The coming of age of gene therapy: A review of the past and path forward

A new gene is injected into an adenovirus vector, which is used to introduce the modified DNA into a human cell. If the treatment is successful, the new gene will make a functional protein.

Credit: US National Library of Medicine

After three decades of hopes tempered by setbacks, gene therapy -- the process of treating a disease by modifying a person's DNA -- is no longer the future of medicine, but is part of the present-day clinical treatment toolkit. The Jan. 12 issue of the journal Science provides an in-depth and timely review of the key developments that have led to several successful gene therapy treatments for patients with serious medical conditions.

Co-authored by Cynthia E. Dunbar, M.D., senior investigator at the Hematology Branch of the National Heart, Lung and Blood Institute (NHLBI), part of the National Institutes of Health, the article also discusses emerging genome editing technologies. According to Dunbar and her colleagues, these methods, including the CRISPR/Cas9 approach, would provide ways to correct or alter an individual's genome with precision, which should translate into broader and more effective gene therapy approaches.
Gene therapy is designed to introduce genetic material into cells to compensate for or correct abnormal genes. If a mutated gene causes damage to or spurs the disappearance of a necessary protein, for example, gene therapy may be able to introduce a normal copy of the gene to restore the function of that protein.
The authors focused on the approaches that have delivered the best outcomes in gene therapy so far: 1) direct in vivo administration of viral vectors, or the use of viruses to deliver the therapeutic genes into human cells; and 2) the transfer of genetically engineered blood or bone marrow stem cells from a patient, modified in a lab, then injected back into the same patient.
Originally envisioned as a treatment solely for inherited disorders, gene therapy is now being applied to acquired conditions such as cancer. For example, the engineering of lymphocytes, white blood cells, that can be used in the targeted killing of cancer cells.
In 2017, a steady stream of encouraging clinical results showed progress in gene therapies for hemophilia, sickle-cell disease, blindness, several serious
inherited neurodegenerative disorders, an array of other genetic diseases, and multiple cancers of the bone marrow and lymph nodes.
Three gene therapies have been approved by the U.S. Food and Drug Administration in the past year, and many more are under active clinical investigation. The authors looked to the future of gene therapies, and the challenges of delivering these complex treatments to patients.
Much of this research has been funded by NIH, and key advances took place in the NIH Clinical Center.
 

Journal Reference:

1. Cynthia E. Dunbar, Katherine A. High, J. Keith Joung, Donald B. Kohn, Keiya Ozawa, Michel Sadelain. Gene Therapy Comes of Age. Science, 12 Jan 2018 DOI: 10.1126/science.aan4672 

Courtesy: ScienceDaily
 

How we judge personality from faces depends on our beliefs about how personality works

NYU researchers tested how much we believe different traits co-occur in other people's personalities--for instance, how much we think competence co-occurs with friendliness in others. They then used a method able to visualize the subjects' mental image of a personality trait, allowing them to see if subjects who believe competent people tend to also be friendly have mental images of a competent face and friendly face that are physically more resembling.

Credit: Ryan Stolier and Jonathan Freeman, New York University

We make snap judgments of others based not only on their facial appearance, but also on our pre-existing beliefs about how others' personalities work, finds a new study by a team of psychology researchers.

Its work, reported in the journal Proceedings of the National Academy of Sciences, underscores how we interpret others' facial features to form impressions of their personalities.

"People form personality impressions from others' facial appearance within only a few hundred milliseconds," observes Jonathan Freeman, the paper's senior author and an associate professor in NYU's Department of Psychology and Center for Neural Science. "Our findings suggest that face impressions are shaped not only by a face's specific features but also by our own beliefs about personality -- for instance, the cues that make a face look competent and make a face look friendly are physically more similar for those who believe competence and friendliness co-occur in other people's personalities."

"Although these impressions are highly reliable, they are often quite inaccurate," Freeman adds. "And yet they are consequential, as previous research has found face impressions to predict a range of real-world outcomes, from political elections, to hiring decisions, criminal sentencing, or dating. Initial impressions of faces can bias how we interact and make critical decisions about people, and so understanding the mechanisms behind these impressions is important for developing techniques to reduce biases based on facial features that typically operate outside of awareness."

The paper's other authors included Ryan Stolier, lead author of the paper and doctoral candidate in NYU's Department of Psychology, Eric Hehman of McGill University, and Matthias Keller and Mirella Walker of the University of Basel in Switzerland.

We have long known that people make some personality impressions of others based merely upon their facial appearance. For instance, we see those with babyish features as agreeable and harmless and those with faces that resemble anger as dishonest and unfriendly.

