million (6.4% of AUM)
• NASDAQ:CNTA: $16.5 million (6.0% of AUM)

As of Friday, Centessa shares were priced at $29.03, up a staggering 65% over the past year and far outperforming the S&P 500, which is up 14% in the same period.

Company Overview

Metric	Value
Price (as of market close Friday)	$29.03
Market capitalization	$4.2 billion
Revenue (TTM)	$15. million
Net income (TTM)	($242.7 million)

Company Snapshot

Centessa Pharmaceuticals is a biotechnology company headquartered in the United Kingdom that is developing a pipeline of clinical-stage biopharmaceutical products, including Lixivaptan for autosomal dominant polycystic kidney disease and SerpinPC for hemophilia, as well as early-stage assets targeting rare diseases and immunological conditions. Centessa targets patients with rare and serious diseases, as evidenced by its clinical programs in conditions such as hemophilia, autosomal dominant polycystic kidney disease, alpha-1-antitrypsin deficiency, pulmonary arterial hypertension, and certain autoimmune diseases. The company serves a global base of patients, healthcare providers, and research institutions focused on rare and underserved medical conditions.

Foolish Take

Trimming a position after a major rally can be as telling as doubling down—especially when the underlying science is still early but showing real momentum. Centessa has become one of the sector’s standout performers, and the biotech-focused fund’s decision to reduce—not exit—its stake signals continued conviction even as the company’s valuation has surged on clinical progress.

Centessa’s orexin agonist platform remains the key driver. In its latest update, management reported Phase 2a data showing “statistically significant, clinically meaningful and dose-dependent” improvements across wakefulness measures for ORX750, with a favorable safety profile across cohorts. CEO Saurabh Saha called the data “significant progress” and highlighted plans to begin a registrational program in the first quarter of 2026. Financially, Centessa posted a third-quarter net loss of $54.9 million and ended the quarter with $349 million in cash, equivalents, and investments—enough to fund operations into mid-2027. The company also strengthened its balance sheet with an announced $250 million public offering at $21.50 per ADS.

For long-term investors, the takeaway is clear: The trimmed position likely reflects portfolio management, not diminishing confidence. The best evidennce is that the fund kept Centessa among its top holdings, underscoring the potential of a pipeline that could reshape treatment for multiple sleep-wake disorders.

Glossary

13F reportable AUM: Assets under management that must be disclosed in quarterly SEC filings by institutional investment managers in the U.S.

Stake: The ownership interest or investment a fund or individual holds in a particular company.

Position: The amount of a specific security or asset held by an investor or fund.

Clinical-stage: Refers to pharmaceutical products currently being tested in human clinical trials but not yet approved for sale.

Pipeline: The portfolio of drug candidates a pharmaceutical company is developing, often at various stages of research and testing.

Autosomal dominant polycystic kidney disease: A genetic disorder causing cysts in the kidneys, leading to kidney enlargement and impaired function.

Immunological conditions: Diseases or disorders related to the immune system’s function or regulation.

Modular R&D model: A research and development approach where projects are managed independently to increase flexibility and speed.

Outperforming: Achieving better returns or results than a benchmark or comparable group.

Assets under management (AUM): The total market value of investments managed by a fund or investment firm.

TTM: The 12-month period ending with the most recent quarterly report.

Net value change: The difference in the value of an investment position after buying or selling securities.

Sana Biotechnology Inc. stocks have been trading up by 8.46 percent following promising data from their latest scientific breakthrough.

Key Highlights

• The company surpassed third-quarter earnings expectations with a loss per share of $0.16, against the consensus forecast of $0.19. This outperformance highlights Sana Biotechnology’s growing strategic focus.

