Edelman in 2009

I was sad to read this - and I feel fortunate to have seen Dr. Edelman speak in a keynote address at the 2013 Evolution of Psychotherapy Conference in December. I have been very influenced by his theory of consciousness and his tendency toward an interdisciplinary approach to science.

Edelman was awarded the 1972 Nobel Prize in Physiology or Medicine (shared with Rodney Robert Porter) for work on the immune system - in which he mapped a key immunological structure — the antibody — that had previously been uncharted.

He later showed that the way the components of the immune system evolve over the life of the individual is analogous to the way the components of the brain evolve in a lifetime. He is also credited with discovery of the neural cell adhesion molecule (NCAM), which allows nerve cells to bind to one another (a kind of "cellular glue") and form the circuits of the nervous system.

His many books for a popular audience include The Remembered Present: A Biological Theory of Consciousness (1990), Bright Air, Brilliant Fire: On The Matter Of The Mind (1992), A Universe Of Consciousness: How Matter Becomes Imagination (2001, with Giulio Tononi), Wider Than the Sky: The Phenomenal Gift of Consciousness (2004) and Second Nature: Brain Science and Human Knowledge (2007). Dr. Edelman was the founder and director of The Neurosciences Institute and was on the scientific board of the World Knowledge Dialogue project.

Here is an obituary from The Washington Post:

Gerald M. Edelman, Nobel Prize-winning scientist, dies at 84

By Emily Langer, Published: May 22

Gerald M. Edelman, a Nobel Prize-winning scientist who was credited with unlocking mysteries of the immune and nervous systems and later ventured into ambitious studies of the human mind, died May 17 at his home in La Jolla, Calif. He was 84.

His son David Edelman confirmed the death and said his father had Parkinson’s disease.

(AP) - Dr. Edelman, shown here in 1972 at his laboratory at Rockefeller University, shared the Nobel Prize in physiology or medicine for his discoveries related to the chemical structure of antibodies.

Once an aspiring violinist, Dr. Edelman ultimately pursued a scientific career that spanned decades and defied categorization. His Nobel Prize in physiology or medicine, which he shared in 1972 with the British scientist Rodney R. Porter, recognized his discoveries related to the chemical structure of antibodies.

Antibodies are agents used by the immune system to attack bacteria, viruses and other intruders in the body. But Dr. Edelman did not consider himself an immunologist.

He later embraced neuroscience, and particularly the study of how the nervous system is constructed beginning in the embryonic stage.

He was credited with leading the seminal discovery of a sort of cellular glue, called the neural cell adhesion molecule (NCAM), which allows nerve cells to bind to one another and form the circuits of the nervous system. But he concluded that such biochemical discoveries, however significant, could not fully elucidate the workings of the brain.

Dr. Edelman was associated for many years with Rockefeller University in New York City, where he directed the Neurosciences Institute that today is located in La Jolla. He delved into questions on the vanguard of neuroscience, including the study of human consciousness, and developed a theory of brain function called neural Darwinism.

Some scientists regarded his later work as unverifiable or muddled. The late Francis H.C. Crick, co-discoverer of the double-helix structure of DNA, was said to have dismissed neural Darwinism as “neural Edelmanism.” Others admired Dr. Edelman for daring to broach one of the most vexing questions in science.

He “straddled . . . frontier fields in biology and biomedical science in the last century,” said Anthony-Samuel LaMantia, the director of the Washington-based George Washington Institute for Neuroscience, describing Dr. Edelman as “one of the major intellects in science.”

In his earliest noted work, Dr. Edelman essentially mapped a key immunological structure — the antibody — that had previously been uncharted. “Never before has a molecule approaching this complexity been deciphered,” the New York Times reported in 1969, when the extent of Dr. Edelman’s findings were announced.

Dr. Edelman also was credited with recasting scientific understanding of how antibodies operate. When an antigen, or foreign agent, enters the body, a healthy immune system produces antibodies to attack it. Before Dr. Edelman’s studies, many scientists accepted the notion that antibodies altered their characteristics in order to match the features of the antigen.

