Guardian of the Cell


Scientists unravel the structure, key features of a human immune-surveillance protein, setting the stage for more-precise immune therapies

protein structure
Scientists have identified the key structural and functional features of a critical immune protein in humans that guards against cancer, viral and bacterial infections.

 

The human body is built for survival. Each one of its cells is closely guarded by a set of immune proteins armed with nearly foolproof radars that detect foreign or damaged DNA.

One of the cells’ most critical sentinels is a “first responder” protein known as cGAS, which senses the presence of foreign and cancerous DNA and initiates a signaling cascade that triggers the body’s defenses.

The 2012 discovery of cGAS ignited a firestorm of scientific inquiry, resulting in more than 500 research publications, but the structure and key features of the human form of the protein continued to elude scientists.

Now, scientists at Harvard Medical School and Dana-Farber Cancer Institute have, for the first time, identified the structural and functional differences in human cGAS that set it apart from cGAS in other mammals and underlie its unique function in people.

A report on the team’s work, published July 12 in Cell, outlines the protein’s structural features that explain why and how human cGAS senses certain types of DNA, while ignoring others.

“The structure and mechanism of action of human cGAS have been critical missing pieces in immunology and cancer biology,” said senior investigator Philip Kranzusch, assistant professor of microbiology and immunobiology at Harvard Medical School and Dana-Farber Cancer Institute. “Our findings detailing the molecular makeup and function of human cGAS close this critical gap in our knowledge.” Importantly, the findings can inform the design of small-molecule drugs tailored to the unique structural features of the human protein—an advance that promises to boost the precision of cGAS-modulating drugs that are currently in development as cancer therapies. “Several promising experimental immune therapies currently in development are derived from the structure of mouse cGAS, which harbors key structural differences with human cGAS,” Kranzusch said. “Our discovery should help refine these experimental therapies and spark the design of new ones. It will pave the way toward structure-guided design of drugs that modulate the activity of this fundamental protein.”

The team’s findings explain a unique feature of the human protein—its capacity to be highly selective in detecting certain types of DNA and its propensity to get activated far more sparingly, compared with the cGAS protein in other animals.

Specifically, the research shows that human cGAS harbors mutations that make it exquisitely sensitive to long lengths of DNA but render it “blind” or “insensitive” to short DNA fragments.

“Human cGAS is a highly discriminating protein that has evolved enhanced specificity toward DNA,” said co-first author Aaron Whiteley, a postdoctoral researcher in the Department of Microbiology and Immunobiology at Harvard Medical School. “Our experiments reveal what underlies this capability.”

Location, location, location

In all mammals, cGAS works by detecting DNA that’s in the wrong place. Under normal conditions, DNA is tightly packed and protected in the cell’s nucleus—the cellular “safe”—where genetic information is stored. DNA has no business roaming freely around the cell. When DNA fragments do end up outside the nucleus and in the cell’s cytosol, the liquid that encases the cell’s organelles, it’s usually a sign that something ominous is afoot, such as damage coming from within the cell or foreign DNA from viruses or bacteria that has made its way into the cell.

The cGAS protein works by recognizing such misplaced DNA. Normally, it lies dormant in cells. But as soon as it senses the presence of DNA outside the nucleus, cGAS springs into action. It makes another chemical—a second messenger—called cGAMP, thus setting in motion a molecular chain reaction that alerts the cell to the abnormal presence of DNA. At the end of this signaling reaction, the cell either gets repaired or, if damaged beyond repair, it self-destructs.

But the health and integrity of the cell are predicated on cGAS’ ability to distinguish harmless DNA from foreign DNA or self-DNA released during cell damage and stress. “It’s a fine balancing act that keeps the immune system in equilibrium. An overactive cGAS can spark autoimmunity, or self-attack, while cGAS that fails to detect foreign DNA can lead to tumor growth and cancer development,” said co-first author Wen Zhou, a postdoctoral researcher at Harvard Medical School and Dana-Farber Cancer Institute.

The current study reveals the evolutionary changes to the protein’s structure that allow human cGAS to ignore some DNA encounters while responding to others.

A foe, an accomplice

For their work, the team turned to an unlikely collaborator—Vibrio cholerae, the bacterium that causes cholera, one of humankind’s oldest scourges.

Taking advantage of a cholera enzyme that shares similarities with cGAS, the scientists were able to recreate the function of both human and mouse cGAS in the bacterium.

Teaming up with colleagues from the lab of Harvard Medical School bacteriologist John Mekalanos, the scientists designed a chimeric, or hybrid, form of cGAS that included genetic material from both the human and mouse forms of the protein. Then they compared the ability of the hybrid cGAS to recognize DNA against both the intact mouse and intact human versions of the protein.