Healthcare industry expert:

Analyst sentiment – positive

Market Position & Fundamentals: Sana Biotechnology is positioned in the biotechnology sector with a focus on genetic and cellular therapy. The company’s financial ratios reveal growing pains, as evidenced by a low price-to-book ratio of 5.86 and an extremely unfavorable return on equity at -96.11. The quick and current ratios of 4.3 and 4.6, respectively, indicate sufficient liquidity to cover short-term obligations. However, negative cash flow from operations at -$29.4 million and a gross loss position ($42.1 million net income loss) reflect a firm struggling to harness its R&D expenses into profitability. Despite the accumulated operational losses, equity financing has amplified its cash reserves, as seen in net stock issuance activities. This financial snapshot suggests Sana is in a high cash-burn phase, necessitating strategic revisions to offset its losses.

Technical Analysis & Trading Strategy: The recent trading activity shows Sana Biotechnology experiencing bullish momentum, with its stock rising from a low of $3.51 to $4.36 by the week’s end. Notably, the price broke the $4.00 resistance level, confirmed by the week’s increased volume, marking a positive shift in investor sentiment. The dominant trend is upward, and trading strategies should capitalize on this bullish sentiment. A specific actionable strategy would be to buy on pullbacks around the $4.00 level, with stops slightly below $3.90 to manage risk. Breaking above $4.50 would be a trigger for further long entries, projecting the next target at $4.80, contingent on sustaining trading volumes.

Catalysts & Outlook: Sana Biotechnology has outperformed recent earnings estimates, reporting a lower-than-expected Q3 EPS loss, which has provided a boost in market confidence reflected in recent price action. Strategic shifts towards their SC451 program for type 1 diabetes and the in vivo CAR T platform, while suspending less successful programs, emphasize an optimization of resources towards high-potential pipelines. Participation at prominent healthcare conferences could influence investor perception and lend further momentum. Compared to sector benchmarks, Sana remains a high-risk speculative play but offers a favorable outlook with current support seen at $4.00 supporting near-term bullish continuation. Given Sana’s strategic pivot, firm financial reserves, and favorable technical trends, the overall sentiment is cautiously optimistic.

• Efforts are intensifying on SC451 treatment for type 1 diabetes and the in vivo CAR T platform. Resources have been strategically redirected from suspended allogeneic CAR T programs to these promising ventures.
• Presentation at upcoming December 2025 investor conferences, including Citi’s Global Healthcare and the Evercore Healthcare conferences will engage investors looking to align with Sana’s future growth agendas.

Weekly Update Nov 24 – Nov 28, 2025: On Sunday, November 30, 2025 Sana Biotechnology Inc. stock [NASDAQ: SANA] is trending up by 8.46%! Discover the key drivers behind this movement as well as our expert analysis in the detailed breakdown below.

Quick Financial Overview

Sana Biotechnology’s recent earnings report paints a picture of both challenge and progress. The company reported a third-quarter adjusted loss of $0.15 per share, beating the expected loss of $0.18. This result indicates an effective cost management amidst ongoing strategic shifts. The resolute commitment to advancing SC451 for diabetes and an enhanced focus on their in vivo CAR T programs reflect a targeted approach towards high-impact therapeutics. Notably, the suspension of allogeneic CAR T projects freed up resources, signifying a deliberate resource reallocation to maximize opportunities in their strongest prospects.

Analyzing recent stock movements, Sana’s share price trajectory has witnessed significant open and close variations. On November 24, 2025, the stock opened at $3.54, climbed to close at $3.55, showing marginal volatility. The upward momentum persisted through subsequent days, as displayed on November 26, where it closed strongly at $4.10. Daily highs suggest investor optimism potentially stemming from strategic clarity and earnings performance, with intraday peaks such as $4.36 on November 28, emphasizing this upward trend.

Despite a negative price-to-cash-flow ratio of -9.7, which often signals cash outflow challenges, Sana’s operational movements focus on future financial robustness. The robust current ratio of 4.6 exemplifies their ability to cover short-term liabilities, while a low total debt-to-equity ratio of 0.42 demonstrates prudent financial leverage. Acknowledging these figures within broader market conditions, the outlook for Sana remains cautiously optimistic.

