R.I.P. Dr. Vera Rubin

How are elements created in space, stars, and in laboratories? The latest edition of #PeriodicGraphics in C&EN takes a look! http://bit.ly/2UXWoPD http://bit.ly/2YbuBNE

Today is World Anaesthesia Day! Here’s a look at the chemistry behind a range of anaesthetics. More info here and here.

(Image caption: An fMRI scan shows regions of the brain that become active when devoutly religious study participants have a spiritual experience, including a reward center in the brain, the nucleus accumbens. Credit: Jeffrey Anderson)

This is your brain on God

Religious and spiritual experiences activate the brain reward circuits in much the same way as love, sex, gambling, drugs and music, report researchers at the University of Utah School of Medicine. The findings were published in the journal Social Neuroscience.

“We’re just beginning to understand how the brain participates in experiences that believers interpret as spiritual, divine or transcendent,” says senior author and neuroradiologist Jeff Anderson. “In the last few years, brain imaging technologies have matured in ways that are letting us approach questions that have been around for millennia.”

Specifically, the investigators set out to determine which brain networks are involved in representing spiritual feelings in one group, devout Mormons, by creating an environment that triggered participants to “feel the Spirit.” Identifying this feeling of peace and closeness with God in oneself and others is a critically important part of Mormons’ lives — they make decisions based on these feelings; treat them as confirmation of doctrinal principles; and view them as a primary means of communication with the divine.

During fMRI scans, 19 young-adult church members — including seven females and 12 males — performed four tasks in response to content meant to evoke spiritual feelings. The hour-long exam included six minutes of rest; six minutes of audiovisual control (a video detailing their church’s membership statistics); eight minutes of quotations by Mormon and world religious leaders; eight minutes of reading familiar passages from the Book of Mormon; 12 minutes of audiovisual stimuli (church-produced video of family and Biblical scenes, and other religiously evocative content); and another eight minutes of quotations.

During the initial quotations portion of the exam, participants — each a former full-time missionary — were shown a series of quotes, each followed by the question “Are you feeling the spirit?” Participants responded with answers ranging from “not feeling” to “very strongly feeling.”

Researchers collected detailed assessments of the feelings of participants, who, almost universally, reported experiencing the kinds of feelings typical of an intense worship service. They described feelings of peace and physical sensations of warmth. Many were in tears by the end of the scan. In one experiment, participants pushed a button when they felt a peak spiritual feeling while watching church-produced stimuli.

“When our study participants were instructed to think about a savior, about being with their families for eternity, about their heavenly rewards, their brains and bodies physically responded,” says lead author Michael Ferguson, who carried out the study as a bioengineering graduate student at the University of Utah.

Based on fMRI scans, the researchers found that powerful spiritual feelings were reproducibly associated with activation in the nucleus accumbens, a critical brain region for processing reward. Peak activity occurred about 1-3 seconds before participants pushed the button and was replicated in each of the four tasks. As participants were experiencing peak feelings, their hearts beat faster and their breathing deepened.

In addition to the brain’s reward circuits, the researchers found that spiritual feelings were associated with the medial prefrontal cortex, which is a complex brain region that is activated by tasks involving valuation, judgment and moral reasoning. Spiritual feelings also activated brain regions associated with focused attention.

“Religious experience is perhaps the most influential part of how people make decisions that affect all of us, for good and for ill. Understanding what happens in the brain to contribute to those decisions is really important,” says Anderson, noting that we don’t yet know if believers of other religions would respond the same way. Work by others suggests that the brain responds quite differently to meditative and contemplative practices characteristic of some eastern religions, but so far little is known about the neuroscience of western spiritual practices.

The study is the first initiative of the Religious Brain Project, launched by a group of University of Utah researchers in 2014, which aims to understand how the brain operates in people with deep spiritual and religious beliefs.

Neuroscientists’ Study Sheds Light on How Words Are Represented in the Brain

Reading is a relatively modern and uniquely human skill. For this reason, visual word recognition has been a puzzle for neuroscientists because the neural systems responsible for reading could not have evolved for this purpose. “The existence of brain regions dedicated to reading has been fiercely debated for almost 200 years,” said Avniel Ghuman, an assistant professor in the University of Pittsburgh Department of Neurological Surgery. “Wernicke, Dejerine, and Charcot, among the most important and influential neurologists and neuroscientists of the 19th century, debated whether or not there was a visual center for words in the brain.”

