Category → Ripped From the Pages
This post was written by C&EN reporter Jyllian Kemsley.
In the July 23 print Newscripts column, I wrote about olympicene, a molecule composed of five fused rings that was synthesized by chemists at the University of Warwick and resembles the Olympic rings. Now the Periodic Table of Videos has tackled the subject, and the University of Nottingham’s Martyn Poliakoff ups the ante. Poliakoff says that to truly mimic the Olympic rings, chemists need to interconnect circular molecules rather than fuse them together. He suggests ways that it might be done using catenanes and challenges viewers to make it happen.
Can any Newscripts readers out there think of other ways to make interconnected Olympic ring mimics? Share your ideas here.
These days it seems like everything’s turning green. Cars. Buildings. And now, thanks to a team led by University of Brasilia Ph.D. nutritionist Renata P. Zandonadi, even pasta is turning green.
For her doctoral thesis, Zandonadi used unripe, green bananas to develop an alternative for individuals, such as those with the autoimmune condition celiac disease, who are allergic to the gluten normally found in pasta. The results were recently published in the Journal of the Academy of Nutrition & Dietetics
Typically pasta is made with wheat flour (which contains gluten) and whole eggs. Zandonadi’s team, however, cooked up a pasta with green banana flour (which does not contain gluten), egg whites, water, and guar and xantham gum. According to Zandonadi’s teammate Raquel Botelho, green banana flour serves as a great replacement for wheat flour because the fruit’s resistant starch “forms a net similar to gluten” that traps water inside the pasta, ensuring a moist and elastic consistency.
Unripe fruit might not sound like the most appetizing of ingredients, but the experimental pasta actually proved quite tasty. The team cooked a meal of green banana pasta for a focus group of 25 people with celiac disease as well as a meal of green banana pasta and whole-wheat pasta for another group of 50 with no gluten allergies. The team then asked the tasters to rate their experience. The diners raved about the experimental pasta, ranking it ahead of whole-wheat pasta in terms of aroma, flavor, texture, and all-around quality. Not bad for pasta that contains 98% less fat than its whole-wheat counterpart. Another benefit, says Botelho: Green banana pasta serves as a source of inulin, a polysaccharide that stimulates the development of “good,” immunity-boosting intestinal bacteria. Continue reading →
Chemistry is everywhere, as we’re fond of saying in the pages of C&EN. So I was excited to let my taste buds partake in the biochemistry at the Fancy Food Show, which rolled into DC this past weekend. Sponsored by the National Association for the Specialty Food Trade, the Show is a mecca for makers of specialty foods such as cheeses, confections, and snacks. It draws the most diverse group of attendees I’ve ever encountered–on the expo floor I ran into folks from nerd gift emporium ThinkGeek, agribusiness giant Cargill, and the U.S. State Department.
Chew on some tidbits of science I picked up at the show, some of which are connected to past C&EN coverage. Continue reading →
The e-mail arrived in David Kaiser’s inbox late last year. “Would you like to meet an internationally-renowned hip-hop artist?” the subject beckoned. “There’s only one response to that,” says Kaiser, the Germeshausen Professor of the History of Science at MIT. “And that’s, ‘Yes, how can I help?’”
With that, one of the most interdisciplinary collaborations of Kaiser’s career was born. In December, he made the acquaintance of GZA, a founding member of legendary rap group the Wu-Tang Clan. At the time, GZA was in the planning stages for an album entitled “Dark Matter,” which as reported in this week’s issue is inspired by science in general and the quantum world and the cosmos in particular. GZA and Kaiser have sat down twice for freewheeling conversations about quantum theory and cosmology. Together with three other physicists, they’ve even discussed the similarities and differences in how budding rappers and budding academicians seek out mentors. Kaiser’s just one of the many scientists with whom GZA, a.k.a. Gary Grice, has powwowed about science. The list includes some of the most illustrious names in the business, including MIT marine biologist Penny Chisholm and Hayden Planetarium director Neil DeGrasse Tyson.