Dr. Edelman’s research, which relied on the laboratory examination of quickly reproducing cancer cells, revealed another system in place, said Patricia Maness, a former colleague of Dr. Edelman’s who today is a professor of biochemistry at the University of North Carolina at Chapel Hill.

Research led by Dr. Edelman showed that the body has a “repertoire” of antibody-producing cells, she said. When a foreign agent enters the body, the immune system recognizes the intruder and begins producing in quantity the antibody best equipped for the battle. It was a process of selection, Maness explained, not adaptation or instruction, as had previously been thought.

“There is an enormous storehouse of lymphoid cells which are locks but don’t know they are locks — like a character in a Pirandello play — until the key finds them,” Dr. Edelman once told an interviewer.

The announcement of the Nobel Prize credited Dr. Edelman and his co-recipient with having made “a break-through that immediately incited a fervent research activity the whole world over, in all fields of immunological science, yielding results of practical value for clinical diagnostics and therapy.”

Dr. Edelman led a similarly groundbreaking discovery in neuroscience. Before his work, scientists did not know with certainty how nerve cells combine to form the nervous system. Through his work, Dr. Edelman showed that nerve cells do not affix themselves to each another like Velcro, LaMantia explained.

Rather, two nerve cells connect when surface molecules — NCAMs — recognize each other, setting off a chemical reaction that links the cells and in time forms a system.

Later in his career, Dr. Edelman went beyond chemistry to develop his theory of brain function. He postulated that the brain is not like a computer, hard-wired for certain capacities, but rather is sculpted over time through experiences that strengthen neuronal connections.

Some scientists who seemingly should have been able to understand the theory said simply that they did not. Others regarded Dr. Edelman as a pioneer. Oliver Sacks, the noted neurologist and writer, credited him with having offered “the first truly global theory of mind and consciousness, the first biological theory of individuality and autonomy.”

Gerald Maurice Edelman was born July 1, 1929, in Queens. His father was a general physician in the era when doctors made house calls.

After pursuing classical music training, Dr. Edelman shifted to the sciences, receiving a bachelor’s degree in chemistry in 1950 from Ursinus College in Collegeville, Pa., and a medical degree in 1954 from the University of Pennsylvania.

Following service as an Army doctor in France — it was his F. Scott Fitz-Edelman period, he told the New Yorker magazine — he received a PhD in chemistry in 1960.

In addition to his other appointments, Dr. Edelman was a professor at the Scripps Research Institute in La Jolla. He wrote prolifically for academic audiences and general readers. His volumes included “Neural Darwinism: The Theory of Neuronal Group Selection” (1987), “Bright Air, Brilliant Fire: On the Matter of the Mind”(1992) and “Wider Than the Sky: The Phenomenal Gift of Consciousness” (2004).

Survivors include his wife of 64 years, Maxine Morrison Edelman of La Jolla; and three children, Eric Edelman of New York City, David Edelman of Bennington, Vt., and Judith Edelman of La Jolla.

“I know that people have tried to reduce human beings to machines,” Dr. Edelman once told the Times, seeking to explain the limits he saw in some prevailing notions of science, “but then they are not left with much that we consider truly human, are they?’’

Among Its Many Benefits, Resveratrol May Inhibit Rheumatoid Arthritis

In this new study, the researchers looked at the ability of resveratrol to suppress T cell activity, which may seem like a bad thing since T cells are a powerful part of the immune system. However, when T cells are activated in large quantities, there is a corresponding increase in cytokines, a large group of cell messengers and cell regulators that includes several involved in immune response, including the inflammatory response.

In this study, the use of the term cytokine refers to immunomodulating agents, such as interleukins (specifically: IL-2, IL-4, IL-5) and interferons (IFNy). They found that resveratrol (through a series of processes) increases the expression of Sirt1, and the activation of Sirt1 decreases the expression of various immunomodulating chemicals, which reduces inflammation. Additionally, when Sirt1 is inhibited, cells become less responsive to insulin, so it likely plays a role in the development of diabetes.