In recent years, much of this debate has centered on the left mid-fusiform gyrus, which some call the visual word form area. A recent study by Pitt neuroscience researchers addresses this debate and sheds light on our understanding of the neurobiology of reading.

In a study published July 19 in the Proceedings of the National Academy of Sciences, Ghuman, Elizabeth Hirshorn of Pitt’s Learning Research and Development Center (LRDC), and colleagues from the Department of Psychology and Center for the Neural Basis of Cognition used direct neural recordings and brain stimulation to study the role of the visual word form area in reading in four epileptic patients. The patients chose surgical treatment for their drug-resistant epilepsy and volunteered to participate in the research study. As part of the surgical treatment, neurosurgeons implanted electrodes in the patients’ visual word form area, providing an unprecedented opportunity to understand how the brain recognizes printed words.

First, painless electrical brain stimulation was used through the electrodes to disrupt the normal functioning of the visual word form area, which adversely affected the patients’ ability to read words. One patient dramatically misperceived letters, and another felt that there were words and parts of words present that were not in what she was reading. Stimulation to this region did not disrupt their ability to name objects or faces. A brief video of the stimulation can be seen here.

In addition to stimulating through these electrodes, the activity from the area was recorded while the patients read words. Using techniques from machine learning to analyze the brain activity that evolved over a few hundred milliseconds from this region, the researchers could tell what word a patient was reading at a particular moment. This suggests that neural activity in the area codes knowledge about learned visual words that can be used to discriminate even words that are only one letter different from one another (for example, “hint” and “lint”).

“This study shows that the visual word form area is exquisitely tuned to the fine details of written words and that this area plays a critical role in refining the brain’s representation of what we are reading. The disrupted word and letter perception seen with stimulation provides direct evidence that the visual word form area plays a dedicated role in skilled reading,” said Hirshorn. “These results also have important implications for understanding and treating reading disorders. The activity in the visual word form area, along with its interactions with other brain areas involved in language processing, could be a marker for proficient reading. Having a better understanding of this neural system could be critical for diagnosing reading disorders and developing targeted therapies.”

“It is exciting that with modern brain-recording techniques and advanced analysis methods, we are finally able to start answering questions about the brain and the mind that people have asked for centuries and contribute to our understanding of reading disorders,” said Ghuman.

Manufacturing Dopamine in the Brain with Gene Therapy

Parkinson’s patients who take the drug levodopa, or L-Dopa, are inevitably disappointed. At first, during a “honeymoon” period, their symptoms (which include tremors and balance problems) are brought under control. But over time the drug becomes less effective. They may also need ultrahigh doses, and some start spending hours a day in a state of near-frozen paralysis.

A biotech company called Voyager Therapeutics now thinks it can extend the effects of L-Dopa by using a surprising approach: gene therapy. The company, based in Cambridge, Massachusetts, is testing the idea in Parkinson’s patients who’ve agreed to undergo brain surgery and an injection of new DNA.

Parkinson’s occurs when dopamine-making neurons in the brain start dying, causing movement symptoms that afflicted boxing champ Muhammad Ali and actor Michael J. Fox, whose charitable foundation has helped pay for the development of Voyager’s experimental treatment.

The cause of Parkinson’s isn’t well understood, but the reason the drug wears off is. It’s because the brain also starts losing an enzyme known as aromatic L-amino acid decarboxylase, or AADC, that is needed to convert L-Dopa into dopamine.

Voyager’s strategy, which it has begun trying on patients in a small study, is to inject viruses carrying the gene for AADC into the brain, an approach it thinks can “turn back the clock” so that L-Dopa starts working again in advanced Parkinson’s patients as it did in their honeymoon periods.

Videos of patients before and after taking L-Dopa make it obvious why they’d want the drug to work at a lower dose. In the ‘off’ state, people move in slow motion. Touching one’s nose takes an effort. In an ‘on’ state, when the drug is working, they’re shaky, but not nearly so severely disabled.

