From an insular culture to harm to teens' body image, Haugen told US senators what she saw inside the company.

Here are some highlights of her testimony:

Frankenstein Facebook

"If you split Facebook and Instagram apart, it's likely that most advertising dollars will go to Instagram and Facebook will continue to be this Frankenstein... that is endangering lives around the world... these systems are going to continue to exist and be dangerous even if broken up."

Release company studies

"I believe it is vitally important that we establish mechanisms where Facebook's internal research must be disclosed to the public on a regular basis."

Insular culture

"Facebook has a culture that emphasizes that insularity is the path forward, that if information is shared with the public, it will just be misunderstood."

Change won't be ruinous

"A lot of the changes I'm talking about are not going to make Facebook an unprofitable company," she said. "It just won't be a ludicrously profitable company like it is today."

Increase age limit

"I strongly encourage raising age limits to 16 or 18 years old, based on looking at the data around problematic use or addiction on the platform and children's self-regulation issues," she said.

The official limit presently is 13 years old to join Facebook.

Facebook needs help

"You can declare moral bankruptcy, you can admit you did something wrong. And we can move forward."

Eating disorder dangers

"I also want to emphasize that eating disorders are serious, there are going to be women walking around this planet in 60 years with brittle bones because of the choices that Facebook made around emphasizing profit today."

Parents don't understand

"Facebook knows that parents today, because they... have never experienced this addictive experience with a piece of technology, they give their children bad advice. They say things like 'Why don't you just stop using it?'"

Structural problems

"Facebook has set up an organization where the parts of the organization responsible for growing and expanding are separate and not regularly cross-pollinated with the parts of the company that focus on the harms the company has caused."

CEO Mark Zuckerberg decides

"In the end, the buck stops with Mark. There is no one currently holding Mark accountable but himself."

Hits of dopamine

"Facebook knows that content that elicits an extreme reaction from you is more likely to get a click, a comment or re-share," she said.

"Those clicks and comments and re-shares aren't necessarily for your benefit... They prioritize content in your feed so that you will give little hits of dopamine to your friends so they will produce more content."

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An award for understanding complex systems, including the climate.

Physics Nobel goes to complexity, both general and climatic

The impressive trajectory of the Internet age and social media’s dominance of how we get our information was put on display Monday night when Facebook and its companies, Instagram and WhatsApp, crashed worldwide.

Large swaths of the world rely on these platforms and services, which are largely unregulated by governments, to send messages, make calls, receive information and coordinate meetings and daily life.

This is not just a small part of people’s lives in the modern age. The age of the Internet has rapidly shifted power into the hands of a few large tech giants that operate as monopolies for hosting, distributing and disseminating information.

However, they also control other networks that increasingly serve as stand-ins for phone networks.

A computer engineer checks equipment at an internet service provider in Tehran February 15, 2011 (credit: CAREN FIROUZ / REUTERS)

When the Internet age began in the 1990s, it provided a radical new way for people to access information; previously, there was only print media, television and radio. The nature of the Internet, interactive in ways the other three weren’t, meant it rapidly began to inhabit a multiplicity of places in people’s lives that hitherto were not thought possible.

Soon after, the Internet provided an alternative way to watch television – streaming sites and YouTube. This quickly became true for radio and other mediums. News went online, battering major legacy media and challenging its survival. Product sales, or shopping, moved online, as did the creation of portals for people to chat, message, communicate and create virtual versions of themselves.

The most recent revolution has been the binding of these various elements under the power of Big Tech companies – like Facebook. What this means is that while the Internet age of the late 1990s and early 2000s was a unique free-for-all Wild West, the new age reflects more the era of the robber barons of the US in the late 19th century – the monopolies and trusts that came to dominate the industry through horizontal and vertical integration.

Big Tech companies are so large they now have gobbled up swaths of the Internet and control the way in which most information and communications flow.

AN OUTAGE like the one that occurred on Monday is not unprecedented. Various large Big Tech sites have crashed in the past, usually for a short time. There has also been an increase in cyber incidents over the last few years, including cyberattacks that have targeted critical infrastructure, whether in Israel, the US or other places.

The question that should be asked increasingly by governments is how they can replicate or maintain communication and major Internet systems in case of an outage among major companies that are too big to fail.

This is not an arbitrary thought experiment.

The world is entering an era of uncertainty, reflected not only in the pandemic, but also in great power competition. This is because the world order that emerged after the Cold War, which led to the global dominance of the United States, has now shifted to a league of authoritarian countries that are at odds with Washington and Western democracies.

Most of them also censor certain parts of the Internet or fear widespread citizen use of it as a whole. This includes Turkey, Iran, China, Russia and other states.

Big Tech companies often must weigh the demands of authoritarian regimes to crack down on them, balancing them with their own budgets and business goals. This means, in some cases, succumbing to the authoritarians.

For example, Big Tech companies, after complaints from Western leaders, have labeled some information as “misinformation” in order to do what they deem is a public service during the pandemic. They might also sometimes cater to the authoritarian request to remove groups linked to dissidents in places like Turkey. They must struggle with those questions.

Large authoritarian regimes may realize that Big Tech is the soft underbelly of the Western democracies. Let enough people rely on just one or two tech giants for everything they do, and you create a Pearl Harbor-like vulnerability. The exception is that in this case, it’s even bigger than a Pearl Harbor incident because it sits astride so much of what happens in the world.

IN A future rife with growing conflict between the US and other regimes, will Big Tech be a target? And how will it respond if it is not regulated and closely monitored by governments that have an interest in maintaining its security?

Do groups of countries like the Five Eyes (Australia, Canada, New Zealand, UK and US) have an interest in protecting the workings of things like WhatsApp, for instance?

While it is true that the corporations that run these platforms are private, Western governments have understood that when it comes to large corporate networks – whether phone companies, radio, rail or transportation – even if some aspects of the industry are private, there is a need to use these industries in times of peril.

For this very reason, there is an emergency broadcast system in the US. Governments that value the role Big Tech has in our lives would be smart to begin to think about how to step in and maintain these systems should they be under attack or go “dark” in the future.

They should consider duplicating or archiving these systems, rather than relying on private corporations to do so. There is no doubt there is already a partnership between major governments and Big Tech because messaging, such as relating to vaccines, is already part of the way large Western governments encourage Big Tech to disseminate information. There is already a dialogue.

Unregulated and without checks and balances on their operation, Big Tech could be a threat to the West; this revelation is one of the important lessons of the recent outage.

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The story of stem cells is one of potential. Like a talented young student, or a canvas awaiting the first stroke of an artist’s brush, these cells are not yet the finished article, and still have the capacity to follow many paths. It has long been thought that these self-renewing, shape-shifting cells could be the key to regenerating all manner of tissues damaged by injury or disease. So far, the dream has outpaced reality — only a handful of therapies involving stem cells have shown definitive efficacy. But researchers are starting to learn what makes stem cells tick, leading to clinical trials of therapies for various diseases.

In Parkinson’s disease, for example, scientists are investigating whether replacing lost neurons in the brain can relieve symptoms. Stem-cell therapies to restore sight are also advancing — researchers are using the cells to restore the cornea’s ability to heal itself and to replenish the light-sensing retina. And trials of stem-cell therapies in people with spinal cord injuries are gradually leading scientists towards techniques that could restore movement and sensation.

Stem cells also have the potential to be powerful research tools. The ability to make human embryo-like structures — and the relaxation of guidance on how long such structures can be cultured for — provides a window onto human development. Researchers are also getting better at coaxing stem cells to form 3D structures containing more than one cell type, which could lead to an improved understanding of how organs develop. It is even hoped that stem-cell technology could be used to bring extinct animal species back to life.

But before these promised applications become a reality, there are issues for the field to address. Manufacturing stem-cell therapies on a commercial scale, rather than on a laboratory bench, is one challenge that several firms are working to overcome. And it is of course impossible to discuss stem-cell technology without debating where ethical lines should be drawn — not least when it comes to the production of human–animal hybrids to provide transplantable organs.

We are pleased to acknowledge the financial support of Bayer AG in producing this Outlook. As always, Nature retains sole responsibility for all editorial content.

Nature 597, S5 (2021)

doi: https://doi.org/10.1038/d41586-021-02620-5

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The Israeli Antiquities Authority said the smooth, carved limestone toilet was found in a rectangular cabin that was part of a sprawling mansion overlooking what is now the Old City. It was designed for comfortable sitting, with a deep septic tank dug underneath.

“A private toilet cubicle was very rare in antiquity, and only a few were found to date,” said Yaakov Billig, the director of the excavation.

“Only the rich could afford toilets,” he said, adding that a famed rabbi once suggested that to be wealthy is “to have a toilet next to his table.”

Animal bones and pottery found in the septic tank could shed light on the lifestyle and diet of people living at that time, as well as ancient diseases, the antiquities authority said.

The archaeologists found stone capitals and columns from the era, and said there was evidence of a nearby garden with orchards and aquatic plants — more evidence that those living there were quite wealthy.

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MOSCOW (AP) — A Russian actor and a film director rocketed to space Tuesday on a mission to make the world’s first movie in orbit, a project the Kremlin said will help burnish the nation’s space glory.

Actor Yulia Peresild and director Klim Shipenko blasted off for the International Space Station in a Russian Soyuz spacecraft together with cosmonaut Anton Shkaplerov, a veteran of three space missions. Their Soyuz MS-19 lifted off as scheduled at 1:55 p.m. (0855 GMT) from the Russian space launch facility in Baikonur, Kazakhstan and arrived at the station after about 3½ hours.

Shkaplerov took manual controls to smoothly dock the spacecraft at the space outpost after a glitch in an automatic docking system.

The trio reported they were feeling fine and spacecraft systems were functioning normally.

Peresild and Klimenko are to film segments of a new movie titled “Challenge,” in which a surgeon played by Peresild rushes to the space station to save a crew member who suffers a heart condition. After 12 days on the space outpost, they are set to return to Earth with another Russian cosmonaut.

Kremlin spokesman Dmitry Peskov said the mission will help showcase Russia’s space prowess.

“We have been pioneers in space and maintained a confident position,” Peskov said. “Such missions that help advertise our achievements and space exploration in general are great for the country.”

Speaking at a pre-flight news conference Monday, 37-year-old Peresild acknowledged that it was challenging for her to adapt to the strict discipline and rigorous demands during the training.

“It was psychologically, physically and morally hard,” she said. “But I think that once we achieve the goal, all that will seem not so difficult and we will remember it with a smile.”

Shipenko, 38, who has made several commercially successful movies, also described their fast-track, four-month preparation for the flight as tough.

“Of course, we couldn’t make many things at the first try, and sometimes even at a third attempt, but it’s normal,” he said.

Shipenko, who will complete the shooting on Earth after filming the movie’s space episodes, said Shkaplerov and two other Russian cosmonauts now on board the station — Oleg Novitskiy and Pyotr Dubrov — will all play parts in the new movie.

Russia’s state-controlled Channel One television, which is involved in making the movie, has extensively covered the crew training and the launch.

“I’m in shock. I still can’t imagine that my mom is out there,” Peresild’s daughter, Anna, said in televised remarks minutes after the launch.

Dmitry Rogozin, head of the Russian state space corporation Roscosmos, was a key force behind the project, describing it as a chance to burnish the nation’s space glory and rejecting criticism from some Russian media.

Some commentators argued that the film project would distract the Russian crew and could be awkward to film on the Russian segment of the International Space Station, which is considerably less spacious compared to the U.S. segment. A new Russia lab module, the Nauka, was added in July, but it is yet to be fully integrated into the station.

On the space station, the three newcomers join Thomas Pesquet of the European Space Agency; NASA astronauts Mark Vande Hei, Shane Kimbrough and Megan McArthur; Roscosmos cosmonauts Novitskiy and Dubrov; and Aki Hoshide of the Japan Aerospace Exploration Agency.

Novitskiy, who will star as the ailing cosmonaut in the film, will take the captain’s seat in a Soyuz capsule to take the film crew back to Earth on Oct. 17.

