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or email [email protected] ContentsVOLUME 95, NUMBER 40 October 9, 2017

Cover story Driving cancer beyond the brink Emboldened by real-world success and powered by CRISPR, a new wave of biotech firms is revisiting the concept of synthetic lethality in cancer Page 42

Quote of the week Features “We are effectively operating in a regime where we can’t directly see the stuff we are 24 Drug-resistant 34 Perspectives: roundworms prompt A new world for trying to remove.” search for new pharma contractors treatments Trade association chief Gil —James O’Neill, chief Hardy parasites have appeared in 32 As computer Roth describes his move from technology officer, Entegris livestock around the world chips shrink, cleaning the trenches of journalism to Page 32 needs grow the front line on regulatory and 28 Cambrex bucks Suppliers of electronic cleaning legislative issues the pharmaceutical chemicals seek to remove even service trend trace contaminants 36 Career Ladder: But the small-molecule stalwart Michael Malaska may surprise with its next Chemist turned a hobby into a investment job in space science

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4 C&EN | CEN.ACS.ORG | OCTOBER 9, 2017 ▸ Highlights Circadian rhythm pioneers honored with Medicine Nobel 6 A simple test to tell Zika virus from dengue 7 Detection of gravitational waves wins Physics Nobel 8 Concentrates Organic material has long-lasting luminescence 10 Chemical makers step up dumping claims 17 Chinese carmaker backs lithium company 18 Chemistry news from the week Cancer drug start-up Navire launches 19 Journals push for copyright control 22

NOBEL PRIZE Cryo-EM earns chemistry Nobel Three scientists honored for developing technique that provides unprecedented views of biomolecules The 2017 Nobel Prize in Chemistry has the technique to handle some structures been awarded to Jacques Dubochet of the that crystallography and NMR cannot. For University of Lausanne, Joachim Frank of example, it eliminates the need to crystal- Columbia University, and Richard Hender- lize biomolecules, which can be difficult. son of the MRC Laboratory of Molecular In addition, cryo-EM specialist Sarah Biology. They earned the prize “for devel- Butcher of the University of Helsinki es- oping cryo-electron microscopy for the timates that the technique can analyze high-resolution structure determination of 100-fold larger structures than NMR or Henderson (from biomolecules in solution.” The scientists crystallography can, including whole vi- left), Frank, and will equally share the $1.11 million award. ruses and even frozen cells. That makes Dubochet In cryo-electron microscopy (cryo-EM), it “much, much more adaptable to lots of a beam of electrons is sent through a bio- different types of biological questions” than images obtained molecular sample that has been frozen. the other two techniques, she says. with weak electron The material deflects the electrons in a way Henderson set the groundwork for beams. During that permits researchers to determine the cryo-EM in 1975, when he used electron the next decade, biomolecule’s structure. Electron beams microscopy to determine a three-dimen- Frank, then at the physically damage biomolecules, but sional model of bacteriorhodopsin by Wadsworth Center, freezing them, the “cryo” part of cryo-EM, averaging multiple in Albany, developed image-processing protects them from electron damage and technology for converting conventional prevents them from getting dehydrated in 2-D electron microscopy images into 3-D the instrument’s vacuum chamber. structures. Structures obtained by cryo-EM and In the early 1980s Dubochet devised related techniques are of fundamental methods for rapidly freezing biomolec- importance for understanding life chem- ular samples, and in 1990, Henderson ob- istry, and they can help scien- tained the first atomic-reso- tists develop drugs by elucidat- lution cryo-EM structure, ing the way bioactive agents of bacteriorhodopsin. interact with biomolecules. In the past decade, “Proteins are in all living advances in electron-detec- things—humans, plants, ani- tion technology, particularly mals, bacteria,” says Allison A. the development of direct electron Campbell, president of ACS. The detectors, have greatly improved cryo- prize “highlights the role that chemistry EM’s resolution capabilities. These plays in every aspect of our lives. From detectors, now commercially avail- the medicines we take to the plants we able, and data-handling improvements grow, understanding proteins—and “caused a huge revolution in the quality the chemistry of those proteins—is of cryo-EM data,” Butcher says. “Now critical.” Artistic representation of cryo-EM structures that means we can recover all the in- Traditionally, scientists turned to of glutamate dehydrogenase with increasing formation and go to atomic resolution, X-ray crystallography and nuclear mag- resolution from left to right. Electron detector which is what crystallographers do. But netic resonance spectroscopy to obtain technology advances played a key role in making we can do it without having to make biomolecular structures. Progress in it possible for cryo-EM to routinely attain atomic crystals, and crystals are a pain.”— STU

CREDIT: MARTIN HÖGBOM/STOCKHOLM UNIVERSITY (STRUCTURE); MRC LABORATORY OF MOLECULAR BIOLOGY (HENDERSON); COLUMBIA UNIVERSITY MEDICAL COLLEGE (FRANK); U OF LAUSANNE (DUBOCHET) U OF LAUSANNE (FRANK); COLLEGE MEDICAL UNIVERSITY COLUMBIA (HENDERSON); BIOLOGY OF MOLECULAR LABORATORY MRC (STRUCTURE); UNIVERSITY HÖGBOM/STOCKHOLM MARTIN CREDIT: cryo-EM, however, eventually enabled resolution (ribbon structure, far right). BORMAN

OCTOBER 9, 2017 | CEN.ACS.ORG | C&EN 5 Science Concentrates

NOBEL PRIZE Circadian rhythm pioneers win Medicine Nobel Trio honored for discovering mechanisms that control our biological clock

The 2017 Nobel Prize in Physiology or Young discovered genes that encode Medicine has been awarded to Jeffrey other proteins involved in regulating PER’s C. Hall, Michael Rosbash, and Michael cyclic production in cells. The Timeless W. Young for their pioneering efforts to protein binds to PER and helps shuttle it elucidate the molecular mechanisms that from a cell’s cytoplasm into its nucleus, drive organisms’ inner biological clocks. where it can inhibit the expression of the The prize, which is worth approximately $1.1 million, will be split equally among the three winners. Biological clocks, which allow organisms to adapt to daily light cycles, control many biological functions, including hor- mone levels, sleep, body temperature, and metabolism. In humans, tempo- Hall (from left), Rosbash, and Young rary disruption of these 24-hour circadian clocks as a result of trav- period gene. The Doubletime protein is a el causes jet lag. Chronic disruptions, such kinase that phosphorylates PER to increase as those experienced by people who work its degradation and thereby slow its accu- night shifts, can lead to increased risk of mulation, helping keep the 24-hour clock various diseases. Scientists are now looking on time. to improve treatment of cardiovascular and “The fundamental discoveries of how other diseases by coordinating delivery of the circadian clock regulates the daily drugs with a patient’s clock. cycles of human physiology have import- This year’s “laureates unraveled the ant implications for pharmaceutical drug first, coherent molecular mechanism for a development,” says Timothy Willson, a circadian clock and unquestionably led this research professor at the Eshelman School field,” says Andrew Millar, who of Pharmacy at the University studies biological clocks of North Carolina, Chapel at the University of Hill, who advocated Edinburgh. incorporating circa- In 1984, Hall and dian clocks in drug Rosbash, collabo- discovery when rating at Brandeis he worked in the University, and pharmaceutical Young, at Rocke- industry. “The feller University, efficacy, toxicity, independently and metabolism isolated a gene of drugs can be in fruit flies that influenced by the controls daily bio- clock, providing logical rhythm. This opportunities to gene, called period, Organisms’ biological clocks are controlled optimize time encodes a protein by oscillations in the level of PER, a protein and frequency called PER, whose produced from the period gene (1). When of dosing of new amounts peak at complexed with the Timeless protein, or and existing night and decline TIM (2), PER accumulates in the nucleus, drugs.”—CELIA