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AstraZeneca says it expects to invest $2 billion to expand its long-standing manufacturing footprint in Maryland. This includes a significant expansion of its flagship biologics manufacturing facility in Frederick and construction of a new facility in Gaithersburg for the development and clinical supply of innovative molecules to be used in clinical trials, according to a company spokesperson, who adds that the investment will support 2,600 jobs across the two sites in the state, including the retention of local roles, construction activity, and the creation of 300 highly skilled jobs.

The Frederick facility currently produces biologics. The planned expansion will nearly double commercial manufacturing capacity, enabling increased supply of existing medicines and, for the first time, production across the company’s rare disease portfolio. It is expected to be operational in 2029.

In parallel, AstraZeneca will build a new clinical manufacturing facility to expand its footprint in Gaithersburg. The facility is planned to be fully operational by 2029. Both the expanded facility in Frederick and the new facility in Gaithersburg will leverage AI, automation, and data analytics and be built to the highest environmental standards.

“Today marks a landmark moment for Maryland and American patients,” noted Pascal Soriot, CEO, AstraZeneca. “As the state’s largest biopharmaceutical employer, we are deepening our long-standing commitment to Maryland—supporting 2,600 jobs, catalyzing economic growth, and bringing our extensive rare disease portfolio onshore for the first time. This investment strengthens the resilience of the U.S. medicines supply chain and accelerates access to transformative therapies for patients across America and around the world.”

Today’s announcement is part of AstraZeneca’s $50 billion investment announced in July and follows a series of U.S. commitments over the past six months, including unveiling a new cell therapy manufacturing facility in Rockville, MD, a new drug substance manufacturing facility in VA, and the expansion of the company’s existing manufacturing facility in Coppell, TX.

The U.S. is AstraZeneca’s largest market by sales and is also home to 19 R&D, manufacturing, and commercial sites. The company’s U.S. workforce exceeds more than 25,000 people and supports more than 100,000 jobs overall across the country. In 2025, AstraZeneca created approximately $20 billion of overall value to the American economy, point out company officials.

A Garvan Institute of Medical Research-led clinical trial has found that using the type 2 diabetes (T2D) drug metformin reduces insulin needs in type 1 diabetes (T1D), a finding that could potentially point to improved management of the disorder. For years, doctors have prescribed metformin, an old but common and inexpensive type 2 diabetes medication, to treat insulin resistance in type 1 diabetes. This use has been largely based on anecdotal evidence. The newly reported Garvan-led clinical trial found that metformin does not counteract insulin resistance in type 1 diabetes, but instead reduces the amount of insulin needed to maintain blood sugar levels in the ideal range.

The surprising findings could improve how doctors manage type 1 diabetes and ease the significant burden that people with the condition face when using insulin alone. In their published paper in Nature Communications (“Effect of metformin on insulin resistance in adults with type 1 diabetes: a 26-week randomized double-blind clinical trial,”) the team, co-led by endocrinologist Jennifer Snaith, PhD, and professor Jerry Greenfield, PhD, wrote, “These results do not support prescribing metformin to reduce insulin resistance in adults with type 1 diabetes but suggest that metformin may reduce insulin dose via mechanisms independent of insulin resistance.”

Type 1 diabetes is an autoimmune condition affecting over 130,000 Australians, in which the immune system incorrectly attacks the insulin-producing cells of the pancreas. As a result, people with type 1 diabetes need to administer insulin for the rest of their lives to regulate their blood sugar levels. “Type 1 diabetes is characterized by immune-associated destruction of insulin-producing pancreatic beta cells resulting in a lifelong reliance on insulin replacement,” the authors wrote. Managing blood sugar levels with insulin is not easy, with estimates indicating that people living with type 1 diabetes have to make 180 extra decisions per day related to their diabetes management.
In some people with type 1 diabetes, long-term insulin use can lead to insulin resistance, where the body’s cells no longer respond effectively to the drug. This means that people need ever-increasing amounts of insulin to keep blood sugar levels under control.