“They do well at first but then respond very erratically to L-Dopa,” says Krystof Bankiewicz, the University of California scientist who came up with the gene-therapy plan and is a cofounder of Voyager. “This trial is to restore the enzyme and allow them to be awakened, or ‘on,’ for a longer period of time.”

Voyager was formed in 2013 and later went public, raising about $86 million. The company is part of a wave of biotechs that have been able to raise money for gene therapy, a technology that is starting to pay off: after three decades of research, a few products are reaching the market.

Unlike conventional drug studies, those involving gene therapy often come with very high expectations that the treatment will work. That’s because it corrects DNA errors for which the exact biological consequences are known. Genzyme, a unit of the European drug manufacturer Sanofi, paid Voyager $65 million and promised hundreds of millions more in order to sell any treatments it develops in Europe and Asia.

“We’re working with 60 years of dopamine pharmacology,” says Steven Paul, Voyager’s CEO, and formerly an executive at the drug giant Eli Lilly. “If we can get the gene to the right tissue at the right time, it would be surprising if it didn’t work.”

But those are big ifs. In fact, the concept for the Parkinson’s gene therapy dates to 1986, when Bankiewicz first determined that too little AADC was the reason L-Dopa stops working. He thought gene therapy might be a way to fix that, but it wasn’t until 20 years later that he was able to test the idea in 10 patients, in a study run by UCSF.

In that trial, Bankiewicz says, the gene delivery wasn’t as successful as anticipated. Not enough brain cells were updated with the new genetic information, which is shuttled into them by viruses injected into the brain. Patients seemed to improve, but not by much.

Even though the treatment didn’t work as planned, that early study highlighted one edge Voyager’s approach has over others. It is possible to tag AADC with a marker chemical, so doctors can actually see it working inside patients’ brains. In fact, ongoing production of the dopamine-making enzyme is still visible in the brains of the UCSF patients several years later.

It is possible to tag AADC with a marker chemical, so doctors can actually see it working inside patients’ brains. Image Source: MIT Technology Review.

In some past studies of gene therapy, by contrast, doctors had to wait until patients died to find out whether the treatment had been delivered correctly. “This is a one-and-done treatment,” says Paul. “And anatomically, it tells us if we got it in the right place.”

A new trial under way, this one being carried out by Voyager, is designed to get much higher levels of DNA into patients’ brains in hopes of achieving better results. To do that, Bankiewicz developed a system to inject the gene-laden viral particles through pressurized tubes while a patient lies inside an MRI scanner. That way, the surgeon can see the putamen, the brain region where the DNA is meant to end up, and make sure it’s covered by the treatment.

There are other gene therapies for Parkinson’s disease planned or in testing. A trial developed at the National Institutes of Health seeks to add a growth factor and regenerate cells. A European company, Oxford BioMedica, is trying to replace dopamine.

Altogether, as of this year, there were 48 clinical trials under way of gene or cell replacement in the brain and nervous system, according to the Alliance for Regenerative Medicine, a trade group. The nervous system is the fourth most common target for this style of experimental treatment, after cancer, heart disease, and infections.

Voyager’s staff is enthusiastic about a study participant they call “patient number 6,” whom they’ve been tracking for several months—ever since he got the treatment. Before the gene therapy, he was on a high dose of L-Dopa but still spent six hours a day in an “off” state. Now he’s off only two hours a day and takes less of the drug.

That patient got the highest dose of DNA yet, covering the largest brain area. That is part of what makes Voyager think higher doses should prove effective. “I believe that previous failure of gene-therapy trials in Parkinson’s was due to suboptimal delivery,” says Bankiewicz.

Image Credit: L.A. JOHNSON

Source: MIT Technology Review (by Antonio Regalado)

This year’s Halloween special wraps up the chemistry behind making a mummy: http://wp.me/p4aPLT-26m

Plantibodies and Plant-Derived Edible Vaccines

Throughout history, humans have used plants in the treatment of disease. This includes more traditional methods involving direct consumption with minimal preparation involved and the extraction of compounds for use in modern pharmaceuticals. One of the more recent methods of using plants in medicine involves the synthesis and application of plantibodies and plant produced antigens. These are recombinant antibodies and antigens respectively, which have been produced by a genetically modified plant (1, 2).        