There is a potential downside to this, as well. It's possible that for some people whose immune systems are compromised there would a greater vulnerability to disease with the down-regulation of T cells and immune system agents.

The wider implication of this study is that resveratrol may be a useful treatment to prevent diabetes and possibly, as well, to treat autoimmune disorders, such as rheumatoid arthritis or lupus.

I'm just posting the abstract, but you can read the whole article at the link in the title.

Resveratrol Inhibits CD4+ T Cell Activation by Enhancing the Expression and Activity of Sirt1

Ting Zou, Yi Yang, Fei Xia, Anfei Huang, Xiaoming Gao, Deyu Fang, Sidong Xiong, Jinping Zhang

Abstract

Resveratrol, a natural polyphenol compound, has broad effects on critical events, including inflammation, oxidation, cancer and aging. However, the function and molecular mechanisms of resveratrol on T cell activation are controversial. In the present study, we found that resveratrol significantly inhibits the activation and cytokine production of T cells in vitro and in vivo. Sirt1 expression was up-regulated in resveratrol-treated T cells. Once Sirt1 was down-regulated in the T cells, the resveratrol-induced inhibition of T cell activation noticeably diminished. The acetylation of c-Jun decreased and its translocation was impeded in the resveratrol-treated T cells. The incidence and severity of collagen-induced arthritis in the resveratrol-treated mice were considerably reduced.

Full Citation: 
Zou T, Yang Y, Xia F, Huang A, Gao X, et al. (2013, Sep 20). Resveratrol Inhibits CD4+ T Cell Activation by Enhancing the Expression and Activity of Sirt1. PLoS ONE, 8(9): e75139. doi:10.1371/journal.pone.0075139

Putting the Brakes on Inflammation - T-Cells and Protein S

Current research has linked heart disease, diabetes, depression, Alzheimer's Disease, stroke, and cancer to a common denominator - chronic inflammation. 

While inflammation is one of the body's defense mechanisms in response to injury and exogenous irritants, too much inflammation - resulting from an unhealthy diet (especially sugars and trans-fats), smoking, excessive body fat, or even constant stress or sleep deprivation - can cause the immune system to become over-activated and increase the risk for disease. When inflammation reaches chronic levels, it can damage the heart, damage brain cells, cause strokes, increase insulin resistance (primary cause of diabetes), and we now know that chronic inflammation is associated with the development of cancer.

Researchers led by the University of Arizona's Sourav Ghosh, an assistant professor in the department of cellular and molecular medicine at the UA College of Medicine, as well as a member of the University of Arizona Cancer Center, have identified a cellular signal that prevents the immune system from "spinning out of control."

Here is the press release about the study, from Daniel Stolte in the University Communications office.

Putting the Brakes on Inflammation

By Daniel Stolte, University Communications | July 22, 2013

Researchers have uncovered a signal that prevents the immune system from spinning out of control. The findings could help develop more effective therapies for autoimmune disorders, allergies, chronic inflammation and cancer.

In this microscopic image, three cells of the innate immune response (red with blue cell nuclei) are seen next to two T-cells. T-cells appear blue when they’re not active. Only when they make contact with and are activated by the innate cells do the T-cells turn on Protein S, causing them to glow green. (Photo: Lidia Bosurgi)

A team led by a University of Arizona researcher has discovered a previously unknown mechanism that prevents the immune system from going into overdrive, shedding light not only on how our body controls its response to pathogens but on conditions such as autoimmune diseases, allergies and chronic inflammation as well.

The group found a protein previously believed to only play a role in blood clotting acts as a negative feedback signal, telling defense cells to calm down, thereby preventing an immune reaction from spiraling out of control. The results, which could lead to new therapeutics for a variety of disorders caused by a faulty immune response, are published in the scientific journal Immunity. 