during the day. where it inhibits period gene activity (3). ARNAUD (YOUNG); UNIVERSITY MARIO MARGADO/ROCKEFELLER (HALL AND ROSBASH); OF HONG KONG UNIVERSITY CHINESE CREDIT: (FIGURE) INSTITUTE KAROLINSKA AT NOBEL ASSEMBLY

6 C&EN | CEN.ACS.ORG | OCTOBER 9, 2017 INFECTIOUS DISEASE Distinguishing between Zika and dengue Dipstick test can rapidly differentiate infections of closely related viruses

The mosquito-borne viruses Zika and 53-person international team to develop a dengue fever plague developing coun- simple dipstick test that uses pairs of highly tries around the world. Dengue can cause specific antibodies, allowing the scientists Dipstick tests for dengue (left) and Zika hemorrhagic fever, and Zika can lead to to distinguish between the two viruses (right) accurately identify the presence devastating congenital neurological defects. (Sci. Transl. Med. 2017, DOI: 10.1126/sci- of Zika virus protein in a sample. Properly diagnosing someone with one of translmed.aan1589). these infections is challenging, however, be- The team generated hundreds of anti- accumulate on a test area on the dipstick, cause the viruses are closely related. bodies against NS1 using animal and cell creating a red spot. The team confirmed Flavivirus nonstructural 1 (NS1) protein, models and then tested hundreds of anti- the accuracy of these tests using serum the viral protein commonly targeted by an- body pairs to determine which combina- samples from people with dengue and Zika tibody-based diagnostic tests, has approx- tions would be most sensitive and specific from North and South America and India. imately 70% sequence similarity between to the dengue and Zika viral proteins. The “This is an excellent piece of work,” Zika and dengue viruses, says Kimberly Ha- best pairs were used in the dipstick tests. comments Shamala Devi Sekaran, an im- mad-Schifferli, an engineer at the Universi- In the assay, gold nanoparticles tagged munologist at the University of Malaya. “It ty of Massachusetts, Boston. “It’s very hard with one antibody bind to viral proteins in certainly is very impressive, and they man- to make antibodies that can distinguish patient serum. The dipstick, coated with a aged to evaluate a number of samples from between them.” second virus-specific antibody, wicks up the different geographical areas, albeit not all.” To tackle this problem, Hamad-Schifferli serum. In roughly 15 minutes, the virus pro- The team hopes to use the new method and Lee Gehrke, an immunobiologist at tein is “sandwiched” between the two an- to develop rapid tests for other mosqui-

CREDIT: MIT CREDIT: MIT and Harvard Medical School, led a tibodies, and the tagged gold nanoparticles to-borne diseases.—EMMA HIOLSKI

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17-01-201 AZ API contract manufacturing, 179x117mm, engl.indd 1 17.08.17 11:07 OCTOBER 9, 2017 | CEN.ACS.ORG | C&EN 7 Science Concentrates The 4-km-long arms of the LIGO interferometer, NOBEL PRIZE seen here, top and left, extend into the countryside of Detection of gravitational Livingston, La. waves wins Physics Nobel Trio of scientists honored for finding a way to observe black-hole mergers The LIGO team determined that the first detected signal came from gravita- “For decisive contributions to the LIGO detect “ripples in space-time” that were tional waves that were generated 1.3 billion detector and the observation of gravita- predicted by Albert Einstein just over years ago. The waves formed when two tional waves,” the Royal Swedish Academy 100 years ago. According to his theory, black holes—roughly 29 and 36 times the of Sciences has awarded the 2017 Nobel as gargantuan bodies such as black holes mass of the sun—merged, forming a single Prize in Physics to Rainer Weiss, Barry C. accelerate because of gravity, they emit black hole. A few months later, in Decem- Barish, and Kip S. Thorne. Weiss will re- vast amounts of energy and generate grav- ber 2015, the LIGO team detected another ceive half of the approximately $1.1 million itational waves that propagate through black-hole merger. the universe, At the press conference announcing this sometimes passing year’s prize, Weiss, who spoke by phone, through Earth. said that like many of his team members, Those waves re- he did not believe that the first signal de- mained elusive for tected in 2015 was real. The signal could a century. But in have been a fake result that was injected 2015, LIGO’s enor- into the data stream to test the equipment mous and ultrasen- and the team’s ability to recognize such sitive interferom- signals. It took team members two months eters for the first to convince themselves that the observa- time picked up the tions were real, Weiss said. Weiss (from left), Thorne, and Barish tiny signals, which in the past had been “Gravitational waves are allowing us swamped by numerous sources of noise. to open a completely new window on the prize. Barish and Thorne will share the One of the instruments is located in Liv- cosmos,” says University of Pisa physicist other half. ingston, La.; the other is in Hanford, Wash. Massimiliano Razzano. He’s a member of Weiss is an emeritus professor of phys- The instruments consist of a powerful the team that runs Virgo, the new gravi- ics at MIT. Barish and Thorne are emeritus laser and an interferometer with a pair of tational-wave detector near Pisa, Italy. In professors of physics at Caltech. 4-km-long arms. A gravitational wave pass- late September, the LIGO and Virgo teams LIGO, the Laser Interferometer Grav- ing through the area of the detector causes announced jointly that all three detectors itational-Wave Observatory, is a highly a momentary subatomic-scale change in measured signals that correspond to yet an-

sensitive optical instrument designed to the length of one arm relative to the other. other black-hole merger.—MITCH JACOBY (THORNE AND BARISH) ASSOCIATION ALUMNI MIT (WEISS); CALTECH (INTERFEROMETER); LIGO CREDIT:

8 C&EN | CEN.ACS.ORG | OCTOBER 9, 2017 BIOCHEMISTRY Fluorescent sensor measures ionic strength ® Sensor could help monitor property T3P – The New Standard in Peptide Bond Formation linked to protein aggregation in cells and Other Conden sations A fluorescent biosensor is the first to quantify the ionic strength inside living cells (ACS Chem. Biol. 2017, DOI: 10.1021/ Amide Bond Formations: acschembio.7b00348). The sensor could enable cell biologists High Yields – Simple Work-up – No Epimerization to follow changes in ionic strength over time or at different locations in a cell, changes that are key for controlling protein T3P is an outstanding reagent to achieve quick aggregation. breakthroughs even for most challenging applications. Ionic strength is the measure of the concentration of unbound T3P can reduce overall costs by 20%. F ions floating in a cell. It affects many biological processes, in- Boc O cluding protein folding and assembly and the catalytic activity of HN F T3P DIPEA Boc enzymes and ribozymes. Measuring ionic strength could help re- OH O N N + HN searchers better understand protein misfolding and aggregation, N one pot O H NH2 two key processes in the formation of amyloid fibers, which are F F linked to neurodegenerative disease and type 2 diabetes. To build a cellular ionic strength sensor, Boqun Liu, Bert Pool- F F man, and Arnold J. Boersma at the University of Groningen made use of Förster resonance energy transfer, which relies on the transfer of energy between two different fluorescent molecules. The intensity of fluorescence of the molecule receiving the energy depends on the distance between it and the other molecule.

Coupling Agent Yield (%) Epimerization (%) T3P 87 1.8 DCC/HOBt 61 5.9 EDC/HOBt 67 11.1 HBTU 66 16.1 TBTU 53 9.1 PyBOP 63 14.2 The researchers built sensor molecules carrying a cyan and a yellow fluorescent protein, separated by two charged peptide he- Advantages of T3P – lices (shown). In a solution of low ionic strength, positive charges Propane Phosphonic Acid Anhydride on one helix (purple) attract the negative charges on the other (red). The helices fold together like the arms of tweezers, draw- • High yields and broad functional group tolerance • Easy processes and work-up (only water-soluble byproducts) ing the fluorescent proteins at the tips close together (left). In a • Mild conditions, typically lowest level of racemization / solution of higher ionic strength, ions surround the helices and epimerization without additives neutralize their charges, keeping the helices, and thus the fluores- • Safe handling, non-toxic, no sensitizing properties cent proteins, separated (right). • Reduced overall process costs (already several large-scale When the proteins come close together at low ionic strength, pharma applications existing; 20% cost savings possible) the cyan fluorescent protein, excited by blue light, efficiently • We have produced T3P for decades as a 50% (w/w) solution transfers energy to the yellow fluorescent protein, which emits in many different solvents yellow light. But in high ionic strength, the glowing cyan protein • Application examples: amide bond formation, esterifcations, dominates the fluorescent signal since it is unable to transfer its conversion of amides / acids into nitriles, isonitrile formation, energy to the other protein. oxidations and many more The researchers introduced the sensor to human embryonic kidney cells and correlated the sensor’s response to the concentration of potassium chloride inside the cells, which they controlled with the help of potassium membrane transport Request our T3P Application molecules. Package or Free Samples: “This is a beautiful example of using fundamental chemistry

ACS CHEM. BIOL. CHEM. ACS [email protected] to design a sensor that is simple but intelligent,” says Xin Zhang, who studies cellular protein folding at Pennsylvania State Univer-

CREDIT: CREDIT: sity.— MELISSAE FELLET, special to C&EN

OCTOBER 9, 2017 | CEN.ACS.ORG | C&EN 9 Science Concentrates

PHOTONICS Organic material sets glowing record

Persistently luminescent material could find The new material is transparent and po- applications in road paints and street signs tentially flexible, although flexibility was not achieved in this initial study. It is also A new glow-in-the-dark organic material positive charge, or hole. While the hole soluble in organic solvents and does not emits light for over an hour at room tem- transfers to TMB, the electron jumps from require high-temperature processing. perature when excited by ultraviolet or vis- one PPT molecule to another, getting Despite these advantages over inorganic ible white light (Nature 2017, DOI: 10.1038/ passed around like a hot potato. The elec- luminescent materials, the organic mate- nature24010). The achievement is a new tron eventually recombines with the hole rial’s visible excitation is weak and could record, as other luminescent organic mate- on a TMB molecule, causing light emis- use improvement, says photonics materials glow for at most a few minutes. sion. Some electrons recombine quickly rials expert Jianrong Qiu of South China The new material’s long-lasting glow is with a hole, but many remain isolated for University of Technology. an “extraordinary” finding, says photoma- a long time and terials specialist Runfeng Chen of Nanjing recombine later, University of Posts & Telecommunications, causing the glow who was not involved in the work. Daniel to persist for over Scherman of Paris Descartes University, an hour after the who has developed nanophosphors for bio- excitation light logical imaging applications, agrees and be- has been turned lieves that the material could spark indus- off. The material trial interest. Potential applications include currently emits glow-in-the-dark paints for illuminating green light, and building corridors, roads, and street signs; the researchers glowing fabrics and windows; and biocom- believe other col- Films (1 cm2) of TMB, a TMB-PPT mixture, and PPT sit patible probes for biological imaging. ors will be readily under weak ambient light (left). In the dark after getting To make the new materials, Ryota accessible. excited by UV light, the TMB-PPT combination film glows Kabe and Chihaya Adachi of Kyushu Uni- Luminescent (right). versity’s Center for Organic Photonics inorganic mate- & Electronics Research melted together rials that glow for long times—typically The new material is also sensitive to ox- the electron donor N,N,N´,N´-tetrameth- more than 10 hours but up to 360 hours ygen and water, Kabe and Adachi say. But ylbenzidine (TMB) and the electron in one extraordinary case—are widely they think transparent protective barriers acceptor 2,8-bis(diphenylphosphoryl) used commercially on watches and signs. could protect the material from exposure. dibenzo[b,d] thiophene (PPT). When PPT But they are not transparent, are rigid In future work, they hope to create new absorbs incident light, the energy creates and insoluble, and require fabrication versions of the material with improved

an isolated electron and a corresponding temperatures of over 1,000 °C. properties.— STU BORMAN KABE RYOTA CREDIT:

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10 C&EN | CEN.ACS.ORG | OCTOBER 9, 2017 ANALYTICAL CHEMISTRY A benchtop test for biofuel authenticity Prototype spectrometer can differentiate biofuels and fossil fuels For those seeking carbon credits for sell- Measuring 14C is typically done with ac- Biofuel or not? A new analytical method ing or using biofuels, it’s important to celerator mass spectrometry, which has a could make it easier to be sure. know that the fuel is legit. Researchers precision of 0.2–0.4%. But it’s very expen- now have an easier way of determining sive, and most scientists ship samples to a sulting in a precision of 11% for samples of whether hydrocarbons come from bio- dedicated facility. CO2 produced by the combustion of fossil fuels or fossil fuels. A team from the U.S. Adam J. Fleisher, David A. Long, and fuels and bioethanol. National Institute of Standards & Tech- colleagues at NIST tested cavity ring-down Jocelyn C. Turnbull, a radiocarbon sci- nology has designed a benchtop spectrom- absorption spectrometry as a benchtop entist at GNS Science, a geoscience con- eter that could do radiocarbon analysis alternative. In this method, laser light sultancy firm, calls the result impressive. more easily and cheaply than standard tuned to the wavelength absorbed by 14C But she says the instrument’s precision methods (J. Phys. Chem. Lett. 2017, DOI: is bounced between two mirrors inside would need to improve considerably—to 10.1021/acs.jpclett.7b02105). an optical cavity until the signal leaks out, 0.2%—to be useful for tracing fossil-fuel Fossil fuels and biofuels differ in their or “rings down,” and is detected by the emissions in the atmosphere. carbon isotope composition: Fossil fuels instrument. When a sample of 14C-con- The NIST team is now targeting this are made of plants that have been dead taining gas is introduced into the cavity, threshold. The company Planetary Emis- for hundreds of millions of years, so all it absorbs some of the light, changing the sions Management, which focuses on ap- their carbon-14, with a 5,730-year half-life, ring-down interval, which can be used to plications for monitoring greenhouse gas radioactively decayed long ago. Biofuels, calculate the amount of 14C present. emissions, has signed an agreement with meanwhile, retain a detectable, but minus- The team designed a finely tuned unit NIST to commercialize the technology. 14 CREDIT: SHUTTERSTOCK CREDIT: cule, C signal. with a stable temperature of –55 °C, re- — DEIRDRE LOCKWOOD, special to C&EN

OCTOBER 9, 2017 | CEN.ACS.ORG | C&EN 11 CHEMISTRY Do science, take pictures, win money. Enter our photo contest at IN PICTURES cen.chempics.org or email [email protected]. Selections from cen.chempics.org, where C&EN showcases the beauty of chemistry

Pollution-fighting flowers When light shines on these flower- and leaf- shaped crystals, they can break down pollutants in water. The energy from the light excites electrons in the copper(I) oxide (Cu2O) that makes up the crystals. The excited electrons leave holes in the crystal’s electronic structure, and to fill those holes, the material starts sucking in electrons from the molecules around it. In a water-based solution, the flowers take electrons from water molecules, creating hydroxyl radicals that can then oxidize soluble pollutants. As a result, the pollutants decompose into less harmful chemicals.—MANNY MORONE

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New: In Stock and Made-to-Order Grignard and Organozinc reagents Synthonix can provide custom Grignards or organozinc reagents from commercially available halides in 2-4 days. Freshly made in USA. [email protected] | 919-875-9277 synthonix.com Science Concentrates PHYSICAL CHEMISTRY DIAGNOSTICS ▸▸Helping doctors pick Downsizing the proton The radius of the proton has been puzzling scientists since 2010, when a study the best antibiotic of muonic hydrogen, in which the hydrogen atom’s electron is replaced by a heavier muon, suggested that the proton’s radius is significantly smaller In just 30 minutes, a new method can de- than the consensus value from other experiments—about 0.84 femtometers termine if the bacteria in a person’s urine compared with sample are vulnerable to a certain antibi- 0.88 fm. New New measurements support a smaller proton. otic (Sci. Transl. Med. 2017, DOI: 10.1126/ spectroscopic Muonic hydrogen spectroscopy (2010) scitranslmed.aal3693). Such a test could work on normal CODATA (2014) help doctors better manage antibiotic hydrogen now Hydrogen spectroscopy (2017) use when treating urinary tract infections bolsters the (UTIs) by allowing them to reserve valu- 2010 result (Sci- able, potent drugs for when other drugs ence 2017, DOI: 0.82 0.83 0.84 0.85 0.86 0.87 0.88 0.90 will not work. In the new method, Rustem 10.1126/science. Proton radius, femtometers F. Ismagilov of California Institute of Tech- aah6677). Sci- Sources: International Council for Science Committee on Data for Science & nology and colleagues incubate bacteria in entists measure Technology, 2014; Nature 2010, DOI: 10.1038/nature09250; Science 2017, a urine sample either with or without an the proton DOI: 10.1126/science.aah6677 antibiotic of choice for 15 minutes. By com- radius using paring the bacterial DNA levels between hydrogen spectroscopy or electron scattering. In the new work, a team led by the two conditions, the Axel Beyer and Lothar Maisenbacher of the Max Planck Institute of Quantum researchers can deter- Optics tightly controlled hydrogen spectroscopy experimental conditions to mine if the infectious yield a proton radius of 0.8335 fm. The researchers note that both the 2010 strain is susceptible value and the new value fall within the error ranges of some individual earli- to the drug. To detect er experiments. The discrepancy occurs when those other, earlier values are such small differences combined into a recommended standard radius by the International Council in DNA levels, the team for Science’s Committee on Data for Science & Technology (CODATA). Within uses an optimized ver- their experimental errors, the 2010 muonic hydrogen and latest standard hy- sion of loop-mediated drogen experimental values do not overlap with the CODATA radius. The new A 30-minute isothermal amplifica- hydrogen spectroscopy data also yield a value for the related Rydberg constant, test could help tion on a microfluidic 10,973,731.568076 m–1, that is outside the error margins of the CODATA value, doctors assess chip to count the copies 10,973,731.568508 m–1.— JYLLIAN KEMSLEY the antibiotic of a certain piece of susceptibility DNA from Escherichia of bacteria in coli—the most com- urine samples. mon bacterial culprit in fluorine into all types of molecules and micromolar to millimolar levels. They also UTIs. The team tested materials. But one strategy they haven’t demonstrated that a polymerase enzyme the method on 54 patient samples and explored much is commandeering the main the engineered cells can act on the found that, 94% of the time, the results chinery in living cells to biosynthetically fluorinated diketide monomer to produce agreed with those from the standard OH O produce fluorinated com- the corresponding fluorinated poly(hy- culture-based method for determining pounds. The challenge is droxyalkanoate). Poly(hydroxyalkanoates) antibiotic susceptibility, which takes O– that cells lack the ability are found in products like biodegradable days to yield results. Joseph C. Liao, a F to make many fluorinat- forks and spoons. Chang notes that using urologist at Stanford University School ed organic compounds biosynthesis for commercial bioplastic of Medicine, thinks performing such a Fluorinated or to metabolize them. production isn’t yet cost-effective, but this measurement in 30 minutes is a technical diketide A team led by Michelle strategy could allow chemists to control tour de force. He’s interested in seeing the C. Y. Chang of the University of Califor- polymer chain length and other properties team apply the method to a wider range of nia, Berkeley, in trying to overcome that in designer applications.—TIEN NGUYEN microbes and drugs.— MICHAEL TORRICE limitation, has engineered Escherichia coli host cells to convert a stable, nontoxic compound called fluoromalonate into ADHESIVES SYNTHETIC BIOLOGY 2-fluoro-3-hydroxybutyrate, a fluorinated diketide (Angew. Chem. Int. Ed. 2017 DOI: ▸▸Strong, stretchy ▸▸Engineering 10.1002/anie.201706696). Chang’s group previously focused on using fluoroacetate surgical glue cells to pump out as a starting material, but it’s a compound fluoropolymers that can poison cells when it’s metabo- After surgery, holding tissue together lized. Now, using malonate transporters allows incisions to heal. This closure is of- to introduce fluoromalonate into the ten accomplished with stitches or staples, Chemists have worked extensively to de- cells, the chemists were able to improve but such materials can further damage