Source

• The outage marked the longest stretch of downtime for Facebook since 2008.

• “To all the people and businesses around the world who depend on us, we are sorry for the inconvenience caused by today’s outage across our platforms,” said Santosh Janardhan, Facebook’s VP of infrastructure, in a blogpost late Monday.

• Facebook shares closed down almost 5% on Monday but they were up over 1% in pre-market trading on Tuesday.  

Facebook has apologized for the mass outage that left billions of users unable to access Facebook, Instagram, WhatsApp and Messenger for several hours.

“To all the people and businesses around the world who depend on us, we are sorry for the inconvenience caused by today’s outage across our platforms,” said Santosh Janardhan, Facebook’s VP of infrastructure, in a blogpost late Monday.

The outage, which prevented users from refreshing their feeds or sending messages, was caused by “configuration changes on the backbone routers,” Janardhan said, without specifying exactly what the changes were.

The changes caused “issues” that interrupted the flow of traffic between routers in Facebook’s data centers around the world, he added.

“This disruption to network traffic had a cascading effect on the way our data centers communicate, bringing our services to a halt,” Janardhan said.

Facebook, Instagram and WhatsApp stopped working shortly before noon ET, when the websites and apps for Facebook’s services were responding with server errors.

Just after 7 p.m. ET, around six hours after the platforms went offline, Facebook CEO Mark Zuckerberg wrote on his Facebook page: “Facebook, Instagram, WhatsApp and Messenger are coming back online now.”

He added: “Sorry for the disruption today – I know how much you rely on our services to stay connected with the people you care about.”

The outage marked the longest stretch of downtime for Facebook since 2008, when a bug knocked the site offline for about a day, affecting about 80 million users. The platform currently has around 3 billion users.

In 2019, a similar outage lasted about an hour. Facebook blamed a server configuration change for that outage.

The outage came one day after the whistleblower who leaked private internal research to both The Wall Street Journal and Congress revealed herself ahead of an interview with “60 Minutes.” The documents, first reported in a series of Journal stories, revealed that the company’s executives understood the negative impacts of Instagram among younger users and that Facebook’s algorithm enabled the spread of misinformation, among other things.

Facebook shares closed down almost 5% on Monday but they were up over 1% in pre-market trading on Tuesday.  

Source

• The London-based research firm recorded a profit of £43.8 million ($59.6 million) in 2020 after posting losses of hundreds of millions for the last several years.

• Turnover at the company more than tripled from just £265.5 million in 2019 to £826.2 million in 2020, according to the annual results filing on Companies House.

• Elsewhere, staff costs rose modestly from £467 million to £473 million, suggesting that DeepMind’s hiring frenzy may have come to an end.

LONDON — DeepMind, one of the world’s premier artificial intelligence labs, has turned a profit for the first time ever, according to a filing with the U.K. company registry published Tuesday.

The London-based research firm recorded a profit of £43.8 million ($59.6 million) in 2020 after posting losses of hundreds of millions for the last several years. It reported a loss of $649 million in 2019, for example.

Turnover at DeepMind more than tripled from just £265.5 million in 2019 to £826.2 million in 2020, according to the annual results filing on Companies House. DeepMind, which is owned by Google parent Alphabet, did not provide a specific reason for the revenue jump.

DeepMind doesn’t sell products directly to consumers and it hasn’t announced any deals with private companies outside of the Alphabet umbrella. It does, however, sell software and services to Alphabet’s companies including Google, YouTube and X, which is the moonshot division.

A DeepMind spokesperson told CNBC the company is “powering products and infrastructure that enrich the lives of billions through the many collaborations we have worked on across Alphabet over the years.”

A person in the AI industry, with knowledge of DeepMind, told CNBC that the revenue jump could be down to “creative accounting.” DeepMind did not immediately respond when asked to comment on the claim.

“I don’t think DeepMind have many or any revenue streams,” the CNBC source said, asking to remain anonymous due to the nature of the discussion. “So all that income is based on how much Alphabet pays for internal services, and that can be entirely arbitrary.”

Elsewhere, staff costs and other related costs rose modestly from £467 million to £473 million, suggesting that DeepMind’s hiring frenzy may have come to an end.

DeepMind employs some of the world’s leading AI research scientists, who can command annual salaries of more than $1 million.

These top people, who often have PhDs from the likes of Oxford, Cambridge, Stanford or MIT, can get large packages because they’re also sought after by Big Tech companies like Facebook, Apple, Amazon and Microsoft.

DeepMind did not specify how many people it added to its team in 2020 but it said it now employs over 1,000 people. Last year it said it had around 1,000 people.

Source

But what actually caused the outage?

What does Facebook say happened?

In an apologetic blog post, Santosh Janardhan, Facebook's vice president of infrastructure, said that "configuration changes on the backbone routers that coordinate network traffic between our data centres caused issues that interrupted this communication".

Can you explain that in plain English?

Cyber experts think the problem boils down to something called BGP, or Border Gateway Patrol—the system the internet uses to pick the quickest route to move packets of information around.

Sami Slim of data centre company Telehouse compared BGP to "the internet equivalent of air traffic control".

In the same way that air traffic controllers sometimes make changes to flight schedules, "Facebook did an update of these routes," Slim said.

But this update contained a crucial error.

It's not yet clear how or why, but Facebook's routers essentially sent a message to the internet announcing that the company's servers no longer existed.

Why did it take so long to fix the problem?

Experts say Facebook's technical infrastructure is unusually reliant on its own systems—and that proved disastrous on Monday.

After Facebook sent the fateful routing update, its engineers got locked out of the system that would allow them to communicate that the update had, in fact, been an error. So they couldn't fix the problem.

"Normally it's good not to put all your eggs in one basket," said Pierre Bonis of AFNIC, the association that manages domain names in France.

"For security reasons, Facebook has had to very strongly concentrate its infrastructure," he said.

"That streamlines things on a daily basis—but because everything is in the same place, when that place has a problem, nothing works."

The knock-on effects of the shutdown included some Facebook employees being unable to even enter their buildings because their security badges no longer worked, further slowing the response.

Is this unprecedented?

Social media outages are not uncommon: Instagram alone has experienced more than 80 in the past year in the United States, according to website builder ToolTester.

This week's Facebook outage was rare in its length and scale, however.

There is also a precedent for BGP meddling being at the root of a social media shutdown.

In 2008, when a Pakistani internet service provider was attempting to block YouTube for domestic users, it inadvertently shut down the global website for several hours.

And the outage's impact?

Between Facebook, Instagram, WhatsApp and Facebook Messenger, "billions of users have been impacted by the services being entirely offline", the Downdetector tracking service said.

Facebook, whose shares fell nearly five percent over the outage, has stressed there is "no evidence that user data was compromised as a result of this downtime".

But even though it lasted just a few hours, the impact of the shutdown ran deep.

Facebook's services are crucial for many businesses around the world, and users complained of being cut off from their livelihoods.

Facebook accounts are also commonly used to log in to other websites, which faced additional problems due to the company's technical meltdown.

Rival instant messaging services meanwhile reported that they had benefited from the fact that WhatsApp and Facebook Messenger were down.

Telegram went from the 56th most downloaded free app in the US to the fifth, according to monitoring firm SensorTower, while Signal tweeted that "millions" of new users had joined.

And among the more curious side-effects, several domain name registration companies listed Facebook.com as available for purchase.

"There was never any reason to believe Facebook.com would actually be sold as a result, but it's fun to consider how many billions of dollars it could fetch on the open market," said cyber security expert Brian Krebs.

Source

This is a short tale. One of despair and intrigue, as we realise the fragility of the global internet that we all so love and adore. On Monday 4th October 2021, people stopped scrolling through Facebook, they gave up posting selfies to Instagram, they ceased texting on WhatsApp, and Facebook employees abandoned doing any work. For all Facebook-owned websites were down, thanks to a couple of three letter acronyms: DNS and BGP.

While Facebook have not released any key details nor a postmortem, the internet is built on a series of open source standards and protocols that allow us to remotely inspect some of the fallout.

When you type facebook.com, riskledger.com or any other name into your web browser of choice, an invisible background process begins. This starts with the Domain Name System, or DNS for short. It is often said to be the phone book of the internet. It is responsible for converting long series of arcane numbers, useful only to machines, to something memorable.

The DNS system is contacted by your web browser asking simply, "what is the internet address for facebook.com?". Now if one device was answering every DNS question, it would quickly become overwhelmed, so over the years a distributed hierarchy formed. This starts with a DNS implementation built right into your device's operating system, to devices called "recursers" operated by your ISP and sometimes large organizations such as Google or CloudFlare, and even scaling up to central "root" devices that know the whereabouts of every .com, .co.uk and more.

Facebook in this case, operates a set of intermediary DNS servers that are responsible for everything between your ISP's recursers and the roots. These are responsible for facebook.com, instagram.com, whatsapp.com and everything else they operate. These servers are not responding. This is what we see above from our web browser when it hints to us the error is DNS_PROBE_FINISHED_NXDOMAIN. Our web browser tried it's best to work out the internet address for Facebook, but it didn't get a reply.

While DNS may allow our computers to rapidly translate from names useful to humans to numbers useful for computers, how does your device, with it's own internet address, traverse the global internet to reach Facebook?

No two devices on the internet are directly connected. At home, you will have your residential ISP. In a datacentre, there will be multiple commercial ISPs. Given two internet addresses, how do the two communicate? This is where routing comes in.

Routing is the system by which a path between two devices is calculated and established, potentially traversing dozens of ISP networks in the process. Given there must be tens-of-thousands of ISPs, how do we ensure they all can speak to each other?

We establish a standard! In 1989 no less, the Border Gateway Protocol, or BGP for short, was accepted by the internet community as RFC 1105. The document laid out a protocol by which routers operated by different companies and ISPs could exchange routing information which each other.

So what does this have to do with Facebook? We discussed earlier how our web browsers were not receiving a response to their DNS questions, this was however not a result of DNS itself, it was a result of Facebook's routers ceasing to speak BGP with the rest of the internet, and ultimately all of our ISP's routers stopped knowing where to send our DNS requests, or any traffic to Facebook for that matter.

While we can speculate all day as to exactly what issue occurred on the 4th of October in Facebook's infrastructure, it is however fun to arm-chair investigate using open source information, and send #hugops to the Facebook's network operations team!

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1. Drinking is associated with lots of health problems.
2. Heavy drinking is bad for you.

Here’s a graph of some associations.

Someone who averages 10 drinks per day is 50x more likely to get cirrhosis than someone who doesn’t drink at all (controlling for age, sex, and drinking history). This looks bad, but there are two caveats.

First, it doesn’t establish causality. It could be—if all you had was this figure—that cirrhosis causes hormonal changes that create urges to drink more.

But we do know that heavy drinking is bad. That’s partly because we know how alcohol causes problems. It causes cirrhosis by destroying liver cells. It causes cancer by getting converted to acetaldehyde and then damaging DNA. There are also randomized controlled trials (RCTs) that take heavy drinkers and get them to drink less. These inevitably show improved health (either health outcomes or biomarkers like blood pressure).

The second caveat is the little dip for diabetes and heart disease around 1-2 drinks. Some people think alcohol is causing this dip. Lots of mechanisms have been proposed: Maybe it reduces inflammation. Or maybe it impairs the cells that build up plaques in arteries. Or maybe it creates a hormonal imbalance that changes blood pressure regulation. Or maybe it increases HDL-cholesterol or insulin sensitivity or adiponectin levels.

Or, maybe alcohol doesn’t help diabetes and heart disease at all. Mathews et al. (2015) try to model how alcohol affects the heart, ending up with this terrifying figure:

Alcohol does a lot of different things and interacts with a lot of other factors. It’s great to try to unravel all this, but I don’t trust anyone who says they understand everything with confidence.

If alcohol doesn’t improve heart health, then why the dip? Well, it could just be that the same people who drink moderately also tend to exercise and eat well.