The researchers discovered a negative feedback loop preventing our immune system from overreacting: Dendritic cells (DC) activate T-cells, which, once activated, trigger a signal telling the dendritic cells to stop. (Illustration by Cynthia Orensztajn)

When pathogens such as viruses or bacteria invade our body, the immune system reacts by producing a flurry of chemical signals, known as chemokines that act as a bugle call recruiting specialized defender cells to the scene, such as macrophages, which devour the intruders. This first line of defense is known as inflammation.

"Inflammation is a necessary defense mechanism – you can't live without it," said Sourav Ghosh, assistant professor in the department of cellular and molecular medicine at the UA College of Medicine and lead author of the study. "On the flip side, if you can't regulate the inflammation, it can damage the body."

To be effective against pathogens, yet prevent collateral damage from the body's own defenses, the immune system has to maintain just the right level of inflammation, explained Ghosh, who is also a member of the University of Arizona Cancer Center and the UA's BIO5 Institute.

"It needs to be not too high and not too low," he said. "The question had always been, how does the immune system maintain that balance? Our discovery explains this."

Using a technique that makes the presence of Protein S visible under the microscope, samples taken from lymph nodes with resting T-cells reveal no sign of the protein (A), while dark staining indicates the presence of Protein S in activated T-cells (B). (Photo: Anthony Perry)

All organisms, even plants, have some kind of immune system at their disposal that acts as an army fighting against the onslaught of microbes, viruses, parasites and other pathogens in the environment. Vertebrates have evolved the most sophisticated arsenal of "soldiers" and "weapons," relying on two powerful lines of defense: a non-specific, or innate, immune response and the specific, or adaptive, immune response.

In the non-specific response, the immune system throws a first wave of countermeasures at the intruders, consisting of – among other things – aggressive chemicals, destructive enzymes and kamikaze-like neutrophils, specialized white blood cells that destroy the attackers by devouring them, killing themselves in the process.

"First you don't know who the enemy is, so you fire everywhere with your eyes closed," Ghosh explained. "But once you know the enemy, you need to shut off this first response firing and bring in the special ops so to speak."

The special ops come in the form of the specific immunity, capable of targeting pathogens very precisely, taking out the enemy in a sniper-like fashion, while sparing friendly microbes and cells belonging to the body. Most importantly, this portion of the immune system contains cells that remember every attacker trying to conquer an organism throughout its lifetime, allowing the immune system to summon the most effective, specialized task force to counter a pathogen it recognizes from a previous battle.

"The innate immune response is necessary to activate the adaptive response," Ghosh said. "But once activated, there has to be a mechanism that prevents the adaptive response from going into overdrive. From previous studies, we knew there had to be some kind of signal that does this, but we didn't know the nature of that signal. Now we do."

Two kinds of immune cells turned out to be the key players in mediating the immune response: the dendritic cells, so called because of the tree-like branches they grow during their development ("dendron" means "tree" in Greek), which belong to the first wave of defense; and the T-cells, so named because they mature in the thymus gland of the second, which are part of the second wave, the specific immune response.

"The dendritic cells activate the T-cells," Ghosh explained. "Only when they're activated, not when they're resting, do the T-cells produce this protein that we knew only from the blood clotting process, called Protein S."

The T-cells display Protein S on their surface, where it makes contact with a receptor the dendritic cells carry on their surface. This triggers a signal telling the dendritic cell to stop switching on T-cells, causing the immune response to slow down.

"We thought about which cells could be the source of that signal," said Carla Rothlin of the School of Medicine at Yale University, who led the study together with Ghosh. "You don't want to put the brakes on from the very beginning, or otherwise the immune response would never amount to anything. But you want to slow it down once it starts going too fast."

"We figured that once the specific response is underway, you don't really need the unspecific response anymore, so the T-cells appeared to be the best candidates for the source of this signal."