Of course, it’s far from the first time someone’s rapped about chemistry. We’ve covered chemists who produce tracks with a college-chemistry-major education bent. And as reader Barney Grubbs, an associate professor of chemistry at Stony Brook University, points out, Sacramento hip-hop duo Blackalicious produced a number called “Chemical Calisthenics”.
But that music lacks the public outreach mission that GZA says “Dark Matter” has. When the album drops this fall, it will come with a companion illustrated book, and possibly also a glossary, the Wall Street Journal reports. “Neil DeGrasse Tyson calls himself a ‘popularizer of science,’ ” GZA says. “I would like to be that someday as well.”
Crafting lyrics for “Dark Matter” will be about more than just random utterances of scientific terms to fit a rhythm, GZA adds. In fact, he says words’ meanings have always been integral to his creative process. Nicknamed “The Genius,” GZA is known for lyrics that refer to philosophy and chess in addition to science, and a voracious curiosity about many fields. “I would never force in a term–science-related or not– just because it seems right,” he says.
Still, “Dark Matter” is likely to become a talking point among chemists who get frustrated that science is portrayed inaccurately in the entertainment world. When it comes to balancing scientific accuracy and artistry, GZA says he stands in the middle. “I think it’s important that science be represented but it should be accurate, particularly because shows hire scientists as consultants,” he says. “As an avid chess player, I might notice errors on the screen on a chess board, but it wouldn’t necessarily get under my skin as a viewer. But if I were the director, I would absolutely correct it.”
GZA hasn’t spoken to any chemists– yet. But he’s certainly open to the idea. In other words, Newscripts readers, keep an eye on your e-mail.
Virulent bacteria are growing increasingly resilient against our best antibiotics. Each day seems to bring a new story: MRSA outbreaks, resistant salmonella, or tough-to-treat tuberculosis. Just last week, World Health Organization director-general Dr. Margaret Chan delivered an address in Copenhagen, where she cautioned: “We are losing our first-line antimicrobials . . . in terms of replacement antibiotics, the pipeline is virtually dry. The cupboard is nearly bare.” (Click here for The Haystack’s past coverage of the development of new antibacterials).
Why have our drugs stopped working?
Recent research from St. Jude’s (Science, 2012, 1110) attempted to answer that question. Using X-ray crystallography, a technique used to see structures at the atomic level, the researchers were able to capture a critical moment when a drug binds to DHPS, its bacterial enzyme target. The scientists could then predict how bacteria evolve to dodge further biocidal bullets.
The antibacterial medicines caught in the act by the St. Jude’s researchers are the sulfa drugs (see right), former front-line treatments many doctors push to the bottom of treatment regimens, due to increasingly resistant bacterial strains. Researchers knew resistance had something to do with the drugs’ mechanism of action; sulfa drugs mimic the binding of PABA – para-aminobenzoic acid, a compound found in many sunscreens (Chemical Note: PABA occurs naturally as bacterial vitamin H1, and can also be found in yeast and plants. Chemists often borrow naturally-occurring compounds for industrial uses; two prominent examples are vanillin and Vitamin C).
Disruption of this PABA binding shuts down bacterial DNA replication, stopping reproduction. Before now, however, no one had succeeded in growing crystals of the active site that actually showed the drugs interacting with the enzymatic intermediate.
Let’s take one more step back: how does PABA attach itself? The enzyme we’re discussing, DHPS, catalyzes bond formation between PABA and intermediates known as pterins (see picture, left). Earlier researchers believed that this molecular hook-up operated by an SN2 mechanism, a reaction where the PABA kicks out a small piece of the pterin to form a new C-N bond. We chemists would say that SN2 means concerted bond formation, meaning that PABA would bind at the same time as the leaving group (OPPi), well, leaves.
Turns out that picture’s not quite right: it’s more SN1-like, which means that the pterin first forms a positively-charged, enzyme-stabilized species! As you can imagine, this is no small feat, since the reaction works at physiological pH, in water, which could hydrate the intermediate (but doesn’t). Nope – instead, this charged molecule sits around waiting for a PABA – or a sulfa drug – to bind to it. When PABA binds, the complex exits the enzyme, but when the drug binds, it locks up the active site.