What's less clear is how widespread this process is and how, precisely, it transpires.

In their PNAS study, the researchers explored these questions through a series of experiments, specifically seeking to determine whether our own pre-existing beliefs about how personality works affect the way we "see" it on others' faces.

The experiments' 920 subjects indicated how much they believed different traits co-occur in other people's personalities. For example, they would indicate how much they believe competence co-occurs with friendliness in others. The subjects were each then shown dozens of faces on a computer screen and quickly judged those faces on competence and friendliness, allowing the researchers to see if subjects thought the same faces that are competent are also friendly -- or not friendly. In all, subjects were asked about several personality traits, including the following: "agreeable," "aggressive," "assertive," "caring," "competent," "conscientious," "confident," "creative," "dominant," "egotistic," "emotionally stable," "extroverted," "intelligent," "mean," "neurotic," "open to experience," "responsible," "self-disciplined," "sociable," "trustworthy," "unhappy," and "weird."

Overall, the findings confirmed what the researchers predicted. The more that subjects believed any two traits, such as competence and friendliness, co-occurs in others predicted their impressions of those two traits on faces to be more similar.

In a final experiment, the researchers measured the exact facial features used to make personality impressions using a cutting-edge method that can visualize subjects' mental image of a personality trait in their mind's eye. They found that the facial features used to judge personality indeed change based upon our beliefs. For instance, people who believe competent others tend to also be friendly have mental images of what makes a face look competent and what makes a face look friendly that are physically more resembling.

"Generally, the results suggest that beliefs about personality drive face impressions, such that people who believe any set of personality traits are related tend to see those traits similarly in faces," says Stolier. "This may explain how humans can make any set of impressions from a face."

The results lend evidence for the researchers' perspective that most traits perceived from others' faces are not unique but merely derived from one another, with a few core traits driving the process.

"For instance, while a face may not appear right away to be conscientious, it may appear to be agreeable, intelligent, and emotional -- personality traits a perceiver may believe underlie creativity, resulting in them seeing a face as conscientious," adds Stolier.

The results also provide an explanation for how people can make so many different impressions of someone just from a handful of features present on a face.

"We may only see cues in a face that directly elicit several personality impressions, such as 'submissiveness' for those who have 'baby faces,' " observes Stolier. "However, the perceptual system may take these few impressions and add them together, such that we see a face as conscientious or religious, to the extent we think the personality judgment is related to those impressions we initially make from a face -- such as agreeableness and submissiveness."

The research was supported, in part, by grants from the National Institutes of Health (F31-MH114505) and the National Science Foundation (BCS-1654731).

Journal Reference:

1. Ryan M. Stolier, Eric Hehman, Matthias D. Keller, Mirella Walker, Jonathan B. Freeman. The conceptual structure of face impressions. Proceedings of the National Academy of Sciences, 2018; 201807222 DOI: 10.1073/pnas.1807222115

 Courtesy: ScienceDaily

Key aspects of human cell aging reversed by new compounds

Key aspects of the ageing of human cells can be reversed by new compounds developed at the University of Exeter, research shows.

In a laboratory study of endothelial cells -- which line the inside of blood vessels -- researchers tested compounds designed to target mitochondria (the "power stations" of cells).
In the samples used in the study, the number of senescent cells (older cells that have deteriorated and stopped dividing) was reduced by up to 50%. The Exeter team also identified two splicing factors (a component of cells) that play a key role in when and how endothelial cells become senescent.
The findings raise the possibility of future treatments not only for blood vessels -- which become stiffer as they age, raising the risk of problems including heart attacks and strokes -- but also for other cells.
"As human bodies age, they accumulate old (senescent) cells that do not function as well as younger cells," said Professor Lorna Harries, of the University of Exeter Medical School.
"This is not just an effect of ageing -- it's a reason why we age.
"The compounds developed at Exeter have the potential to tweak the mechanisms by which this ageing of cells happens.
"We used to think age-related diseases like cancer, dementia and diabetes each had a unique cause, but they actually track back to one or two common mechanisms.
"This research focuses on one of these mechanisms, and the findings with our compounds have potentially opened up the way for new therapeutic approaches in the future.
"This may well be the basis for a new generation of anti-degenerative drugs."
Professor Harries said the goal was to help people stay healthier for longer. She added: "This is about health span and quality of life, rather than merely extending lifespan."
In a paper published last year, the team demonstrated a new way to rejuvenate old cells in the laboratory.
However, the new research looked at precisely targeting and rejuvenating mitochondria in old cells.
Each one of our genes is capable of making more than one product, and splicing factors are the genes that make the decision about which of these products are made.
In this new work, using novel chemicals, the researchers were able to very specifically target two splicing factors (SRSF2 or HNRNPD) that play a key role in determining how and why our cells change with advancing age.
"Nearly half of the aged cells we tested showed signs of rejuvenating into young cell models," said Professor Harries.
The researchers tested three different compounds, all developed at the University of Exeter, and found each produced a 40-50% drop in the number of senescent blood vessel cells.
The compounds in question -- AP39, AP123 and RT01 -- have been designed by the Exeter team to selectively deliver minute quantities of the gas hydrogen sulfide to the mitochondria in cells and help the old or damaged cells to generate the 'energy' needed for survival and to reduce senescence.
"Our compounds provide mitochondria in cells with an alternative fuel to help them function properly," said Professor Matt Whiteman, also from the University of Exeter.
"Many disease states can essentially be viewed as accelerated ageing, and keeping mitochondria healthy helps either prevent or, in many cases using animal models, reverse this.
"Our current study shows that splicing factors play a key role in determining how our compounds work."
The research was funded by Dunhill Medical Trust and the Medical Research Council.
 

