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 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.
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.'
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Researchers hope the technology will further our understanding of the brain, but lawmakers may not be ready for the ethical challenges.
- Researchers at the Yale School of Medicine successfully restored some functions to pig brains that had been dead for hours.
- They hope the technology will advance our understanding of the brain, potentially developing new treatments for debilitating diseases and disorders.
- The research raises many ethical questions and puts to the test our current understanding of death.
The image of an undead brain coming back to live again is the stuff of science fiction. Not just any science fiction, specifically B-grade sci fi. What instantly springs to mind is the black-and-white horrors of films like Fiend Without a Face. Bad acting. Plastic monstrosities. Visible strings. And a spinal cord that, for some reason, is also a tentacle?
But like any good science fiction, it's only a matter of time before some manner of it seeps into our reality. This week's Nature published the findings of researchers who managed to restore function to pigs' brains that were clinically dead. At least, what we once thought of as dead.
What's dead may never die, it seems
The researchers did not hail from House Greyjoy — "What is dead may never die" — but came largely from the Yale School of Medicine. They connected 32 pig brains to a system called BrainEx. BrainEx is an artificial perfusion system — that is, a system that takes over the functions normally regulated by the organ. The pigs had been killed four hours earlier at a U.S. Department of Agriculture slaughterhouse; their brains completely removed from the skulls.
BrainEx pumped an experiment solution into the brain that essentially mimic blood flow. It brought oxygen and nutrients to the tissues, giving brain cells the resources to begin many normal functions. The cells began consuming and metabolizing sugars. The brains' immune systems kicked in. Neuron samples could carry an electrical signal. Some brain cells even responded to drugs.
The researchers have managed to keep some brains alive for up to 36 hours, and currently do not know if BrainEx can have sustained the brains longer. "It is conceivable we are just preventing the inevitable, and the brain won't be able to recover," said Nenad Sestan, Yale neuroscientist and the lead researcher.
As a control, other brains received either a fake solution or no solution at all. None revived brain activity and deteriorated as normal.
The researchers hope the technology can enhance our ability to study the brain and its cellular functions. One of the main avenues of such studies would be brain disorders and diseases. This could point the way to developing new of treatments for the likes of brain injuries, Alzheimer's, Huntington's, and neurodegenerative conditions.
"This is an extraordinary and very promising breakthrough for neuroscience. It immediately offers a much better model for studying the human brain, which is extraordinarily important, given the vast amount of human suffering from diseases of the mind [and] brain," Nita Farahany, the bioethicists at the Duke University School of Law who wrote the study's commentary, told National Geographic.
An ethical gray matter
Before anyone gets an Island of Dr. Moreau vibe, it's worth noting that the brains did not approach neural activity anywhere near consciousness.
The BrainEx solution contained chemicals that prevented neurons from firing. To be extra cautious, the researchers also monitored the brains for any such activity and were prepared to administer an anesthetic should they have seen signs of consciousness.
Even so, the research signals a massive debate to come regarding medical ethics and our definition of death.
Most countries define death, clinically speaking, as the irreversible loss of brain or circulatory function. This definition was already at odds with some folk- and value-centric understandings, but where do we go if it becomes possible to reverse clinical death with artificial perfusion?
"This is wild," Jonathan Moreno, a bioethicist at the University of Pennsylvania, told the New York Times. "If ever there was an issue that merited big public deliberation on the ethics of science and medicine, this is one."
One possible consequence involves organ donations. Some European countries require emergency responders to use a process that preserves organs when they cannot resuscitate a person. They continue to pump blood throughout the body, but use a "thoracic aortic occlusion balloon" to prevent that blood from reaching the brain.
The system is already controversial because it raises concerns about what caused the patient's death. But what happens when brain death becomes readily reversible? Stuart Younger, a bioethicist at Case Western Reserve University, told Nature that if BrainEx were to become widely available, it could shrink the pool of eligible donors.
"There's a potential conflict here between the interests of potential donors — who might not even be donors — and people who are waiting for organs," he said.
It will be a while before such experiments go anywhere near human subjects. A more immediate ethical question relates to how such experiments harm animal subjects.
Ethical review boards evaluate research protocols and can reject any that causes undue pain, suffering, or distress. Since dead animals feel no pain, suffer no trauma, they are typically approved as subjects. But how do such boards make a judgement regarding the suffering of a "cellularly active" brain? The distress of a partially alive brain?
The dilemma is unprecedented.
Setting new boundaries
Another science fiction story that comes to mind when discussing this story is, of course, Frankenstein. As Farahany told National Geographic: "It is definitely has [sic] a good science-fiction element to it, and it is restoring cellular function where we previously thought impossible. But to have Frankenstein, you need some degree of consciousness, some 'there' there. [The researchers] did not recover any form of consciousness in this study, and it is still unclear if we ever could. But we are one step closer to that possibility."
She's right. The researchers undertook their research for the betterment of humanity, and we may one day reap some unimaginable medical benefits from it. The ethical questions, however, remain as unsettling as the stories they remind us of.
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