So we don’t know if moderate drinking is bad for you. It almost certainly causes harms like cancer, but it might help heart disease enough to offset those harms. In the US, around 20% of adults drink 1-2 drinks per day. Even if the effects are modest, the collective impact is huge. Second perhaps to caffeine, alcohol is humanity’s favorite drug. We need to know what it does.

This is the story of a trial that came close to answering this question and then exploded. At first, this looks like a story of simple corruption but when you look closely it’s a very complicated story of corruption.

• We need an RCT
• A solution
• Timeline
• Skepticism
• A defense of the main characters
• Rage

We need an RCT

You might be thinking, “what we need to do is compare the health of people who drink different amounts, while controlling for income, diet, education, exercise, etc.” The problem is that to a first approximation, “controlling” for things doesn’t work. It requires tons of different assumptions, like what you control for, how you code stuff, and how you model everything. Reasonable people can disagree about those assumptions. For alcohol, reasonable people do disagree, and so they get estimates that are all over the place.

So what do we do? We take the long, slow, hard path:

1. Get a large group of people.
2. Tell some of them to drink moderately, tell the others not to drink at all.
3. Wait years, monitoring people to make sure they are actually drinking (or not) like they’re supposed to.
4. Follow up and see which group is healthier.

Lots of things make this hard. Because the expected effects aren’t huge, you need a large group of people. Because culture and genetics vary, you need people from around the world. Because diseases take a long time to show up, you need to wait years. And imagine the challenge of telling people how much to drink and then making sure they follow your instructions.

An international effort monitoring thousands of people around the world for years—does that sound expensive?

A solution

Back around 2013, the NIH’s National Institute on Alcohol Abuse and Alcoholism (NIAAA) got interested in funding this. They figured it would cost on the order of $100 million for the full trial. This doesn’t seem crazy given the NIAAA’s $500 million annual budget, but the NIAAA has lots of other priorities and didn’t feel they had the money.

You know who has a lot of money, though? The alcohol industry. Worldwide, $100 million of booze is sold every 30 minutes. In principle, the industry could directly fund a study, but who would trust it?

In 2016, it looked like the NIAAA had found an elegant solution:

• Five alcohol companies would donate money for a trial.
• The NIH would ask researchers to send proposals for how they’d run a trial.
• The NIH would choose the scientifically best proposal, just like they do with any government-funded grant. The donors would have no influence on the process.
• The make the results trustworthy, there would be a “firewall”, with no communication between the industry and the research team.

Sounds promising. But if we go forward a couple of years, everything suddenly blows up.

June 15, 2018

What happened? You might imagine banal corruption, with cocaine and overseas bank accounts, but it’s nothing like that.

The real story is a much more interesting cocktail of science, academia, bureaucratic maneuvering, ambition, politics, capitalism, the “deep state”, secret emails, and slippery ethical slopes. It’s particularly interesting because it’s a huge stroke of luck that we know about any of this. You have to ask how often similar things happen and don’t blow up.

If you’re brave, you can read the 165-page report the NIH prepared before canceling the program. But I warn you: It’s mostly out-of-order redacted emails written by people who wanted to conceal what was happening. There’s an executive summary, but it’s written in a frustratingly “government” style. There are also newspaper stories, but they don’t try to reconstruct everything.

After spending way too much time reconstructing things, here’s the story as best as I can tell.

Timeline

If you want an even-more-obsessive amount of information about the timeline, you can click on (more) after each of the sections.

2001 - 2013. Kenneth Mukamal, a physician at Beth Israel medical center and faculty member at Harvard Medical School, publishes many papers that argue that moderate alcohol consumption has health benefits, usually for heart disease or diabetes. During the same period, John Krystal, a psychiatrist and professor at Yale publishes many papers on alcohol, mostly focusing on addiction and mental health. (Many other researchers will be involved in this study, but these two are most prominent.)

(more)

Early 2013. Some NIAAA staff are convinced that moderate drinking is good for you, and an RCT could prove it conclusively enough that doctors might recommend it to patients like they do with aspirin now. (We don’t know who these staff were, but Margaret Murray was probably among them.) They have the idea of getting the alcohol industry to fund the study but face two problems. First, the alcohol industry wants lots of details before forking over any cash. Second, the NIAAA isn’t allowed to solicit from industry. They try to get around these problems by having outside researchers (including Mukamal and Krystal) meet with industry to give details on how such a trial might work. This creates a dynamic where everyone (the NIAAA, the alcohol industry, Mukamal) wants to coordinate with each other, but maintain a pretense of being isolated. There’s lots of scheming about how information should flow to maintain this pretense.

(more)

July 12, 2013. After getting some positive feedback from the industry, NIAAA staff decide to create a “planning grant”. This was supposed to be open to anyone, but the staff conspire to steer the money to Mukamal by having a super-short deadline (overruled by NIH-central) requiring pre-approval (also overruled, sort of), and asking for a very specific clinical trial. Two staff go as far as to take fake “personal vacations” to travel to Boston and help Mukamal write the grant. When the window to apply for the grant closes on November 1, Mukamal is the only applicant.

(more)

November 21, 2013. There is a meeting at the Distilled Spirits Council in Washington, DC between the alcohol industry, the NIAAA, and three researchers, including Mukamal and Krystal. Someone from industry later reported to NIAAA staff that “he was tremendously enthused about the project” and that they would need similar meetings with other companies. He specifically wanted to hear more from Mukamal and Krystal. There was another meeting at the same location on Jan 28, 2014.

(more)

January 2014. The preliminary planning grant is reviewed. One reviewer was concerned about the alcohol industry, but NIAAA staff were able to exclude the reviewer from voting on procedural grounds. When responding to reviewer comments, Mukamal states that he “tried to be discrete [sic] about the industry stuff.” The grant is formally awarded on March 20, 2014.

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February 26, 2014. There is a meeting in Palm Beach, Florida, including the alcohol industry, at least one NIAAA staffer, and outside researchers. Mukamal’s slides stated, “A definitive clinical trial represents a unique opportunity to show that moderate alcohol consumption is safe and lowers risk of common diseases.”

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February 28, 2014. Wine Industry Insights publishes “US Govt Asking Industry To Fund Most Of $50 Million Alcohol/Health Study”, causing a ton of concern inside the NIAAA from people who didn’t know what was going on. The people involved openly discuss how to best conceal information.

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June 21, 2014. There’s a meeting in Seattle, led by Mukamal, and including NIAAA staff and the alcohol industry. Afterward, representatives from industry send Mukamal a list of technical concerns about the design of the RCT, including what outcomes to measure, the treatment population, adherence, dropouts, monitoring, using beer vs. spirits, and incentives to participate. Mukamal sends back a detailed response, sort of saying “well, this is what I would do if I happened to win the grant…” and then giving some reasonable answers.

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November-December, 2014. A large joint conference call is coordinated between the alcohol industry, NIAAA staff, and researchers including Mukamal. Here are three topics that industry asks about:

1. Will the data be shared with other researchers? Mukamal states that they would make “controlled data sets” available one year after the study ends.
2. Might industry funding call the study into doubt? Mukamal reassures that it’s fine because there will be a “firewall” between research and industry.
3. Will results will be published even if they are negative? Mukamal says yes, but they will “most certainly” see a positive impact at least for diabetes.

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February 26, 2015. Murkamal and NIAAA senior staffers coordinate edits to an email that will be sent to someone in industry. This email states that yes, they really need $100 million, and “one of the important findings will be showing that moderate drinking is safe.”

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Oct 5, 2015. The NIAAA publishes the funding opportunity for the big RCT. The published document implies that only someone who won the earlier planning grant—meaning only Mukamal—should apply. In December, Mukamal applies, and in January the opportunity closes without receiving any other applications.

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March-September 2016. The proposal is reviewed by the NIH, and eventually awarded to Mukamal.

The project begins on September 30.

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July 3, 2017. The New York Times publishes “Is Alcohol Good for You? An Industry-Backed Study Seeks Answers”. This quotes Margaret Murray of the NIAAA as saying that five companies had pledged $67.7 million, and has a lot of general skepticism of the reliability of industry-sponsored research. There’s this quote from George Koob, then director of the NIAAA:

“This study could completely backfire on the alcoholic beverage industry, and they’re going to have to live with it,” Dr. Koob said. “The money from the Foundation for the N.I.H. has no strings attached. Whoever donates to that fund has no leverage whatsoever — no contribution to the study, no input to the study, no say whatsoever.”

There’s also this:

Dr. Mukamal […] said he was not aware that alcohol companies were supporting the trial financially. “This isn’t anything other than a good old-fashioned N.I.H. trial,” he said. “We have had literally no contact with anyone in the alcohol industry in the planning of this.”

October 26, 2017. Wired publishes “A Massive Health Study on Booze, Brought to You by Big Alcohol”. Aside from more general skepticism of industry funding research, it also points out that Murray and Koob at the NIAAA seem to have a cozy relationship with the industry. It’s got some quotes from a researcher in South Africa that sort of make Mukamal look like a jerk, and finally this:

Yet when I spoke to Mukamal in February 2017, he said he didn’t know about the Foundation’s negotiation for industry contributions “until relatively recently.” […] “We have no contact with funders other than NIAAA itself whatsoever,” he wrote.

Feb 5, 2018. The trial begins enrolling patients.

March 17, 2018. The New York Times publishes “Federal Agency Courted Alcohol Industry to Fund Study on Benefits of Moderate Drinking”. They interviewed former federal officials and used Freedom of Information Act requests to get emails and travel vouchers related to the grant. This story reveals that, contrary to Mukamal’s claims, there were various meetings in 2013 and 2014. This includes a “working lunch” at the Beer Institute convention in Philadelphia that’s not in my timeline above because I can’t figure out when it happened.

March 20, 2018. Based on the previous above article, NIH director Francis Collins orders an investigation into the trial.

April 11, 2018. Collins appears before the House Appropriations Subcommittee on Labor, Health and Human Services to discuss the NIH’s budget. When asked about the trial, Collins responds that he is very concerned and is investigating the issue as a matter of priority. (You can watch the video here.)

May 10, 2018. The NIH suspends enrollment in the trial.

June 8, 2018. Anheuser-Bush pulls its funding.

June 15, 2018. Based on a recommendation from an NIH working group, Collins terminates the study.

Skepticism

You might think I’m out of my mind, but it’s hard for me to celebrate this trial being canceled. Obviously, lots of inappropriate stuff happened. But when you think about why you’d cancel the trial, the arguments aren’t as strong as you might think. Here are the arguments I’ve seen:

The NIAAA and Mukamal lied to the public.

True. They claimed this was just like any other NIH grant, where any researcher could propose a study design, and the NIH would choose the best entirely based on scientific merit. In reality, the NIAAA intentionally steered the money to one pro-alcohol researcher who coordinated the plan with the alcohol industry.

That was bad. But this doesn’t necessarily imply cancelation, if the study would have been useful. If the point is to punish people, let’s not hurt ourselves in the process, right?

If the study were done, no one would trust the results.

Possibly true, but let’s be careful. Are we claiming that no one should believe the results, or just that no one would? If it’s the latter, isn’t that kind of a weird reason to cancel a trial? Let’s break this down. Why might you not trust the results?

I don’t trust the research team.

Clearly, Mukamal thought the trial would show a benefit, but that doesn’t mean he was right. Anyone who’s worked in science knows what it’s like to confidently run an experiment, only to get smacked in the face by reality’s indifference to your pet theories and career goals.

But OK, say you don’t trust the research team. What do you think they are going to do, fabricate data? The study was a collaboration of a large team around the world. The data would be stored at a Data Management Center (whatever that is) at a different university and inspected every six months by a monitoring board. Here’s the organizational structure for the study:

This isn’t some excel spreadsheet stored on one grad student’s laptop. You’d need a big conspiracy.

Or maybe you don’t think they’d falsify data, but that for publication they would use some tortured data analysis to spin the results. The thing is, it’s not unusual to have researchers who want to find a given result—that’s every researcher everywhere! We have a system for this, which is that studies pre-register their statistical analysis. This study did that, and the plan seems fine (although, see below). There just aren’t many places to hide the bodies.