velop synthetic methods to incorporate the fluorinated compound’s uptake from tissue, particularly in the case of delicate SHUTTERSTOCK CREDIT:

14 C&EN | CEN.ACS.ORG | OCTOBER 9, 2017 ASTROCHEMISTRY Chloromethane detected in deep space

An injured rat lung (bottom) is repaired Because phytoplankton and other microorganisms produce chloromethane with MeTro gel surgical glue (top). (CH3Cl), astrobiologists have postulated the halocarbon could be indicative of extraterrestrial life. But that theory may not hold up now that a team led tissue like lungs. Surgical glue is needed by Edith C. Fayolle, formerly of the Harvard-Smithsonian Center for Astro- that can seal lung tissue without the need physics and now at NASA’s Jet Propulsion Laboratory, has discovered chloro- for using sutures or staples first. Although methane around a forming star system and surgical sealants are commercially avail- in the thin atmosphere of a comet (Nat. able, none of them has the right combi- Astronomy 2017, DOI: 10.1038/s41550-017- nation of elasticity, shear strength, and 0237-7). Fayolle and colleagues identified adhesion to work well with lung tissue on chloromethane in the gas surrounding their own. Nasim Annabi of Northeastern protostar IRAS 16293–2422—the first time University, Ali Khademhosseini of Har- it’s been found in deep space—using the vard Medical School, and coworkers now Atacama Large Millimeter/submillimeter report a strong and stretchy surgical glue Array (ALMA) to detect the compound’s they call MeTro gel that works well with unique radio spectrum. The team also lung tissue (Sci. Transl. Med. 2017, DOI: detected chloromethane in the coma of 10.1126/scitranslmed.aai7466). MeTro comet 67P/Churyumov-Gerasimenko using gel is a protein-based hydrogel made the Rosetta Orbiter Spectrometer for Ion ALMA antennae in the of human tropoelastin modified with & Neutral Analysis (ROSINA) instrument Chilean Andes helped spot methacryloyl groups that cross-link when on the Rosetta probe, which combines two chloromethane in space. activated by ultraviolet light. The materi- mass spectrometers and a pressure sensor. al’s adhesive and mechanical properties The finding demonstrates that the halocarbon, found in similar abundance depend on the amount of protein and around the protostar and the comet, forms naturally in places no life exists the extent of methacryloyl substitution. and suggests it can stick around long enough to become part of a forming so- The strongest and most elastic MeTro gel lar system. This, Fayolle says, raises the question, “How much of the comet’s contains 20% protein (weight/volume) organic content is directly inherited from the early stages of star formation?” with a high degree of methacryloyl A more extensive look for halocarbons around other protostars and comets substitution. The researchers used the will be needed to find an answer, she says.—BETHANY HALFORD adhesive to seal surgically induced cuts and holes in rat arteries and lungs and in pig lungs. Animals treated with the seal- ant demonstrated no leakage and could up of a 2,2'-bipyridine core flanked by Fe, Co, Ni, Cu, or Zn or a combination of breathe normally. The researchers plan to triazolyl-pyridine groups. This combina- two of the metals. In continuing the work, develop new versions of the material that tion leads to formation of unusual trime- the team has now systematically used can be cross-linked using visible light. Ef- tallic triple-stranded helicate complexes, electrospray ionization mass spectrometry 6+ forts are under way to commercialize the (L3M3) , where L is the ligand and M is to study the formation mechanism and technology.—CELIA ARNAUD thermodynamic stabilities of the helicates when mixtures of metals are used. The N Fe researchers have found that some met-

INORG. CHEM. (HELICATE) INORG. INORGANIC CHEMISTRY als outcompete others for binding sites, N leading some of the helicates to be inter- ▸▸Chemists triple down N N converted into others. In one case, they 6+ observed formation of (L3FeZnCu) on metal helicates (shown), the first example of such a N complex containing three different Chemists have come far in using met- metals. However, this trinuclear species al-assisted self-assembly of organic N Metal salts only appears as an intermediate on the Zn 6+ building blocks to construct molecules way to (L3Cu3) , which is the most stable with three-dimensional architectures. For isolable helicate (Inorg. Chem. 2017, DOI: example, a team led by supramolecular NN 10.1021/acs.inorgchem.7b01980). Ghosh chemistry specialists Pradyut Ghosh of N and Schalley say the magnetic properties the Indian Association for the Cultiva- Cu of the trimetallic helicates will be of inter- tion of Science and Christoph A. Schalley N est for developing smart materials, in par- of Free University of Berlin has been ticular for the versions having a combi- matching various metal salts with a mul- nation of diamagnetic and paramagnetic

CREDIT: ESO/C. MALIN (ANTENNAE); NASIM ANNABI (GLUE); ANNABI (GLUE); MALIN (ANTENNAE); NASIM ESO/C. CREDIT: tidentate ligand it developed that is made Ligand Trimetallic helicate metals.— STEVE RITTER

