Expanded Access: FDA Describes Efforts to Ease Application Process


The following was extracted from FDA Voice and posted on October 3, 2017.


FDA has a long history of supporting patient access to investigational new treatments. This includes working with drug and device companies through the clinical trial process that may lead to FDA approval of the treatment. FDA also offer expanded access programs that provide investigational drugs and devices to patients with serious conditions (generally prior to product approval), when there is no therapeutic alternative.


Each year, FDA receives over 1,000 applications for the treatment of patients through expanded access, also known as compassionate use, and the agency authorizes the vast majority (about 99%). FDA recognizes that time is critical for these seriously ill patients who do not have alternative therapies, and who cannot take part in a clinical trial of an investigational therapy. Submissions are usually authorized quickly, often in a matter of days. In the case of emergencies, FDA will typically provide authorization over the phone in a matter of hours. In an effort to eliminate potential hurdles that might delay or even discourage applications, FDA streamlined the expanded access process by introducing a new application form which a physician may use to request expanded access for their patient. Form FDA 3926 reduced the number of required information fields and attachments, and is estimated to take only 45 minutes for a physician to complete. Before expanded access can occur, the drug company must decide whether or not to provide the product. FDA cannot require a manufacturer to provide a product.


FDA is lifting another potential burden for physicians who apply to FDA to use an investigational drug to treat their patient. Prior to treating a patient under expanded access, the physician must obtain approval from the Institutional Review Board (IRB) at their facility. This is an important step to protect the rights, safety and well-being of human subjects in clinical research – but assembling the full board may cause delays because it may not routinely meet. As part of a plan to simplify the process for physicians seeking access to an investigational product to treat their patient, FDA has announced that just one IRB member – the chair or another appropriate person – can now approve the treatment. Dr. Gottlieb, FDA Commissioner, believes the simplified IRB process will facilitate access while still protecting patients.


More simplifications and clarifications are also in the pipeline. FDA has seen some reluctance among companies to provide investigational drugs for expanded access. This may have been due, in part, to uncertainty about how data for adverse events that occur during treatment under expanded access are viewed by FDA. Companies have voiced concerns that any apparent negative effects might jeopardize the product’s development. FDA recognizes that patients receiving expanded access are usually treated outside of a controlled clinical trial setting. As a result, they may have more advanced disease than clinical trial participants, be receiving other drugs at the same time, and have other diseases. FDA recognizes that these factors make it more difficult to determine the cause an adverse reaction. To clarify how adverse event data in these circumstances are viewed, FDA has updated the guidance for industry entitled, ?Expanded Access to Investigational Drugs for Treatment Use: Questions and Answers’ (questions 25 and 26). The guidance clarifies that suspected adverse reactions must be reported “only if there is evidence to suggest a causal relationship between the drug and the adverse event.“ Dr. Gottlieb is confident these changes will help to address recent issues raised by the Government Accountability Office (GAO), which said that FDA “should further clarify how adverse event data are used.“ FDA is still evaluating the GAO recommendations to identify other possible ways to respond to their concerns.


FDA is committed to helping patients and physicians fully understand the expanded access process. Dedicated staff in the Office of Health and Constituent Affairs and CDER’s Office of Communications, Division of Drug Information, already assist physicians and patients in navigating this system. FDA issued three final guidance documents last year to clarify and explain the process. This past July, FDA collaborated with the Reagan-Udall Foundation, patient advocacy groups, the pharmaceutical industry, and other federal agencies to launch a new online tool called the Expanded Access Navigator. This includes a directory where companies can submit public links to their expanded access policies, the criteria used by companies to determine whether to make a drug available through expanded access, and contact information. The directory offers patients and physicians a helpful starting point for researching available investigational therapies. In addition, FDA is working with the Reagan-Udall Foundation to expand this new tool. FDA is pleased to announce that Reagan-Udall will expand its portfolio to include FDA’s Rare Disease Program, with the goal of promoting more expanded access to treatments for rare disorders.


Manhattan Seafood Medley with Amazing Sauce

The success of this entree begins by making sure you buy the freshest seafood from a trusted fishmonger and spending the time to collect all the spices needed to give the sauce its rich depth. Make the sauce the day before you serve it and the herbs and spices will infuse my entire recipe, even more. Instead of serving the seafood and amazing sauce over rice or cous cous or potato or quinoa, I chose orzo, which worked wonderfully well. My second choice would have been either cauliflower rice or mashed cauliflower. ©Joyce Hays, Target Hays, Target Health Inc.


If you make the sauce the night before, as easy as that is, there’s practically nothing to do the next day, except cook the orzo (or your choice) in chicken stock or broth, and fry the seafood quickly in a very hot skillet. Because this fragrant recipe is impressive and attractive, your family and/or your dinner guests will regard you as a top chef. Try it. As long as there are no allergies or other reasons not to eat seafood, your complements will come rolling in. ©Joyce Hays, Target Health Inc.


Dinner for Two

Seafood Ingredients

1/2 pound shrimp, shelled, deveined & cleaned

1/2 pound sea scallops

1 glug extra virgin olive oil

2 or 3 fresh garlic cloves, mashed right in skillet, with a fork, or use a garlic press

Amazing Sauce

2 Tablespoons extra virgin olive oil

2 Tablespoons butter

1 cup chopped onion

2 scallions, chopped

1/2 cup chopped green bell pepper

10 gloves garlic, sliced

1 cup diced ripe tomatoes with a little of their juice

One 28 ounce can of Cento San Marzano Certified Peeled Tomatoes with Basil Leaf

2.5 Tablespoons dry oregano

1/2 teaspoon dried thyme

1 Tablespoon chickpea flour

1 cup clam juice in the bottle

1 Tablespoon Cento tomato paste

1/2 cup cream sherry

1/2 cup heavy cream

2 teaspoons Worcestershire sauce

2 dashes Tabasco

1 pinch Salt

1 pinch black pepper

1 pinch chili flakes

1 teaspoon curry powder

1 Tablespoon flax seeds

1 cup fresh cilantro, well chopped

Keep some chicken stock or broth handy, while cooking the sauce.