If the full data would have been public, that would be another major safeguard against selective data analysis, and made it even harder for anyone to fake things. I can't tell exactly what would have been public. Mukamal mentions making it public when planning the grant with industry. But then the actual grant proposal says nothing about it.

The study seems designed to deliver a pro-alcohol result.

Two concerns have been made about the study design. For one, it’s plausible that the biggest harms of alcohol (e.g. cancer) appear later, while cardiovascular and diabetes benefits (if they exist) happen quickly. So a five-year study might find alcohol reduces mortality while a ten-year study could show the opposite.

Fine, but what’s the principle here? Should we cancel all studies where there’s a much more expensive and difficult variant that would be more conclusive? We know this is an issue now, and we’d still know it when interpreting results after the study is done.

Another concern is that the study population maximizes the chances for alcohol to look good: It would only enroll people who are either ≥75 years old or at elevated risk for cardiovascular disease while excluding anyone with liver disease, a personal history of colon/liver/breast cancer, a family history of breast cancer, suicidal ideation, or dementia. If I wanted to maximize the chance that alcohol could be beneficial while minimizing the chance that alcohol could be harmful, this is the population I would choose.

If you want a final verdict on if moderate drinking is safe, I agree this seems like stacking the deck. I’d prefer a random sample of all adults. You can call this a “bias”. But you can also call it “refusing to take the sampling scheme into account when interpreting results”. There’s still value in knowing how alcohol affects a restricted population. And we can extrapolate—a neutral result in this study population would suggest alcohol is harmful to the average person.

You might also argue that it’s ethically required to exclude people who are at higher risk for being harmed by alcohol. I don’t really agree, but I’d imagine many people would.

The premise of the study is flawed: Recent evidence says alcohol is harmful to cardiovascular health.

This was brought up by the extra reviewers brought in to check the scientific merit of the study for the big NSF investigation. Some recent research suggests that alcohol could be bad for cardiovascular health. One strategy is “Mendelian randomization”: The ADH1B gene (which we’ve talked about before) makes it hard to metabolize alcohol. People who have it drink less. If you assume that gene is random in the population and that it’s causing reduced drinking, then you can treat it like a random assignment to drink less. Holmes et al. (2014) did this and found that carriers of ADH1B had better cardiovascular health by every measure. This suggests alcohol makes cardiovascular disease worse, not better. There’s also a recent meta-analysis of observational studies by Wood et al. (2018) that suggests that even small amounts of alcohol hurt cardiovascular health.

I don’t get this. Is the point that alcohol is definitely harmful? That’s wrong, the research in the previous paragraph is great, but it isn’t conclusive. Or is the point just that an RCT could fail to prove alcohol was helpful? Then… umm… isn’t that the entire point of doing the RCT?

The study would be misrepresented.

Imagine that the trial was done and that it showed little overall effect on health. Sure, you might say, you’ll remember that it used a special population and maybe didn’t run long enough to catch cancer. Clever people like you will interpret this as meaning that alcohol is probably harmful to the average person.

But do you trust journalists to understand these subtleties and convey them to the general public? Or would we just end up with headlines like “Gold-standard trial shows that moderate alcohol consumption is safe”?

This worries me, but less than you might think. For one thing, don’t most people already think moderate drinking is safe? The CDC just says not to drink more than 1-2 drinks a day. Tyler Cowen—the Internet’s greatest teetotaler—often points out the massive harms of alcohol. Yet he’s stated that he believes that by refusing to drink at all, he’s sacrificing a small amount of health.

Put that aside, though. Let’s make the logic more explicit: This is suggesting that because journalists might do something dumb, we should not run a trial that could give knowledge humanity has needed for generations.

Sure, I agree journalists might oversimplify things and confuse people. (Can anyone disagree given recent history?) I just don’t think that we can live in fear. We have to believe that once the scientific community has found the truth, it will eventually make its way into public consciousness. The solution to bad journalism is better journalism, not scientists refusing to do research on anything that could be misinterpreted.

It just looks bad.

The final NIH report notes that the researchers do not have “equipoise”. You could interpret this two ways. One, you might say the whole thing seems rotten and damn the logic of it. The other is that it looks bad for the NIH—that even if useful, it needs to be canceled to preserve trust in the institution. I understand this. But if that’s the reason to cancel, it makes me sad.

A defense of the main characters

When I first read about this trial blowing up, I was stupefied—how could everyone have been so shameless? What were they thinking?

Before criticizing people, it’s good to try to imagine the strongest defense of their actions. So let me try to do that here.

The alcohol industry

I mean, OK, this is an industry entirely devoted to selling an addictive substance that kills, by WHO estimates, three million people per year.

Something like 75% of alcohol is sold to raging alcoholics. This isn’t a nonprofit organic vegetable farm. But we live in a capitalist system. We expect companies to try to make money, and selling alcohol is legal. Let’s not conflate this particular trial with general objections to the alcohol industry’s existence.

Think about their perspective. The NIAAA came to them and said, “We think moderate alcohol consumption is good for you! You should fund a trial to prove this. Win-win for everyone!” The NIAAA sent fancy researchers from fancy places to present to them. Those researchers told them, “I, fancy person, am sure moderate drinking is good! Give me money to prove it!”

The alcohol industry was straightforward they wouldn’t fund anything without knowing what would happen in the trial. The NIAAA could have given up at that point, but they bent the rules instead. The industry was worried, “Won’t it look bad that we’re funding this?” Again, they were told, “Nah, it’s fine! There will be a firewall!”

They were told by well-credentialed people that they could make money and do good at the same time. Is it so terrible that they believed them?

NIAAA staff

You might criticize NIAAA staff for becoming convinced that moderate drinking was healthy, even though the science is inconclusive. That’s bad, but if you criticize everyone who’s wrong about stuff, you’re not going to get much sleep.

You can also criticize them for stretching the rules and misleading the public. This is a more clear failing. But imagine you knew a study would be valuable, but there’s some bureaucratic rule that prevents you from doing it. Wouldn’t you be tempted to stretch the rules?

Think about the NIAAA staff who took “personal vacations” to visit Mukamal to help him write the original planning grant. When they did this, I bet they saw themselves as heroes. This is what you see in movies: There’s a big problem in the world. People in power know there’s a problem, but for institutional reasons, it’s hard to fix. Most of the people in power are blankfaces, more concerned with covering their asses than helping people. The heroes are the ones who are willing to bend the rules to solve the problem—even if that means taking on personal risks.

If you think that no one in government should bend any rules, then I bet you haven’t interacted with the government much. Often, the rules were made by people so removed from what’s actually happening that the abstractions in the rules don’t even make sense.

Here’s an example. Say you’re a scientist and you want to send a grant to the National Science Foundation (NSF). According to The Rules, you will propose a detailed plan of future work. In some (more theoretical) fields this is absurd: You have to do half the work in order to write that plan! And in other (less theoretical) fields, your grant will be reviewed by other scientists who will expect to see “preliminary work” to show your idea has promise. This leads to a funny situation where people do much of the research and then “propose” it afterward.

Everyone involved knows that this is happening! The grant reviewers aren’t fooled. The people at NSF aren’t fooled. (Though if they’ve been around for a while, they might not notice the doublethink anymore.) When Congress set up the NSF, they had a mental model of how research works.

When that model doesn’t fit, people do the best thing they can: They collectively follow a parallel set of slightly different rules while simultaneously going through the motions of the rules as written. Congress didn’t mean to set up a system like this. Bending the rules allows their spirit to be followed as closely as possible.

At the NIAAA, The Rules say that you can’t solicit grants from industry. But what exactly is “soliciting”? You might imagine there’s some oracle somewhere ready to lend definitive answers, but I doubt it. Instead, what you probably see is some people doing things that are a little like soliciting, and it’s fine. Other people do things that look slightly more like soliciting, and again it’s fine. Eventually, someone pushes things slightly too far (or is just unlucky) and gets into trouble. The rules get clarified a bit then, but without acknowledging the institutional incentives that made everyone bend the rules in the first place. The person who got in trouble probably feels like a duck shot out of a flock.

So that’s what I guess happened at the NIAAA. The staffers are used to bending the rules because that’s what everyone does all the time because it’s the only way to do anything. They think that the alcohol study would be beneficial, and go for it, and over time things sort of spiral out of control.

Mukamal

There are lots of quotes from Mukamal where he appears to be promising to deliver a positive result. At first glance, these might look like red flags, but I don’t think they’re as bad as they seem.

For one thing, Mukamal didn’t start claiming alcohol was safe as a cynical ploy to get his hands on grant money. He had been publishing on the health effects of alcohol for years. There is no reason to doubt that he sincerely believed that moderate drinking had cardiovascular and diabetes benefits. (And he may well be correct!)

Can Mukamal be trusted? We can look at his track record. In 2007, he was first author on a paper that randomly assigned patients to consume black tea or not. They looked at tons of different biomarkers and found that the tea did… basically nothing. This is the kind of case where it would be easy to p-hack your way to force some conclusion, but they straightforwardly state they found no evidence.

So I don’t think these quotes represent a promise to falsify data but rather his confidence for what the study really would show when honestly performed.

Then there’s the lying. Mukamal said there was no communication with industry and that he had no idea industry funding was even involved. Lying is bad, but still: When Mukamal was describing a “firewall” between industry and research, he was probably thinking of a firewall that started existing sometime after industry committed to funding the study. As far as we know, such a firewall did actually exist: Mukamal wrote the final study plan without (further) interference from industry, and the trial would have run without any industry contact.

Would this “late firewall” have meant anything? Maybe so! The biggest question is if industry would have had an opportunity to bury the results if they didn’t look good. Maybe the firewall really would have stopped that.

So why did he hide the earlier meetings? Likely, Mukamal felt the public couldn’t handle it. Take a look at the first New York Times story on the subject. It is dripping with implications that the study is totally compromised when the only thing known (at the time) was that industry had funded things. It’s understandable that Mukamal might have felt that the media was out to get him.

So my guess is that Mukamal was basically a well-intentioned researcher who happened to have pro-alcohol views. He took an opportunity to try to prove his pet theory, and then kind of fell down a slippery slope where he was making gradually larger and larger ethical compromises in pursuit of a goal that he thought was worthy.

Rage

Having written that defense, I’d now like to explain why it’s wrong and I’m furious about every aspect of this story.

First, we can only compensate for biases if we know about them. I’m open to industry-funded research. I don’t necessarily mind a lead researcher who was chosen because they believe what industry likes. I can even live with industry having influence on the study design. I stubbornly hold all this even when the study has a goal of proving it’s safe to use humanity’s most harmful drug.

But my (possibly delusional) open-mindedness is based on the idea that it’s possible to compensate for the biases these issues create. That’s not possible if we don’t know about them. If you think research still has value despite these issues, fine, but you need to make that argument openly, not pretend the issues don’t exist.

Second, the firewall was fake. Say you’re OK with a “late firewall” where there’s tons of contact with industry early on, but no influence after the trial starts. This didn’t happen. How do I know? Well, did you notice the part where Anheuser-Bush pulled its funding? Having the power to shut down the entire trial whenever you want qualifies as influence.

Third, slippery slopes aren’t much of an excuse. Yes, we all face them, but that’s why it’s important to have principles—lines you won’t cross. If you haven’t run into one of those lines before you start lying to the New York Times, something is wrong.

Fourth, many people are complicit in silence. Maybe the alcohol industry really didn’t think anything underhanded was happening. Well, they knew on July 7, 2017, when the first New York Times story came out, including untrue or misleading statements from Mukamal and the NIAAA. They had months to correct the record, but they did nothing. The same is true for many of the other researchers involved.

Fifth, the general idea of industry funding with a firewall could be tremendously valuable but was tarnished by everyone here. Take nutritional supplements. Every time someone actually checks, we find out what’s in them bears little resemblance to what’s on the label (e.g. melatonin off by a factor of 10, or “ginkgo biloba extract” containing zero ginko biloba or tons of supplements containing heavy metals.) Some rare companies publish lab tests, but these always seem to be a test of some batch from two years ago by an unknown lab with no reputation who only tests three things and labels them “within spec”.