OCTOBER 9, 2017 | CEN.ACS.ORG | C&EN 15 Business Concentrates EDC route Cl H HCl H H + NH3 PROCESS CHEMISTRY H Cl NH2 Ethylene H2N dichloride Ethylenediamine A new route to and higher amines MEA route OH ethyleneamines H N + NH3 2 AkzoNobel says its new production Monoethanolamine H N R2 technology is a ‘game changer’ 1 N New AkzoNobel route R H AkzoNobel says it has developed a ence of a hydrogenation-dehydroge- H CO CO N and related products breakthrough process for making higher nation catalyst. The second involves 1 OH R 2 ethyleneamines and derivatives. The new reacting ethylene dichloride (EDC) H2NR process will reduce raw material consump- with ammonia. AkzoNobel operates R1 NNR2 tion and substantially improve cost and two ethyleneamines plants in Europe, each The new process O environmental performance compared of which uses one of the processes. generates high yields with existing processes, the firm says. But the MEA process is ineffective at of amines that contain at least three eth- Ethyleneamines are intermediate chem- producing high yields of important ethylen- ylene units, including diethylenetriamine icals for products such as epoxy curing eamines featuring three or more ethylene and triethylenetetramine, the firm says. It agents, which are in demand for wind units. The EDC process is expensive and claims that the new technology will mark- turbine fabrication. They are also additives involves undesirable chlorine chemistry. edly strengthen its product portfolio. for oil, road materials, and paper. The AkzoNobel is keeping tight-lipped about AkzoNobel is also confident that its global ethyleneamines market is between the specifics of its new chemistry. But a breakthrough can unseat existing pro- 550,000 and 600,000 metric tons per year, company patent published in August 2017 cesses. “We strongly believe it has the according to IHS Markit. outlines a process to make ethyleneamines potential to become a game changer in the The manufacture of ethyleneamines is “by reacting an ethanolamine functional industry,” says Joppe Smit, general manag- currently dominated by two routes. One compound with an amine functional com- er of the firm’s ethyleneamines business. involves the reaction of monoethanol- pound in the presence of a carbon oxide It plans to build a demonstration plant for amine (MEA) and ammonia in the pres- delivering agent.” the technology in 2018.—ALEX SCOTT PEPTIDE GENERIC APIs BACHEM Bachem is the leading independent supplier of active pharmaceutical ingredients (APIs) for the human and veterinary pharmaceutical market. • Atosiban • Glucagon • Goserelin Acetate • Leuprolide Acetate • Octreotide Acetate • Teriparatide Acetate • Tetracosactide • Triptorelin Acetate

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16 C&EN | CEN.ACS.ORG | OCTOBER 9, 2017 TRADE Chemical makers step up dumping claims Congress, Administration signal willingness to probe low-priced imports Cheap imports of polyethylene terephthalate resins, used to make soda U.S.-based chemical makers are pressing ing them financial injury and are asking bottles, have caused a trade dispute. claims that overseas competitors are un- the U.S. government to impose antidump- derpricing exports in an effort to steal mar- ing duties on the imports. They point out mestic producers are truly harmed by the ket share, a practice known as dumping. that U.S. imports of PET from the coun- practice. The government can impose an- The trade complaints come as Congress tries rose by 305% to over 270 million kg tidumping duties to level the playing field. and the Trump Administration say they will from 2014 to 2016. Domestic manufacturers are likely take aggressive action to protect domestic Separately, the U.S.-based chemical emboldened by the Trump Administra- manufacturers from unfair trade practices. company Chemours claims that Chinese tion’s tough talk on enforcing trade rules, Four major polymer companies with and Indian producers of polytetrafluoroeth- according to trade attorneys contacted operations in the U.S.—DAK Americas, ylene, a resin that Chemours sells under the by C&EN. In addition, Congress has also Indorama Ventures USA, M&G Polymers trade name Teflon, are dumping products tightened trade provisions to make it USA, and Nan Ya Plastics —have filed in the U.S. Chemours says the Indian com- harder to evade antidumping duties. petitions alleging that polyethylene tere- panies unfairly benefit from export subsi- “I think there is definitely a trend in phthalate (PET) resin makers in Brazil, dies awarded by the government of India. more filings,” says George Tuttle III, a Indonesia, Pakistan, South Korea, and Tai- The petitions will kick off investigations San Francisco-based trade attorney. “We wan are pricing exports to the U.S. at less by the U.S. Commerce Department to really see a tightening down, with the than fair value. determine if imported products are un- U.S. government trying to quell all of this PET is used to make basic goods includ- fairly priced and by how much. If dumping industry complaint and a congressional ing soda bottles and polyester fibers. The allegations hold up, the U.S. International fervor for action to protect domestic

CREDIT: SHUTTERSTOCK CREDIT: U.S. producers claim that dumping is caus- Trade Commission then determines if do- industry.”— MELODY BOMGARDNER

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HELSINN - Chemical & Eng News - October 2017.indd 1 20/09/17 09:22 OCTOBER 9, 2017 | CEN.ACS.ORG | C&EN 17 Business Concentrates

BY THE NUMBERS ENERGY STORAGE Carmaker invests in lithium

Highlighting auto industry concern because of rising demand for electric about access to battery raw materials, vehicles powered by lithium-ion bat- a Chinese carmaker has agreed to in- teries. In the U.S., the car company vest in an Australian lithium mining Tesla is ramping up production at its operation. Gigafactory battery plant in Nevada. 1 Great Wall Motor, China’s largest Co-owned with Panasonic, it’s called producer of SUVs, will pay $22 million the world’s largest lithium-ion battery for a 3.5% stake in Pilbara Minerals. plant. Meanwhile, in China, authorities Under the agreement, Great Wall will have ordered carmakers to get 10% of Billion buy 75,000 metric tons per year of lith- their total sales from hybrid and elec- ium carbonate for lithium-ion batteries tric vehicles by 2019. for the next five years. The deal gives The stock prices of the established The number of base pairs that the Chinese firm the option to buy lithium chemical makers Albemarle synthetic biology firm Ginkgo Bioworks another 75,000 metric tons annually by and SQM are up more than 50% this will buy from DNA manufacturer Twist loaning an additional $39 million. year and many other companies, in- Bioscience under a new contract. The figure Pilbara will use the $22 million in cluding Pilbara, are trying to get into represents one-third of the world market funding to complete the construction the business. for synthetic DNA. The synthetic DNA will of its Pilgangoora Lithium-Tantalum Great Wall’s investment in Pilbara, be used to supply Ginkgo’s third organism- Project. The additional $39 million though unusual, is not unprecedented. design facility, which will open in November. would help fund the construction of a In 2010, the Chinese electric vehicle Ginkgo’s designed microbes produce phase-two expansion at the site. maker BYD invested about $30 million ingredients used in fragrances, cosmetics, Demand for lithium carbonate and in a lithium mine in Tibet.—JEAN- nutrition, agriculture, and food. lithium hydroxide is surging worldwide FRANÇOIS TREMBLAY Source: Ginkgo Bioworks

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18 C&EN | CEN.ACS.ORG | OCTOBER 9, 2017 START-UPS Cancer drug start-up Navire sets sail