In a series of experiments, the scientists observed activation patterns between the different types of cGAS, progressively narrowing down the key differences that accounted for differential DNA activation among the three.

The experiments revealed that out of the 116 amino acids that differ in human and mouse cGAS, only two accounted for the altered function of human cGAS. Indeed, human cGAS was capable of recognizing long DNA with great precision but it ignored short DNA fragments. The mouse version of the protein, by contrast, did not differentiate between long and short DNA fragments

“These two tiny amino acids make a world of difference,” Whiteley said. “They allow the human protein to be highly selective and respond only to long DNA, while ignoring short DNA, essentially rendering the human protein more tolerant of DNA presence in the cytosol of the cell.”

Plotting the genetic divergence on an evolutionary timescale, the scientists determined that the human and mouse cGAS genes parted ways sometime between 10 million and 15 million years ago.

The two amino acids responsible for sensing long DNA and tolerating short DNA are found solely in humans and nonhuman primates, such as gorillas, chimps and bonobos. The scientists hypothesize that the ability to ignore short DNA but recognize long DNA must have conferred some evolutionary benefits. “It could be a way to guard against an overactive immune system and chronic inflammation,” Kranzusch said. “Or it could be that the risk of certain human diseases is lowered by not recognizing short DNA.”

In a final set of experiments, the team determined the atomic structure of the human cGAS in its active form as it binds to DNA. To do so, they used a visualization technique known as X-ray crystallography, which reveals the molecular architecture of protein crystals based on a pattern of scattered X-ray beams.

Profiling the structure of cGAS “in action” revealed the precise molecular variations that allowed it to selectively bind to long DNA, while ignoring short DNA.

“Understanding what makes the structure and function of human cGAS different from those in other species was the missing piece,” Kranzusch said. “Now that we have it, we can really start designing drugs that work in humans, rather than mice.”

Other investigators included Carina de Oliveira Mann, Benjamin Morehouse, Radosław Nowak, Eric Fischer, and Nathanael Gray. The work was supported by the Claudia Adams Barr Program for Innovative Cancer Research, by the Richard and Susan Smith Family Foundation, by the Charles H. Hood Foundation, by a Cancer Research Institute CLIP Grant, by the National Institute of Allergy and Infectious Diseases grant AI-01845, by National Cancer Institute grant R01CA214608, by the Jane Coffin Childs Memorial Fund for Medical Research, by a Cancer Research Institute Eugene V. Weissman Fellow award, and by a National Institutes of Health T32 grant 5T32CA207021-02.

Relevant Disclosures: The Dana-Farber Cancer Institute and Harvard Medical School have patents pending for human cGAS technologies, on which the authors are inventors.

Harvard Medical School Harvard Medical School (http://hms.harvard.edu) has more than 11,000 faculty working in 10 academic departments located at the School’s Boston campus or in hospital-based clinical departments at 15 Harvard-affiliated teaching hospitals and research institutes: Beth Israel Deaconess Medical Center, Boston Children’s Hospital, Brigham and Women’s Hospital, Cambridge Health Alliance, Dana-Farber Cancer Institute, Harvard Pilgrim Health Care Institute, Hebrew SeniorLife, Joslin Diabetes Center, Judge Baker Children’s Center, Massachusetts Eye and Ear/Schepens Eye Research Institute, Massachusetts General Hospital, McLean Hospital, Mount Auburn Hospital, Spaulding Rehabilitation Network and VA Boston Healthcare System.

Can Faith in God Help Alleviate Depression?


faith

Story at-a-glance

  • Modern, unhealthy lifestyles predispose you to non-alcoholic fatty liver disease which may lead to liver cancer. Recent research suggests that regular exercise reduces the risk of developing liver cancer
  • Previous research has shown that breast and colon cancer patients who exercise regularly have half the recurrence rate than non-exercisers, and the cumulative evidence strongly indicates that exercise really should be part of standard cancer care
  • Many recent studies have shown that exercise provides a level of protection against stress-related disorders and depression, and recent research demonstrates that these protective benefits are induced even if the exercise is forced as a mandatory part of a program, such as doctor’s orders, school curriculum or military service
  • Mounting evidence shows that our healthcare and clinical guidelines are based in large part on fraudulent studies that report untruthful results in order to accommodate the interests of corporations. In one review, scientists could NOT replicate 47 of the 53 published studies—all of which were considered important and valuable for the future of cancer treatments

 

Can faith in a higher power help you overcome mental illness, the most common of which is depression? To find out, researchers at McLean hospital, a psychiatric institution affiliated with Harvard Medical School, asked 159 patients with prominent symptoms of depression how strongly they believed in a god.1

They also asked how credible the patients thought their treatment was, and how effective they believed it would be in relieving their symptoms. The patients’ symptoms were assessed when admitted, and again upon release from the program.