To test their hypothesis, the researchers studied the immune response in mice in which the gene coding for Protein S had been deactivated selectively in their T-cells, rendering them unable to communicate with the dendritic cells.

As expected, these mice were unable to regulate their immune response, resulting in higher levels of inflammation compared to their normal counterparts.

To assess the relevance of their findings to humans, Ghosh and his co-workers then studied blood from patients with inflammatory bowel diseases such as ulcerative colitis and Crohn's disease. Consistent with their previous results, patients suffering from increased inflammation had lower levels of Protein S in their blood stream compared to healthy volunteers.

The findings could help scientists and clinicians develop better treatments for inflammatory diseases, for example by designing drugs that substitute for insufficient Protein S. According to Ghosh, patients with inflammatory bowel disease are 20 times more likely to develop colon cancer, further underlining the significance of this study.

Study co-author Dr. Jonathan Leighton reported anecdotal evidence from the clinical practice that is in line with the dual roles Protein S is believed to play.

"Patients with inflammatory bowel disease can develop blood clots if they have active disease," said Leighton, a UA alumnus who holds the Chair of the Division of Gastroenterology at Mayo Clinic in Scottsdale, Ariz. "From a clinical standpoint, we think that three factors predispose to inflammation in inflammatory bowel disease – genetic, environmental and the immune system. This research is exciting because it focuses on the immune system. No one has found a consistent inflammatory pathway that explains all the clinical manifestations, and it may be that different pathways are affected in different patients. We don't understand how it all relates quite yet, but this study is a step toward a better understanding that will ultimately help us treat patients more effectively."

Abstract and Citation:

T Cell-Derived Protein S Engages TAM Receptor Signaling in Dendritic Cells to Control the Magnitude of the Immune Response

Immunity, Volume 39, Issue 1, 160-170, 11 July 2013
Copyright © 2013 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.immuni.2013.06.010

Authors:
Eugenio A. Carrera Silva, Pamela Y. Chan, Leonel Joannas, Andrea E. Errasti, Nicola Gagliani, Lidia Bosurgi, Maurice Jabbour, Anthony Perry, Faye Smith-Chakmakova, Daniel Mucida, Hilde Cheroutre, Tal Burstyn-Cohen, Jonathan A. Leighton, Greg Lemke, Sourav Ghosh, Carla V. Rothlin

Highlights

• Activated T cells express Protein S (Pros1)
• T cell-derived Pros1 limits DC activation through the TAM receptor tyrosine kinases
• Ablation of Pros1 in mouse T cells enhances immune responses
• PROS1 expression and function is conserved in human T cells

Summary

Dendritic cell (DC) activation is essential for the induction of immune defense against pathogens, yet needs to be tightly controlled to avoid chronic inflammation and exaggerated immune responses. Here, we identify a mechanism of immune homeostasis by which adaptive immunity, once triggered, tempers DC activation and prevents overreactive immune responses. T cells, once activated, produced Protein S (Pros1) that signaled through TAM receptor tyrosine kinases in DCs to limit the magnitude of DC activation. Genetic ablation of Pros1 in mouse T cells led to increased expression of costimulatory molecules and cytokines in DCs and enhanced immune responses to T cell-dependent antigens, as well as increased colitis. Additionally, PROS1 was expressed in activated human T cells, and its ability to regulate DC activation was conserved. Our results identify a heretofore unrecognized, homeostatic negative feedback mechanism at the interface of adaptive and innate immunity that maintains the physiological magnitude of the immune response.

Andrew Miller, MD - An Evolutionary View of Depression

Generally, as I have mentioned here more times than I can remember, I think evolutionary psychology is about 75% crap and only 25% useful (I just pulled those numbers out of my arse, so don't hold me to them). Occasionally, however, something useful comes out of this field.

One of the places where there seems to be some merit is in looking at the evolution or mental illness. For example, there is some strong evidence that schizophrenia is an unfortunate by-product of brain evolution.