In principle, firewalled research could be the solution. Supplement companies could pay to have tests done by independent researchers.

Consumers would have a quality signal for what products to trust, and the companies that make good stuff would make more money. Everyone would win (except the people selling crap products).

This trial has discredited this idea. Obviously, I blame the main characters, but the media is also part of this. Take the first New York Times article again. Remember that when this was written, the firewall was valid, as far as anyone knew. But the article is almost an editorial disguised as journalism. Besides mentioning that the study exists and is funded by industry (which is totally legit) it’s largely a collection of whatever random suspicious connections they could dig up between anyone even vaguely connected to the study and the alcohol industry. There are also quotes about how industry funding skews research, but it doesn’t engage with the fact that that’s why there was supposed to be a firewall in this case.

Obviously, I’m glad the New York Times followed up on this story and revealed holes in the firewall. I just wish there was a more nuanced tone that engaged with the premise that the problems with industry funding are possible to overcome, at least in principle.

Sixth, in the final review, the NIH made no attempt at cost/benefit analysis. Their final report is a fair summary of the problems with the trial. But it doesn’t consider the information that was lost by cancellation, or the fact that that there was little cost to taxpayers. (Though Collins’ letter to Senator Grassley reveals the NIH did pay around $4 million out of pocket.) Could a different principal investigator be put in charge? Could the study design be modified to address the concerns? Could the monitoring bodies have been strengthened so people could trust the results? Maybe the trial was unsalvageable, but it’s telling that the NIH didn’t bother to make that argument.

Finally, why have there been so few consequences? Collins says that “three individuals are no longer employed” at the NIH, and they made process changes to avoid similar problems in the future.

That’s something, but what about the researchers? To their credit, Harvard and Beth Israel did do an investigation of Mukamal, which led to him formally apologizing, and them putting in additional safeguards to make sure no future employees would do anything similar.

Hahahaha, no. Here’s what actually happened:

1. Mukamal stated, “We stand fully and forcefully behind the scientific integrity” and “Every design consideration was carefully and deliberately vetted with no input or direction whatsoever from private sponsors.” (Yes, these are real quotes from after the study was canceled.)
2. As far as we know, there were no investigations by Harvard, Beth Israel, or any of the other researchers’ institutions. No one faced any penalty of any kind.
3. In 2020, in what might be the most brazen display of academic shamelessness in history, the researchers published a paper on how awesome the study would have been. Here’s a quote from that paper’s “sponsorship” section:

The Foundation for the National Institutes of Health (FNIH) supported the trial financially and managed contact between public and private organizations on behalf of NIH. The funds provided by FNIH for this project were contributed to FNIH by the brewing and distilling industries following contract negotiations that established an intellectual and financial firewall between MACH15 investigators and private contributors. The corporations providing support agreed to have, and had, no contact with trial investigators about any aspect of the study after their commitment of funding, and they agreed to receive no data or updates until they became publicly available. Ultimately, however, the most important safeguard for impartiality lies in the execution of a rigorous, transparent protocol following independent, expert peer review, and in the conduct of the statistical analyses as described in the protocol.

Emphasis mine. You can’t make this stuff up.

Source

Discoveries triggered a wave of findings about how we sense our environments.

Understanding how we sense touch, temperature earns a Nobel

Larger hagfish produce larger, stronger thread cells to better ward off predators.

Scientists are still learning cool new things about gooey hagfish slime

A peek at Down Detector (or your Twitter feed) reveals the problems are widespread. While it’s unclear exactly why the platforms are unreachable for so many people, their DNS records show that, like last week’s Slack outage, the problem is apparently DNS (it’s always DNS). Cloudflare senior vice president Dane Knecht notes that Facebook’s border gateway protocol routes — BGP helps networks pick the best path to deliver internet traffic — have been “withdrawn from the internet.”

Instagram.com is flashing a 5xx Server Error message, while the Facebook site merely tells us that something went wrong. The problem also appears to be affecting its virtual reality arm, Oculus. Users can load games they already have installed and the browser works, but social features or installing new games does not. The outage is thorough enough that it’s affecting Workplace from Facebook customers and, according to Jane Manchun Wong, Facebook’s internal sites.

There’s no word yet from Facebook about what may be causing the problem or when those sites, including Messenger and WhatsApp, will be operational again, but we will update this article with more information when it’s available.

source

Among the Stars, a six-part docu-series that premieres Oct. 6 on Disney+, is a classic hero’s journey. Filmed over two years, just before COVID, the arc of the story follows the astronauts currently onboard the International Space Station—including NASA astronaut Captain Chris Cassidy as he completes his last mission—plus those on Earth supporting the missions.

But when we got a sneak peek at the episodes ahead of the transmission date, one person stood out: Nobel Prize-winning physicist Dr. Samuel Ting from MIT—in part because he’s searching for the origins of the universe.

Via his mega-experiment, the Alpha Magnetic Spectrometer (AMS), a 7.5-ton module that sits atop the ISS, Dr. Ting has been "sifting space" since 2011, looking for evidence of dark matter. The AMS involves 44 institutions from America, Europe, and Asia, and is sponsored by the US Department of Energy and NASA. We spoke with Professor Ting recently to find out more.

Delving Into Dark Matter

To become more than a single-planet species (because, spoiler alert, this one has a termination date), we need to know What’s Out There. Right now, 95% of it is classified as "unknown." We’ve measured 5%, but the rest is—well, that’s what the AMS is trying to find out. We can’t pass through space en route to other galaxies unless we know that, and we can’t examine dark energy, dark matter, and whatever else is lurking beyond our own galaxy, from Earth.

Dr. Ting working on the AMS. (Photo: NASA)

"All the elements we have on Earth also exist in space; those particles carry signals of how the universe is created, how particles travel, but you cannot measure them on the ground,” explains Dr. Ting. “Because we live under 100 kilometers of atmosphere, particles entering into the atmosphere just break apart.”

Which is why the AMS is in space, where it can not only collect and model the particles before they hit Earth’s atmosphere, but examine the properties of these particles, and, crucially, how they are charged, where they came from, and so on. It’s an extraordinary piece of scientific equipment, which has modeled 180 billion cosmic rays (to date) into 300,000 data channels that are analyzed by its 600 onboard computers. 

Activating Antimatter

Dr. Ting at a 2013 press conference at NASA’s Johnson Space Center. (Photo: NASA/James Blair)

However, to model energy and momentum, you need a magnet to observe the particle spin (positive one way, negative the other). A magnet on a space station? Isn’t that dangerous? Yes. But Dr. Ting found a way to have a magnet that doesn't rotate in space, one of the many groundbreaking innovations that make up the AMS.

“My first experiment was in 1965,” says Dr. Ting of the project's origins. “This was the first heavy antimatter ever found, the Anti Deuterons." (A Deuteron is a proton plus a neutron; Anti Deuterons is an antiproton plus an anti neutron.)

Cut to April 1994, when Dr. Ting was walking in the backyard of his house in France, thinking about what he should do next. “By that point, I’d been doing experiments on accelerators my whole life, [and thought] maybe I should do something new. Something I know nothing about, something that nobody thought was possible. That’s when I thought about putting a Magnetic Spectrometer in space to look for dark matter, to understand the origin of the cosmic universe. Initially it was quite difficult because nobody thought such a thing could go to space. But eventually we figured out a way to do that.“

T-Minus 10 - 9 - 8 

(Photo: NASA)

Under the auspices of the European Organization for Nuclear Research (CERN), NASA, and other international space agencies, Professor Ting worked on the project for decades, alongside a team of scientists from 16 countries. By 2011, the AMS was ready to go up and be installed on the ISS; it was transported by the Space Shuttle Endeavour's last mission.

Dr. Ting with the AMS team in 2011 (Photo: NASA)

Dr. Ting recalls going to the Kennedy Space Center to witness take-off. “Somebody from the Kennedy Space Center took a photo of me. And I remember my whole feeling, my whole body was ice cold. And I was so tense. The night before the launch, I went with my wife to the launch pad. We could not go in; they were fueling the liquid into the shuttle. So coming back, I must be extremely nervous because I was driving at a rather high speed. The Kennedy Space Center police stopped me, and said: ‘You’re driving awfully fast.’  That’s when I realized I wasn’t even carrying my license either.”

Houston, We Have a Problem

More than 10 years later, the drama continues in Among the Stars, which details an unsettling problem with the AMS: The $2 billion dollar space instrument has a cooling issue and needs urgent repairs. This is not a simple matter when one is orbiting 260 miles above Earth in an extreme environment where temperatures swing between 250 degrees Fahrenheit in direct sunlight to minus 200 degrees by nightfall.

Surrounded by the documentary makers’ cameras, the NASA team fuels up on sodas and chips while staring down at their laptops as Dr. Ting cross-examines them. It’s a fascinating behind-the-scenes glimpse into how one maintains control over a massive scientific experiment, the likes of which may never be repeated in our lifetime.

The AMS is scheduled to remain up on the ISS for the length of its service, which is tentatively scheduled to end in 2024. NASA would like to extend its life, but political spats with international partners like Russia, not to mention aging equipment, mean that's still up in the air.

In the meantime, as the docu-series reveals, the cooling issue situation requires an entirely custom toolset. This is not stuff you can just pick up at the hardware store, after all. In an interesting episode segment, aerospace engineer Heather Bergman lets us into her lab at NASA's Johnson Space Center, where she talks us through the SWAGE tool (a metal-on-metal seal that won’t leak), bolt cutters, and other space-ready materials. 

ESA astronaut Luca Parmitano during a November 2019 spacewalk to fix the AMS. (Photo: NASA)

In particularly breathtaking footage, we see the astronauts on a spacewalk to carry out repairs, while, below at NASA Johnson, Dr. Ting and the team participate on a live feed. It’s nail-biting stuff and—no spoilers here—clearly a lot is at stake (like the future of our species).  

“The unique feature of humans is curiosity,” Professor Ting says. “If you do not do research, you'll never know what happened. A few 100 years ago, we thought the Earth was flat, that we were in the center of the universe. After a few 100 years of research, we realize Earth is a very small part of the universe. So, if you don't do research, you would never know this. That’s what we’re doing with the AMS.” 

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When scientists discovered the energy embedded within atoms, it transformed how we think about the long-term future of humanity, writes the historian Thomas Moynihan.

Just over 100 years ago, an ocean liner – twin to the Titanic – returned to Normandy from the US with a very special item. It was a summer's day in 1921, and travelling on board was the scientist Marie Sklodowska-Curie, accompanied by her daughters, Irène and Ève. In their possession was a single gram (0.04oz) of radium, locked away in a lead box within the ship's safe. In today's money, it would be worth $1,500,000.

It had been presented to her by none other than the US president. But it was purchased with donations from thousands of American women, following a fundraising initiative kickstarted by journalist Marie Meloney.

Curie had secured celebrity by unleashing the theory of radioactivity upon the world, revealing for the first time the atom's innards: the microcosm of activity, and cornucopia of energy, within.  She had discovered new radioactive elements, the most famous of which was radium. For this, she won her first Nobel Prize.

We all know how nuclear physics went on to alter our world forever. The gram gifted to Curie helped further research on the atom that, ultimately, led to the development of nuclear weapons. What is less known, however, is that – decades before the bomb – radioactivity had already revolutionised our world in ways that were just as profound, if more subtle.

Eclipsed by the infamy of atomic warfare, this is the near-forgotten story of how radium forever transformed attitudes to time and where we may be within history – creating the first efflorescence of truly long-term thinking. Until that point, we knew the Earth was old, but hadn't fully embraced how many more millions – or even billions – of years could lie ahead for humanity and the planet.

Appropriately, Curie came away from the US exhausted but with a conviction of "unlimited possibilities for the future".

Marie Sklodowska-Curie (seated) with her daughters Irene and Eve and Marie Meloney (centre), on RMS Olympic in 1921 (Credit: Getty Images)

Our sense of where we are in history rests on our sense of how much future history we expect is left ahead. In Europe, for generations, Christians assumed they were much closer to time's end than its beginning. Judgement Day was anticipated soon.

The first scientific treatments on the matter, based on extrapolations of physical process rather than scriptural prophecy, emerged in the 1700s. Naturalists began attempting to forecast how long Earth would remain habitable.

People also began realising that, compared to the geological past, humanity had not existed very long – civilisation even less so. In this context, it became sensible to suggest everything humanly achievable had perhaps not already been achieved. The future became a canvas for hope. Optimists suggested our species could continue inquiring, inventing, improving until the Earth becomes uninhabitable.

The problem was that, by Victorian times, science's judgement on how much future lay ahead was somewhat austere. Physicists had started calculating how long the Sun could continue to shine for, but because they falsely believed that it generates heat by collapsing under its own weight, their estimates were far too short.

In 1854, it was forecast by Scottish mathematician Lord Kelvin that there were only 300,000 years left. After this, he declared, Earth will be sterilised by cold. Estimates on the deadline varied between physicists, but by the century's closing decades the community converged upon the very low tens of millions.

For many thinkers of the period, it was the ratio of "time ahead", to "time spent", that proved particularly depressing. Expressing the general mood in 1893, one Irish astronomer pronounced that our "Sun had already dissipated about four-fifths of the energy with which it may have originally been endowed". Evolution had come thus far; it didn't have time to go much further.

As the 1800s closed, there was little room for grand optimism regarding humanity's far-flung future on Earth.

As the 1900s dawned, "radio-mania" captivated culture, inspiring music and consumer products (Credit: Getty Images)

Then, the 1900s dawned, and radioactivity was discovered. This changed everything.

In March 1903, the Curies demonstrated that radium continuously emanates a surprising amount of heat. This came from inside radium's own atoms, rather than from exchange with its surroundings. Radioactive atoms were furnaces.

Measures of the amount of energy within atoms were shocking. Previously considered indestructible, this wealth was being gradually disbursed asthe atom itself disintegrated – sometimes over billions of years. Perhaps the most evocative example of this long, atomic reach into the future was a clock made in 1903, powered by radium: it was projected to keep "ticking" for millennia.

These revelations triggered a flurry of excited responses from scientists. Within months, an astronomer suggested that radioactivity may "afford a clue to the source of energy in the Sun". Another celebrated Curie's "unexpected" discovery of this "new source of energy": suggesting that, if the Sun powers itself by "liberating atomic energy" – rather than languorously collapsing –then we will have to extend the "cosmical time-scale" by several factors.

Wassily Kandinsky's Ship & Red Sun. In 1913, the artist remarked the discovery of disintegrating atoms made "everything precarious, unsteady, pliant" (Credit: Kandinsky)

The UK newspaper The Daily Mail swiftly ran an article in response. "Radium to the Rescue", it boldly relayed: from meagre millions, Earth's habitable future had just swollen by "several hundred million years". By 1920, experts were granting "15 billion years" of further sunlight.

Having grown up believing Earth was "plunging on" to "final winter in the near future", scientists welcomed the discovery of these little "atomic stoves" – within the heart of matter – which could seemingly fuel our world for orders of magnitude longer. No longer can we believe "ours is a decadent Sun", with the "red-yellow tinge" of solar senility, one journalist exclaimed: radium had come "to the rescue", extending "indefinitely the backward and forward sweep of the cosmical timetable".

During the 1920s, estimates on the future continued to expand. One prominent physicist, James Jeans – describing atoms as "pure bottled energy" – boldly estimated our Sun retains enough "unbroken bottles" for a whopping trillion years more sunlight. While this later proved excessive – its expected lifespan was slashed to 5 billion years in the 1960s – it speaks to just how far the horizons of the time were expanding.

Communicating the potential scale of the future to the public in 1929, Jeans visualised a stamp atop a penny, balanced upon a 20m-high (66ft) obelisk. The stamp's thickness represented. recorded history. The stamp and penny combined represented our species' existence. The distance from the stamp down to the obelisk-base was the age of Earth. 

Jeans didn't stop there. He calculated the height of postage stamps, stacked one atop the other, you'd need for a trillion further years of habitability on Earth. "A pile as high as Mont Blanc", he concluded.

A postcard depicting Cleopatra's Needle, just over 20m (66ft) tall, gifted to the UK in 1819 (Credit: Alamy)

Jeans deemed us "creatures of the dawn", with "unimaginable opportunities for accomplishment" and "unexplored potentialities" ahead.

Others would reach similar conclusions. Geologists concurred that "Homo sapiens is still a youthful species". And radiochemists celebrated a "profound reversal of mental outlook": from a sense that the pinnacles of achievement lay in some past "Golden Age", physics now suggested they may lie within the roomy future.

In sum, Curie's discoveries completely inverted the ratio of expected future to established past. From thinking they lived near history's end, people now recognised they could be living during its very beginning. Humanity's universe, no longer decrepit, now seemed positively youthful.

Jeans deemed us "creatures of the dawn", with "unimaginable opportunities for accomplishment" and "unexplored potentialities" ahead

Compared to the "cosmical" past, it appeared Homo sapiens had emerged only in the latest splinter of time. Serious, scientific attempts to improve the species' material conditions had only just emerged within a splinter of that splinter.

Given all this, geologists claimed that, if we suppose humanity unique in its capability to respond to moral reasoning, then (extremely fallible though this faculty of ours evidently remains) the epoch of ethical agency on Earth may only just be dawning.

The generous prospect ahead "becomes almost stupefying", one writer rhapsodised in 1921, "if we pay attention to the modern rate of progress".

We can but "dimly conceive" what might be accomplished in the eons ahead, if the "rate we are going" continues to be even minimally retained.

After radium's revelations, Jeans explained that the message of physics was one "of responsibility, because we are drawing plans and laying foundations for a longer future than we can well imagine".

Thomas Chrowder Chamberlin had a beard as prodigious as the glacial drifts he studied (Credit: Getty Images)

In September 1928, these new responsibilities to humanity's deep future were presciently articulated by the geologist Thomas Chrowder Chamberlin, two months before he died.

When a journalist interviewed him in his Chicago study, Chamberlin gave a crinkled smile and said he was "a declared believer in large opportunity" for humanity.

Chamberlin pointed to the fact that humanity had only just discovered the "enormous energies" corked up in atoms. "So I think we are really just in the beginning of things, just beginning to learn how to think". Our speciesis like an infant, he continued. "From the standpoint of the Earth, I am an advocate of a great future".

More than most, he had already pondered the ethical implications of a ballooning future. Across a 60-year career, he had pioneered theories about climate change: proposing, in 1899, that CO2 causes global warming. He even suggested human activities are altering Earth's future climate. This demands "altruistic purpose", in regulating present "action", to safeguard "generations that may live tens of thousands of years hence".

And in June 1898 – a month before Curie glacial introduced the term radio-activité – Chamberlin was asserting that our ignorance regarding subatomic processes means that we should be suspicious of Kelvin's estimates of a meagre future.

When advances in nuclear physics rapidly proved him right on his bullish predictions for Earth's prospects, he began insisting that the expanding future demands heightening responsibility.

By 1903, he was, on these grounds, claiming that the best actions are those that – compounding over time – snowball into "great things" in the "long ages" ahead.

The "protracted influence" of altruistic actions, rippling forward through eons, amplifies their positive "contribution". But, by the same token, the same applies to the "ulterior" impact of damaging actions. Prudence therefore demands being mindful of our usage of Earth's finite "resources", he sagely suggested.

A model for a rocket, following Konstantin Tsiolkovsky's blueprints (Credit: Alamy)

Meanwhile, the discovery of radium was expanding perspectives of humanity's place in the Universe in other ways: it also promised new methods to catapult civilisationoff-world.

Prior physics came with a low ceiling on future time – and the same applied to assumptions of available energy. But here, in mundane matter – of which we are all awash in abundance – were revealed energetic coffers "of a magnitude of which we have no experience". So wrote Frederick Soddy, co-discoverer of radioactive decay. "The energy is there. The knowledge that can utilise is not – not yet".

Though migrations within our Solar System had been envisaged before, it's hard to find people anticipating crewed travel to other stars before 1900. But, by revealing generous headroom in expected future and untapped energy, nuclear physics made interstellar travel suddenly seem feasible… at least, eventually.

The biochemist J.B.S. Haldane claimed that, if it became star-hopping, civilisation could last for 80,000,000,000,000 years

The visionary Russian engineer, Konstantin Tsiolkovsky, was the first to put all this together. In 1911, he stated that, if you could tap the energy within radium, then you could propel a rocket to the nearest sun within 10-40 years.

What's important here is that achieving interstellar exodus would uncouple the lifespan of humanity from the lifespan of our Sun, exploding the ceiling on the size of humanity’s future once again.

"A pinch of radium would be enough for a ton rocket to sever all ties with the Solar System", Tsiolkovsky surmised. Humanity could then migrate "from Sun to Sun", persisting for cosmological timescales.

By 1927, the biochemist J.B.S. Haldane claimed that, if it became star-hopping, civilisation could last for the lifespan of the entire galaxy. He guesstimated that this could be 80,000,000,000,000 years.

"And there are other galaxies", he piquantly added.

Illustrations from Haldane’s short story "The Last Judgment", in The Graphic, Saturday 26, February, 1927 (Credit: John Archibald Austen)

A voluminous future for galactic humanity beckoned. But, as Chamberlin acknowledged, possibility and "opportunity" doesn't "ensure actual realization". Jeans, likewise, warned that "accident may replace our Mont Blanc of postage-stamps by a truncated column of only a fraction…"

As one journalist asked at the time: we may "paint optimistic pictures of the future on the hazy horizon of the million years ahead", but what of the potential for mishaps that may extinguish humanity, cancelling our "alluring hopes of progress" and the "world-picture of coming grandeur"? There may indeed be "almost infinite possibilities of betterment", he wrote, but this only deepens the tragedy of lost potential should humanity somehow go prematurely extinct "within the next thousand years, the approaching century, or even on a succeeding day".

Scientists were confident that the risks from nature were comfortingly low. The same, unfortunately, could not quite be guaranteed for the potential perils posed by humanity’s own inventiveness. Ever since 1903, there had been recurrent fears – in both the press and scientific literature – that uncorking an atom might ignite the Earth "like a barrel of powder". Some suggested that, if the Earth is packed with radioactive ores, then we live upon a "storehouse stuffed with explosives": tampering with atoms might trigger a cascading reaction, immolating our planet.

Before the atomic bomb was developed, people also worried that we'd accidentally trigger a catastrophic nuclear reaction within the Earth (Credit: Getty Images)

In 1924, one melodramatic engineer, at Sheffield University, caused panic with boasts that he was about to successfully smash an atom. Sensationally, newspapers reported that this might detonate the planet. He received terrified letters from the British public, begging him not to complete his experiment.

No such "cosmocataclysm" happened, of course. Atomic tinkering didn't ignite the Earth or turn our planet into a new star. But serious discussions were had, for the first time, assessing whether humanity may soon pose a greater risk to itself – through accumulated technological might – than threats from nature. Suggestions that have since become darkly true. After developing thermonuclear weapons in the 1950s, humanity began to emulate the subatomic processes within suns successfully enough to destroy itself and its extended future.

The irony is that the nuclear discoveries – kickstarted by Curie – that have latterly put that future in jeopardy were precisely the same ones that first brought a spacious future, with vast potentials, into view.

Insights for today

There are important lessons here for those seeking to take a long-term view in the present day. First, be cautious claiming "never" with anticipated technological breakthroughs, particularly when the consequences of their invention may change the course of civilisation forever. A century ago, prominent physicists maintained that unbottling atoms was definitively impossible. One, in 1930, dismissed the "hobgoblin" of nuclear energy as "myth". He advised everyone "sleep in peace", knowing God has put child-locks on his "handiwork", such that humanity cannot disturb the universe. Eight years later, nuclear fission was unlocked by Lise Meitner.

