Creamy Blueberry Angel
If you like your healthy blueberries – melt-in-your-mouth-gooey – then this is the dessert for you! Plus, this is a low calorie, dessert, especially if you make your own angel food cake and don’t use a store bought mix. ©Joyce Hays, Target Health Inc.
12 ounces frozen blueberries
2 Tablespoons granulated Splenda
2 Tablespoons cornstarch
1/4 cup cold water
Squeeze of fresh lemon juice (about 1/2 tablespoon)
Cake-Cut-Into-Cubes and Cream:
Baked, cooled and cubed angel food cake
16 ounces Tofutti, softened to room temperature
2/3 cup almond milk or evaporated milk
2/3 cup granulated Splenda
Whipped Cream Topping:
1 1/2 cups fat-free Cool Whip
2 teaspoons powdered Splenda, or 2 packets
First make the vanilla angel food cake. See the directions below. While baking and then, while cake is cooling off, make the other parts of this dessert. If you use a store bought mix or buy a ready-made angel food cake, the calories will be much higher.
Stirring the blueberry mixture. This whole recipe is very easy. ©Joyce Hays, Target Health Inc.
For the blueberry filling: in a medium saucepan, combine the blueberries, sugar, cornstarch, water and lemon juice. Bring the mixture to a simmer and cook until thickened, 5-7 minutes, stirring often. Remove from the heat and let cool to room temperature.
Here, I’m about to add the cubes to the creamy mixture. ©Joyce Hays, Target Health Inc.
For the cake and cream layer: In a blender or with an electric mixer (handheld or stand mixer), whip together the cream cheese, half-and-half or evaporated milk and sugar until smooth and creamy. Transfer the mixture to a bowl if you used a blender.
Now, fold in the angel food cake cubes. Keep in mind (from the note above) that you may not use all the cake cubes, especially if using an angel food cake mix. Add cake cubes until they are all thickly coated with a layer of cream. If making this in advance, it can dry out if there is too much angel food cake added.
For the Cool Whip Topping: Whisk together the Cool Whip and powdered sugar until fully incorporated. Set aside in fridge until ready to use.
This is the very first layer of the cake cubes, slathered on all sides, with the creamy mixture. ©Joyce Hays, Target Health Inc.
To Assemble: in a trifle dish or in a large glass bowl, spread half of the angel food cake mixture as bottom layer. Top with half of the blueberries, spreading evenly across, and then spread half of the Cool Whip mixture. Repeat the layers a second time.
Cover and refrigerate at least 2 hours or up to 24 hours. Serve chilled in pretty dessert dishes or on a dessert plate with a few fresh blueberries as garnish.
A total of 4 layers have already been done here. This is going to be the 2nd layer of the blueberry mixture about to be smoothed over the 2nd layer of creamy cake cubes. On top of these blueberries will be the last layer of Cool Whip. Then this bowl goes into the fridge for at least 2 hours or overnight.
©Joyce Hays, Target Health Inc.
Here’s the bowl after 2 hours in fridge, with two people dining on dessert. LOL BTW, this cake gets even better with time. Also, the next time I make this recipe, I’m gonna try putting the final layers into a square glass container, so that after left in the fridge for several days, I can cut it like a layer cake.
Vanilla Angel Food Cake Recipe
I used a square cake pan. Here the cake has been cooled and cut into cubes. ©Joyce Hays, Target Health Inc.
1 cup almond flour
3/4 cup granulated Splenda
1/2 teaspoon salt
For the egg white mixture:
3/4 cup granulated Splenda
12 large egg whites (make sure not to get any of the shell or egg yolk in with the whites or they won’t beat-to-peak properly)
1 teaspoon vanilla extract
1 1/2 teaspoon cream of tartar
Preheat the oven to 325 degrees.
In a medium bowl, whisk together the flour, cocoa powder (if using), sugar and salt and set aside.
In another bowl place the egg whites and add the vanilla. With a hand mixer (or with a stand mixer), beat the egg whites and vanilla on medium-high until the mixture is just frothy, about one minute.
Sprinkle the cream of tartar on the top of the foamy egg whites and continue beating on medium-high until soft peaks form, another 2-3 minutes.
To the egg whites, add the sugar 1/4 cup at a time until fully incorporated. Continue beating until the whites are stiff and glossy. This may take several minutes, depending on the type of mixer you are using.
Now, with a whisk, gently fold the dry ingredients into the beaten egg whites. Pour the batter evenly into an ungreased angel food cake pan and smooth the top with a rubber spatula. Place the cake on a rack in the center of the oven and bake for 40-45 minutes, until the top of the cake is golden brown and the cake springs back when lightly touched and the cracks are dry to the touch.
Place the cake (still in the cake pan) upside down on cooking rack, to cool.
When cake is cool, slide a knife around the edges of the pan and gently remove the cake.
After removing cake from pan, allow it to cool even more. When cake is cool to your touch, cut the whole cake into cubes, about 1 inch by 1 inch. You will be using these cake cubes in the Tofutti part of the recipe.
Be careful with the cream/cake mixture – only add cake cubes while they are all evenly coated with a thick layer of cream. Too many cake cubes and it might dry out (especially if it is made in advance). Speaking of making it ahead, this can be assembled and refrigerated up to 24 hours in advance.
Note: To make a chocolate version, substitute 1/4 cup cocoa powder for 1/4 cup of the flour.
©Joyce Hays, Target Health Inc.
He had just come back from a meeting in DC and had a veggie burger on the train. He was tired and not hungry. We poured some wine. He wanted red, I wanted white. I put dinner away and pulled the Blueberry Angel Dessert out of the fridge. We dined on dessert.
Any greater proof of the (so-called) pudding?
We polished off the two dessert dishes in photo above (top of this section) and then dug into the bowl.
A cautionary note: because this whole evening was play-as-you-go, no attention was paid to choosing the wine. As a result, both wines did not go with the dessert. If there had been some semblance of a plan, we would have had a liqueur like Maraschino or Amaretto. But we had each other, and that was what really mattered.
From Our Table to Yours!
Bon Appetit !
Embryonic stem (ES) cells, which originate in early development, are capable of differentiating into any type of cell. Until now, scientists have only been able to revert ‘adult’ human cells (for example, liver, lung or skin) into pluripotent stem cells with slightly different properties that predispose them to becoming cells of certain types. Authentic ES cells have only been derived from mice and rats.
“Reverting mouse cells to a completely ‘blank slate’ has become routine, but generating equivalent naïve human cell lines has proven far more challenging,” says Dr Paul Bertone, Research Group Leader at EMBL-EBI and a senior author on the study. “Human pluripotent cells resemble a cell type that appears slightly later in mammalian development, after the embryo has implanted in the uterus.”
At this point, subtle changes in gene expression begin to influence the cells, which are then considered ‘primed’ towards a particular lineage. Although pluripotent human cells can be cultured from in vitro fertilised (IVF) embryos, until now there have been no human cells comparable to those obtained from the mouse.
Wiping cell memory
“For years, it was thought that we could be missing the developmental window when naïve human cells could be captured, or that the right growth conditions hadn’t been found,” Paul explains. “But with the advent of iPS cell technologies, it should have been possible to drive specialised human cells back to an earlier state, regardless of their origin — if that state existed in primates.”
Taking a new approach, the scientists used reprogramming methods to express two different genes, NANOG and KLF2, which reset the cells. They then maintained the cells indefinitely by inhibiting specific biological pathways. The resulting cells are capable of differentiating into any adult cell type, and are genetically normal.
The experimental work was conducted hand-in-hand with computational analysis.
“We needed to understand where these cells lie in the spectrum of the human and mouse pluripotent cells that have already been produced,” explains Paul. “We worked with the EMBL Genomics Core Facility to produce comprehensive transcriptional data for all the conditions we explored. We could then compare reset human cells to genuine mouse ES cells, and indeed we found they shared many similarities.”
Together with Professor Wolf Reik at the Babraham Institute, the researchers also showed that DNA methylation (biochemical marks that influence gene expression) was erased over much of the genome, indicating that reset cells are not restricted in the cell types they can produce. In this more permissive state, the cells no longer retain the memory of their previous lineages and revert to a blank slate with unrestricted potential to become any adult cell.
Unlocking the potential of stem cell therapies
The research was performed in collaboration with Professor Austin Smith, Director of the Wellcome Trust-Medical Research Council Stem Cell Institute.
“Our findings suggest that it is possible to rewind the clock to achieve true ground-state pluripotency in human cells,” said Professor Smith. “These cells may represent the real starting point for formation of tissues in the human embryo. We hope that in time they will allow us to unlock the fundamental biology of early development, which is impossible to study directly in people.”
The discovery paves the way for the production of superior patient material for translational medicine. Reset cells mark a significant advance for human stem cell applications, such as drug screening of patient-specific cells, and are expected to provide reliable sources of specialised cell types for regenerative tissue grafts.
- Yasuhiro Takashima, Ge Guo, Remco Loos, Jennifer Nichols, Gabriella Ficz, Felix Krueger, David Oxley, Fatima Santos, James Clarke, William Mansfield, Wolf Reik, Paul Bertone, Austin Smith. Resetting Transcription Factor Control Circuitry toward Ground-State Pluripotency in Human. Cell, 2014; 158 (6): 1254 DOI:10.1016/j.cell.2014.08.029
European Bioinformatics Institute EMBL-EBI. “Scientists revert human stem cells to pristine state.” ScienceDaily. ScienceDaily, 11 September 2014. <www.sciencedaily.com/releases/2014/09/140911125047.htm>.
The Assessment for Decision-Makers, a summary document of the Scientific Assessment of Ozone Depletion 2014, is being published by the United Nations Environment Programme (UNEP) and the World Meteorological Organization (WMO), and is the first comprehensive update in four years.
The stratospheric ozone layer, a fragile shield of gas, protects Earth from harmful ultraviolet rays of the sun. Without the Montreal Protocol and associated agreements, atmospheric levels of ozone depleting substances could have increased tenfold by 2050. According to global models, the Protocol will have prevented 2 million cases of skin cancer annually by 2030, averted damage to human eyes and immune systems, and protected wildlife and agriculture, according to UNEP.
The phase-out of ozone depleting substances has had a positive spin-off for the global climate because many of these substances are also potent greenhouse gases. However, the assessment report cautions that the rapid increase in certain substitutes, which are themselves also potent greenhouse gases, has the potential to undermine these gains. The assessment also notes that there are possible approaches to avoiding the harmful climate effects of these substitutes.
“There are positive indications that the ozone layer is on track to recovery towards the middle of the century. The Montreal Protocol — one of the world’s most successful environmental treaties — has protected the stratospheric ozone layer and avoided enhanced UV radiation reaching the earth’s surface,” said UN Under-Secretary-General and UNEP Executive Director Achim Steiner.
“However, the challenges that we face are still huge. The success of the Montreal Protocol should encourage further action not only on the protection and recovery of the ozone layer but also on climate. On September 23, the UN Secretary General will host Heads of State in New York in an effort to catalyse global action on climate. The Montreal Protocol community, with its tangible achievements, is in a position to provide strong evidence that global cooperation and concerted action are the key ingredients to secure the protection of our global commons,” he added.
“International action on the ozone layer is a major environmental success story,” said WMO Secretary-General Michel Jarraud. “This should encourage us to display the same level of urgency and unity to tackle the even greater challenge of climate change. This latest assessment provides solid science to policy-makers about the intricate relationship between ozone and climate and the need for mutually-supportive measures to protect life on earth for future generations.”
“Human activities will continue to change the composition of the atmosphere. WMO’s Global Atmosphere Watch programme will therefore continue its crucial monitoring, research and assessment activities to provide scientific data needed to understand and ultimately predict environmental changes, as it has done for the past 25 years” said Mr Jarraud.
Actions taken under the Montreal Protocol on Substances that Deplete the Ozone Layer are enabling the return of the ozone layer to benchmark 1980 levels.
- Under full compliance with the Montreal Protocol, the ozone layer is expected to recover to 1980 benchmark levels- the time before significant ozone layer depletion- before the middle of the century in mid-latitudes and the Arctic, and somewhat later in the Antarctic.
- The Montreal Protocol and associated agreements have led to decreases in the atmospheric abundance of gases, such as CFCs (chlorofluorocarbons) and halons, once used in products such as refrigerators, spray cans, insulation foam and fire suppression.
- Total column ozone declined over most of the globe during the 1980s and early 1990s. It has remained relatively unchanged since 2000, but there are recent indications of its future recovery.
- The Antarctic ozone hole continues to occur each spring and it is expected to continue occurring for the better part of this century given that ozone depleting substances persist in the atmosphere, even though their emissions have ceased.
- The Arctic stratosphere in winter/spring 2011 was particularly cold, which led to large ozone depletion as expected under these conditions.
The climate benefits of the Montreal Protocol could be significantly offset by projected emissions of HFCs (hydrofluorocarbons) used to replace ozone depleting substances.
- The Montreal Protocol has made large contributions toward reducing global greenhouse gas emissions. In 1987, ozone-depleting substances contributed about 10 gigatonnes CO2-equivalent emissions per year. The Montreal Protocol has now reduced these emissions by more than 90 per cent. This decrease is about five times larger than the annual emissions reduction target for the first commitment period (2008-2012) of the Kyoto Protocol on climate change.
- Hydrofluorocarbons (HFCs) do not harm the ozone layer but many of them are potent greenhouse gases. They currently contribute about 0.5 gigatonnes of CO2-equivalent emissions per year. These emissions are growing at a rate of about 7 per cent per year. Left unabated, they can be expected to contribute very significantly to climate change in the next decades.
- Replacements of the current mix of high-GWP HFCs with alternative compounds with low GWPs or not-in-kind technologies would limit this potential problem.
The annual Antarctic ozone hole has caused significant changes in Southern Hemisphere surface climate in the summer.
- Ozone depletion has contributed to cooling of the lower stratosphere and this is very likely the dominant cause of observed changes in Southern Hemisphere summertime circulation over recent decades, with associated impacts on surface temperature, precipitation, and the oceans.
- In the Northern Hemisphere, where the ozone depletion is smaller, there is no strong link between stratospheric ozone depletion and tropospheric climate.
CO2, Nitrous Oxide and Methane will have an increasing influence on the ozone layer
- What happens to the ozone layer in the second half of the 21st century will largely depend on concentrations of CO2, methane and nitrous oxide — the three main long-lived greenhouse gases in the atmosphere. Overall, CO2 and methane tend to increase global ozone levels. By contrast, nitrous oxide, a by-product of food production, is both a powerful greenhouse gas and an ozone depleting gas, and is likely to become more important in future ozone depletion.
The Scientific Assessment Panel is expected to present the key findings of the new report at the annual Meeting of the Parties to the Montreal Protocol, to be held in Paris in November 2014. The full body of the report will be issued in early 2015.
The Scientific Assessment of Ozone Depletion 2014 was prepared and reviewed by 282 scientists from 36 countries (Argentina, Australia, Austria, Belgium, Botswana, Brazil, Canada, People’s Republic of China, Comoros, Costa Rica, Cuba, Czech Republic, Denmark, Finland, France, Germany, Greece, India, Israel, Italy, Japan, Korea, Malaysia, New Zealand, Norway, Poland, Russia, South Africa, Spain, Sweden, Switzerland, The Netherlands, Togo, United Kingdom, United States of America, Zimbabwe.)
Co-Chairs of the ozone assessment are: Prof. Ayité Lô Nohende Ajavon, Université de Lomé, Togo; Prof. John Pyle, University of Cambridge and National Centre for Atmospheric Science, UK; Dr. Paul Newman, NASA/ Goddard Space Flight Center, USA; Prof. A.R. (Ravi) Ravishankara, Colorado State University, USA.
The pre-print version of the ADM can be downloaded from:http://ozone.unep.org/Assessment_Panels/SAP/SAP2014_Assessment_for_Decision-Makers.pdf
Relevant links include http://www.wmo.int/pages/prog/arep/gaw/ozone/index.html andwww.unep.org/ozone
United Nations Environment Programme. “Earth’s ozone layer on track to recovery, scientists report.” ScienceDaily. ScienceDaily, 10 September 2014. <www.sciencedaily.com/releases/2014/09/140910162324.htm>.
New seismology data are now confirming that such narrow jets don’t actually exist, says Don Anderson, the Eleanor and John R. McMillian Professor of Geophysics, Emeritus, at Caltech. In fact, he adds, basic physics doesn’t support the presence of these jets, called mantle plumes, and the new results corroborate those fundamental ideas.
“Mantle plumes have never had a sound physical or logical basis,” Anderson says. “They are akin to Rudyard Kipling’s ‘Just So Stories’ about how giraffes got their long necks.”
Anderson and James Natland, a professor emeritus of marine geology and geophysics at the University of Miami, describe their analysis online in the September 8 issue of the Proceedings of the National Academy of Sciences.
According to current mantle-plume theory, Anderson explains, heat from Earth’s core somehow generates narrow jets of hot magma that gush through the mantle and to the surface. The jets act as pipes that transfer heat from the core, and how exactly they’re created isn’t clear, he says. But they have been assumed to exist, originating near where Earth’s core meets the mantle, almost 3,000 kilometers underground — nearly halfway to the planet’s center. The jets are theorized to be no more than about 300 kilometers wide, and when they reach the surface, they produce hot spots.
While the top of the mantle is a sort of fluid sludge, the uppermost layer is rigid rock, broken up into plates that float on the magma-bearing layers. Magma from the mantle beneath the plates bursts through the plate to create volcanoes. As the plates drift across the hot spots, a chain of volcanoes forms — such as the island chains of Hawaii and Samoa.
“Much of solid-Earth science for the past 20 years — and large amounts of money — have been spent looking for elusive narrow mantle plumes that wind their way upward through the mantle,” Anderson says.
To look for the hypothetical plumes, researchers analyze global seismic activity. Everything from big quakes to tiny tremors sends seismic waves echoing through Earth’s interior. The type of material that the waves pass through influences the properties of those waves, such as their speeds. By measuring those waves using hundreds of seismic stations installed on the surface, near places such as Hawaii, Iceland, and Yellowstone National Park, researchers can deduce whether there are narrow mantle plumes or whether volcanoes are simply created from magma that’s absorbed in the sponge-like shallower mantle.
No one has been able to detect the predicted narrow plumes, although the evidence has not been conclusive. The jets could have simply been too thin to be seen, Anderson says. Very broad features beneath the surface have been interpreted as plumes or super-plumes, but, still, they’re far too wide to be considered narrow jets.
But now, thanks in part to more seismic stations spaced closer together and improved theory, analysis of the planet’s seismology is good enough to confirm that there are no narrow mantle plumes, Anderson and Natland say. Instead, data reveal that there are large, slow, upward-moving chunks of mantle a thousand kilometers wide.
In the mantle-plume theory, Anderson explains, the heat that is transferred upward via jets is balanced by the slower downward motion of cooled, broad, uniform chunks of mantle. The behavior is similar to that of a lava lamp, in which blobs of wax are heated from below and then rise before cooling and falling. But a fundamental problem with this picture is that lava lamps require electricity, he says, and that is an outside energy source that an isolated planet like Earth does not have.
The new measurements suggest that what is really happening is just the opposite: Instead of narrow jets, there are broad upwellings, which are balanced by narrow channels of sinking material called slabs. What is driving this motion is not heat from the core, but cooling at Earth’s surface. In fact, Anderson says, the behavior is the regular mantle convection first proposed more than a century ago by Lord Kelvin. When material in the planet’s crust cools, it sinks, displacing material deeper in the mantle and forcing it upward.
“What’s new is incredibly simple: upwellings in the mantle are thousands of kilometers across,” Anderson says. The formation of volcanoes then follows from plate tectonics — the theory of how Earth’s plates move and behave. Magma, which is less dense than the surrounding mantle, rises until it reaches the bottom of the plates or fissures that run through them. Stresses in the plates, cracks, and other tectonic forces can squeeze the magma out, like how water is squeezed out of a sponge. That magma then erupts out of the surface as volcanoes. The magma comes from within the upper 200 kilometers of the mantle and not thousands of kilometers deep, as the mantle-plume theory suggests.
“This is a simple demonstration that volcanoes are the result of normal broad-scale convection and plate tectonics,” Anderson says. He calls this theory “top-down tectonics,” based on Kelvin’s initial principles of mantle convection. In this picture, the engine behind Earth’s interior processes is not heat from the core but cooling at the planet’s surface. This cooling and plate tectonics drives mantle convection, the cooling of the core, and Earth’s magnetic field. Volcanoes and cracks in the plate are simply side effects.
The results also have an important consequence for rock compositions — notably the ratios of certain isotopes, Natland says. According to the mantle-plume idea, the measured compositions derive from the mixing of material from reservoirs separated by thousands of kilometers in the upper and lower mantle. But if there are no mantle plumes, then all of that mixing must have happened within the upwellings and nearby mantle in Earth’s top 1,000 kilometers.
The paper is titled “Mantle updrafts and mechanisms of oceanic volcanism.”
- Don L. Anderson and James H. Natland. Mantle updrafts and mechanisms of oceanic volcanism. PNAS, September 8, 2014 DOI: 10.1073/pnas.1410229111
California Institute of Technology. “Textbook theory behind volcanoes may be wrong.” ScienceDaily. ScienceDaily, 8 September 2014. <www.sciencedaily.com/releases/2014/09/140908152924.htm>.
Writing in the journal Nature Climate Change, Professor Nadine Unger of the Yale School of Forestry & Environmental Studies (F&ES) reports that large-scale forest losses during the last 150 years have reduced global emissions of biogenic volatile organic compounds (BVOCs), which control the atmospheric distribution of many short-lived climate pollutants, such as tropospheric ozone, methane, and aerosol particles.
Using sophisticated climate modeling, Unger calculated that a 30-percent decline in BVOC emissions between 1850 and 2000, largely through the conversion of forests to cropland, produced a net global cooling of about 0.1 degrees Celsius. During the same period, the global climate warmed by about 0.6 degrees Celsius, mostly due to increases in fossil fuel carbon dioxide emissions.
According to her findings, the climate impact of declining BVOC emissions is on the same magnitude as two other consequences of deforestation long known to affect global temperatures, although in opposing ways: carbon storage and the albedo effect. The lost carbon storage capacity caused by forest conversion has exacerbated global warming. Meanwhile, the disappearance of dark-colored forests has also helped offset temperature increases through the so-called albedo effect. (The albedo effect refers to the amount of radiation reflected by the surface of the planet. Light-colored fields, for instance, reflect more light and heat back into space than darker forests.)
Unger says the combined effects of reduced BVOC emissions and increased albedo may have entirely offset the warming caused by the loss of forest-based carbon storage capacity.
“Land cover changes caused by humans since the industrial and agricultural revolutions have removed natural forests and grasslands and replaced them with croplands,” said Unger, an assistant professor of atmospheric chemistry at F&ES. “And croplands are not strong emitters of these BVOCs — often they don’t emit any BVOCs.”
“Without doing an earth-system model simulation that includes these factors, we can’t really know the net effect on the global climate. Because changes in these emissions affect both warming and cooling pollutants,” she noted.
Unger said the findings do not suggest that increased forest loss provides climate change benefits, but rather underscore the complexity of climate change and the importance of better assessing which parts of the world would benefit from greater forest conservation.
Since the mid-19th century, the percentage of the planet covered by cropland has more than doubled, from 14 percent to 37 percent. Since forests are far greater contributors of BVOC emissions than crops and grasslands, this shift in land use has removed about 30 percent of Earth’s BVOC sources, Unger said.
Not all of these compounds affect atmospheric chemistry in the same way. Aerosols, for instance, contribute to global “cooling” since they generally reflect solar radiation back into space. Therefore, a 50 percent reduction in forest aerosols has actually spurred greater warming since the pre-industrial era.
However, reductions in the potent greenhouse gases methane and ozone — which contribute to global warming — have helped deliver a net cooling effect.
These emissions are often ignored in climate modeling because they are perceived as a “natural” part of Earth system, explained Unger. “So they don’t get as much attention as human-generated emissions, such as fossil fuel VOCs,” she said. “But if we change how much forest cover exists, then there is a human influence on these emissions.”
These impacts have also been ignored in previous climate modeling, she said, because scientists believed that BVOC emissions had barely changed between the pre-industrial era and today. But a study published last year by Unger showed that emissions of these volatile compounds have indeed decreased. Studies by European scientists have produced similar results.
The impact of changes to ozone and organic aerosols are particularly strong in temperate zones, she said, while methane impacts are more globally distributed.
The sensitivity of the global climate system to BVOC emissions suggests the importance of establishing a global-scale long-term monitoring program for BVOC emissions, Unger noted.
The above story is based on materials provided by Yale School of Forestry & Environmental Studies. The original article was written by Kevin Dennehy. Note: Materials may be edited for content and length.
- Nadine Unger. Human land-use-driven reduction of forest volatiles cools global climate. Nature Climate Change, 2014; DOI: 10.1038/nclimate2347
Yale School of Forestry & Environmental Studies. “How conversion of forests to cropland affects climate.” ScienceDaily. ScienceDaily, 8 September 2014. <www.sciencedaily.com/releases/2014/09/140908135431.htm>.
DPharm Disruptive Innovations Meeting in Boston – A Must
Disruptive Innovations will again be at The Fairmont Copley Plaza, Boston, MA this year (September 11-12, 2014). This is one of our favorite meetings of the year as we are always challenged by stimulating speakers from pharma and device companies, patients, regulators, clinical sites, etc.
Our friends and colleagues Andreas Koester, MD, PhD, VP, Clinical Trial Innovation & External Alliances, Janssen; Jeff Kasher, PhD, VP, Clinical Innovation & Implementation, Eli Lilly; Craig Lipset, MBA, Head of Clinical Innovation, R&D, Pfizer, Inc.; and Komathi Stem, Senior Director, Product Development, Innovation Lead, Genentech, are the Co-Chairs of the conference.
Jules Mitchel, MBA, PhD, President of Target Health, is on the Advisory Board and an active contributor to this conference since its inception in 2011. Dr. Mitchel will be presenting at 12 pm on Thursday in a session chaired by Komathi Stem (Genentech), entitled Where Are They A Year Later? We plan to share very exciting news from our programs using Target e*CTR® (eClinical Trial record), our web-based (browser independent) novel and regulatory compliant eSource solution for clinical trials. As a full-service CRO, not only do we have to have robust technology solutions, we also have to get products approved by regulatory agencies.
ON TARGET is the newsletter of Target Health Inc., a NYC-based, full-service, contract research organization (eCRO), providing strategic planning, regulatory affairs, clinical research, data management, biostatistics, medical writing and software services to the pharmaceutical and device industries, including the paperless clinical trial.
For more information about Target Health contact Warren Pearlson (212-681-2100 ext. 104). For additional information about software tools for paperless clinical trials, please also feel free to contact Dr. Jules T. Mitchel or Ms. Joyce Hays. 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
New Study: Diseased Cells Synthesize Their Own Drug
Illustration of cells (stock image). We’re using a cell as a reaction vessel and a disease-causing defect as a catalyst to synthesize a treatment in a diseased cell, explained Professor Matthew Disney. Credit:© Jezper / Fotolia
In a new study that could ultimately lead to many new medicines, scientists from the Florida campus of The Scripps Research Institute (TSRI) have adapted a chemical approach to turn diseased cells into unique manufacturing sites for molecules that can treat a form of muscular 1) ___. We’re using a cell as a reaction vessel and a disease-causing defect as a catalyst to synthesize a treatment in a diseased cell, said TSRI Professor Matthew Disney. Because the treatment is synthesized only in diseased 2) ___, the compounds could provide highly specific therapeutics that only act when a disease is present. This means we can potentially treat a host of conditions in a very selective and precise manner in totally unprecedented ways. The promising research was published recently in the international chemistry journal Angewandte Chemie.
In general, small, low molecular weight compounds can pass the blood-brain 3) ___, while larger, higher weight compounds tend to be more potent. In the new study, however, small molecules became powerful inhibitors when they bound to targets in cells expressing an RNA defect, such as those found in myotonic dystrophy. Myotonic dystrophy type 2, a relatively mild and uncommon form of the progressive muscle weakening 4) ___, is caused by a type of RNA defect known as a tetranucleotide repeat, in which a series of four nucleotides is repeated more times than normal in an individual’s genetic code. In this case, a cytosine-cytosine-uracil-guanine (CCUG) repeat binds to the protein MBNL1, rendering it inactive and resulting in RNA splicing abnormalities that, in turn, results in the disease.
In the study, a pair of small molecule modules the scientists developed binds to adjacent parts of the defect in a living cell, bringing these groups close together. Under these conditions, the adjacent parts reach out to one another and, as Disney describes it, permanently hold hands. Once that connection is made, the small 5) ___ binds tightly to the defect, potently reversing disease defects on a molecular level. When these compounds assemble in the cell, they are 1,000 times more potent than the small molecule itself and 100 times more 6) ___ than our most active lead compound, said Research Associate Suzanne Rzuczek, the first author of the study. This is the first time this has been validated in live cells.
The basic process used by Disney and his colleagues is known as click chemistry — a process invented by Nobel laureate K. Barry Sharpless, a chemist at TSRI, to quickly produce substances by attaching small units or modules together in much the same way this occurs naturally. In my opinion, this is one unique and a nearly ideal application of the process Sharpless and his colleagues first developed, Disney said. Given the predictability of the process and the nearly endless combinations, translating such an approach to cellular systems could be enormously productive, Disney said. RNAs make ideal targets because they are modular, just like the compounds for which they provide a molecular template. Not only that, he added, but many similar 7) ___ cause a host of incurable diseases such as ALS (Lou Gehrig’s Disease), Huntington’s disease and more than 20 others for which there are no known 8) ___, making this approach a potential route to develop lead therapeutics to this large class of debilitating diseases.
Click chemistry is a term applied to chemical synthesis tailored to generate substances quickly and reliably by joining small units together. Click chemistry is not a single specific reaction, but describes a way of generating products that follows examples in nature, which also generates substances by joining small modular units. Click chemistry has also been used for selectively labeling biomolecules within biological systems. A Click reaction that is to be performed in a living system must meet an even more rigorous set of criteria than in an in vitro reaction. It must be bioorthogonal, meaning the reagents used may not interact with the biological system in any way, nor may they be9) ___. The reaction must also occur at neutral pH and at or around body temperature. Most Click reactions have a high energy content. The reactions are irreversible and involve carbon-hetero atom bonding processes. An example is the Staudinger ligation of azides.
Click chemistry in combination with combinatorial chemistry, high-throughput screening and building chemical libraries speeds up new drug 10) ___ by making each reaction in a multistep synthesis fast, efficient and predictable. Mimicking nature in organic synthesis may facilitate the discovery of new pharmaceuticals given the large number of possible structures.
Click chemistry has widespread applications. Some of them are:
- Two-dimensional gel electrophoresis separation
- preparative organic synthesis of 1,4-substituted triazoles
- modification of peptide function with triazoles
- modification of natural products and pharmaceuticals
- natural product discovery
- drug discovery
Sources: The above article is based on materials from Scripps Research Institute and Wikipedia; Journal Reference: Suzanne G. Rzuczek, HaJeung Park, Matthew D. Disney. A Toxic RNA Catalyzes the In Cellulo Synthesis of Its Own Inhibitor. Angewandte Chemie International Edition, 2014; DOI: 10.1002/anie.201406465
ANSWERS: 1) dystrophy; 2) cells; 3) barrier; 4) disease; 5) molecule; 6) potent; 7) RNAs; 8) cures; 9) toxic; 10) discoveries
Karl Barry Sharpless PhD, Nobel Prize Winner (b. 1941 to Present)
Dr. K. Barry Sharpless is an American chemist known for his work on stereoselective reactions. He earned a Ph.D in chemistry from Stanford University in 1968, and continued post-doctoral work at Stanford University (1968-1969) and Harvard University.(1969-1970). He holds honorary degrees from the Royal Institute of Technology, Stockholm (1995) Technical University of Munich (1995), Catholic University Louvain, Belgium (1996) and Weselyan University (1999). He was blinded in one eye during a lab accident in 1970, shortly after he arrived at MIT as an assistant professor. Sharpless has been a professor at the Massachusetts Institute of Technology (1970-1977, 1980-1990) and Stanford University (1977-1980) and currently holds the W. M. Keck professorship in chemistry at The Scripps Research Institute (1990- to Present).
Sharpless developed stereoselective oxidation reactions, and showed that the formation of an inhibitor with femtomolar potency can be catalyzed by the enzyme acetylcholinesterase, beginning with an azide and an alkyne. He discovered several chemical reactions which have transformed asymmetric synthesis from science fiction to the relatively routine, including aminohydroxylation, dihydroxylation, and the Sharpless asymmetric epoxidation. In 2001 he won a half-share of the Nobel Prize in Chemistry for his work on chirally catalysed oxidation reactions (Sharpless epoxidation, Sharpless asymmetric dihydroxylation, Sharpless oxyamination). The other half of the year’s Prize was shared between William S. Knowles and Ryoji Noyori (for their work on stereoselective hydrogenation). He also successfully epoxidized (using racemic tartaric acid) a C-86 Buckminster Fullerene ball, employing p-Cresol as solvent. More recently he has been an important figure in the new field of click chemistry. This involves a set of highly selective, exothermic reactions which occur under mild conditions; the most successful example is the azide alkyne Huisgen cycloaddition to form 1,2,3-triazoles.
Sharpless married Jan Dueser on 28 April 1965. They have three children; Hannah (b. 1976), William (b. 1978), and Isaac (b. 1980). [Editor's note: Because of its unique style, we include, below, the Nobel Prize acceptance speech given by K. Barry Sharpless in 2001]:
The Nobel Prize in Chemistry 2001: William S. Knowles, Ryoji Noyori, K. Barry Sharpless
From 6th through 12th grades I attended a Quaker school on the Philadelphia city line. Twice a week the entire school attended Quaker Meeting, silent gatherings except when someone received a personal call to speak. I never got a call, but nonetheless my head was full: I thought about fishing and boats. Or else I thought about when next I could get from Philadelphia to our cottage on the New Jersey Shore in order to go out fishing in a boat. Beneath my picture in one high school yearbook it says, I’m going to the Shore. While I had an overwhelming passion for fishing, school I merely enjoyed and I never planned to be a scientist. In fact, passion, not planning, is the engine driving all my thought and action. The almost unimaginably good fortune of my youth was that other people made such very, very good plans and choices for me.
My parents selected the excellent Friends Central School where, fortuitously, Clayton Farraday was both a science teacher and the school’s beloved Mr. Chips. The counselors there decided, wisely, that I should attend a college rather than a large university, and I departed Philadelphia for Dartmouth College in the fall of 1959. Though literature courses there were my favorites, I was a pre-medical student solely because my parents always hoped that I’d become an MD like my father. Pre-meds majored in chemistry or biology, and between the two I leaned toward chemistry. I didn’t get really interested, however, until I had two semesters of organic my sophomore year from a young chemistry professor who chose me to do research in his lab. When I graduated Dartmouth a few years later, in 1963, the same prof called my next move, a PhD in organic chemistry instead of medical school. He even chose the graduate school I attended and my research supervisor there. Such a strong intervention in a student’s life is no doubt unusual, but the precipitating events were unusual, too.
Generally speaking, colleges have the best undergraduate teaching, and universities, whose labs are filled by graduate and post-graduate students, have the best research. When I arrived at Dartmouth College in 1959, the chemistry department had a graduate program, which meant great teachers who were just as good at research. However, the program was small, and only a master’s degree was awarded, so consequently professors were perpetually hungry for more manpower for their labs, more hands. Undergraduates who performed well in lab courses were actively recruited to do real graduate- level research.
Thomas A. Spencer, a brand-new assistant professor of chemistry, arrived at Dartmouth when I did, and I was part of his research group for three years. Because Tom was (and still is) so smart and such a good chemist, he could recognize not just talent, but the potential to do something significant; because Tom was also born a great teacher, he was obliged to give a swift kick to my comfortable obliviousness. Fishing, now in the form of working all summer on charter boats, continued as my abiding passion, which meant I continued to need a wise person to make good decisions for me. If some variables in my adult life were changed, I might still have made it onto these pages, but it never would have happened without Tom Spencer.
Since some family background and professional activities (and lots more about fishing) are in the Nobel lecture that follows, and since the standard biographical folderol is most easily found online at www.scripps.edu/chem/sharpless/, I hope to provide a more interesting read with the highly subjective and largely unorthodox personal information that follows.
I met my future wife, Jan Dueser, at a beach party at San Gregorio, west across the foothills from Stanford University. I was a first-year graduate student, and she was a Stanford sophomore and, on that day, my roommate’s date. I admired her touch football form, and she entrusted me with her delicate wristwatch, which I lost in the sand. We were married about a year-and-a-half later, on April 28, 1965, my 24th birthday, at the Palo Alto courthouse. David Schooley, a fellow chemistry grad student and now a professor at University of Nevada, Reno, was our best man. Jan and I practiced with dogs before we had children; chemists still ask about our first, the black and enormous Lionel, a regular laboratory and classroom visitor at MIT. Our daughter Hannah (whose nickname Pippi, comes from pipette, not from Miss Longstocking) was born in 1976, and is a middle school teacher in Boston. To chemists who’ve attended my seminars, she is permanently six years old, the familiar Alice in Wonderland who gazes at the huge book of Looking Glass Sugars. William (Will) and Isaac (Ike) followed Hannah at two-year intervals. Both of our sons are still college undergraduates. None of our children has much interest in science, and I’m sorry, but not disappointed, that that is so.
His passion for chemistry was preceded by a passion for fishing
With no children at home any more, dogs are, once again, our companions of choice – for play, for exercise and for hanging out with in bed. I haven’t gone fishing for probably over thirty years, but the ocean is still programmed into me like the birth stream of a salmon. One of the glories of moving to Scripps in 1990 has been seeing the Pacific Ocean every day, and, when its temperature reaches 70o (July or August), swimming in it every day as well. In windy New England I wind-surfed and we loved our little catamaran; San Diego’s sail-less ocean vistas still seem weird.
My most important award, the greatest honor I’ve ever received, and the grandest and most memorable occasions I’ve ever witnessed, are, of course, benefits of sharing the 2001 Nobel Prize in Chemistry. But other honors have peerless characteristics as well, notably:
The heaviest object in our bank deposit box is the 1995 King Faisal Prize for Science medal; the most beautiful one is the 1988 Prelog Medal from the Swiss Federal Institute of Technology (ETH). Its exquisite relief rendering of Old Vlado’s profile rivals the most beautiful portraits found on coins from antiquity, and the gold has a gorgeous, pliant, velvety warmth that has to be seen to be believed (by appointment only). A friend once asked, quite appropriately, if the portrait was of Alexander the Great. Three unique objects, and I treasure each one, celebrate the day in 1995 when I received an honorary doctorate from Stockholm’s Royal Institute of Technology. My only top hat, frequently brought out for guests to admire, bears the Institute’s seal; my only ring, always admired when I wear it, is a heavy gold band surrounded by a garland of leaves and acorns in deep relief. These two I share with all the Institute’s doctoral recipients, but I also have a large brass cannon shell casing, fired during the cannon salute that accompanied the conferring of the degree and the ceremonial placing of the hat on my head. The shell sits on my desk at home.
Only one award commemoration of mine is lettered on real vellum, and it is the largest one, as well: in both English and Hebrew the 1998 Harvey Science and Technology Prize of the Israel Institute of Technology, Haifa’s Technion, is proclaimed. In the category news received most delightfully, the winner is — an April, 1984, telephone call Jan took in a Jacksonville, Florida, hotel room all five of us were sharing while I attended a meeting. On the line from Washington, D.C. was my MIT colleague George Buchi, the most generous and thoughtful colleague I have ever known. George said he was calling because it was announced just minutes before that I had been elected to membership in the National Academy of Sciences. When Jan replied that she’d pass the message on, George said, no, she must go immediately to the meeting room and give me the message. Our children were too young to be left alone, especially since the meeting room was next to a swimming pool. I was giving my talk when I saw Jan and the three children, and all of them on tiptoes, enter the room and move along the back in the semi-darkness. She was looking for a familiar face, and she whispered the message when she found one. I stopped talking as Jan’s informant walked to the front of the room and asked for the lights to be brought up so he could make an important announcement. Why the audience was so enthusiastic I wasn’t quite sure. Not only did I not know I’d been nominated, I didn’t even know one had to be nominated. I thought the National Academy was something like a high-level appointed government advisory committee. Learning otherwise was a wonderful surprise.
Inaugural events always have special significance and vivid memories; these firsts mean a lot to me: Receiving the first Paul Janssen Prize for Creativity in Organic Synthesis, presented by HRH Prince (now King) Albert of Belgium. Security forces were everywhere that day in 1986, and I asked Prince Albert if having to travel with such a large group wasn’t inconvenient. No, he replied, all those soldiers were required because I was an American – he didn’t need them.
Being Texas A & M’s first Barton Lecturer, 1997. Nothing is dearer me than having been selected by Sir Derek, my career-long scientific role model and mentor, to deliver the first edition of a lectureship endowed in his honor, the only Barton Lecture to take place before his death in 1998. Launching the University of Sydney’s Cornforth Foundation for Chemistry (which honors both Rita and Kappa) with the inaugural Cornforth lecture in 2002. Like Sir Derek, Sir John is one of our gods; I stand awed at having participated in these events honoring them. And, finally, if I had a crown, its jewels would be the 75-or-so former Sharpless Group members who are research professors. The training received in the group is neither predictable nor quantifiable; likewise, it is not intended to produce a product that, for example, industry wants. Since nothing original is intentionally discovered by scientists who cannot tolerate (indeed, they should welcome it) a high degree of uncertainty, group membership does not guarantee results. Because of the nature of our research, however, group members preselect themselves and possess a remarkably high degree of independence of thought as well as scientific motives tilted toward discovery, not reward. As a group, they hold superior standards for judging the significance of research, and I share with all them all of the glory that is a Nobel Prize.
Click, to play the game, Eye of the Donkey based on a Nobel Prize
NIH To Launch Human Safety Study of Ebola Vaccine Candidate
Initial human testing of an investigational vaccine to prevent Ebola virus disease is being initiated by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health. The early-stage trial will begin initial human testing of a vaccine co-developed by NIAID and GlaxoSmithKline (GSK) and will evaluate the experimental vaccine’s safety and ability to generate an immune system response in healthy adults. Testing will take place at the NIH Clinical Center in Bethesda, Maryland.
The study is the first of several Phase 1 clinical trials that will examine the investigational NIAID/GSK Ebola vaccine and an experimental Ebola vaccine developed by the Public Health Agency of Canada and licensed to NewLink Genetics Corp. The others are to launch in the fall. These trials are conducted in healthy adults who are not infected with Ebola virus to determine if the vaccine is safe and induces an adequate immune response. In parallel, NIH has partnered with a British-based international consortium that includes the Wellcome Trust and Britain’s Medical Research Council and Department for International Development to test the NIAID/GSK vaccine candidate among healthy volunteers in the United Kingdom and in the West African countries of Gambia (after approval from the relevant authorities) and Mali. Additionally, the U.S. Centers for Disease Control and Prevention has initiated discussions with Ministry of Health officials in Nigeria about the prospects for conducting a Phase 1 safety study of the vaccine among healthy adults in that country.
The pace of human safety testing for experimental Ebola vaccines has been expedited in response to the ongoing Ebola virus outbreak in West Africa. According to the World Health Organization (WHO), more than 1,400 suspected and confirmed deaths from Ebola infection have been reported in Guinea, Liberia, Nigeria, and Sierra Leone since the outbreak was first reported in March 2014.
The investigational vaccine now entering Phase 1 trials was designed by Nancy J. Sullivan, Ph.D., chief of the Biodefense Research Section in NIAID’s Vaccine Research Center (VRC). She worked in collaboration with researchers at the VRC, the U.S. Army Medical Research Institute of Infectious Diseases, and Okairos, a Swiss-Italian biotechnology company acquired by GSK in 2013.
The NIAID/GSK Ebola vaccine candidate is based on a type of chimpanzee cold virus, called chimp adenovirus type 3 (ChAd3). The adenovirus is used as a carrier, or vector, to deliver segments of genetic material derived from two Ebola virus species: Zaire Ebola and Sudan Ebola. Hence, this vaccine is referred to as a bivalent vaccine. The Zaire species of the virus is responsible for the current Ebola outbreak in West Africa. The vaccine candidate delivers one part of Ebola’s genetic material to human cells, but the adenovirus vector does not replicate. Rather, the Ebola gene that it carries allows the cells of the vaccine recipient to express a single Ebola protein, and that protein prompts an immune response in the individual. It is important to know that the Ebola genetic material contained in the investigational vaccine cannot cause a vaccinated individual to become infected with Ebola.
The Phase 1 clinical trial, called VRC 207, will be led by principal investigator Julie E. Ledgerwood, D.O., chief of the VRC’s clinical trials program, and will be conducted among 20 healthy adults ages 18 to 50 years. Participants will be divided into two groups of 10 participants each. One group will receive an intramuscular injection of the NIAID/GSK experimental vaccine. The second group will receive a single injection of the same vaccine but at a higher dose. A number of safety features are built into the study’s design, including daily and weekly reviews of patient data by clinical staff and the study protocol team. Additionally, the trial features a staged enrollment plan that requires interim safety reviews after three participants have been vaccinated and have undergone three days of follow up before enrolling additional study participants into the group. Participants in both groups will be seen and evaluated by clinical staff nine times over a 48-week period.
Shared Biology of Human, Fly and Worm Genomes
According to an article published online in Nature (28 August 2014), researchers analyzing human, fly, and worm genomes have found that these species have a number of key genomic processes in common, reflecting their shared ancestry. The findings offer insights into embryonic development, gene regulation and other biological processes vital to understanding human biology and disease. The studies highlight the data generated by the modENCODE Project and the ENCODE Project, both supported by the National Human Genome Research Institute (NHGRI), part of the National Institutes of Health. Integrating data from the three species, the model organism ENCyclopedia Of DNA Elements (modENCODE) Consortium studied how gene expression patterns and regulatory proteins that help determine cell fate often share common features. Investigators also detailed the similar ways in which the three species use protein packaging to compact DNA into the cell nucleus and to regulate genome function by controlling access to DNA.
Launched in 2007, the goal of modENCODE is to create a comprehensive catalog of functional elements in the fruit fly and roundworm genomes for use by the research community. Such elements include genes that code for proteins, non-protein-coding genes and regulatory elements that control gene expression. The current work builds on initial catalogs published in 2010. The modENCODE projects complement the work being done by the ENCyclopedia Of DNA Elements (ENCODE) Project, which is building a comprehensive catalog of functional elements in the human and mouse genomes.
In one study, scientists led by Dr. Gerstein and others, analyzed human, fly and worm transcriptomes, the collection of gene transcripts (or readouts) in a genome. They used large amounts of gene expression data generated in the ENCODE and modENCODE projects — including more than 67 billion gene sequence readouts — to discover gene expression patterns shared by all three species, particularly for developmental genes. Investigators showed that the ways in which DNA is packaged in the cell are similar in many respects, and, in many cases, the species share programs for turning on and off genes in a coordinated manner. More specifically, they used gene expression patterns to match the stages of worm and fly development and found sets of genes that parallel each other in their usage. They also found the genes specifically expressed in the worm and fly embryos are re-expressed in the fly pupae, the stage between larva and adult.
The authors also found that in all three organisms, the gene expression levels for both protein-coding and non-protein-coding genes could be quantitatively predicted from chromatin features at the promoters of genes. A gene’s promoter tells the cell’s machinery where to begin copying DNA into RNA, which can be used to make proteins. DNA is packaged into chromatin in cells, and changes in this packaging can regulate gene function. Another group of scientists investigated how chromatin is organized and how it influences gene regulation in the three species. Using both modENCODE and ENCODE data, scientists compared patterns of modifications in chromatin that are needed for the cell to access the DNA inside, and the changes in DNA replication patterns as a result of these modifications. The investigators discovered that many features of chromatin were similar in all three species.
In a third study, similarities in genome regulation were explored. The study focused on transcription-regulatory factors, key protein regulators that determine which progenitor cells eventually become skin cells and kidney cells and eye cells. These are the key coordinators – they bind to switches that control a cell’s fate and one of the big questions in genomics is to determine what factors work together to turn on which genes. Investigators found that the transcription factors tend to bind to similar DNA sequences in the three species’ genomes, indicating that the general properties of how regulatory information is laid out in the genomes are conserved in the three species, Dr. Snyder noted. The general principles of regulation are more or less similar. Still, they found differences as well. The transcription factors bind very few of the same targets across species, and they are mostly expressed at different times.