Antibodies are a diverse set of proteins which serve the purpose of aiding the body in eliminating foreign pathogens. They are secreted by effector B lymphocytes which are a type of white blood cell that circulate throughout the body. An antigen is a molecule or a component of a molecule, such as a protein or carbohydrate, which can stimulate an immune response. The human body is capable of producing around 1012  different types of antibodies, each of which can bind to a specific antigen or a small group of related motifs (3). When an antibody encounters the antigen of a foreign pathogen to which it has high affinity, it binds to it which can disable it or alert the immune system for its destruction (4).

Figure 1: Each type of antibody has the ability to bind to a specific antigen or group of antigens with high affinity.

Plants do not normally produce antibodies and thus must be genetically modified to produce plantibodies as well as foreign protein antigens. Plantibodies produced in this manner function the same way as the antibodies native to the human body (1). The main ways to do this are to stably integrate foreign DNA into a host cell and place it into a plant embryo resulting in a permanent change of the nuclear genome, or to induce transient gene expression of the specified protein (5). In both cases, the genetic material introduced to the plant codes for the protein of choice. Several of the methods used to induce permanent transgene expression include agrobacterium-mediated transformation, particle bombardment using a gene gun, or the transformation of organelles such as chloroplasts. Transient transgene expression can be done using plant viruses as viral vectors or agroinfiltration (2). Once the genetic material has been inserted, the specified protein is produced via the plant endomembrane and secretory systems, after which it can be recovered through purification of the plant tissue to be used for injection (1). The production of these proteins can also be directed to specific organs of the plant such as the seeds using targeting signals (2). Stable integration techniques are generally used for more large scale production and when the gene in question has a high level of expression, while transient techniques are used to produce a greater yield in the short term (5).

Figure 2: A gene gun being used to introduce genetic material into the leaves of a plant.

Now how can plantibodies and plant produced antigens help us as humans? The primary purpose of producing plantibodies is for the treatment of disease via immunotherapy. Immunotherapy is a method of treatment in which one’s immune response to a particular disease is enhanced. Specific plantibodies can be produced in order to target a particular disease and then be applied to patients via injection as a means of treatment (6). Doing so provides a boost to the number of antibodies against the targeted disease in the patient’s body which helps to enhance their immune system response against it. An example of this is CaroRx, the first clinically tested plantibody which has the ability to bind to Streptococcus mutans. CaroRx has been shown to be effective in the treatment of tooth decay caused by this species of bacteria (1). More recently, a plantibody known as ZMapp has shown potential in the treatment of Ebola. A study by Qiu et al showed that when administered up to 5 days after the onset of the disease, 100% of rhesus macaques that were administered the drug were shown to have recovered from its effects while all of the control group animals perished as a result of the disease (7). In addition, it has been experimentally administered to some humans who later recovered from the disease, although its role in their recovery was not fully ascertained (8).

Plant produced antigens on the other hand can be used to produce oral vaccines (9). Vaccines are typically biological mixtures containing a weakened pathogen and its antigens. Injection of this results in priming of the body’s adaptive immune system against the particular pathogen so that it can more easily recognize and respond to the threat in the future (4). By producing the antigens of targeted pathogens in plants through transgenic expression, edible vaccines can be created if the plant used is safe to eat. Tobacco, potato, and tomato plants have typically been used in past attempts to create them, showing success in both animal studies and a number of human trials. The advantages of using an oral vaccine include ease of administration and lower costs since specialised personel are not required for administration (9). In addition, oral vaccines are more effective in providing immunity against pathogens at mucosal surfaces as they can be directly applied to the gastrointestinal tract (1). The primary issue with the usage of oral vaccines is that protein antigens must avoid degradation in the stomach and intestines before they can reach the targeted sites in the body. Several solutions to this dilemma include using other biological structures such as liposomes and proteasomes as a means of delivery. This helps to prevent the proteins from being degraded by digestive enzymes and the acidic environment of the stomach before they can reach their destination (1, 9).

Figure 3: An overview of one method of producing an edible vaccine using a potato plant. A gene coding for the protein of a human pathogen is used in agrobacterium-mediated transformation to produce a transgenic potato plant. The potatoes from this plant can then serve as an edible vaccine against pathogen from which the protein originated.

There are a number of advantages to using these plant based pharmaceuticals. First of all, they can be produced on a large scale at a relatively low cost through agriculture and are convenient for long-term storage due to the resiliency and size of plant seeds (5). There is also a low risk of contamination by mammalian viruses, blood borne pathogens, and oncogenes which can remove the need for expensive removal steps (1). In addition, purification steps can be skipped if the plants used are edible and ethical problems that come with animal production can be avoided (5). The disadvantages include the potential for allergic reactions to plant antigens and contamination by pesticides and herbicides. There is also the possibility of outcrossing of transgenic pollen to weeds or related crops which would lead to non-target crops also expressing the pharmaceutical.This could lead to public concern along with the potential that other species which ingest these plants may be negatively affected (9).  While plantibodies and plant produced antigens have not yet been extensively tested in clinical trials, going forward they represent a new treatment option with great promise.

References

1. Jain P, Pandey P, Jain D, Dwivedi P. Plantibody: An overview. Asian journal of Pharmacy and Life Science. 2011 Jan;1(1):87-94.

2. Stoger E, Sack M, Fischer R, Christou P. Plantibodies: applications, advantages and bottlenecks. Current Opinion in Biotechnology. 2002 Apr 1;13(2):161-166.

3. Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P. Molecular Biology of the Cell. 4th Edition. New York: Garland Science; 2002.

4. Parham P. The immune system. 4th Edition. New York: Garland Science; 2014.

5. Ferrante E, Simpson D. A review of the progression of transgenic plants used to produce plantibodies for human usage. J. Young Invest. 2001;4:1-0.

6. Smith MD. Antibody production in plants. Biotechnology advances. 1996 Dec 31;14(3):267-81.

7. Qiu X, Wong G, Audet J, Bello A, Fernando L, Alimonti JB, Fausther-Bovendo H, Wei H, Aviles J, Hiatt E, Johnson A. Reversion of advanced Ebola virus disease in nonhuman primates with ZMapp. Nature. 2014 Aug 29.

8. Sneed A. Know the Jargon. Scientific american. 2014 Dec 1;311(6):24-24.

9. Daniell H, Streatfield SJ, Wycoff K. Medical molecular farming: production of antibodies, biopharmaceuticals and edible vaccines in plants. Trends in plant science. 2001 May 1;6(5):219-26.

Rosalind Franklin was born #OTD in 1920. Her work was instrumental in the discovery of the structure of DNA: http://wp.me/s4aPLT-franklin

Scientists discover new arsenic-based broad-spectrum antibiotic

"We are running out of tools to fight these diseases. We need a new potent antibiotic to solve this problem," says Yoshinaga, the other co-senior author. "We showed that this new novel arsenic compound can be a potent antibiotic,"

Antibiotic resistance has been called one of the biggest public health threats of our time. There is a pressing need for new and novel antibiotics to combat the rise in antibiotic-resistant bacteria worldwide.

Researchers from Florida International University’s Herbert Wertheim College of Medicine are part of an international team that has discovered a new broad-spectrum antibiotic that contains arsenic. The study, published in Nature’s Communication Biology, is a collaboration between Barry P. Rosen, Masafumi Yoshinaga, Venkadesh Sarkarai Nadar and others from the Department of Cellular Biology and Pharmacology, and Satoru Ishikawa and Masato Kuramata from the Institute for Agro-Environmental Sciences, NARO in Japan.

“The antibiotic, arsinothricin or AST, is a natural product made by soil bacteria and is effective against many types of bacteria, which is what broad-spectrum means,” said Rosen, co-senior author of the study published in the Nature journal, Communications Biology. “Arsinothricin is the first and only known natural arsenic-containing antibiotic, and we have great hopes for it.”

Although it contains arsenic, researchers say they tested AST toxicity on human blood cells and reported that “it doesn’t kill human cells in tissue culture.”

Continue Reading.

After the four new additions, here’s a look at the origins of all the element names in the periodic table! High-res image/PDF: http://wp.me/p4aPLT-1Ru

Also featured in The Conversation UK alongside an article from Professor Mark Lorch here: https://goo.gl/g60pGU