So how do these models help us to understand resistance?
The group noticed something odd: sulfathiazole (STZ) and sulfamethoxazole (SMX), two standard sulfas, both bound in the normal PABA cavity of DHPS. Unlike PABA, however, they hang their heterocyclic rings “outside” the normal pocket. The researchers built upon earlier observations by another group (Proc. Natl. Acad. Sci. U.S.A., 2010, 20986), speculating that the resistance might not have to do with the active site at all: it’s the external region, where the heterocycle bumps into the protein. To cheat death, all the bacterium needs to do is mutate an amino acid from this “outside” region (nearby proline and phenylalanine residues, see picture), which shuts down drug binding.
Could we design better drugs based on this model? Sure, we could synthesize a complimentary heterocycle, one that binds to the “outside” of mutant
enzymes (more polar for certain mutations, less for others). Another option? Cut the drug down to size: sulfonilamide, the grandfather of the sulfa drugs, should fit almost as snugly in the cavity as PABA, which might function perfectly against resistant bugs.
On Monday, we highlighted outtakes from our interview with Michael Ehlers, Pfizer’s CSO for neuroscience research, for our story on the state of neuroscience R&D. Today, we wanted to offer a view from academia: Jeff Conn is head of the Vanderbilt Center for Neuroscience Drug Discovery, which in the past several years has generated a number of CNS drug candidates.
While Ehler is focused on the growing body of genetic information that could pave the way for new neuroscience targets, Conn’s lab is taking a somewhat different approach. By scouring the literature for evidence–in humans–of a molecule or target’s activity, the lab then sinks substantial resources into understanding the basic biology driving that activity and designing molecules to exploit it.
In depression, for example, R&D has been stalled by a lack of new targets. But Conn’s lab is intrigued by studies showing that ketamine, an animal tranquilizer (and club drug), swiftly and effectively reduces the symptoms of major depressive disorder. “When I talk to scientists at Vanderbilt, its an approach they’re using for their most refractory patients,” Conn says.
A laundry list of side effects makes wider use of ketamine improbable. As such, Conn’s lab is looking at ways to design molecules that produce the same kind of results on depression without the adverse effects.
Conn, a former Merck researcher, also discussed ways that discovery efforts inside academia can build a scientific case for CNS programs that pharma might otherwise overlook. Vanderbilt scientists spend “twice as much effort in basic science than for the drug discovery itself, and to me, that’s absolutely critical,” Conn says. When the team finds that molecules have different profiles in vitro, they spend a lot of time trying to understand how that will translate into adverse effects in vivo. “In pharma, you have to stay on such a narrow, direct path, that you have to ignore all that,” Conn says. In the academic lab, researchers take a longer, more methodical approach that entails optimizing many different molecules, then putting those in animals to understand what properties a final drug candidate needs to have.
That approach has enabled Vanderbilt scientists to tackle drug targets that have tripped up industry. “mGluR5 is a good example where, early on, we started seeing different properties of molecules in vitro,” he says. “Instead of putting blinders on and moving forward or ignoring it,” an avenue industry scientists are often forced to take, “we deliberately put a lot of effort into optimizing those properties.”
As a result, the Vanderbilt group and its collaborator, J&J, recently moved forward what Conn calls “very safe” schizophrenia drug candidates targeting mGlur5. “I don’t think we ever could have done that in my pharma days because its too far off the critical path,” he says.
This post was written by Emily Bones, a member of the Editing & Production group here at C&EN.
At the ripe young age of 11, actor and science advocate Alan Alda asked his science teacher, “What is a flame?”
And she responded, “It’s oxidation.”
To an 11-year-old, that doesn’t mean much. And at 76, Alda’s still searching for a suitable response. Along with the State University of New York, Stony Brook’s Center for Communicating Science, Alda has presented the world with a challenge, appropriately called the Flame Challenge.
The task is simple: “Answer the question—‘What is a flame?’—in a way that an 11-year-old would find intelligible and maybe even fun,” flamechallenge.org states.