Journal Reference:

1. Eva Latorre, Roberta Torregrossa, Mark E. Wood, Matthew Whiteman, Lorna W. Harries. Mitochondria-targeted hydrogen sulfide attenuates endothelial senescence by selective induction of splicing factors HNRNPD and SRSF2. Aging, 2018; DOI: 10.18632/aging.101500 

Courtesy: ScienceDaily
 

Mere expectation of checking work email after hours harms health of workers and families

Employer expectations of work email monitoring during nonwork hours are detrimental to the health and well-being of not only employees but their family members as well.

William Becker, a Virginia Tech associate professor of management in the Pamplin College of Business, co-authored a new study, "Killing me softly: electronic communications monitoring and employee and significant-other well-being," showing that such expectations result in anxiety, which adversely affects the health of employees and their families.
"The competing demands of work and nonwork lives present a dilemma for employees," Becker said, "which triggers feelings of anxiety and endangers work and personal lives."
Other studies have shown that the stress of increased job demands leads to strain and conflict in family relationships when the employee is unable to fulfill nonwork roles at home -- "such as when someone brings work home to finish up."
Their new study, he said, demonstrates that employees do not need to spend actual time on work in their off-hours to experience the harmful effects. The mere expectations of availability increase strain for employees and their significant others -- even when employees do not engage in actual work during nonwork time.
Unlike work-related demands that deplete employee resources, physical and psychological, by requiring time away from home, "the insidious impact of 'always on' organizational culture is often unaccounted for or disguised as a benefit -- increased convenience, for example, or higher autonomy and control over work-life boundaries," Becker said.
"Our research exposes the reality: 'flexible work boundaries' often turn into 'work without boundaries,' compromising an employee's and their family's health and well-being."
As negative health outcomes are costly to them, what can employers do to mitigate the adverse effects identified by the study? Becker said policies that reduce expectations to monitor electronic communication outside of work would be ideal.
When that is not an option, the solution may be to establish boundaries on when electronic communication is acceptable during off-hours by setting up off-hour email windows or schedules when employees are available to respond.
Additionally, he said, organizational expectations should be communicated clearly. "If the nature of a job requires email availability, such expectations should be stated formally as a part of job responsibilities." Knowing these expectations upfront may reduce anxiety in employees and increase understanding from their family members, he said.
As for employees, they could consider practicing mindfulness, which has been shown to be effective in reducing anxiety, Becker said. Mindfulness may help employees "be present" in family interactions, which could help reduce conflict and improve relationship satisfaction. And, he added, mindfulness is within the employee's control when email expectations are not.
Becker, whose research interests include work emotion, turnover, organizational neuroscience, and leadership, is based at Virginia Tech's National Capital Region campus in metro Washington, D.C.
His study, co-authored with Liuba Y. Belkin, of Lehigh University; Samantha A. Conroy, of Colorado State University; and Sarah Tuskey, a Virginia Tech Ph.D. student in executive business research, will be presented at the Academy of Management annual meeting in Chicago on August 10-14.
"Employees today must navigate more complex boundaries between work and family than ever before," said Becker. "Employer expectations during nonwork hours appear to increase this burden, as employees feel an obligation to shift roles throughout their nonwork time.
"Efforts to manage these expectations are more important than ever, given our findings that employees' families are also affected by these expectations."
 