Of the participants, 71 percent reported believing in a god or a higher power to some extent. Those whose belief in a god was stronger, regardless of the god or religious affiliation (including non-affiliation), were twice as likely to respond well to the treatment and experiencing better outcomes, such as:

  • Lessening of depression
  • Reductions in self-harm
  • Increases in psychological well-being (peace of mind, ability to have fun, general satisfaction)

As reported by The Atlantic:2

“The researchers point out that people who believed in a god, or were affiliated with a religion, were also more likely to believe their psychiatric treatment was credible and to expect positive results.

It may be, they write, that ‘the tendency to have faith in conventional social constructs’ can be generalized both to religion and the medical establishment. Since other studies have shown that faith in a given treatment is an important predictor of its effectiveness, that could help explain the association with improved outcomes found here.”

The Stigma of Mental Illness Within the Church

The recent suicide of 27-year-old Matthew Warren,3 youngest son of Pastor Rick Warren, founder of the mega-church Saddleback Valley Community Church in California, brought mental illness back into view for many within the confines of religion.

NPR4 recently featured an interview with journalist and Evangelical Christian Christine Scheller on the sometimes complicated relationship between faith and mental illness. Scheller also lost her son to suicide five years ago.

While the stigma of mental illness does not cling to all denominations, some churches can tend to marginalize mental health problems and view them as issues that are best approached by reading the bible or praying.

In Scheller’s experience, the anti-psychiatry rhetoric used in some churches can delay much-needed treatment. When it became clear that Scheller’s younger son also suffered with depression, she decided to ignore the advice of the church, opting instead to seek professional help for her son.

“[S]tigma about mental illness is not unique to the evangelical community. We have our own particular ways in which it’s stigmatized, but it’s a pervasive problem,” she says.

Depressive Thinking Can Go Viral

In related research published in the journal Clinical Psychological Science, researchers suggest that certain types of depressive thinking can “go viral,” spreading to others living in close proximity. As reported in Time Magazine:6

“Although many people see depression as a chemical imbalance in the brain, scientists say social context and the way you see yourself and the world can be critical in causing and sustaining the illness… ‘Thinking styles are a really important factor in risk for depression,’ says the study’s lead author Gerald Haeffel, associate professor of clinical psychology at Notre Dame University. ‘How one thinks about life stress and negative moods is one of the best predictors that we have of future depression.’”

The two thinking styles explored in the study were:

  • Rumination; constant brooding or worrying about what might go wrong
  • Hopelessness

Both of these thinking styles have previously been linked to depression. But whereas the first places your focus on your negative mood, the other reflects on your lack of self worth and the consequences of an event. Says lead researcher Haeffel:

“For example, a person who feels hopeless might lose a job and see it as a personal failure and a sign that he will never be employable again. A more resilient person might blame the economy or see the situation as an opportunity to get a better position.”

The latter, hopelessness, was not found to be contagious, but rumination was. A suggested reason for this is because hopelessness centers around your own thoughts and deeply embedded beliefs about yourself, and so therefore may be less likely to have a major influence on the way others think about themselves and their lives. Ruminating and constant brooding, however, which focuses on all the bad things that might happen and sees the worst in every situation, is a mode that is more easily spread and mirrored by others.

“Interestingly, depression symptoms themselves were not contagious: simply having a roommate with symptoms of the disorder did not increase risk of developing the mental illness. But those who picked up a ruminative style of thinking from their roommates during the first three months of school had more than double the number of depressive symptoms of those who either weren’t exposed to this perspective or didn’t adopt the rumination three months later. And the risk was magnified if they experienced high levels of stress,” Time reports.

Positive Thinking Is Contagious Too!

Fortunately, the study also found that healthier modes of thinking were equally contagious, with the capacity to make a roommate adopt a more optimistic outlook as well. More than likely, you didn’t need a study to take notice of this. Most people will at some point or another have encountered someone in their life that either made you feel more positive or negative, simply by spending time with them.

A question they could not answer, however, was what the determining factor was that decided which roommate would adopt a thinking style more closely mirroring that of the other. Why are some people’s thinking styles more likely to dominate, rather than be influenced?

“Such information could enhance the current findings and contribute to new ways of treating and preventing depression,”Time writes. “The results suggest that depressive thinking styles can still be influenced during young adulthood — so this risk factor can be minimized even if it has already developed during high school or earlier. Targeting ruminative thinking might also enhance therapy.