In an editorial in Science this month, Alda reminds readers that “scientists urgently need to be able to speak with clarity to funders, policymakers, students, the general public, and even other scientists.” In the article, he announces the challenge to promote science talk and avoid science jargon.
Answers to the burning question are due to flamechallenge.org by April 2. Entries can be in the form of a recorded explanation, a written response, or an illustration.
The winner will receive a VIP pass to the 5th annual World Science Festival in New York City, held May 30 to June 3, organized by the nonprofit Science Festival Foundation.
To support the mission of the challenge, after a team of well-seasoned scientists has screened the entries for accuracy, a panel of 11-year-olds will choose the final winner. To learn how to be a panelist, contact email@example.com.
And next week, at the ACS national meeting in San Diego, attendees can answer the question by visiting booth 638 in the exposition. There will be video cameras on hand to record answers, and these recordings can be submitted to the Flame Challenge.
We hope Newscripts readers will enter. After all, who better to explain a flame than a chemist?
In this week’s issue, I look at the perceived exodus by pharma companies from neuroscience R&D. Between AstraZeneca’s recent cutbacks, the closure of Novartis’ neuroscience research facility in Basel, and earlier moves by GSK and Merck, industry watchers are understandably worried that the neuroscience pipeline will dry up.
One person who isn’t worried is Michael Ehlers, Pfizer’s chief scientific officer for neuroscience research. Ehlers came to Pfizer a year and a half ago from Duke, with the explicit mission to revamp how the company finds and develops drugs for brain diseases. The scientist is convinced that the field is ripe for new and better drugs, and that by staying in the game, Pfizer will be in a good position to capitalize on what he believes will be a healthy flow of new discoveries.
Many drug companies argue that the risk in neuroscience simply doesn’t justify the investment. The overarching sentiment is that the brain is still a black box: good targets are few and far between; clinical trials are long and unpredictable; regulatory approval is tough; and generic competition is plentiful. For many big pharma firms, the math just doesn’t add up.
“I personally don’t find that calculus to give you the total picture,” Ehlers says. Shifting resources away from neuroscience to focus on areas like oncology, where the environment looks favorable—clear clinical trial endpoints, the opportunity for fast-track approval, an easier chance for reimbursement from payors—only makes sense in the short term, Ehlers says. But that thinking “is short sighted as to where the fundamental state of biology is in neuroscience,” he says.
Why is Ehlers so encouraged about a field that so many are walking away from? He believes that neuroscience is poised to benefit from the kind of genetic links that generated so many targets—and eventually so many targeted-drugs—in oncology. “There is going to be kind of a revolution in the next five years—it’s not going to be tomorrow…but you have to think about that inflection of opportunity over the five-to-ten year time horizon.”
To take advantage of each new genetic clue, Ehlers has revamped Pfizer’s approach to neuroscience R&D. As this week’s story explains:
In the past, big pharma often gave its scientists a mandate to work in areas such as Alzheimer’s or schizophrenia, regardless of tractable drug targets. Now at Pfizer, Ehlers says, his team is “indication agnostic.” Any program that Pfizer undertakes must have a critical mass of biological knowledge—for example, human genetics, human phenotyping, and evidence of dysfunctional neurocircuits—to convince Ehlers it’s worth pursuing. “We start there,” he says. “That hasn’t always been the case.”
Moreover, Pfizer no longer relies on mouse models as predictors for responses in humans. “We’ve for the most part stopped all rodent behavior as a model for disease and are much more about what’s happening in the brain,” he says. Scientists measure human responses to prove experimentally that a drug works.
Pfizer’s goal, according to Ehlers, is to tackle fewer projects but have more confidence in their potential for success. The result should be a drug pipeline “rooted in something more than optimism.”
He cites Huntington’s disease as one area that, even before coming to Pfizer, he saw as a prime scientific opportunity. “You know the gene, you know a fair bit about what’s going on, you have a wealth of data, tons of models, a clear clinical course, and an identifiable patient population,” he says. “If we can’t deal with that, we’re in trouble.”