Despite predictions to the contrary only years earlier, Lise Meitner would unlock nuclear fission (Credit: Getty Images)

Second, predicting timelines on such breakthroughs is difficult. Writing on humanity’s long-run future in 1927, Haldane (amongst the most skilled forecasters of his generation) thought it sensible to portray return trips from the Moon as eluding humanity until AD8,000,000. This feat was accomplished, by Apollo 11, just 42 years later.

Soddy, writing in 1919, warned that, once people discover how to weaponise isotopes, unprecedented destructive potential will be unleashed. All he could do was hope “this discovery will not be made” until humanity has the prudence not to misuse it.

Haldane’s prediction, and Soddy’s hope, proved misguided. The point here is that we, exactly a century later, stand in an identical position with regards to various new emerging technologies, from artificial intelligence to synthetic biology, which could imperil our entire future. For example, it seems plausible that engineering deadly pathogens will only become cheaper and easier, but we do not know how long it will take before it becomes easy enough to pose a serious threat to everyone.

We need more than “hope” that we tackle the challenges promised by oncoming technologies before they are unlocked and unleashed. As happened with atomic power, world-changing technologies can be developed sooner than experts expect, so it pays to be prepared rather than complacent.

Equipped with better understanding of how the Sun will age, and how sensitive Earth’s climate will be to its aging, today’s predictions on future habitability have decreased from the trillion years forecast by Jeans. Many scientists now predict something under­­­ 1 billion years left for complex Earth-bound life. However, balancing this, nothing has yet been found – in heavens nor Earth – to imply that humanity cannot achieve interstellar diaspora before this time. And estimates on how long the wider Universe may remain capable of supporting complex life are truly eye-watering.

"Dawn", by Joseph Farquharson, painted in 1903: the year Marie Curie won her Nobel Prize for discovering radium (Credit: Joseph Farquharson)

Humanity's future could be astronomically large, as scientists in the early 1900s first noticed. It could be commodious enough to make some reparation for all the frustrated, snatched, and wasted opportunities of history so far. The most impactful and resonant actions, then, might be those that target safeguarding this long-term prospect. Yet right now, humanity remains like an adolescent: irresponsible, albeit first waking up to the fact that actions can have irreversible, reverberating consequences.

Probably the first "longtermist", Thomas Chamberlin said it best in 1910: "The highest conception of altruism which I am able to form is built on the thought of doing things that are sound enough [to] last and be doing good ages after they have lost the name and superscription of those who set them going."

*Thomas Moynihan is the author of X-Risk: How Humanity Discovered Its Own Extinction and a research fellow at Forethought Foundation and St Benet’s College, Oxford University. He tweets at @nemocentric and can be found at www.thomasmoynihan.xyz.

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Press release

2021-10-04

The Nobel Assembly at Karolinska Institutet

has today decided to award

the 2021 Nobel Prize in Physiology or Medicine

jointly to

David Julius and Ardem Patapoutian

for their discoveries of receptors for temperature and touch

Our ability to sense heat, cold and touch is essential for survival and underpins our interaction with the world around us. In our daily lives we take these sensations for granted, but how are nerve impulses initiated so that temperature and pressure can be perceived? This question has been solved by this year’s Nobel Prize laureates.

David Julius utilized capsaicin, a pungent compound from chili peppers that induces a burning sensation, to identify a sensor in the nerve endings of the skin that responds to heat. Ardem Patapoutian used pressure-sensitive cells to discover a novel class of sensors that respond to mechanical stimuli in the skin and internal organs. These breakthrough discoveries launched intense research activities leading to a rapid increase in our understanding of how our nervous system senses heat, cold, and mechanical stimuli. The laureates identified critical missing links in our understanding of the complex interplay between our senses and the environment.

How do we perceive the world?

One of the great mysteries facing humanity is the question of how we sense our environment. The mechanisms underlying our senses have triggered our curiosity for thousands of years, for example, how light is detected by the eyes, how sound waves affect our inner ears, and how different chemical compounds interact with receptors in our nose and mouth generating smell and taste. We also have other ways to perceive the world around us. Imagine walking barefoot across a lawn on a hot summer’s day. You can feel the heat of the sun, the caress of the wind, and the individual blades of grass underneath your feet. These impressions of temperature, touch and movement are essential for our adaptation to the constantly changing surrounding.

In the 17th century, the philosopher René Descartes envisioned threads connecting different parts of the skin with the brain. In this way, a foot touching an open flame would send a mechanical signal to the brain (Figure 1). Discoveries later revealed the existence of specialized sensory neurons that register changes in our environment. Joseph Erlanger and Herbert Gasser received the Nobel Prize in Physiology or Medicine in 1944 for their discovery of different types of sensory nerve fibers that react to distinct stimuli, for example, in the responses to painful and non-painful touch. Since then, it has been demonstrated that nerve cells are highly specialized for detecting and transducing differing types of stimuli, allowing a nuanced perception of our surroundings; for example, our capacity to feel differences in the texture of surfaces through our fingertips, or our ability to discern both pleasing warmth, and painful heat.

Prior to the discoveries of David Julius and Ardem Patapoutian, our understanding of how the nervous system senses and interprets our environment still contained a fundamental unsolved question: how are temperature and mechanical stimuli converted into electrical impulses in the nervous system?

Figure 1 Illustration depicting how the philosopher René Descartes imagined how heat sends mechanical signals to the brain.

The science heats up!

In the latter part of the 1990’s, David Julius at the University of California, San Francisco, USA, saw the possibility for major advances by analyzing how the chemical compound capsaicin causes the burning sensation we feel when we come into contact with chili peppers. Capsaicin was already known to activate nerve cells causing pain sensations, but how this chemical actually exerted this function was an unsolved riddle. Julius and his co-workers created a library of millions of DNA fragments corresponding to genes that are expressed in the sensory neurons which can react to pain, heat, and touch. Julius and colleagues hypothesized that the library would include a DNA fragment encoding the protein capable of reacting to capsaicin. They expressed individual genes from this collection in cultured cells that normally do not react to capsaicin. After a laborious search, a single gene was identified that was able to make cells capsaicin sensitive (Figure 2). The gene for capsaicin sensing had been found! Further experiments revealed that the identified gene encoded a novel ion channel protein and this newly discovered capsaicin receptor was later named TRPV1. When Julius investigated the protein’s ability to respond to heat, he realized that he had discovered a heat-sensing receptor that is activated at temperatures perceived as painful (Figure 2).

Figure 2 David Julius used capsaicin from chili peppers to identify TRPV1, an ion channel activated by painful heat. Additional related ion channels were identified and we now understand how different temperatures can induce electrical signals in the nervous system.

The discovery of TRPV1 was a major breakthrough leading the way to the unravelling of additional temperature-sensing receptors. Independently of one another, both David Julius and Ardem Patapoutian used the chemical substance menthol to identify TRPM8, a receptor that was shown to be activated by cold. Additional ion channels related to TRPV1 and TRPM8 were identified and found to be activated by a range of different temperatures. Many laboratories pursued research programs to investigate the roles of these channels in thermal sensation by using genetically manipulated mice that lacked these newly discovered genes. David Julius’ discovery of TRPV1 was the breakthrough that allowed us to understand how differences in temperature can induce electrical signals in the nervous system.

Research under pressure!

While the mechanisms for temperature sensation were unfolding, it remained unclear how mechanical stimuli could be converted into our senses of touch and pressure. Researchers had previously found mechanical sensors in bacteria, but the mechanisms underlying touch in vertebrates remained unknown. Ardem Patapoutian, working at Scripps Research in La Jolla, California, USA, wished to identify the elusive receptors that are activated by mechanical stimuli.

Patapoutian and his collaborators first identified a cell line that gave off a measurable electric signal when individual cells were poked with a micropipette. It was assumed that the receptor activated by mechanical force is an ion channel and in a next step 72 candidate genes encoding possible receptors were identified. These genes were inactivated one by one to discover the gene responsible for mechanosensitivity in the studied cells. After an arduous search, Patapoutian and his co-workers succeeded in identifying a single gene whose silencing rendered the cells insensitive to poking with the micropipette. A new and entirely unknown mechanosensitive ion channel had been discovered and was given the name Piezo1, after the Greek word for pressure (í; píesi). Through its similarity to Piezo1, a second gene was discovered and named Piezo2.

Sensory neurons were found to express high levels of Piezo2 and further studies firmly established that Piezo1 and Piezo2 are ion channels that are directly activated by the exertion of pressure on cell membranes (Figure 3).

Figure 3 Patapoutian used cultured mechanosensitive cells to identify an ion
channel activated by mechanical force. After painstaking work, Piezo1 was
identified. Based on its similarity to Piezo1, a second ion channel was found
(Piezo2).

The breakthrough by Patapoutian led to a series of papers from his and other groups, demonstrating that the Piezo2 ion channel is essential for the sense of touch. Moreover, Piezo2 was shown to play a key role in the critically important sensing of body position and motion, known as proprioception. In further work, Piezo1 and Piezo2 channels have been shown to regulate additional important physiological processes including blood pressure, respiration and urinary bladder control.

It all makes sense!

The groundbreaking discoveries of the TRPV1, TRPM8 and Piezo channels by this year’s Nobel Prize laureates have allowed us to understand how heat, cold and mechanical force can initiate the nerve impulses that allow us to perceive and adapt to the world around us. The TRP channels are central for our ability to perceive temperature. The Piezo2 channel endows us with the sense of touch and the ability to feel the position and movement of our body parts. TRP and Piezo channels also contribute to numerous additional physiological functions that depend on sensing temperature or mechanical stimuli. Intensive ongoing research originating from this year’s Nobel Prize awarded discoveries focusses on elucidating their functions in a variety of physiological processes. This knowledge is being used to develop treatments for a wide range of disease conditions, including chronic pain (Figure 4).

Figure 4 The seminal discoveries by this year’s Nobel Prize laureates have explained how heat, cold and touch can initiate signals in our nervous system. The identified ion channels are important for many physiological processes and disease conditions.

Key publications

Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 1997:389:816-824.

Tominaga M, Caterina MJ, Malmberg AB, Rosen TA, Gilbert H, Skinner K, Raumann BE, Basbaum AI, Julius D. The cloned capsaicin receptor integrates multiple pain-producing stimuli. Neuron 1998:21:531-543.

Caterina MJ, Leffler A, Malmberg AB, Martin WJ, Trafton J, Petersen-Zeitz KR, Koltzenburg M, Basbaum AI, Julius D. Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science 2000:288:306-313

McKemy DD, Neuhausser WM, Julius D. Identification of a cold receptor reveals a general role for TRP channels in thermosensation. Nature 2002:416:52-58

Peier AM, Moqrich A, Hergarden AC, Reeve AJ, Andersson DA, Story GM, Earley TJ, Dragoni I, McIntyre P, Bevan S, Patapoutian A. A TRP channel that senses cold stimuli and menthol. Cell 2002:108:705-715

Coste B, Mathur J, Schmidt M, Earley TJ, Ranade S, Petrus MJ, Dubin AE, Patapoutian A. Piezo1 and Piezo2 are essential components of distinct mechanically activated cation channels. Science 2010:330: 55-60

Ranade SS, Woo SH, Dubin AE, Moshourab RA, Wetzel C, Petrus M, Mathur J, Bégay V, Coste B, Mainquist J, Wilson AJ, Francisco AG, Reddy K, Qiu Z, Wood JN, Lewin GR, Patapoutian A. Piezo2 is the major transducer of mechanical forces for touch sensation in mice. Nature 2014:516:121-125

Woo S-H, Lukacs V, de Nooij JC, Zaytseva D, Criddle CR, Francisco A, Jessell TM, Wilkinson KA, Patapoutian A. Piezo2 is the principal mechonotransduction channel for proprioception. Nature Neuroscience 2015:18:1756-1762

David Julius was born in 1955 in New York, USA. He received a Ph.D. in 1984 from University of California, Berkeley and was a postdoctoral fellow at Columbia University, in New York. David Julius was recruited to the University of California, San Francisco in 1989 where he is now Professor.