In these two short video clips, Andrew Miller, MD, of Emory University, talks about an evolutionary view of depression as a possible immune adaption. The idea that depression is some form of evolution adaptation is not new - and those who suffer from depression tend to express horror that anyone would take this view of their suffering - but the article and videos offer a good explanation of this newer theory.

First a brief article and then the two videos.

Depression: an evolutionary byproduct of the ability to fight infection?

Woodruff Health Sciences Center | Feb. 23, 2012

Kathi Baker
404-727-9371
kobaker@emory.edu

Miller and Raison view the relationship between depression and inflammation through an evolutionary lens. Their ideas could have implications for the treatment of depression.

Resources

Molecular Psychiatry paper
Charles Raison (University of Arizona)

Depression is common enough – afflicting one in ten adults in the United States -- that it seems the possibility of depression must be “hard-wired” into our brains. This has led biologists to propose several theories to account for how depression, or behaviors linked to it, can somehow offer an evolutionary advantage.

Some previous proposals for the role of depression in evolution have focused on how it affects behavior in a social context. A pair of psychiatrists addresses this puzzle in a different way, tying together depression and resistance to infection. They propose that genetic variations that promote depression arose during evolution because they helped our ancestors fight infection.

An outline of their proposal appears online in the journal Molecular Psychiatry.

The co-authors are Andrew Miller, MD, William P. Timmie professor of psychiatry and behavioral sciences at Emory and director of psychiatric oncology at Winship Cancer Institute, and Charles Raison, MD, previously at Emory and now at the University of Arizona.

For several years, researchers have seen links between depression and inflammation, or over-activation of the immune system. People with depression tend to have higher levels of inflammation, even if they’re not fighting an infection.

“Most of the genetic variations that have been linked to depression turn out to affect the function of the immune system,” Miller says. “This led us to rethink why depression seems to stay embedded in the genome.”

“The basic idea is that depression and the genes that promote it were very adaptive for helping people—especially young children—not die of infection in the ancestral environment, even if those same behaviors are not helpful in our relationships with other people,” Raison says.

Infection was the major cause of death in humans’ early history, so surviving infection was a key determinant in whether someone was able to pass on his or her genes. The authors propose that evolution and genetics have bound together depressive symptoms and physiological responses that were selected on the basis of reducing mortality from infection. Fever, fatigue/inactivity, social avoidance and anorexia can all be seen as adaptive behaviors in light of the need to contain infection, they write.

The theory provides a new explanation for why stress is a risk factor for depression. The link between stress and depression can be seen as the byproduct of a process that preactivates the immune system in anticipation of a wound, they write.

Similarly, a disruption of sleep patterns can be seen in both mood disorders and when the immune system is activated. This may come from our ancestors’ need to stay on alert to fend off predators after injury, Miller says.

Miller and Raison's theory could also guide future research on depression. In particular, the presence of biomarkers for inflammation may be able to predict whether someone will respond to various treatments for depression.

Miller and Raison are involved in ongoing research on whether certain medications, which are normally used to treat auto-immune diseases, can be effective with treatment-resistant depression.

This is the description that comes with the video:

Background

Depression is common enough -- afflicting one in ten adults in the United States -- that it seems the possibility of depression must be "hard-wired" into our brains. This has led biologists to propose several theories to account for how depression, or behaviors linked to it, can somehow offer an evolutionary advantage.

Some previous proposals for the role of depression in evolution have focused on how it affects behavior in a socialcontext. A pair of psychiatrists addresses this puzzle in a different way, tying together depression and resistance to infection. They propose that genetic variations that promote depression arose during evolution because they helped our ancestors fight infection.

An outline of their proposal appears online in the journal Molecular Psychiatry.

The co-authors are Andrew Miller, MD, William P. Timmie professor of psychiatry and behavioral sciences at Emory and director of psychiatric oncology at Winship Cancer Institute, and Charles Raison, MD, previously at Emory and now at the University of Arizona.

Part One:




Part Two: