People with depression are lacking a single molecule, scientists discover

Acetyl-L-carnitine has long been recognized as important for metabolism of fatty acids in mitochondria. Its newly discovered link to depression could one day change the lives of millions.

A depressed person with their arm reaching out in the blackness. Photo by Cherry Laithang on Unsplash
Photo by Cherry Laithang on Unsplash.

A new study published in PNAS has uncovered a critical biomarker of depression and a promising treatment method based on the body's levels of a single molecule called acetyl-L-carnitine (ALC). This molecule's main job is to help transport fatty acids into mitochondria; in effect, it helps provide cells with energy. By comparing the blood levels of 71 depressed individuals and 45 healthy individuals, it was discovered that ALC levels were significantly lower in those suffering from depression. Not only that, but the more depressed the individual was, the lower their ALC levels.

Depression affects nearly 10% of the population at a given time, and one in four adults will experience a major depressive episode at some point in their lifetime. Although sadness is a major symptom of depression, it's not the only way that it manifests. Rather, depression is a pervasive and persistent experience of symptoms such as a loss of energy, difficulty thinking, a loss of interest in previously pleasurable activities, as well as a sense of sadness.

Of the 71 depressed individuals in the study, 43 were diagnosed with severe depression. Interestingly, these severely depressed individuals had the lowest ALC levels and were more likely to have treatment-resistant depression, to have undergone childhood trauma or abuse, and to be women (likely because depression occurs more often in women than men).

According to the researchers, about 25–30% of all depression sufferers have this type of severe depression. Because ALC levels correlated with the presence and severity of the patients' depression, measuring ALC in the blood can help psychiatrists determine who is at the greatest risk and help develop a treatment plan. In fact, providing ALC supplements to depressed patients might represent a critical treatment method.

A potentially powerful treatment

Medication is available for depression but doesn't work for everyone, and antidepressants can lose their efficacy over time. When they do work, they're often accompanied by symptoms that match the disease for discomfort: nausea, weight gain, a loss of sexual desire, anxiety, and other crummy states of being.


Acetyl-L-carnitine has long been recognized as important for metabolism of fatty acids in mitochondria. Its newly discovered link to depression could one day change the lives of millions. (Image: Creative Commons/Big Think)

But evidence exists that ALC supplementation could be a simple and effective way to treat depression. Carla Nasca, the lead author of the study, previously conducted studies on rodents with low ALC levels and depression. Of course, you can't ask a rat whether they've experienced a loss in their sense of purpose in life, but you can evaluate whether they have depressive-like symptoms, like sleep disruptions; anxious behavior; changes in weight; and changes in the density and function of their hippocampi, amygdalae, and other neural structures affected by depression.

In rodents experiencing depressive-like symptoms, supplementing them with ALC rapidly addressed their symptoms and ameliorated the dysfunction of key, depression-related brain structures. What's more, ALC did all of this within a matter of days, while most antidepressant medication can take weeks to kick in.

According to Dr. Nasca's studies, ALC supplementation would work in depressed individuals by regulating the expression of genes related to synaptic plasticity. Essentially, these genes produce molecules that help the brain strengthen, weaken, and generate new synapses. Depressed individuals aren't able to do this as well as others, causing critical mood-regulating regions in their brain to perform poorly. By regulating these genes, the neural dysfunction normally seen in depression improved.

What's next?


While depression can slow your thinking, sap your interest in the world, and cause constant fatigue, sometimes the medication can feel just as bad. (Image: Ursula Ferrara/Shutterstock)

Unfortunately, it remains to be seen whether ALC supplementation will have the same drastic effects in humans as it did in rats. Subtle genetic differences can have vastly different effects across species, and it remains to be seen how exactly ALC will work in human beings.

On this note, the researchers said, “We've identified an important new biomarker of major depression disorder. We didn't test whether supplementing with that substance could actually improve patients' symptoms. What's the appropriate dose, frequency, duration? We need to answer many questions before proceeding with recommendations, yet. This is the first step toward developing that knowledge, which will require large-scale, carefully controlled clinical trials."

The achievement of this study was in identifying that ALC levels are low in human beings, just as in rats. While this is a major milestone toward finding an effective treatment for depression, questions remain as to whether supplementation can help treat this deadly disease, whether ALC levels are low in at-risk but non-depressive patients, if it is a biomarker for depression only or for other affective disorders as well, and many more.'

U.S. Navy controls inventions that claim to change "fabric of reality"

Inventions with revolutionary potential made by a mysterious aerospace engineer for the U.S. Navy come to light.

U.S. Navy ships

Credit: Getty Images
Surprising Science
  • U.S. Navy holds patents for enigmatic inventions by aerospace engineer Dr. Salvatore Pais.
  • Pais came up with technology that can "engineer" reality, devising an ultrafast craft, a fusion reactor, and more.
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COVID and "gain of function" research: should we create monsters to prevent them?

Gain-of-function mutation research may help predict the next pandemic — or, critics argue, cause one.

Credit: Guillermo Legaria via Getty Images
Coronavirus

This article was originally published on our sister site, Freethink.

"I was intrigued," says Ron Fouchier, in his rich, Dutch-accented English, "in how little things could kill large animals and humans."

It's late evening in Rotterdam as darkness slowly drapes our Skype conversation.

This fascination led the silver-haired virologist to venture into controversial gain-of-function mutation research — work by scientists that adds abilities to pathogens, including experiments that focus on SARS and MERS, the coronavirus cousins of the COVID-19 agent.

If we are to avoid another influenza pandemic, we will need to understand the kinds of flu viruses that could cause it. Gain-of-function mutation research can help us with that, says Fouchier, by telling us what kind of mutations might allow a virus to jump across species or evolve into more virulent strains. It could help us prepare and, in doing so, save lives.

Many of his scientific peers, however, disagree; they say his experiments are not worth the risks they pose to society.

A virus and a firestorm

The Dutch virologist, based at Erasmus Medical Center in Rotterdam, caused a firestorm of controversy about a decade ago, when he and Yoshihiro Kawaoka at the University of Wisconsin-Madison announced that they had successfully mutated H5N1, a strain of bird flu, to pass through the air between ferrets, in two separate experiments. Ferrets are considered the best flu models because their respiratory systems react to the flu much like humans.

The mutations that gave the virus its ability to be airborne transmissible are gain-of-function (GOF) mutations. GOF research is when scientists purposefully cause mutations that give viruses new abilities in an attempt to better understand the pathogen. In Fouchier's experiments, they wanted to see if it could be made airborne transmissible so that they could catch potentially dangerous strains early and develop new treatments and vaccines ahead of time.

The problem is: their mutated H5N1 could also cause a pandemic if it ever left the lab. In Science magazine, Fouchier himself called it "probably one of the most dangerous viruses you can make."

Just three special traits

Recreated 1918 influenza virionsCredit: Cynthia Goldsmith / CDC / Dr. Terrence Tumpey / Public domain via Wikipedia

For H5N1, Fouchier identified five mutations that could cause three special traits needed to trigger an avian flu to become airborne in mammals. Those traits are (1) the ability to attach to cells of the throat and nose, (2) the ability to survive the colder temperatures found in those places, and (3) the ability to survive in adverse environments.

A minimum of three mutations may be all that's needed for a virus in the wild to make the leap through the air in mammals. If it does, it could spread. Fast.

Fouchier calculates the odds of this happening to be fairly low, for any given virus. Each mutation has the potential to cripple the virus on its own. They need to be perfectly aligned for the flu to jump. But these mutations can — and do — happen.

"In 2013, a new virus popped up in China," says Fouchier. "H7N9."

H7N9 is another kind of avian flu, like H5N1. The CDC considers it the most likely flu strain to cause a pandemic. In the human outbreaks that occurred between 2013 and 2015, it killed a staggering 39% of known cases; if H7N9 were to have all five of the gain-of-function mutations Fouchier had identified in his work with H5N1, it could make COVID-19 look like a kitten in comparison.

H7N9 had three of those mutations in 2013.

Gain-of-function mutation: creating our fears to (possibly) prevent them

Flu viruses are basically eight pieces of RNA wrapped up in a ball. To create the gain-of-function mutations, the research used a DNA template for each piece, called a plasmid. Making a single mutation in the plasmid is easy, Fouchier says, and it's commonly done in genetics labs.

If you insert all eight plasmids into a mammalian cell, they hijack the cell's machinery to create flu virus RNA.

"Now you can start to assemble a new virus particle in that cell," Fouchier says.

One infected cell is enough to grow many new virus particles — from one to a thousand to a million; viruses are replication machines. And because they mutate so readily during their replication, the new viruses have to be checked to make sure it only has the mutations the lab caused.

The virus then goes into the ferrets, passing through them to generate new viruses until, on the 10th generation, it infected ferrets through the air. By analyzing the virus's genes in each generation, they can figure out what exact five mutations lead to H5N1 bird flu being airborne between ferrets.

And, potentially, people.

"This work should never have been done"

The potential for the modified H5N1 strain to cause a human pandemic if it ever slipped out of containment has sparked sharp criticism and no shortage of controversy. Rutgers molecular biologist Richard Ebright summed up the far end of the opposition when he told Science that the research "should never have been done."

"When I first heard about the experiments that make highly pathogenic avian influenza transmissible," says Philip Dormitzer, vice president and chief scientific officer of viral vaccines at Pfizer, "I was interested in the science but concerned about the risks of both the viruses themselves and of the consequences of the reaction to the experiments."

In 2014, in response to researchers' fears and some lab incidents, the federal government imposed a moratorium on all GOF research, freezing the work.

Some scientists believe gain-of-function mutation experiments could be extremely valuable in understanding the potential risks we face from wild influenza strains, but only if they are done right. Dormitzer says that a careful and thoughtful examination of the issue could lead to processes that make gain-of-function mutation research with viruses safer.

But in the meantime, the moratorium stifled some research into influenzas — and coronaviruses.

The National Academy of Science whipped up some new guidelines, and in December of 2017, the call went out: GOF studies could apply to be funded again. A panel formed by Health and Human Services (HHS) would review applications and make the decision of which studies to fund.

As of right now, only Kawaoka and Fouchier's studies have been approved, getting the green light last winter. They are resuming where they left off.

Pandora's locks: how to contain gain-of-function flu

Here's the thing: the work is indeed potentially dangerous. But there are layers upon layers of safety measures at both Fouchier's and Kawaoka's labs.

"You really need to think about it like an onion," says Rebecca Moritz of the University of Wisconsin-Madison. Moritz is the select agent responsible for Kawaoka's lab. Her job is to ensure that all safety standards are met and that protocols are created and drilled; basically, she's there to prevent viruses from escaping. And this virus has some extra-special considerations.

The specific H5N1 strain Kawaoka's lab uses is on a list called the Federal Select Agent Program. Pathogens on this list need to meet special safety considerations. The GOF experiments have even more stringent guidelines because the research is deemed "dual-use research of concern."

There was debate over whether Fouchier and Kawaoka's work should even be published.

"Dual-use research of concern is legitimate research that could potentially be used for nefarious purposes," Moritz says. At one time, there was debate over whether Fouchier and Kawaoka's work should even be published.

While the insights they found would help scientists, they could also be used to create bioweapons. The papers had to pass through a review by the U.S. National Science Board for Biosecurity, but they were eventually published.

Intentional biowarfare and terrorism aside, the gain-of-function mutation flu must be contained even from accidents. At Wisconsin, that begins with the building itself. The labs are specially designed to be able to contain pathogens (BSL-3 agricultural, for you Inside Baseball types).

They are essentially an airtight cement bunker, negatively pressurized so that air will only flow into the lab in case of any breach — keeping the viruses pushed in. And all air in and out of the lap passes through multiple HEPA filters.

Inside the lab, researchers wear special protective equipment, including respirators. Anyone coming or going into the lab must go through an intricate dance involving stripping and putting on various articles of clothing and passing through showers and decontamination.

And the most dangerous parts of the experiment are performed inside primary containment. For example, a biocontainment cabinet, which acts like an extra high-security box, inside the already highly-secure lab (kind of like the radiation glove box Homer Simpson is working in during the opening credits).

"Many people behind the institution are working to make sure this research can be done safely and securely." — REBECCA MORITZ

The Federal Select Agent program can come and inspect you at any time with no warning, Moritz says. At the bare minimum, the whole thing gets shaken down every three years.

There are numerous potential dangers — a vial of virus gets dropped; a needle prick; a ferret bite — but Moritz is confident that the safety measures and guidelines will prevent any catastrophe.

"The institution and many people behind the institution are working to make sure this research can be done safely and securely," Moritz says.

No human harm has come of the work yet, but the potential for it is real.

"Nature will continue to do this"

They were dead on the beaches.

In the spring of 2014, another type of bird flu, H10N7, swept through the harbor seal population of northern Europe. Starting in Sweden, the virus moved south and west, across Denmark, Germany, and the Netherlands. It is estimated that 10% of the entire seal population was killed.

The virus's evolution could be tracked through time and space, Fouchier says, as it progressed down the coast. Natural selection pushed through gain-of-function mutations in the seals, similarly to how H5N1 evolved to better jump between ferrets in his lab — his lab which, at the time, was shuttered.

"We did our work in the lab," Fouchier says, with a high level of safety and security. "But the same thing was happening on the beach here in the Netherlands. And so you can tell me to stop doing this research, but nature will continue to do this day in, day out."

Critics argue that the knowledge gained from the experiments is either non-existent or not worth the risk; Fouchier argues that GOF experiments are the only way to learn crucial information on what makes a flu virus a pandemic candidate.

"If these three traits could be caused by hundreds of combinations of five mutations, then that increases the risk of these things happening in nature immensely," Fouchier says.

"With something as crucial as flu, we need to investigate everything that we can," Fouchier says, hoping to find "a new Achilles' heel of the flu that we can use to stop the impact of it."

The misguided history of female anatomy

From "mutilated males" to "wandering wombs," dodgy science affects how we view the female body still today.

Credit: Hà Nguyễn via Unsplash
Sex & Relationships
  • The history of medicine and biology often has been embarrassingly wrong when it comes to female anatomy and was surprisingly resistant to progress.
  • Aristotle and the ancient Greeks are much to blame for the mistaken notion of women as cold, passive, and little more than a "mutilated man."
  • Thanks to this dubious science, and the likes of Sigmund Freud, we live today with a legacy that judges women according to antiquated biology and psychology.
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Mind & Brain

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