Since running aground on a sandbank on May 6, 1682, the wreck of the warship the Gloucester has lain half-buried on the seabed, its exact whereabouts unknown until brothers Julian and Lincoln Barnwell, with their friend James Little, found it after a four-year search.

Due to the age and prestige of the ship, the condition of the wreck, the finds already rescued, and the accident’s political context, the discovery is described by maritime history expert Prof Claire Jowitt, of the University of East Anglia (UEA), as the most important maritime discovery since the Mary Rose.

The Gloucester represents an important ‘almost’ moment in British political history: a royal shipwreck causing the very near-death of the Catholic heir to the Protestant throne at a time of great political and religious tension.

Now a major exhibition is planned for Spring 2023, the result of a partnership between the Barnwell brothers, Norfolk Museums Service, and academic partner UEA. Running from February to July at Norwich Castle Museum & Art Gallery, the exhibition will display finds from the wreck — including the bell that confirmed the ship’s identity — and share ongoing historical, scientific and archaeological research.

Prof Jowitt, a world-leading authority on maritime cultural history, is a co-curator of the exhibition. “Because of the circumstances of its sinking, this can be claimed as the single most significant historic maritime discovery since the raising of the Mary Rose in 1982,” she said. “The discovery promises to fundamentally change understanding of 17th-century social, maritime and political history.

“It is an outstanding example of underwater cultural heritage of national and international importance. A tragedy of considerable proportions in terms of loss of life, both privileged and ordinary, the full story of the Gloucester’s last voyage and the impact of its aftermath needs re-telling, including its cultural and political importance, and legacy. We will also try to establish who else died and tell their stories, as the identities of a fraction of the victims are currently known.”

The Barnwell brothers are Norfolk-based printers, licensed divers and Honorary Fellows in the School of History at UEA. Lincoln said he was partly inspired to search for the wreck after watching the lifting of the Mary Rose on television as a child.

“It was our fourth dive season looking for Gloucester,” he said. “We were starting to believe that we were not going to find her, we’d dived so much and just found sand. On my descent to the seabed the first thing I spotted were large cannon laying on white sand, it was awe- inspiring and really beautiful.

“It instantly felt like a privilege to be there, it was so exciting. We were the only people in the world at that moment in time who knew where the wreck lay. That was special and I’ll never forget it. Our next job was to identify the site as the Gloucester.”

Julian added: “When we decided to search for the Gloucester we had no idea how significant she was in history. We had read that the Duke of York was onboard but that was it. We were confident it was the Gloucester, but there are other wreck sites out there with cannons, so it still needed to be confirmed.

“There is still a huge amount of knowledge to be gained from the wreck, which will benefit Norfolk and the nation. We hope this discovery and the stories that are uncovered will inform and inspire future generations.”

Lord Dannatt, Norfolk Deputy Lieutenant and longstanding resident of the county, is lending his skills and support to the historic rescue project. As former head of the British Army, he works with charities and organisations that have links to the armed services.

“This is going to be Norfolk’s Mary Rose,” said Lord Dannatt. “Julian and Lincoln have touched history, history that could have changed the course of this nation. It’s such an amazing story to tell. Our aim is to bring that story to life and to share it with as many people as possible.”

The Gloucester was commissioned in 1652, built at Limehouse in London, and launched in 1654. In 1682 it was selected to carry James Stuart, Duke of York, to Edinburgh to collect his heavily pregnant wife and their households. The aim was to bring them back to King Charles II’s court in London in time, it was hoped, for the birth of a legitimate male heir.

The ship had set sail from Portsmouth with the Duke and his entourage joining it off Margate, having travelled by yacht from London. At 5.30am on May 6, the Gloucester ran aground some 45km off Great Yarmouth following a dispute about navigating the treacherous Norfolk sandbanks. The Duke, a former Lord High Admiral, had argued with the pilot for control over the ship’s course.

Within an hour the vessel sank with the loss of hundreds of the crew and passengers. The Duke barely survived, having delayed abandoning ship until the last minute.

As well as the Duke of York, the Gloucester carried a number of prominent English and Scottish courtiers including John Churchill, later the 1^st Duke of Marlborough.

Diarist and naval administratorSamuel Pepys, who witnessed events from another ship in the fleet, wrote his own account — describing the harrowing experience for victims and survivors, with some picked up “half dead” from the water.