Ardem Patapoutian was born in 1967 in Beirut, Lebanon. In his youth, he moved from a war-torn Beirut to Los Angeles, USA and received a Ph.D. in 1996 from California Institute of Technology, Pasadena, USA. He was a postdoctoral fellow at the University of California, San Francisco. Since 2000, he is a scientist at Scripps Research, La Jolla, California where he is now Professor. He is a Howard Hughes Medical Institute Investigator since 2014.

Illustrations: © The Nobel Committee for Physiology or Medicine. Illustrator: Mattias Karlén

The Nobel Assembly, consisting of 50 professors at Karolinska Institutet, awards the Nobel Prize in Physiology or Medicine. Its Nobel Committee evaluates the nominations. Since 1901 the Nobel Prize has been awarded to scientists who have made the most important discoveries for the benefit of humankind.

Nobel Prize® is the registered trademark of the Nobel Foundation

To cite this section
MLA style: Press release: The Nobel Prize in Physiology or Medicine 2021. NobelPrize.org. Nobel Prize Outreach AB 2021. Mon. 4 Oct 2021. <https://www.nobelprize.org/prizes/medicine/2021/press-release/>

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Now a team of scientists led by faculty at Yale School of Public Health and the University of North Carolina at Charlotte have an answer: Strong protection following natural infection is short-lived.

"Reinfection can reasonably happen in three months or less," said Jeffrey Townsend, the Elihu Professor of Biostatistics at the Yale School of Public Health and the study's lead author. "Therefore, those who have been naturally infected should get vaccinated. Previous infection alone can offer very little long-term protection against subsequent infections."

The study, published in the journal The Lancet Microbe, is the first to determine the likelihood of reinfection following natural infection and without vaccination.

Townsend and his team analyzed known reinfection and immunological data from the close viral relatives of SARS-CoV-2 that cause "common colds," along with immunological data from SARS-CoV-1 and Middle East Respiratory Syndrome. Leveraging evolutionary principles, the team was able to model the risk of COVID-19 reinfection over time.

Reinfections can, and have, happened even shortly after recovery, the researchers said. And they will become increasingly common as immunity wanes and new SARS-CoV-2 variants arise.

"We tend to think about immunity as being immune or not immune. Our study cautions that we instead should be more focused on the risk of reinfection through time," said Alex Dornburg, assistant professor of bioinformatics and genomics at the University of North Carolina at Charlotte, who co-led the study. "As new variants arise, previous immune responses become less effective at combating the virus. Those who were naturally infected early in the pandemic are increasingly likely to become reinfected in the near future."

The team's data-driven model reveals striking similarities to the reinfection risks over time between SARS-CoV-2 and endemic coronaviruses.

"Just like common colds, from one year to the next you may get reinfected with the same virus," Townsend said. "The difference is that, during its emergence in this pandemic, COVID-19 has proven to be much more deadly."

A hallmark of the modern world is going to be the evolution of new threats to human health, Townsend added. Evolutionary biology—which provided the theoretical foundations for these analyses—is traditionally considered a historical discipline.

"However, our findings underscore its important role in informing decision-making, and provide a crucial steppingstone toward robust knowledge of our prospects of resistance to SARS-CoV-2 reinfection," he said.

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New York (CNN Business)The identity of the Facebook whistleblower who released tens of thousands of pages of internal research and documents — leading to a firestorm for the social media company in recent weeks — was revealed on "60 Minutes" Sunday night as Frances Haugen.

WASHINGTON, Oct 3 (Reuters) - A massive leak of financial documents was published by several major news organizations on Sunday that allegedly tie world leaders to secret stores of wealth, including King Abdullah of Jordan, Czech Prime Minister Andrej Babis and associates of Russian President Vladimir Putin.

The dump of more than 11.9 million records, amounting to about 2.94 terabytes of data, came five years after the leak known as the "Panama Papers" exposed how money was hidden by the wealthy in ways that law enforcement agencies could not detect.

The International Consortium of Investigative Journalists, a Washington, D.C.-based network of reporters and media organizations, said the files are linked to about 35 current and former national leaders, and more than 330 politicians and public officials in 91 countries and territories. It did not say how the files were obtained, and Reuters could not independently verify the allegations or documents detailed by the consortium.

Jordan's King Abdullah, a close ally of the United States, was alleged to have used offshore accounts to spend more than $100 million on luxury homes in the United Kingdom and the United States.

DLA Piper, a London law office representing Abdullah, told the consortium of media outlets that he had "not at any point misused public monies or made any use whatsoever of the proceeds of aid or assistance intended for public use."

The Washington Post, which is part of the consortium, also reported on the case of Svetlana Krivonogikh, a Russian woman who it said became the owner of a Monaco apartment through an offshore company incorporated on the Caribbean island of Tortola in April 2003 just weeks after she gave birth to a girl. At the time, she was in a secret, years-long relationship with Putin, the newspaper said, citing Russian investigative outlet Proekt.

The Post said Krivonogikh, her daughter, who is now 18, and the Kremlin did not respond to requests for comment.

Days ahead of the Czech Republic's Oct. 8-9 parliamentary election, the documents allegedly tied the country's prime minister, Babis, to a secret $22 million estate in a hilltop village near Cannes, France.

Speaking during a television debate on Sunday, Babis denied any wrongdoing.

"The money left a Czech bank, was taxed, it was my money, and returned to a Czech bank," Babis said.

Reuters

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Victoria’s Covid infections have dropped slightly with Melbourne’s 246-day lockdown to become the world’s longest on Tuesday.

And while New South Wales recorded a substantial drop in local Covid-19 cases on Sunday, the state continued to see a rise in Covid-related hospitalisations and deaths.

Victoria reported 1,220 new locally acquired coronavirus cases on Sunday, down from 1,488 the previous day, and three deaths: a man in his 50s, a woman in her 70s, and a man in his 80s.

Victorian premier Daniel Andrews said there were 476 people in hospital across the state, with 98 people in intensive care and 57 on a ventilator. Of those, only five per cent are fully vaccinated.

Andrews said 51.9% of those aged 16 and over in Victoria are fully vaccinated, while 82.6% have now received at least one dose.

Starting Monday, the waiting period between Pfizer doses interval at state-run clinics will go from six weeks to three weeks.

As of Tuesday 5 October, Melbourne will have been in lockdown for 246 days – overtaking Buenos Aires as the city that has spent the most cumulative days under stay-at-home orders.

NSW authorities reported 667 new infections, a drop from the 813 cases recorded in the previous 24-hour period.

NSW health minister Brad Hazzard said this was a “dramatic drop” in new cases. However 10 people had died: two in their 50s, four in their 60s, two in their 70s, and two in their 80s. Of those, four people were not vaccinated, four had received one dose, and two were fully vaccinated.

Hazzard also issued new guidelines for businesses. Businesses will be responsible for taking “reasonable measures” to stop unvaccinated people entering their premises under updated rules for the state’s roadmap out of lockdown.

This means prominent signage, QR code check-ins, staff checking vaccination status on entry and only accepting valid forms of documentation will all fall to business.

Authorised officers will monitor businesses reopening, particularly those with vaccination requirements and penalties, including on-the-spot fines, may apply for non-compliance – up to $1,000 for individuals and $5,000 for businesses.

Authorities also reported that 88.1% of the state’s eligible population have received at least one dose of a Covid-19 vaccine, while 66.5% are fully vaccinated.

NSW chief health officer Dr Kerry Chant said that while declining case numbers were positive, she cautioned that the virus was seeding across regional areas, including in Wollongong, Newcastle, Maitland, Wellington, Queanbeyan and Deniliquin.

Chant said one day of declining case numbers “does not make a trend”, and said health authorities won’t have complete confidence that infections are dropping until Wednesday or Thursday.

She said the next week will be “critical” and urged residents to increase the rate of people getting tested, after 88,000 people got tested in the 24 hours to Sunday.

The state is on track to hit its 70% double-dose vaccine target by midweek. Restrictions will ease to allow fully vaccinated residents to have five visitors to their home, access gyms and indoor sporting facilities, and visit hospitality outlets, with up to 20 people per booking.

Chant also announced that from 11 October, close contacts who are fully vaccinated will only be required to test and isolate for seven days, down from 14 days.

But Hazzard also warned residents not to “ruin” the state’s hard work thus far and breach lockdown restrictions to celebrate Sunday’s NRL grand final.

The warning came after Victoria reported a record high of 1,488 new Covid-19 cases on Saturday, with authorities partly attributing the rise in infections to illegal AFL grand final gatherings last weekend.

Meanwhile, the ACT announced 38 new local Covid-19 infections, a drop after two consecutive days of recording 52 cases.

Of the 38 new cases, 14 were in quarantine during their entire infectious period, while at least 16 people spent some of their infectious period in the community.

Health minister Rachel Stephen-Smith said there are 14 people with Covid-19 in hospital. Of these, five are in intensive care and three require ventilation.

In South Australia, a Mt Gambier woman who flew home to Adelaide from Melbourne on a Jetstar flight, has tested positive for the virus.

Queensland announced no new coronavirus cases in the community.

Queensland chief health officer Dr Jeannette Young said that she was confident that the state has prevented this latest outbreak.

“I think one of the reasons we have been successful in containing nearly 50 incursions of the virus in the last few months is because we are finding pretty much the first case in each outbreak,” she said.

“And that means that we can get on it really quickly and thank you for the help that people give our contact tracers.”

But in Tasmania, premier Peter Gutwein revealed that a 15-year-old teenager had tested positive for the virus after travelling, with permission, from Melbourne on Friday.

The teenager had mild symptoms but was taken to Launceston general hospital, and was transferred with a family member to a quarantine facility. Gutwein said four family members were considered close contacts.

As of Sunday, 79.4% of Australians aged 16 and older have received at least one vaccine dose, while 56.5% have received both jabs.

The Herald Sun reported on Sunday that Australians could receive Covid-19 booster shots “as early as December”, and confirmed that there are enough boosters for every Australian, pending the approval of their use.

Source

JERUSALEM (AP) — Israel restricted its COVID Green Pass on Sunday to allow only those who have received a vaccine booster dose or recently recuperated from coronavirus to enter indoor venues. The new criteria mean that nearly 2 million people will lose their vaccination passport in the coming days.

Israel is the first country to make a booster shot a requirement for its digital vaccination passport. The move is widely seen as a step to encourage booster vaccination among those who have yet to receive a third dose.

Under the new guidelines, people must have received a booster shot to be eligible for a green pass. Those who have received two vaccine doses, and those who have recovered from coronavirus, will be issued passes valid for six months after the date of their vaccination or recovery.

The government’s advisory cabinet on coronavirus was set to convene Sunday to discuss existing restrictions and guidelines.

Technical problems hamstrung the Health Ministry’s rollout of the updated green pass as millions of Israelis tried to reissue digital documentation that would allow entry to shops, restaurants, cultural events, gyms and other indoor venues.

Scores of Israelis staged demonstrations around the country in protest of the green pass system, with convoys of cars clogging morning commutes as many Israelis returned to work Sunday after September’s Jewish High Holidays. Opponents of the system said it is a form of forced vaccination.

“We are totally against any forced vaccinations, or any forced medications, and we are totally against doing anything to our children and grandchildren that we don’t agree with,” said Sarah Felt, who protested along the main highway connecting Jerusalem and Tel Aviv.

Israel raced out of the gate early this year to vaccinate most of its adult population after striking a deal with Pfizer to trade medical data in exchange for a steady supply of doses.

This summer Israel launched an aggressive booster campaign to shore up waning vaccine efficacy in its population. Over 60% of Israel’s population has received two doses of the Pfizer/BioNTech vaccine and nearly 3.5 million of Israel’s 9.3 million citizens have received a booster dose of the vaccine. But at least 2 million more have received just two doses, and many will lose the privileges bestowed by the green pass.

Recent months have seen a surge in new cases of coronavirus in Israel. As of Sunday, over 70% of the 588 serious coronavirus cases in Israeli hospitals were unvaccinated individuals, according to Health Ministry data.

The ministry issued a statement Sunday morning that because of heavy traffic on its green pass website and app, previously existing certificates would be valid in the coming few days.

Source