“Insulin resistance is a growing problem in type 1 diabetes. Not only does it make regulating blood sugar levels difficult, but it is an underappreciated risk factor for heart disease, which is one of the biggest causes of health complications and deaths in those with type 1 diabetes,” said Snaith. “Insulin resistance is of interest in type 1 diabetes as studies, including those with surrogate measures of cardiovascular disease, report an association between insulin resistance and cardiovascular risk,” the authors further commented.

To address this, a Garvan team led by Snaith and Greenfield undertook the world’s first randomised controlled trial—the Insulin Resistance in Type 1 Diabetes Managed with Metformin (INTIMET) study—in adults testing whether metformin, a cheap, oral drug normally used to counteract insulin resistance in type 2 diabetes, could do the same in type 1 diabetes. It is estimated that the drug is currently used off-label by up to 13,000 Australians with type 1 diabetes, but it remains unclear how exactly it works. “Metformin, an inexpensive and safe oral medication, is an ideal candidate to address insulin resistance in type 1 diabetes,” the authors suggested. “Although used first-line in the pharmacological management of type 2 diabetes, its mechanisms of action are not entirely understood.”

Greenfield further explained, “We randomized 40 adults with long-term type 1 diabetes to take either metformin or a placebo for six months. We examined whether their insulin resistance changed over that time through a sophisticated and comprehensive research technique, called a clamp study, that allowed us to map insulin resistance in different parts of the body.” The authors added, “Forty adults with type 1 diabetes, and twenty adults without diabetes were studied in a baseline-only cross-sectional study assessing insulin resistance using the two-step hyperinsulinemic-euglycemic clamp.”

Unexpectedly, the study results indicated that the use of metformin did not lead to improvements in insulin resistance or changes to blood sugar levels. This suggests that, unlike for type 2 diabetes, metformin does not work to counter insulin resistance in type 1 diabetes. However, metformin did decrease the amount of insulin people needed to keep their blood sugars stable. “Although there was no evidence of an effect on measures of insulin resistance, metformin was associated with a reduction in total daily insulin dose by 0.1 units/kg/day relative to the placebo group,” the investigators reported. “Our findings suggest that in adults with type 1 diabetes, metformin may have metabolic impacts that translate to sparing of insulin requirements via effects independent of insulin resistance.”

“Although we didn’t find changes to insulin resistance from the use of metformin, we did show that people taking it used around 12% less insulin than those on placebo,” Snaith said. “This is an important result. Insulin is a relatively old treatment which, while lifesaving, comes with significant mental and physical burden. This means that lowering the amount of insulin used is a priority for many people living with type 1 diabetes. We have shown that a very cheap, accessible medication may serve this purpose and this is very exciting.”

The team is now investigating how metformin may work to lower the amount of insulin needed by those with type 1 diabetes. Greenfield noted, “Metformin has been available in various forms for around 100 years, but its mechanism of action remains unknown. We would have expected that the observed reductions in insulin dose induced by metformin in our study would be due to the body becoming more sensitive to insulin, that is, becoming less insulin resistant. But we have shown that is not the case. Our priority is now working out how metformin is achieving this effect.” The authors added, “The potential cardiovascular benefits of insulin sparing and reducing peripheral hyperinsulinemia warrant further study.”

Snaith further stated, “There is increasing evidence suggesting that metformin may act on the gut. This is why we are now investigating how metformin changes gut flora, also known as the microbiome, in people with type 1 diabetes. This has not been studied before in type 1 diabetes. We’re hoping this will provide clues on metformin’s mechanism of action, so that it can be more widely used in the management of type 1 diabetes.”

“I just can’t make it tonight. You have fun without me.” Across much of the animal kingdom, when infection strikes, social contact shuts down. A study headed by researchers at The Picower Institute for Learning and Memory of MIT has now detailed how the immune and central nervous systems implement this sickness behavior. The scientists and their collaborators used multiple methods to demonstrate causally that interleukin-1 beta (IL-1β) directly modulates activity of IL-1 receptor 1 (IL-1R1)-expressing neurons in the brain’s dorsal raphe nucleus (DRN), activating connections with the intermediate lateral septum to shut down social behavior.