Together with their late father Michael, and two friends including James Little, a former Royal Navy submariner and diver, the Barnwell brothers found the wreck site in 2007, with the Gloucester split down the keel and remains of the hull submerged in sand.

The ship’s bell, manufactured in 1681, was later recovered, and in 2012 it was used by the Receiver of Wreck and Ministry of Defence to decisively identify the vessel.

Due to the time taken to confirm the identity of the ship and the need to protect an ‘at risk’ site, which lies in international waters, it is only now that its discovery can be made public. As well as the Receiver of Wreck and Ministry of Defence, the wreck has been declared to Historic England.

Following the discovery, the brothers completed an underwater archaeology course with the Nautical Archaeology Society.

Artefacts rescued and conserved include clothes and shoes, navigational and other professional naval equipment, personal possessions, and many wine bottles.

One of the bottles bears a glass seal with the crest of the Legge family — ancestors of George Washington, the first US President. The crest was a forerunner to the Stars and Stripes flag. Uniquely, in addition there were also some unopened bottles, with wine still inside – offering exciting opportunities for future research.

The accompanying historical research project, funded by the Leverhulme Trust and led by Prof Jowitt, will explore not only the failures of command at sea before the Gloucester sank, but conspiracy theories about the tragedy’s causes and its political consequences.

It is also hoped that UEA’s scientific expertise and facilities will be used to analyse some of the finds from the wreck.

The Ministry of Defence’s position is that all artefacts remain the property of the Ministry of Defence; however, where items are positively identified as personal property, ownership will then default to the Crown.

Partners already involved in the landmark project alongside the Barnwells, UEA and Norfolk Museums Service include the Ministry of Defence, the National Museum of the Royal Navy in Portsmouth, York Archaeology, the Leverhulme Trust and Maritime Archaeology Trust. The project is also being generously supported by Alan Boswell Group and Birketts LLP.

“In an ideal world, politics and health would be independent of each other and it wouldn’t matter whether one lives in an area that voted for one party or another,” said corresponding author Haider Warraich, MD, of the Division of Cardiovascular Medicine at the Brigham. “But that is no longer the case. From our data, we can see that the risk of premature death is higher for people living in a county that voted Republican.”

Warraich and colleagues used data from the Wide-ranging OnLine Data for Epidemiologic Research (CDC WONDER) database and the MIT (Massachusetts Institute of Technology) Election Data and Science Laboratory. They classified counties as Democratic or Republican based on the way the county had voted in the previous presidential election and adjusted for age when calculating mortality rates.

Overall, the team found that mortality rates in Democratic counties dropped from 850 deaths per 100,000 people to 664 (22 percent), but in Republican counties, mortality rates declined from 867 to 771 (11 percent). When the team analyzed by race, they found that there was little gap between the improvements in mortality rates that Black and Hispanic Americans experienced in Democratic and Republican counties. But among white Americans, the gap between people living in Democratic versus Republican counties was substantial.

The mortality gap remained consistent when the researchers looked only at counties that had voted Republican or Democratic in every presidential election year studied and when they looked at gubernatorial elections. Democratic counties experienced greater reductions in mortality rates across most common causes of death, including heart disease, cancer, chronic lower respiratory tract diseases, diabetes, influenza and pneumonia, and kidney disease.

The authors note that the widening gap in death rates may reflect the influence of politics on health policies. One of the inflection points detected in the study corresponds to the Affordable Care Act (ACA), which was passed in 2010. More Democratic states than Republican states adopted Medicaid expansion under the ACA, which expanded health insurance coverage to people on a low income.

The study detects an association between political environment and mortality but does not definitively determine the direction of the association or the specific factors that may explain the link between the two. The authors did not study the effect of flipping political environments — that is, counties that switched from voting Democratic or Republican to voting for the other party — on health outcomes, which could be an area of future study. The study period ended in 2019, before the start of the COVID-19 pandemic, which may have had an even more profound impact on the mortality gap.

“Our study suggests that the mortality gap is a modern phenomenon, not an inevitability,” said Warraich. “At the start of our study, we saw little difference in mortality rates in Democratic and Republican counties. We hope that our findings will open people’s eyes and show the real effect that politics and health policy can have on people’s lives.”