“The therapist could assess if people in the patient’s life are modeling and providing adaptive cognitive feedback about stress and negative life events,” says Haeffel. “The therapist could then provide those with negative thinking styles with information about the contagion effect along with training that would help them identify negative thought patterns and provide examples of more adaptive ways of thinking.”

The Slow Opening Up to ‘Spiritual Science’

In 1993, only three of the United States’ 125 medical schools offered any sort of course work exploring the area of spirituality and medicine. Today, over 90 of these medical schools have formal courses where they explore randomized controlled studies and the effects of spiritual practices on longevity and health outcomes—a sure sign that what was once considered taboo is beginning to receive the discussion and serious investigation it deserves. Dr. Larry Dossey has written 11 books primarily focused on consciousness, spirituality, and the impact of spirituality on your health, including the book Healing Words: The Power of Prayer and the Practice of Medicine.

“I think we’re opening up,” Dossey said when I interviewed him, three years ago. “I’m sure you remember, about 40 years ago when meditation burst upon the scene in medicine, it was put down. It was called California Woo woo. Nobody wanted to have anything to do with it. But now nobody raises an eye about meditation and yoga, even in medicine. We’re in the same place with spirituality that we were with meditation about 20 years ago. People know you can’t ignore it. The correlation between spiritual practice and health outcomes is just too strong.

For example, the data shows that people who follow some sort of spiritual path in their life live on average seven to 13 years longer than people who do not follow a spiritual practice… We have a huge spectrum of data that shows, I think compellingly, that your thoughts really matter when it comes to getting well.”

Most ancient cultures knew this, and there are few lines dividing spirituality; the mind, and medicine in these cultures. Ironically, modern science now allows us to rediscover these ancient truths, which fell by the wayside with the advent of medical science and its narrow focus on individual parts as opposed to investigating the connections within the whole. Going back to where we started, David Rosmarin, the lead researcher of the featured study in which those with a stronger faith in God experienced far better treatment outcomes for their depression, said:

“Given the prevalence of religious belief in the United States — more than 90 percent of the population — these findings are important in that they highlight the clinical implications of spiritual life. I hope that this work will lead to larger studies and increased funding in order to help as many people as possible.”

The Rise of Energy Psychology

Many people avoid energy psychology as they believe it is an alternative form of New Age spirituality, yet nothing could be further from the truth. It is merely an advanced tool that can effectively address some of the psychological short circuiting that occurs in emotional illnesses. It is not any competition at all with any religion but merely an effective resource you can use with whatever spiritual belief you have.

My favorite technique for this is the Emotional Freedom Technique (EFT), which is the largest and most popular version of energy psychology.

EFT was developed in the 1990s by Gary Craig, a Stanford engineering graduate specializing in healing and self-improvement. It’s akin to acupuncture, which is based on the concept that a vital energy flows through your body along invisible pathways known as meridians. EFT stimulates different energy meridian points in your body by tapping them with your fingertips, while simultaneously using custom-made verbal affirmations. This can be done alone or under the supervision of a qualified therapist.7By doing so, you help your body eliminate emotional “scarring” and reprogram the way your body responds to emotional stressors.

While the following video will teach you how to do EFT, it is VERY important to realize that self-treatment for serious mental health issues is NOT recommended. For serious or complex issues, you need someone to guide you through the process as there is an incredible art to this process and it typically takes years of training to develop the skill to tap on deep-seated, significant issues.

Research Backs the Use of EFT for Depression

I have been a fan of energy psychology for many years, having witnessed its effectiveness in my medical practice and in my own personal life. However, studies have been few and far between as science has been trying to “catch up” with clinical experience. That has finally started to change. Several studies have been published in the last few years, showing just how safe and effective EFT really is.

For example, the following three studies show remarkable progress in a very short amount of time for people with a history of trauma:

  1. A 2009 study8 of 16 institutionalized adolescent boys with histories of physical or psychological abuse showed substantially decreased intensity of traumatic memories after just ONE session of EFT.
  2. An EFT study9 involving 30 moderately to severely depressed college students was conducted. The depressed students were given four 90-minute EFT sessions. Students who received EFT showed significantly less depression than the control group when evaluated three weeks later.
  3. In a study of 100 veterans with severe PTSD10 (Iraq Vets Stress Project),11 after just six one-hour EFT sessions, 90 percent of the veterans had such a reduction in symptoms that they no longer met the clinical criteria for PTSD; 60 percent no longer met PTSD criteria after only three EFT sessions. At the three-month follow-up, the gains remained stable, suggesting lasting and potentially permanent resolution of the problem.

Source: .mercola.com