“Our findings show that social isolation following immune challenge is self-imposed and driven by an active neural process, rather than a secondary consequence of physiological symptoms of sickness, such as lethargy,” said study co-senior author Gloria Choi, PhD, associate professor in The Picower Institute and MIT’s Department of Brain and Cognitive Sciences.

The team, headed by co-senior author Choi, together with co-senior author Jun Huh, PhD, Harvard Medical School associate professor of immunology, and first author Liu Yang, PhD, a research scientist in Choi’s lab, reported on their findings in Cell, in a paper titled “IL-1R1-positive dorsal raphe neurons drive self-imposed social withdrawal in sickness,” in which they concluded “… our findings implicate IL-1β as a primary effector driving social withdrawal during systemic immune activation … Our investigation into IL-1β expands upon growing evidence that cytokines serve as neuromodulators within behavior-relevant neural circuits to orchestrate adaptive responses during inflammatory conditions.”

It makes perfect sense that when we’re battling an infection we lose our desire to be around others. This lets us get much needed rest but also protects others around us from getting sick. “Across the animal kingdom, infections often elicit social withdrawal—an adaptive behavioral response believed to preserve the overall health of the group by isolating the sick individuals and thereby reducing the risk of pathogens being transmitted to others,” the team wrote. What hasn’t been as clear is how this behavior change happens. “… it remains largely unexplored whether social withdrawal arises from self-imposed isolation by the sick individual or avoidance by healthy conspecifics and how such behavioral adaptations are orchestrated by the nervous system,” the investigators noted.

There is a close connection between the nervous system, which regulates behavior, and the immune system, which detects pathogens and mounts protective responses during infection, the team pointed out. There is also growing evidence indicating that cytokines—soluble factors expressed by peripheral immune cells—serve as a molecular link between the immune and nervous systems.

Choi and Huh’s long collaboration has identified cytokines that affect social behavior by latching on to their receptors in the brain. For their newly reported study the team hypothesized that the same kind of dynamic might cause social withdrawal during infection. But which cytokine? And what brain circuits might be affected?

To identify which cytokines might act centrally to mediate social withdrawal, the scientists carried out a behavioral screen in mice. They injected 21 different cytokines, one by one, into the animals’ brains, to see which, if any of the cytokines triggered social withdrawal responses similar to those resulting after administration of lipopolysaccharide (LPS), which is a standard way of simulating infection.

Using a modified sociability assay to investigate behavior the researchers found that only IL-1β injection fully recapitulated the same social withdrawal behavior as did LPS administration. That said, IL-1β also made the mice more sluggish. “Among the cytokines tested, only IL-1β fully recapitulated the behavioral effects of LPS …” they stated. “This observation is consistent with previous studies implicating IL-1β in sickness-associated reduction of social exploration.” In contrast, they reported, IL-1α induced hypoactivity but without affecting sociability. “Thus, of the 21 cytokines tested, IL-1β uniquely elicited robust changes in social behavior.”

IL-1β affects cells when it hooks up with the IL-1R1, so the team next went looking across the brain for where the receptor is expressed. They identified several regions and examined individual neurons in each. The dorsal raphe nucleus stood out among regions, both because it is known to modulate social behavior and because it is situated next to the cerebral aqueduct, which would give it plenty of exposure to incoming cytokines in cerebrospinal fluid.

The team’s experiments identified populations of DRN neurons that express IL-1R1 (IL-1R1DRN neurons), including many involved in making the crucial neuromodulatory chemical serotonin. Collective findings from experiments, they noted, “… indicate that IL-1R1 is predominantly expressed in the serotonergic subset of DRN neurons.”

From there, Yang and the team demonstrated that IL-1β activates those neurons, and that activating the neurons promotes social withdrawal. Moreover, they showed that inhibiting that neural activity prevented social withdrawal in mice treated with IL-1β, and they showed that shutting down IL-1R1 in the DRN neurons also prevented social withdrawal behavior after IL-1β injection or LPS exposure. “Our data indicate the presence of a neural mechanism underlying voluntary social disengagement in sick animals and reveal a function of IL-1R1 signaling in dorsal raphe neurons in regulating social behavior in response to systemic immune activation,” the investigators stated.