Disclosures: Warraich is an advisor for Embrace Prevention Care; co-author Rishi Wadhera receives research support from the National Heart, Lung, and Blood Institute (grant K23HL148525-1); co-author Karen E. Joynt Maddox previously did contract work for the U.S. Department of Health and Human Services.

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Materials provided by Brigham and Women’s Hospital. Note: Content may be edited for style and length.

A study describing the research — which was carried out in isolated cells, in human cancer tissue and in human cancers grown in mice — was published online June 2 in the journal Nature Cancer.

Dr. Jung-Mo Ahn, a co-corresponding author of the study and a UT Dallas associate professor of chemistry and biochemistry in the School of Natural Sciences and Mathematics, has been passionate about his work designing small molecules that target protein-protein interactions in cells for over a decade. Using an approach called structure-based rational drug design, he previously developed potential therapeutic candidate compounds for treatment-resistant breast cancer and for prostate cancer.

In the current work, Ahn and his colleagues tested a novel compound he synthesized called ERX-41 for its effects against breast cancer cells, both those that contain estrogen receptors (ERs) and those that do not. While there are effective treatments available for patients with ER-positive breast cancer, there are few treatment options for patients with triple-negative breast cancer (TNBC), which lacks receptors for estrogen, progesterone and human epidermal growth factor 2. TNBC generally affects women under 40 and has poorer outcomes than other types of breast cancer.

“The ERX-41 compound did not kill healthy cells, but it wiped out tumor cells regardless of whether the cancer cells had estrogen receptors,” Ahn said. “In fact, it killed the triple-negative breast cancer cells better than it killed the ER-positive cells.

“This was puzzling to us at the time. We knew it must be targeting something other than estrogen receptors in the TNBC cells, but we didn’t know what that was.”

To investigate the ERX-41 molecule, Ahn worked with collaborators, including co-corresponding authors Dr. Ganesh Raj, professor of urology and pharmacology at the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern Medical Center, as well as Dr. Ratna Vadlamudi, professor of obstetrics and gynecology at UT Health San Antonio. Dr. Tae-Kyung Lee, a former UTD research scientist in Ahn’s Bio-Organic/Medicinal Chemistry Lab, was involved in synthesizing the compound.

The researchers discovered that ERX-41 binds to a cellular protein called lysosomal acid lipase A (LIPA). LIPA is found in a cell structure called the endoplasmic reticulum, an organelle that processes and folds proteins.

“For a tumor cell to grow quickly, it has to produce a lot of proteins, and this creates stress on the endoplasmic reticulum,” Ahn said. “Cancer cells significantly overproduce LIPA, much more so than healthy cells. By binding to LIPA, ERX-41 jams the protein processing in the endoplasmic reticulum, which becomes bloated, leading to cell death.”

The research team also tested the compound in healthy mice and observed no adverse effects.

“It took us several years to chase down exactly which protein was being affected by ERX-41. That was the hard part. We chased many dead ends, but we did not give up,” Ahn said.

“Triple-negative breast cancer is particularly insidious — it targets women at younger ages; it’s aggressive; and it’s treatment resistant. I’m really glad we’ve discovered something that has the potential to make a significant difference for these patients.”

The researchers fed the compound to mice with human forms of cancerous tumors, and the tumors got smaller. The molecule also proved effective at killing cancer cells in human tissue gathered from patients who had their tumors removed.

They also found that ERX-41 is effective against other cancer types with elevated endoplasmic reticulum stress, including hard-to-treat pancreatic and ovarian cancers and glioblastoma, the most aggressive and lethal primary brain cancer.

“As a chemist, I am somewhat isolated from patients, so this success is an opportunity for me to feel like what I do can be useful to society,” Ahn said.

Ahn is a joint holder of patents issued and pending on ERX-41 and related compounds, which have been licensed to the Dallas-based startup EtiraRX, a company co-founded in 2018 by Ahn, Raj and Vadlamudi. The company recently announced that it plans to begin clinical trials of ERX-41 as early as the first quarter of 2023.

Ahn’s research on this project is supported by the National Cancer Institute, part of the National Institutes of Health (1R01CA223828); the Cancer Prevention and Research Institute of Texas; and The Welch Foundation.

In addition to researchers from UT Southwestern and UT Health San Antonio, other study authors from Howard Hughes Medical Institute’s Janelia Research Campus, Northwest A&F University in China and the Medical College of Xiamen University in China contributed.