Journal Reference:

1. William J. Becker, Liuba Belkin, Sarah Tuskey. Killing me softly: Electronic communications monitoring and employee and spouse well-being. Academy of Management Proceedings, 2018; 2018 (1): 12574 DOI: 10.5465/AMBPP.2018.121 

Courtesy: ScienceDaily
 

Scientists reverse aging-associated skin wrinkles and hair loss in a mouse model

Keshav Singh, Ph.D., and colleagues have done just that, in a mouse model developed at the University of Alabama at Birmingham. When a mutation leading to mitochondrial dysfunction is induced, the mouse develops wrinkled skin and extensive, visible hair loss in a matter of weeks. When the mitochondrial function is restored by turning off the gene responsible for mitochondrial dysfunction, the mouse returns to smooth skin and thick fur, indistinguishable from a healthy mouse of the same age.

The mouse in the center photo shows aging-associated skin wrinkles and hair loss after two months of mitochondrial DNA depletion. That same mouse, right, shows reversal of wrinkles and hair loss one month later, after mitochondrial DNA replication was resumed. The mouse on the left is a normal control, for comparison.

Credit: UAB

 

"To our knowledge, this observation is unprecedented," said Singh, a professor of genetics in the UAB School of Medicine.

Importantly, the mutation that does this is in a nuclear gene affecting mitochondrial function, the tiny organelles known as the powerhouses of the cells. Numerous mitochondria in cells produce 90 percent of the chemical energy cells need to survive.

In humans, a decline in mitochondrial function is seen during aging, and mitochondrial dysfunction can drive age-related diseases. A depletion of the DNA in mitochondria is also implicated in human mitochondrial diseases, cardiovascular disease, diabetes, age-associated neurological disorders and cancer.

"This mouse model," Singh said, "should provide an unprecedented opportunity for the development of preventive and therapeutic drug development strategies to augment the mitochondrial functions for the treatment of aging-associated skin and hair pathology and other human diseases in which mitochondrial dysfunction plays a significant role."

The mutation in the mouse model is induced when the antibiotic doxycycline is added to the food or drinking water. This causes depletion of mitochondrial DNA because the enzyme to replicate the DNA becomes inactive.

In four weeks, the mice showed gray hair, reduced hair density, hair loss, slowed movements and lethargy, changes that are reminiscent of natural aging. Wrinkled skin was seen four to eight weeks after induction of the mutation, and females had more severe skin wrinkles than males.

Dramatically, this hair loss and wrinkled skin could be reversed by turning off the mutation. The photos below show the hair loss and wrinkled skin after two months of doxycycline induction, and the same mouse a month later after doxycycline was stopped, allowing restoration of the depleted mitochondrial DNA.

Little change was seen in other organs when the mutation was induced, suggesting an important role for mitochondria in skin compared to other tissues.

The wrinkled skin showed changes similar to those seen in both intrinsic and extrinsic aging -- intrinsic aging is the natural process of aging, and extrinsic aging is the effect of external factors that influence aging, such as skin wrinkles that develop from excess sun or long-term smoking.

Among the details, the skin of induced-mutation mice showed increased numbers of skin cells, abnormal thickening of the outer layer, dysfunctional hair follicles and increased inflammation that appeared to contribute to skin pathology. These are similar to extrinsic aging of the skin in humans. The mice with depleted mitochondrial DNA also showed changed expression of four aging-associated markers in cells, similar to intrinsic aging.

The skin also showed disruption in the balance between matrix metalloproteinase enzymes and their tissue-specific inhibitor -- a balance of these two is necessary to maintain the collagen fibers in the skin that prevent wrinkling.

The mitochondria of induced-mutation mice had reduced mitochondrial DNA content, altered mitochondrial gene expression, and instability of the large complexes in mitochondria that are involved in oxidative phosphorylation.

Reversal of the mutation restored mitochondrial function, as well as the skin and hair pathology. This showed that mitochondria are reversible regulators of skin aging and loss of hair, an observation that Singh calls "surprising."

"It suggests that epigenetic mechanisms underlying mitochondria-to-nucleus cross-talk must play an important role in the restoration of normal skin and hair phenotype," Singh said, who has a secondary UAB appointment as professor of pathology. "Further experiments are required to determine whether phenotypic changes in other organs can also be reversed to wildtype level by restoration of mitrochondrial DNA."

Journal Reference:

1. Bhupendra Singh, Trenton R. Schoeb, Prachi Bajpai, Andrzej Slominski, Keshav K. Singh. Reversing wrinkled skin and hair loss in mice by restoring mitochondrial function. Cell Death & Disease, 2018; 9 (7) DOI: 10.1038/s41419-018-0765-9 

Courtesy: ScienceDaily