Notably, these experiments did not change the lethargy that followed IL-1β or LPS, helping to demonstrate that social withdrawal and lethargy occur through different means. “We observed that inhibiting IL-1R1DRN neurons reversed social withdrawal without alleviating hypoactivity,” they stated.

With the DRN identified as the site where neurons receiving IL-1β drove social withdrawal, the next question was what circuit they affected that behavior change through. The team traced where the neurons make their circuit projections and found several regions that have a known role in social behavior.

Using optogenetics, a technology that engineers cells to become controllable with flashes of light, the scientists were able to activate the DRN neurons’ connections with each downstream region. Only activating the DRN’s connections with the intermediate lateral septum caused the social withdrawal behaviors seen with IL-1β injection or LPS exposure.
In a final test, they replicated their results by exposing some mice to Salmonella. “Collectively, these results reveal a role for IL-1R1-expressing DRN neurons in mediating social withdrawal in response to IL-1β during systemic immune challenge,” the researchers stated. “Taken together, our findings support the conclusion that social isolation following immune challenge is self-imposed and driven by an active neural process involving IL-1R1DRN neurons in response to IL-1β, rather than a secondary consequence of physiological symptoms of sickness or social exclusion.”

Though the study revealed the cytokine, neurons, and circuit responsible for social withdrawal in mice in detail and with demonstrations of causality, the results still inspire new questions. One is whether IL-1R1 neurons affect other sickness behaviors. Another is whether serotonin has a role in social withdrawal or other sickness behaviors. “Further studies are required to elucidate how social structures reorganize during prolonged infection and whether early-stage withdrawal effectively mitigates pathogen transmission and enhances overall group resilience,” the investigators further stated.

Bracco Imaging and Limula, a life science tools company specializing in automated cell and gene therapy manufacturing solutions, launched a R&D project in collaboration with Nicola Vannini, PhD, who specializes in T-cell metabolism at the University of Fribourg, Switzerland.

“We see tremendous potential in innovative approaches to some of the key cell manipulation steps required to deliver improved patient outcomes,” noted Vannini. “My team is looking forward to evaluating the impact of these new technologies on the fitness of the cell products.”

The complex manufacturing of cell and gene therapies remains a bottleneck to their widespread adoption in the clinic. Cell selection and activation are critical steps in these processes, often followed by genetic manipulation. The goal of the new public-private partnership, funded through an innovation project grant from the Swiss Innovation Agency Innosuisse, is to combine two innovations—lipid-based microbubbles and an automated cell processing technology—to offer an alternative to conventional magnetic beads for affinity-based cell selection and activation.

In this context, microbubbles are used to modify the density of target cells through specific binding, enabling their selection by natural buoyancy.

“Integrating Bracco’s microbubble technology—clinically used for over two decades in imaging—with Limula’s instrumentation offers a compelling approach to improved cell manufacturing, aiming to accelerate access to more affordable therapies for a broader patient population,” said Thierry Bettinger, PhD, director of the Bracco Research Center Geneva.

“This partnership reflects the need for a multidisciplinary approach to innovation in cell and gene therapy. Our collaboration with Bracco and Prof. Vannini will provide us with the complementary expertise needed to deliver value to our biopharma and hospital customers,” added Luc Henry, DPhil, CEO at Limula.

The concept of using buoyancy to capture cells and other components of interest is already being used in life science applications, including in cell and gene therapy manufacturing. Some of the anticipated advantages of the unique lipid formulation provided by Bracco, combined with the gentle cell processing technology developed by Limula, are Traceless reagents that can be easily removed from the cell product during the manufacturing process, significantly simplifying quality control, and gentle manipulations of the cells leading to better yields, purity, and overall product quality and potentially improved clinical outcome for patients.