2 Tablespoons chopped fresh parsley (save some for garnish)


I bought all the ingredients from the following: Whole Foods, FreshDirect, Dean & Deluca, Amazon, Sherry-Lehmann Wines and Spirits. ©Joyce Hays, Target Health Inc.



Make Amazing Sauce the Day Before Serving

1. Do all of the chopping, slicing, cutting now so all sauce ingredients will be ready.


Do all your chopping, slicing, cutting at once, on one board. ©Joyce Hays, Target Health Inc.


2. Melt olive oil with butter in a large skillet, that has a cover that fits well, over a medium flame.

3. Next, saute the scallions, onion, garlic, pepper, until soft.


Saute the scallions, garlic, onion, pepper first. ©Joyce Hays, Target Health Inc.


4. Stir in the can of Cento tomatoes and juice, along with the fresh tomatoes. Add the fresh, cut tomatoes


Cento tomatoes and fresh tomatoes have been added. ©Joyce Hays, Target Health Inc.


5. Add oregano, thyme and all spices, as well as all herbs and flax seeds. Lower heat and cook for 2 or 3 minutes. Sprinkle with the chickpea flour and stir well.

6. Add 1 cup clam juice and cook for 2 to 3 minutes more.

7. Add the Cento tomato paste and stir until blended.


All spices and herbs, plus Cento tomato paste, have been added. ©Joyce Hays, Target Health Inc.


8. Add the Cream Sherry, Worcestershire, 1/3 cup of heavy dairy cream and Tabasco. Stir well to combine all ingredients. If you feel sauce is too thick, slowly add some chicken stock, stir and determine if you need more. If you think sauce is too thin, very slowly, add more chickpea flour, stirring constantly, until you get the consistency you want.


As you can see all final liquids have been added and am ready to stir well to combine everything before simmering for 10 minutes. ©Joyce Hays, Target Health Inc.


9. Once all sauce ingredients have been combined, put the tight-fitting cover on and lower the heat to simmer. Allow the sauce to simmer for 10 minutes, then remove from heat. Keep sauce covered and let it cool down to room temperature. Then put in refrigerator overnight.


Finally, cover and simmer for 10 minutes. ©Joyce Hays, Target Health Inc.



On the day of serving

  1. Follow directions on box and make the orzo (or whatever you chose to serve the seafood and amazing sauce over): I like to use chicken stock or broth to cook in, instead of water, which is always part of the directions on the box. After cooking, keep warm.


Orzo cooked in chicken stock or broth. ©Joyce Hays, Target Health Inc.


2. At this point, when you’re about to serve in 10 minutes, over a low flame, heat up the amazing sauce, so it’s ready when the seafood is done.


Warming up the sauce. ©Joyce Hays, Target Health Inc.

3. Seafood, add one glug of extra virgin olive oil in a large skillet over medium heat and with a fork, mash the garlic. If you have a garlic press, you can use that also. Turn the heat up.

4. To the pan, add the sea scallops and shrimp. Allow them to cook for a full minute, check to see if the scallops have turned a light brown. At that point, turn shrimp and scallops over and let the other side turn a light brown. This should take about 1 minute on each side, over a high flame. When done, remove from heat and set aside. At this point, you’re ready to serve.


Call me fussy, but I like to cook shrimp and scallops separately, so while I’m trying to get the scallops just right on the outside, I don’t overcook the shrimp. If either is overcooked, they get rubbery and really do taste overcooked which would ruin the whole dish. ©Joyce Hays, Target Health Inc.


Cooking the shrimp. ©Joyce Hays, Target Health Inc.


5. Spoon the amazing sauce into individual large pasta-shape bowls and place a portion of orzo (or your choice) in the center of each pasta bowl, over the sauce.

6. Spoon seafood over the orzo and the sauce. Add more sauce if desired, sprinkle some chopped parsley over the top, serve and enjoy!


All this dinner needs is a fresh crispy salad, your favorite warm bread or rolls to sop up the sauce and an icy white wine.


For dessert we had an easy to make fresh berry mousse.


Just a little sauce left over, but that’s about it. This is so-o delicious. ©Joyce Hays, Target Health Inc.


Finally, Fall is in the air, here in the Big Apple. ©Joyce Hays, Target Health Inc.


We are deeply disturbed by all the climate change catastrophes taking place around the world. In our hemisphere we’ve had disasters in: Puerto Rico, Mexico, California, Texas, Florida, as well as ruinous flooding along the whole eastern coast of the U.S.


Climate change is the most dangerous global challenge we all have to contend with.


Let us give up part of our tribal allegiances, and become world citizens working together toward one goal — saving our planet.


From Our Table to Yours

Bon Appetit!


October 12, 2017

Massachusetts Institute of Technology

Researchers have, for the first time, identified neural signatures of explicit and implicit learning.


Researchers have identified neural signatures of explicit and implicit learning.
Credit: © peshkova / Fotolia



Figuring out how to pedal a bike and memorizing the rules of chess require two different types of learning, and now for the first time, researchers have been able to distinguish each type of learning by the brain-wave patterns it produces.

These distinct neural signatures could guide scientists as they study the underlying neurobiology of how we both learn motor skills and work through complex cognitive tasks, says Earl K. Miller, the Picower Professor of Neuroscience at the Picower Institute for Learning and Memory and the Department of Brain and Cognitive Sciences, and senior author of a paper describing the findings in the Oct. 11 edition of Neuron.

When neurons fire, they produce electrical signals that combine to form brain waves that oscillate at different frequencies. “Our ultimate goal is to help people with learning and memory deficits,” notes Miller. “We might find a way to stimulate the human brain or optimize training techniques to mitigate those deficits.”

The neural signatures could help identify changes in learning strategies that occur in diseases such as Alzheimer’s, with an eye to diagnosing these diseases earlier or enhancing certain types of learning to help patients cope with the disorder, says Roman F. Loonis, a graduate student in the Miller Lab and first author of the paper. Picower Institute research scientist Scott L. Brincat and former MIT postdoc Evan G. Antzoulatos, now at the University of California at Davis, are co-authors.

Explicit versus implicit learning

Scientists used to think all learning was the same, Miller explains, until they learned about patients such as the famous Henry Molaison or “H.M.,” who developed severe amnesia in 1953 after having part of his brain removed in an operation to control his epileptic seizures. Molaison couldn’t remember eating breakfast a few minutes after the meal, but he was able to learn and retain motor skills that he learned, such as tracing objects like a five-pointed star in a mirror.

“H.M. and other amnesiacs got better at these skills over time, even though they had no memory of doing these things before,” Miller says.

The divide revealed that the brain engages in two types of learning and memory — explicit and implicit.

Explicit learning “is learning that you have conscious awareness of, when you think about what you’re learning and you can articulate what you’ve learned, like memorizing a long passage in a book or learning the steps of a complex game like chess,” Miller explains.

“Implicit learning is the opposite. You might call it motor skill learning or muscle memory, the kind of learning that you don’t have conscious access to, like learning to ride a bike or to juggle,” he adds. “By doing it you get better and better at it, but you can’t really articulate what you’re learning.”

Many tasks, like learning to play a new piece of music, require both kinds of learning, he notes.

Brain waves from earlier studies

When the MIT researchers studied the behavior of animals learning different tasks, they found signs that different tasks might require either explicit or implicit learning. In tasks that required comparing and matching two things, for instance, the animals appeared to use both correct and incorrect answers to improve their next matches, indicating an explicit form of learning. But in a task where the animals learned to move their gaze one direction or another in response to different visual patterns, they only improved their performance in response to correct answers, suggesting implicit learning.

What’s more, the researchers found, these different types of behavior are accompanied by different patterns of brain waves.

During explicit learning tasks, there was an increase in alpha2-beta brain waves (oscillating at 10-30 hertz) following a correct choice, and an increase delta-theta waves (3-7 hertz) after an incorrect choice. The alpha2-beta waves increased with learning during explicit tasks, then decreased as learning progressed. The researchers also saw signs of a neural spike in activity that occurs in response to behavioral errors, called event-related negativity, only in the tasks that were thought to require explicit learning.

The increase in alpha-2-beta brain waves during explicit learning “could reflect the building of a model of the task,” Miller explains. “And then after the animal learns the task, the alpha-beta rhythms then drop off, because the model is already built.”

By contrast, delta-theta rhythms only increased with correct answers during an implicit learning task, and they decreased during learning. Miller says this pattern could reflect neural “rewiring” that encodes the motor skill during learning.

“This showed us that there are different mechanisms at play during explicit versus implicit learning,” he notes.

Future Boost to Learning

Loonis says the brain wave signatures might be especially useful in shaping how we teach or train a person as they learn a specific task. “If we can detect the kind of learning that’s going on, then we may be able to enhance or provide better feedback for that individual,” he says. “For instance, if they are using implicit learning more, that means they’re more likely relying on positive feedback, and we could modify their learning to take advantage of that.”

The neural signatures could also help detect disorders such as Alzheimer’s disease at an earlier stage, Loonis says. “In Alzheimer’s, a kind of explicit fact learning disappears with dementia, and there can be a reversion to a different kind of implicit learning,” he explains. “Because the one learning system is down, you have to rely on another one.”

Earlier studies have shown that certain parts of the brain such as the hippocampus are more closely related to explicit learning, while areas such as the basal ganglia are more involved in implicit learning. But Miller says that the brain wave study indicates “a lot of overlap in these two systems. They share a lot of the same neural networks.”

Story Source:

Materials provided by Massachusetts Institute of Technology. Original written by Becky Ham. Note: Content may be edited for style and length.

Journal Reference:

  1. Scott L. Brincat, Evan G. Antzoulatos, Earl K. Miller. A Meta-Analysis Suggests Different Neural Correlates for Implicit and Explicit Learning Roman F. LoonisNeuron, October 2017 DOI: 10.1016/j.neuron.2017.09.032


Source: Massachusetts Institute of Technology. “Brain waves reflect different types of learning.” ScienceDaily. ScienceDaily, 12 October 2017. <www.sciencedaily.com/releases/2017/10/171012122820.htm>.

Gases from Inland Northwest blocked out sun, cooling planet

October 11, 2017

Washington State University

Researchers have determined that the Pacific Northwest was home to one of the Earth’s largest known volcanic eruptions, a millennia-long spewing of sulfuric gas that blocked out the sun and cooled the planet. Only two other eruptions — the basalt floods of the Siberian Traps and the Deccan Traps — were larger, and they led to two of the Earth’s great extinctions.


The Palouse River in southeastern Washington State drops nearly 200 feet through cliffs of basalt created by scores of lava flows 10 to 16 million years ago. Washington State University researchers have determined that one flow constituted one of the Earth’s largest known volcanic eruptions, a millennia-long spewing of sulfuric gas that blocked out the sun and cooled the planet.
Credit: Dean Hare, WSU Photo Services



Washington State University researchers have determined that the Pacific Northwest was home to one of the Earth’s largest known volcanic eruptions, a millennia-long spewing of sulfuric gas that blocked out the sun and cooled the planet.

Only two other eruptions — the basalt floods of the Siberian Traps and the Deccan Traps — were larger, and they led to two of the Earth’s great extinctions.

“This would have been devastating regionally because of the acid-rain effect from the eruptions,” said John Wolff, a professor in the WSU School of the Environment. “It did have a global effect on temperatures, but not drastic enough to start killing things, or it did not kill enough of them to affect the fossil record.”

The research, which was funded by the National Science Foundation, appears in Geology, the top journal in the field. Starting 16.5 million years ago, they say, vents in southeast Washington and northeast Oregon put out a series of flows that reached nearly to Canada and all the way to the Pacific Ocean. The flows created the Wapshilla Ridge Member of the Grande Ronde Basalt, a kilometer-thick block familiar to travelers in the Columbia Gorge and most of Eastern Washington. The researchers say it is “the largest mapped flood basalt unit on Earth.”

The researchers estimate that, over tens of thousands of years, the floods put out between 242 and 305 billion tons of sulfur dioxide. That’s more than 4,000 times the output of the 1815 Mount Tambora eruption in present-day Indonesia. That eruption blanketed the Earth in an aerosol veil, creating the “Year Without A Summer” and food shortages across the northern hemisphere.

The volume of gas emitted from the Wapshilla Ridge lavas, said the researchers, “is equivalent to a Tambora eruption every day for 11 to 16 years.”

Most of the lava’s gases were released during the eruptions, but some of the gas remained trapped in crystals near the volcanic vents. Klarissa Davis, lead author of the paper, analyzed the gases as part of her doctoral studies. The other authors are Michael Rowe, now at the University of Auckland, and Owen Neill, now at the University of Michigan.

Wolff puts the eruption into one of three classes of cataclysms, the other two being a caldera eruption like the Yellowstone volcano and the impact of an asteroid. A similar eruption today “would devastate modern society globally,” said Wolff.

The eruption also provides an insight into the workings of climate change. It took place in what is known as the Miocene Climactic Optimum, or MCO, when some 50 million years of cooling was interrupted by 5 to 6 degrees Fahrenheit of warming. But at its peak, the MCO had a brief cooling period that coincides with the Wapshilla eruption and its profusion of sulfur dioxide.

Sulfur dioxide is now bandied about as a possible tool for engineering a break in the Earth’s current warming trend, though Wolff is not particularly keen on the idea.

“I personally think that it’s probably a dangerous thing to do without understanding all of the possible consequences,” he said. “But maybe we’re getting an idea of some possible consequences here.”

Story Source:

Materials provided by Washington State UniversityNote: Content may be edited for style and length.

Journal Reference:

  1. Klarissa N. Davis, John A. Wolff, Michael C. Rowe, Owen K. Neill. Sulfur release from main-phase Columbia River Basalt eruptionsGeology, 2017; DOI: 10.1130/G39371.1


Source: Washington State University. “One of planet’s largest volcanic eruptions: Gases from Inland Northwest blocked out sun, cooling planet.” ScienceDaily. ScienceDaily, 11 October 2017. <www.sciencedaily.com/releases/2017/10/171011091157.htm>.

Study challenges traditional hierarchy of brain decoding; offers insight into how the brain makes perceptual judgements

October 9, 2017

The Zuckerman Institute at Columbia University

New research has contributed to solving a paradox of perception, literally upending models of how the brain constructs interpretations of the outside world. When observing a scene, the brain first processes details — spots, lines and simple shapes — and uses that information to build internal representations of more complex objects, like cars and people. But during recall, the brain remembers those larger concepts first. This could shed light on concepts such as eyewitness testimony to autism.


Visual depiction of one- and two-line tasks that participants were asked to complete and that was key to the paper’s findings.
Credit: Ning Qian/Columbia’s Zuckerman Institute



Scientists at Columbia’s Zuckerman Institute have contributed to solving a paradox of perception, literally upending models of how the brain constructs interpretations of the outside world. When observing a scene, the brain first processes details — spots, lines and simple shapes — and uses that information to build internal representations of more complex objects, like cars and people. But when recalling that information, the brain remembers those larger concepts first to then reconstruct the details — representing a reverse order of processing. The research, which involved people and employed mathematical modeling, could shed light on phenomena ranging from eyewitness testimony to stereotyping to autism.

This study was published in Proceedings of the National Academy of Sciences.

“The order by which the brain reacts to, or encodes, information about the outside world is very well understood,” said Ning Qian, PhD, a neuroscientist and a principal investigator at Columbia’s Mortimer B. Zuckerman Mind Brain Behavior Institute. “Encoding always goes from simple things to the more complex. But recalling, or decoding, that information is trickier to understand, in large part because there was no method — aside from mathematical modeling — to relate the activity of brain cells to a person’s perceptual judgment.”

Without any direct evidence, researchers have long assumed that decoding follows the same hierarchy as encoding: you start from the ground up, building up from the details. The main contribution of this work with Misha Tsodyks, PhD, the paper’s co-senior author who performed this work while at Columbia and is at the Weizmann Institute of Science in Israel, “is to show that this standard notion is wrong,” Dr. Qian said. “Decoding actually goes backward, from high levels to low.”

As an analogy of this reversed decoding, Dr. Qian cites last year’s presidential election as an example.

“As you observed the things one candidate said and did over time, you may have formed a categorical negative or positive impression of that person. From that moment forward, the way in which you recalled the candidate’s words and actions are colored by that overall impression,” said Dr. Qian. “Our findings revealed that higher-level categorical decisions — ‘this candidate is trustworthy’ — tend to be stable. But lower-level memories — ‘this candidate said this or that’ — are not as reliable. Consequently, high-level decoding constrains low-level decoding.”

To explore this decoding hierarchy, Drs. Qian and Tsodyks and their team conducted an experiment that was simple in design in order to have a clear interpretation of the results. They asked 12 people to perform a series of similar tasks. In the first, they viewed a line angled at 50 degrees on a computer screen for half a second. Once it disappeared, the participants repositioned two dots on the screen to match what they remembered to be the angle of the line. They then repeated this task 50 more times. In a second task, the researchers changed the angle of the line to 53 degrees. And in a third task, the participants were shown both lines at the same time, and then had to orient pairs of dots to match each angle.

Previously held models of decoding predicted that in the two-line task, people would first decode the individual angle of each line (a lower-level feature) and the use that information to decode the two lines’ relationship (a higher-level feature).

“Memories of exact angles are usually imprecise, which we confirmed during the first set of one-line tasks. So, in the two-line task, traditional models predicted that the angle of the 50-degree line would frequently be reported as greater than the angle of the 53-degree line,” said Dr. Qian.

But that is not what happened. Traditional models also failed to explain several other aspects of the data, which revealed bi-directional interactions between the way participants recalled the angle of the two lines. The brain appeared to encode one line, then the other, and finally encode their relative orientation. But during decoding, when participants were asked to report the individual angle of each line, their brains used that the lines’ relationship — which angle is greater — to estimate the two individual angles.

“This was striking evidence of participants employing this reverse decoding method,” said Dr. Qian.

The authors argue that reverse decoding makes sense, because context is more important than details. Looking at a face, you want to assess quickly if someone is frowning, and only later, if need be, estimate the exact angles of the eyebrows. “Even your daily experience shows that perception seems to go from high to low levels,” Dr. Qian added.

To lend further support, the authors then constructed a mathematical model of what they think happens in the brain. They used something called Bayesian inference, a statistical method of estimating probability based on prior assumptions. Unlike typical Bayesian models, however, this new model used the higher-level features as the prior information for decoding lower-level features. Going back to the visual line task, they developed an equation to estimate individual lines’ angles based on the lines’ relationship. The model’s predictions fit the behavioral data well.

In the future, the researchers plan to extend their work beyond these simple tasks of perception and into studies of long-term memory, which could have broad implications — from how we assess a presidential candidate, to if a witness is offering reliable testimony.

“The work will help to explain the brain’s underlying cognitive processes that we employ every day,” said Dr. Qian. “It might also help to explain complex disorders of cognition, such as autism, where people tend to overly focus on details while missing important context.”

Story Source:

Materials provided by The Zuckerman Institute at Columbia UniversityNote: Content may be edited for style and length.

Journal Reference:

  1. Stephanie Ding, Christopher J. Cueva, Misha Tsodyks, Ning Qian. Visual perception as retrospective Bayesian decoding from high- to low-level featuresProceedings of the National Academy of Sciences, 2017; 201706906 DOI: 10.1073/pnas.1706906114


Source: The Zuckerman Institute at Columbia University. “Human brain recalls visual features in reverse order than it detects them: Study challenges traditional hierarchy of brain decoding; offers insight into how the brain makes perceptual judgements.” ScienceDaily. ScienceDaily, 9 October 2017. <www.sciencedaily.com/releases/2017/10/171009154946.htm>.

Bacteria with synthetic gene circuit self-assemble to build working device with gold nanoparticles

October 9, 2017

Duke University

By programming bacteria with a synthetic gene circuit that can recruit gold nanoparticles to the surface of their colony, researchers can build functional devices. A proof-of-concept study uses this technique to build dome-shaped pressure sensors with the help of living bacteria.


Black dots mark gold nanoparticles that have been attracted to the surface of pressure-sensitive domes constructed by engineered bacteria.
Credit: Will (Yangxiaolu) Cao, Duke University



Researchers at Duke University have turned bacteria into the builders of useful devices by programming them with a synthetic gene circuit.

As a bacterial colony grows into the shape of a hemisphere, the gene circuit triggers the production of a type of protein to distribute within the colony that can recruit inorganic materials. When supplied with gold nanoparticles by researchers, the system forms a golden shell around the bacterial colony, the size and shape of which can be controlled by altering the growth environment.

The result is a device that can be used as a pressure sensor, proving that the process can create working devices.

While other experiments have successfully grown materials using bacterial processes, they have relied entirely on externally controlling where the bacteria grow and have been limited to two dimensions. In the new study, researchers at Duke demonstrate the production of a composite structure by programming the cells themselves and controlling their access to nutrients, but still leaving the bacteria free to grow in three dimensions.

The study appears online on October 9 in Nature Biotechnology.

“This technology allows us to grow a functional device from a single cell,” said Lingchong You, the Paul Ruffin Scarborough Associate Professor of Engineering at Duke. “Fundamentally, it is no different from programming a cell to grow an entire tree.”

Nature is full of examples of life combining organic and inorganic compounds to make better materials. Mollusks grow shells consisting of calcium carbonate interlaced with a small amount of organic components, resulting in a microstructure three times tougher than calcium carbonate alone. Our own bones are a mix of organic collagen and inorganic minerals made up of various salts.

Harnessing such construction abilities in bacteria would have many advantages over current manufacturing processes. In nature, biological fabrication uses raw materials and energy very efficiently. In this synthetic system, for example, tweaking growth instructions to create different shapes and patterns could theoretically be much cheaper and faster than casting the new dies or molds needed for traditional manufacturing.

“Nature is a master of fabricating structured materials consisting of living and non-living components,” said You. “But it is extraordinarily difficult to program nature to create self-organized patterns. This work, however, is a proof-of-principle that it is not impossible.”

The genetic circuit is like a biological package of instructions that researchers embed into a bacterium’s DNA. The directions first tell the bacteria to produce a protein called T7 RNA polymerase (T7RNAP), which then activates its own expression in a positive feedback loop. It also produces a small molecule called AHL that can diffuse into the environment like a messenger.

As the cells multiply and grow outward, the concentration of the small messenger molecule hits a critical concentration threshold, triggering the production of two more proteins called T7 lysozyme and curli. The former inhibits the production of T7RNAP while the latter acts as sort of biological Velcro that can latch onto inorganic compounds.

The dynamic interaction of these feedback loops causes the bacterial colony to grow in a dome-shaped pattern until it runs out of food. It also causes the bacteria on the outside of the dome to produce the biological Velcro, which grabs onto gold nanoparticles supplied by the researchers, forming a shell about the size of your average freckle.

The researchers were able to alter the size and shape of the dome by controlling the properties of the porous membrane it grows on. For example, changing the size of the pores or how much the membrane repels water affects how many nutrients are passed to the cells, altering their growth pattern.

“We’re demonstrating one way of fabricating a 3-D structure based entirely on the principal of self-organization,” said Stefan Zauscher, the Sternberg Family Professor of Mechanical Engineering & Materials Science at Duke. “That 3-D structure is then used as a scaffold to generate a device with well-defined physical properties. This approach is inspired by nature, and because nature doesn’t do this on its own, we’ve manipulated nature to do it for us.”

To show how their system could be used to manufacture working devices, the researchers used these hybrid organic/inorganic structures as pressure sensors. Identical arrays of domes were grown on two substrate surfaces. The two substrates were then sandwiched together so that each dome was positioned directly across from its counterpart on the other substrate.

Each dome was then connected to an LED light bulb through copper wiring. When pressure was applied to the sandwich, the domes pressed into one another, causing a deformation resulting in an increase in its conductivity. This, in turn, caused the corresponding LED light bulbs to brighten a certain amount depending on the amount of pressure being applied.

“In this experiment we’re primarily focused on the pressure sensors, but the number of directions this could be taken in is vast,” said Will (Yangxiaolu) Cao, a postdoctoral associate in You’s laboratory and first author of the paper. “We could use biologically responsive materials to create living circuits. Or if we could keep the bacteria alive, you could imagine making materials that could heal themselves and respond to environmental changes.”

“Another aspect we’re interested in pursuing is how to generate much more complex patterns,” said You. “Bacteria can create complex branching patterns, we just don’t know how to make them do that ourselves — yet.”

Story Source:

Materials provided by Duke UniversityNote: Content may be edited for style and length.

Journal Reference:

  1. Yangxiaolu Cao, Yaying Feng, Marc D Ryser, Kui Zhu, Gregory Herschlag, Changyong Cao, Katherine Marusak, Stefan Zauscher, Lingchong You. Programmable assembly of pressure sensors using pattern-forming bacteriaNature Biotechnology, 2017; DOI: 10.1038/nbt.3978


Source: Duke University. “Bacteria self-organize to build working sensors: Bacteria with synthetic gene circuit self-assemble to build working device with gold nanoparticles.” ScienceDaily. ScienceDaily, 9 October 2017. <www.sciencedaily.com/releases/2017/10/171009123210.htm>.

eClinical Forum Autumn Meeting


The eClinical Forum is a non-commercial think-tank and a global consortium of organizations involved in clinical research. It provides a platform for member organizations to network and discuss ideas with industry peers in a non-competitive environment. Target Health is a member of the eClinical Forum and Dr. Mitchel, President of Target Health, is a member of the Steering Committee. Les Jordan just returned from Berlin where he attended the European meeting.


The eClinical Forum Autumn Meeting will be held on October 16-18 2017 at the Babson Executive Conference Center, Babson Park, MA.


The objectives of the meeting are to:


1. Leverage the knowledge of eClinical Forum members and develop an unrivalled insight into best practices driving the performance of global clinical research.

2. Remain up-to-date on current thinking  and explore emerging technology, process, people and regulatory trends.

3. Work with peers to design the future of eClinical Research and to develop leading-edge visions and implementable strategies Benefit from an extensive network of peers with global experience and insight for beyond the workshop interaction.


For more information about Target Health contact Warren Pearlson (212-681-2100 ext. 165). For additional information about software tools for paperless clinical trials, please also feel free to contact Dr. Jules T. Mitchel. The Target Health software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health Website.


Joyce Hays, Founder and Editor in Chief of On Target

Jules Mitchel, Editor



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Circadian Biological Clock

Sun and Moon, Nuremberg Chronicle, 1493

Source: Albrecht Durer – This is the scan of historical document, Nuremberg chronicle, from the original book, Nuremberg chronicle, Hartmann Schedel, 1493. This work is in the public domain in its country of origin and other countries and areas where the copyright term is the author’s life plus 100 years or less


A circadian clock, or circadian oscillator, is a hypothetical biochemical oscillator that oscillates with a stable phase relationship to 1) ___ time. Such a clock’s in vivo period, averaged over an earth year, is necessarily almost exactly 24 hours (the earth’s current solar day). In most living things, internally synchronized circadian clocks make it possible for the organism to coordinate its biology and behavior with daily environmental changes corresponding with the day-2) ___ cycle and derived diurnal behavior patterns (e.g. crepuscular feeding).


The term circadian derives from the Latin circa (about) diem (a 3) ___), since when taken away from external cues (such as the day-night cycle), they do not run to exactly 24 hours. Clocks in humans in a lab in constant low light, for example, will average about 24.2 hours per day, rather than 24 hours exactly. The normal body clock oscillates with an endogenous period of exactly 24 hours, it entrains, when it receives sufficient daily corrective signals from the environment, primarily daylight and darkness. Circadian clocks are the central mechanisms that drive 4) ___ rhythms. They consist of three major components:


1. a central biochemical oscillator with a period of about 5) ___ hours that keeps time;

2. a series of input pathways to this central oscillator to allow entrainment of the clock;

3. a series of output pathways tied to distinct phases of the oscillator that regulate overt rhythms in biochemistry, physiology, and behavior throughout an organism.


The clock is reset as an organism senses environmental time cues of which the primary one is 6) ___. Circadian oscillators are ubiquitous in tissues of the body where they are synchronized by both endogenous and external signals to regulate transcriptional activity throughout the day in a tissue-specific manner. The circadian 7) ___ is intertwined with most cellular metabolic processes and it is affected by the aging of an organism. The basic molecular mechanisms of the biological clock have been defined in vertebrate species, Drosophila melanogaster, plants, fungi, bacteria, and presumably also in Archaea.


While a precise 24-hour circadian clock is found in many organisms, it is not universal. Organisms living in the high Arctic or high Antarctic do not experience solar time in all seasons, though most are believed to maintain a circadian rhythm close to 24 hours, such as bears during hibernation. Much of the earth’s biomass resides in the dark biosphere, and while these organisms may exhibit rhythmic physiology, for these organisms the dominant rhythm is unlikely to be circadian. For east-west migratory organisms – and especially should an organism circumnavigate the globe – the absolute 24-hour phase might deviate over months, seasons, or years.


In vertebrates, the master circadian clock is contained within the suprachiasmatic nucleus (SCN), a bilateral nerve cluster of about 20,000 neurons. The SCN itself is located in the hypothalamus, a small region of the 8) ___ situated directly above the optic chiasm, where it receives input from specialized photosensitive ganglion cells in the retina via the retinohypothalamic tract. The SCN maintains control across the body by synchronizing “slave oscillators“, which exhibit their own near-24-hour rhythms and control circadian phenomena in local tissue. Through intercellular signaling mechanisms such as vasoactive intestinal peptide, the SCN signals other hypothalamic nuclei and the pineal gland to modulate body temperature and production of hormones such as cortisol and melatonin; these 9) ___ enter the circulatory system, and induce clock-driven effects throughout the organism. It is not, however, clear precisely what signal (or signals) enacts principal entrainment to the many biochemical clocks contained in tissues throughout the body.


A key feature of clocks is their ability to synchronize to external stimuli. The presence of cell autonomous oscillators in almost every cell in the 10) ____ raises the question of how these oscillators are temporally coordinated. The quest for universal timing cues for peripheral clocks in mammals has yielded principal entrainment signals such as feeding, temperature, and oxygen. Both feeding rhythms and temperature cycles were shown to synchronize peripheral clocks and even uncouple them from the master clock in the brain (e.g., daytime restricted feeding). Recently, oxygen rhythms were found to synchronize clocks in cultured cells.

Sources: nih.gov; Wikipedia


ANSWERS: 1) solar; 2) night; 3) day; 4) circadian; 5) 24; 6) light; 7) clock; 8) brain; 9) hormones; 10) body

The Nobel Prize in Physiology or Medicine 2017


The distinguished award goes to: Jeffrey C. Hall, Michael Rosbash, Michael W. Young, for their discoveries of molecular mechanisms controlling the circadian rhythm.

Michael Rosbash: Photo credit: Howard Hughes Medical Institute


Jeffrey Hall                                                                 Michael Young

Photo credit: Wikipedia                                        Photo credit: Wikipedia


Life on Earth is adapted to the rotation of our planet. For many years we have known that living organisms, including humans, have an internal, biological clock that helps them anticipate and adapt to the regular rhythm of the day. But how does this clock actually work? Jeffrey C. Hall, Michael Rosbash and Michael W. Young were able to peek inside our biological clock and elucidate its inner workings. Their discoveries explain how plants, animals and humans adapt their biological rhythm so that it is synchronized with the Earth’s revolutions.


Nobel winner, Jeffrey C. Hall was born 1945 in New York, USA. He received his doctoral degree in 1971 at the University of Washington in Seattle and was a postdoctoral fellow at the California Institute of Technology in Pasadena from 1971 to 1973. He joined the faculty at Brandeis University in Waltham in 1974. In 2002, he became associated with University of Maine.


Nobel winner, Michael Rosbash was born in 1944 in Kansas City, USA. He received his doctoral degree in 1970 at the Massachusetts Institute of Technology in Cambridge. During the following three years, he was a postdoctoral fellow at the University of Edinburgh in Scotland. Since 1974, he has been on faculty at Brandeis University in Waltham, USA.


Nobel winner, Michael W. Young was born in 1949 in Miami, USA. He received his doctoral degree at the University of Texas in Austin in 1975. Between 1975 and 1977, he was a postdoctoral fellow at Stanford University in Palo Alto. From 1978, he has been on faculty at the Rockefeller University in New York.


The earliest recorded account of a circadian process dates from the 4th century BCE, when Androsthenes, a ship captain serving under Alexander the Great, described diurnal leaf movements of the tamarind tree. The observation of a circadian or diurnal process in humans is mentioned in Chinese medical texts dated to around the 13th century, including the Noon and Midnight Manual and the Mnemonic Rhyme to Aid in the Selection of Acu-points According to the Diurnal Cycle, the Day of the Month and the Season of the Year. The first recorded observation of an endogenous circadian oscillation was by the French scientist Jean-Jacques d’Ortous de Mairan in 1729. He noted that 24-hour patterns in the movement of the leaves of the plant Mimosa pudica continued even when the plants were kept in constant darkness, in the first experiment to attempt to distinguish an endogenous clock from responses to daily stimuli. In 1896, Patrick and Gilbert observed that during a prolonged period of sleep deprivation, sleepiness increases and decreases with a period of approximately 24 hours. In 1918, J.S. Szymanski showed that animals are capable of maintaining 24-hour activity patterns in the absence of external cues such as light and changes in temperature.


In the early 20th century, circadian rhythms were noticed in the rhythmic feeding times of bees. Extensive experiments were done by Auguste Forel, Ingeborg Beling, and Oskar Wahl to see whether this rhythm was due to an endogenous clock. Ron Konopka and Seymour Benzer isolated the first clock mutant in Drosophila in the early 1970s and mapped the “period“ gene, the first discovered genetic determinant of behavioral rhythmicity. Joseph Takahashi discovered the first mammalian circadian clock mutation (clock delta19) using mice in 1994. However, recent studies show that deletion of clock does not lead to a behavioral phenotype (the animals still have normal circadian rhythms), which questions its importance in rhythm generation.


The term circadian was coined by Franz Halberg in the 1950s.


Using fruit flies as a model organism, this year’s Nobel laureates isolated a gene that controls the normal daily biological rhythm. They showed that this gene encodes a protein that accumulates in the cell during the night, and is then degraded during the day. Subsequently, they identified additional protein components of this machinery, exposing the mechanism governing the self-sustaining clockwork inside the cell. We now recognize that biological clocks function by the same principles in cells of other multicellular organisms, including humans. With precision, our inner clock adapts our physiology to the dramatically different phases of the day. The clock regulates critical functions such as behavior, hormone levels, sleep, body temperature and metabolism. Our well-being is affected when there is a temporary mismatch between our external environment and this internal biological clock, for example when we travel across several time zones and experience “jet lag.“ There are also indications that chronic misalignment between our lifestyle and the rhythm dictated by our inner timekeeper is associated with increased risk for various diseases.


Most living organisms anticipate and adapt to daily changes in the environment. During the 18th century, the astronomer Jean Jacques d’Ortous de Mairan studied mimosa plants, and found that the leaves opened towards the sun during daytime and closed at dusk. He wondered what would happen if the plant was placed in constant darkness. He found that independent of daily sunlight the leaves continued to follow their normal daily oscillation. Plants seemed to have their own biological clock. Other researchers found that not only plants, but also animals and humans, have a biological clock that helps to prepare our physiology for the fluctuations of the day. This regular adaptation is referred to as the circadian rhythm, originating from the Latin words circa meaning “around“ and dies meaning “day“. But just how our internal circadian biological clock worked remained a mystery.


During the 1970’s, Seymour Benzer and his student Ronald Konopka asked whether it would be possible to identify genes that control the circadian rhythm in fruit flies. They demonstrated that mutations in an unknown gene disrupted the circadian clock of flies. They named this gene period. But how could this gene influence the circadian rhythm?


This year’s Nobel Laureates, who were also studying fruit flies, aimed to discover how the clock actually works. In 1984, Jeffrey Hall and Michael Rosbash, working in close collaboration at Brandeis University in Boston, and Michael Young at the Rockefeller University in New York, succeeded in isolating the period gene. Hall and Rosbash then went on to discover that PER, the protein encoded by period, accumulated during the night and was degraded during the day. Thus, PER protein levels oscillate over a 24-hour cycle, in synchrony with the circadian rhythm. The next key goal was to understand how such circadian oscillations could be generated and sustained. Hall and Rosbash hypothesized that the PER protein blocked the activity of the period gene. They reasoned that by an inhibitory feedback loop, PER protein could prevent its own synthesis and thereby regulate its own level in a continuous, cyclic rhythm. The model was tantalizing, but a few pieces of the puzzle were missing. To block the activity of the period gene, PER protein, which is produced in the cytoplasm, would have to reach the cell nucleus, where the genetic material is located. Hall and Rosbash had shown that PER protein builds up in the nucleus during night, but how did it get there? In 1994 Michael Young discovered a second clock gene, timeless, encoding the TIM protein that was required for a normal circadian rhythm. In elegant work, he showed that when TIM bound to PER, the two proteins were able to enter the cell nucleus where they blocked period gene activity to close the inhibitory feedback loop. Such a regulatory feedback mechanism explained how this oscillation of cellular protein levels emerged, but questions lingered. What controlled the frequency of the oscillations? Michael Young identified yet another gene, double-time, encoding the DBT protein that delayed the accumulation of the PER protein. This provided insight into how an oscillation is adjusted to more closely match a 24-hour cycle. The paradigm-shifting discoveries have established key mechanistic principles for the biological clock. During the following years other molecular components of the clockwork mechanism were elucidated, explaining its stability and function. For example, this year’s laureates identified additional proteins required for the activation of the period gene, as well as for the mechanism by which light can synchronize the clock. The biological clock is involved in many aspects of our complex physiology. We now know that all multicellular organisms, including humans, utilize a similar mechanism to control circadian rhythms. A large proportion of our genes are regulated by the biological clock and, consequently, a carefully calibrated circadian rhythm adapts our physiology to the different phases of the day. Since the seminal discoveries by the three laureates, circadian biology has developed into a vast and highly dynamic research field, with implications for our health and wellbeing.


The circadian clock anticipates and adapts our physiology to the different phases of the day. Our biological clock helps to regulate sleep patterns, feeding behavior, hormone release, blood pressure, and body temperature.


Read more about Michael Rosbash

Read more about Jeffrey Hall

Read more about Michael Young

Excellent article: New Yorker


Sources: Nobel Foundation: “2017 Nobel Prize in Physiology or Medicine: Molecular mechanisms controlling the circadian rhythm;“ ScienceDaily, 2 October 2017; Wikipedia


Experimental Treatment For Niemann-Pick Disease Type C1


Niemann-Pick disease type C1 (NPC1) is a rare genetic disorder that primarily affects children and adolescents, causing a progressive decline in neurological and cognitive functions. The U.S. Food and Drug Administration has not approved any treatments for the condition.


According to an article published in The Lancet (10 August 2017), an experimental drug appears to slow the progression of NPC1. The drug, 2-hydroxypropyl-beta-cyclodextrin (VTS-270), is being tested under a cooperative research and development agreement, or CRADA, between NIH and Sucampo Pharmaceuticals. In April 2017, Sucampo acquired Vtesse Inc., which previously had been developing VTS-270.


The study was a phase 1/2a clinical trial designed to test the drug’s safety and effectiveness. A group of 14 participants, ranging from ages 4 to 23 years, received the experimental drug once a month at NIH for 12 to 18 months. Another group of three participants received the drug every two weeks for 18 months at Rush University Medical Center in Chicago. Initially, participants were divided into groups receiving different doses of the drug, but after observing that the drug was safe and well-tolerated by those receiving the highest doses, the dose was increased for all participants. Clinical progress was compared to a previous group of 21 NPC1 participants enrolled in an earlier study that documented disease progression.


In terms of safety, no serious adverse outcomes related to the drug were observed. However, the participants, most of whom had already experienced hearing loss because of the disease, had additional hearing loss after treatment. Earlier studies had shown that the treatment carries the risk for hearing loss. In the current study, hearing loss was compensated with hearing aids, which enabled participants to go about their daily lives. Because NPC1 symptoms result from cholesterol buildup in brain cells, the authors also measured cholesterol metabolism in the participants’ central nervous system. Results showed that after treatment, a molecule derived from cholesterol metabolism in neurons, 24(S)-hydroxycholesterol, had increased. In addition, most participants had lower levels of two proteins indicative of brain injury, FABP3 and calbindin D, implying that there was less damage in the brain. According to the study authors, these results suggest that VTS-270 can improve cholesterol metabolism in neurons, thereby targeting the root of the problem. The authors also evaluated the drug’s effectiveness using a neurological severity score, where higher scores indicate more severe effects from the disease. Compared to an earlier group of patients who had not received the drug, VTS-270-treated participants had lower scores in measures of cognition and speech, with mobility scores also trending lower. The authors believe these differences indicate that treatment with the drug can stabilize or slow disease progression.


NICHD researchers led the design, data collection and analysis of the phase 1/2a clinical trial. VTS-270 was provided by Janssen Research & Development, a Johnson & Johnson company. Researchers are now working on a randomized, controlled phase 2b/3 clinical trial (NCT02534844) has been approved by the FDA and the European Medicines Agency. The trial is sponsored by Sucampo, and its results will help determine which symptoms are most responsive to the drug and provide information for refining the dose and dosing frequency. The goal of this trial is to obtain regulatory approval of VTS-270.


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