Firm will develop small-molecule SHP2 inhibitors previously a vice president at Genentech. with $30 million from BridgeBio Pharma “Tyrosine phosphatases have been viewed as a graveyard of drug devel- BridgeBio Pharma and the University of G. Neel, director of New York Universi- opment for decades,” Neel says. One Texas MD Anderson Cancer Center have ty’s Perlmutter Cancer Center. Neel, who reason, he says, is that previous com- launched a new company called Navire has studied the proteins since 1992, is a pounds targeting SHP2’s highly charged Pharma. Backed by $30 million in financ- scientific cofounder of Navire and chair active site don’t readily enter cells. But ing from BridgeBio, Navire will develop of its scientific advisory board. in 2016, chemists at Novartis reported a small-molecule inhibitors of an enzyme SHP2 belongs to the tyrosine phospha- compound that fills a tunnel in SHP2’s called SHP2, implicated in many cancers. tase family of proteins, which help relay closed or inactive state. Neel says both “I’ve been working on this protein for chemical messages controlling cell growth the Novartis and Navire compounds act longer than I want to admit, so this is ex- and division. MD Anderson is contributing like “molecular glue,” holding three enzy- citing,” says Benjamin its SHP2 inhibitors to the collaboration matic domains of SHP2 together to turn and will continue to spearhead off its activity. studies until a compound is BridgeBio was formed in 2015 but ready for human trials. remained in stealth mode until January Researchers think that 2017. Its strategy is to launch laser-fo- blocking SHP2 could halt the cused subsidiaries rather than manage ev- growth of tumors spurred by erything under one portfolio. That gives malfunctions in the pathway Navire “a tremendous amount of freedom in front of or behind SHP2. going forward,” Virani says. “We are interested in ge- Neel is hopeful that the molecular glue netically driven tumors and strategy could work on other tyrosine J. MED. CHEM. /NOVARTIS MED. J. An inhibitor from Novartis are agnostic to where those phosphatases. “I think we will see a re- binding with the SHP2 tumors are,” explains Navire birth of targeting phosphatases for many

CREDIT: CREDIT: protein. CEO Shafique Virani, who was diseases.” he says.—RYAN CROSS

OCTOBER 9, 2017 | CEN.ACS.ORG | C&EN 19 Business Concentrates FOOD INGREDIENTS MERGERS & ACQUISITIONS ▸▸Arsenal divests Chewing-gum workers urethane firm Accella sue over butter flavor

Private equity firm Arsenal Capital Part- More than 20 chewing-gum factory workers say they have lung disease be- ners has agreed to sell polyurethane cause of their exposure to diacetyl and acetylpropionyl, butter flavorings used systems maker Accella Performance in popcorn and other foods such as candy, baked goods, and flavored coffee. Materials for $670 million to Carlisle A spate of such suits by popcorn factory Companies, an industrial products firm. workers about a decade ago blamed diacetyl O O Accella was assembled from more than a for causing bronchiolitis obliterans, a disease dozen acquisitions since 2012, including characterized by shortness of breath, fatigue, Covestro’s North American spray polyure- and ultimately death. Acetylpropionyl, a O O thane foam business. Today it has annual structurally similar butter flavor, is named Diacetyl Acetylpropionyl sales of $430 million. Arsenal continues for what might be the first time in the new to invest in other specialty chemical suits, filed in Chicago’s Cook County Court. Workers from a now-shuttered businesses and recently bought the che- Wrigley gum factory are seeking more than $50,000 each in damages. Named miluminescent glow-stick maker Cyalume as defendants are more than 15 flavor makers, including Givaudan, Sensient Technologies.— MARC REISCH Technologies, and International Flavors & Fragrances. Jacob Plattenberger, an attorney at TorHoerman Law who is pressing the cases, says Wrigley is not named because workers’ compensation laws limit legal remedies available to GREEN CHEMISTRY the workers. The U.S. National Institute for Occupational Safety & Health proposed restrictions on acetyl propionyl in November 2016.— MARC REISCH ▸▸FRX raises funds for flame retardants lia, a distance of 3,000 km. Covestro will PETROCHEMICALS FRX Polymers has raised about $12 million take advantage of the region’s harsh con- in a funding round led by a major Chinese ditions—45 °C temperatures and strong ▸▸Aramco funds private equity fund. FRX says the money ultraviolet radiation— to test the perfor- will be a bridge to an initial public offering mance of its 70% biobased coating hard- Malaysian project of stock next year. Based in Chelmsford, ener. Made from pentamethylene diisocya- Mass., FRX is developing halogen-free nate, it’s part of a urethane coating system Saudi Aramco will pay $900 million for flame retardants based on polyphospho- from PPG Industries. The coating will a 50% share of the polymer operations nates. It plans to use the funds to expand grace the Sonnenwagen race car, designed in a complex that Petronas is building its staff and double capacity at its plant in by students at Germany’s RWTH Aachen in Pengerang, Malaysia, near Singapore. Antwerp, Belgium.— MICHAEL MCCOY University and Aachen University of Ap- Expected to cost a total of $27 billion, the plied Sciences.— MELODY BOMGARDNER complex will consist of both oil refineries and petrochemical plants. Details of the BIOBASED MATERIALS agreement between Aramco and Petronas SPECIALTY CHEMICALS are vague, but the Saudi firm will become a ▸▸Solar race car tests crude oil supplier to the project. The deal ▸▸Two paper chemical follows a visit to Malaysia by Saudi Arabia’s biobased hardener King Salman bin Abdul-Aziz Al Saud in businesses are sold February.— JEAN-FRANÇOIS TREMBLAY This week, 40 teams will race solar-powered cars from Darwin to Adelaide, Austra- BASF will sell a plant in Pischelsdorf, Austria, that makes styrene-butadiene OUTSOURCING paper coating dispersions to Synthomer for $35 million. All of the site’s 42 staffers ▸▸Lonza nabs U.S. will transfer to Synthomer. BASF says it will hold onto styrene-acrylic dispersion biologics site activities in Pischelsdorf and continue to produce styrene-butadiene dispersions in Lonza will acquire a clinical-stage mam- Ludwigshafen, Germany; and Hamina, Fin- malian biologics manufacturing site land. Separately, Ecolab will acquire Geor- in Hayward, Calif., from the Irish drug gia-Pacific’s paper chemicals unit, which company Shire. The 5,400-m2 facility, reported 2016 sales of about $43 million. which has 1,000- and 2,000-L single-use The business sells products that enhance bioreactors, will supplement the Swiss The solar Sonnenwagen racecar sports a the strength, softness, and durability of contract manufacturer’s clinical-stage ca-

biobased coating hardener from Covestro. paper.— ALEX SCOTT pabilities in Slough, England. Lonza says COVESTRO CREDIT:

20 C&EN | CEN.ACS.ORG | OCTOBER 9, 2017 it is offering the current staff of about 100 rheumatoid arthritis, Crohn’s disease, Eastman says an opportunity to continue working at the multiple sclerosis, and more. A second pro- its Tritan resin site.— RICK MULLIN gram for inhibitors of STING (stimulator lends to the new of interferon genes) could help prevent chairs’ crystal innate immune system activation in auto- appearance. PHARMACEUTICAL CHEMICALS immune diseases like lupus. The pact gives Celgene the option to acquire the Nimbus ester in a new line of chairs, ▸▸Nippon Shokubai programs.— RYAN CROSS called Luxtiera, that are characterized by a molded invests in APIs diamond pattern. Nanae INFORMATICS Imbe, a Kawajun designer, says Nippon Shokubai is entering the business the chair design was too demanding for of producing active pharmaceutical ingre- ▸▸Evotec invests polypropylene. Polymethyl methacrylate dients (APIs) for peptide and nucleic acid didn’t provide the desired toughness, and drugs. The company will build a plant in $18 million in Exscientia polycarbonate lacked needed chemical re- Suita, Japan, where it opened an API syn- sistance.— MICHAEL MCCOY thesis lab last year. The facility will be able The German contract research firm Evotec to produce APIs in quantities ranging from is expanding a partnership with the AI- milligrams to kilograms. Nippon Shokubai, based drug discoverer Exscientia and ac- START-UPS best known as the world’s largest producer quiring an $18 million stake in the compa- of superabsorbent polymers used in dia- ny. Evotec’s collaboration with the British ▸▸CRISPR-focused pers and sanitary pads, has a strategy to firm began 18 months ago to design immu- expand in the medical field over the next no-oncology drugs that purposefully bind KSQ launches three years.— JEAN-FRANÇOIS TREMBLAY two targets. Evotec CEO Werner Lanthaler liked what he saw. The new deal makes KSQ Therapeutics has emerged from the two firms 50:50 partners on their drug stealth mode with $76 million in funding DRUG DISCOVERY discovery program, Lanthaler says, adding from Polaris Partners to use the powerful that it is unlikely Evotec would take a com- gene-editing tool CRISPR to crack open a ▸▸Nimbus, Celgene pound to the clinic alone.— RYAN CROSS swath of new drug targets. Building on the work of its academic cofounders—David form autoimmune pact Sabatini and Tim Wang from MIT; William POLYMERS Hahn from Broad Institute; and Jonathan Celgene and the computational chemistry Weissman from the University of Califor- company Nimbus Therapeutics are team- ▸▸Eastman plastic nia, San Francisco—KSQ has developed a ing up to advance R&D on small molecules high-throughput method of using CRISPR that could treat a suite of immunology con- is sitting pretty to probe gene function. The biotech firm, ditions. One Nimbus program is designing which already has 40 employees, will ini- inhibitors of the inflammation-linked The Japanese furniture maker Kawajun is tially focus on oncology and immunology enzyme Tyk2, which has applications in using Eastman Chemical’s Tritan copoly- drugs.— LISA JARVIS

Tiancheng Wanfeng Chemical acetate-ethylene copoly- Business Roundup Technology are forming an mer-based powder disper- $80 million joint venture that sions in Ulsan, South Korea. ▸▸Bayer has ceded control of University of Delaware, and will combine their fatty acid The $94 million project will Covestro, its former plastics the State of Delaware, has chloride and alkyl ketene di- double the site’s capacity business, after selling an received a $3 million grant mer (AKD) wax businesses in for the dispersions, used to additional 6.9% stake in the from the U.S. Department of Yanzhou, China. Made from make construction mortar. firm. The sale, which raised Commerce. The award will fatty acid chloride, AKD helps $1.2 billion, reduces Bayer’s help adapt a research build- paper resist liquid absorption. ▸▸Arbutus Biopharma has stake in Covestro to 24.6%. ing at DowDuPont’s Exper- received $116 million from imental Station to support ▸▸Avara Pharmaceutical Ser- Roivant Sciences, an invest- ▸▸Stamicarbon, a Dutch small-business innovations. vices has agreed to acquire ment vehicle founded by urea technology licensor, has a GlaxoSmithKline plant Vivek Ramaswamy. Arbutus invested $5.5 million in the ▸▸Lanxess will cease produc- in Aiken, S.C., that makes will use the funds to further U.S. start-up Pursell Agri- tion of lubricant precursors solid-dose, over-the-counter develop its hepatitis B virus Tech. Pursell is developing in Ankerweg, the Nether- drugs. Solid-dose capabilities treatments and RNA-based a low-cost coating for con- lands, by November 2018. are in high demand in the drug delivery technology. trolled-release fertilizers. Part of Lanxess’s Chemtura U.S., according to Avara. Ramaswamy was an early in- acquisition, the site is oper- vestor in OnCore Biopharma, ▸▸Delaware Innovation ated by a staff of 100. ▸▸Wacker Chemie will which merged with Tekmira Space, a business incubator build a spray dryer and an Pharmaceuticals to form set up by DowDuPont, the ▸▸Kemira and China’s additional reactor for vinyl Arbutus. CREDIT: EASTMAN CHEMICAL EASTMAN CREDIT:

OCTOBER 9, 2017 | CEN.ACS.ORG | C&EN 21 Policy Concentrates

PUBLISHING Journals push for copyright control Legal actions pursued against ResearchGate, Sci-Hub

Several scientific publishers, including the After material was uploaded, an automated American Chemical Society, are expand- system would check to see if the article was ing their legal actions against sites that licensed to share publicly or privately. facilitate sharing of scientific articles in violation of copyright law. The publishers are preparing to issue what could be millions of notices to the scientific networking site Re- searchGate asking it to remove copy- ResearchGate encourages users to upload full text, righted material. supplementary material, and figures, as shown in this screen ACS and Elsevier shot from a C&EN story referenced on the site. have also sued Re- searchGate for copyright infringement. ResearchGate declined the proposal. Founded in 2008, ResearchGate is a Publishers now have “no other choice” for-profit company that now has more than but to issue takedown notices and sue the 13 million members and 100 million publi- company, the Coalition for Responsible cations, according to its website. Its fund- Sharing says in a press release. Research- ing comes from venture capital investment; Gate is located in Germany, and the law- investors include Bill Gates, Goldman suits were filed in Europe. Sachs Investment Partners, and Wellcome ACS, which publishes C&EN, estimates Trust. ResearchGate also sells advertise- that more than 100,000 of its articles ments that appear alongside its content. are hosted illegally by ResearchGate. Re- But as many as 7 million articles that searchGate did not respond to requests appear on ResearchGate do so in violation for comment. of copyright law, publishers allege. ACS-copyrighted material also appears “We have invested heavily in curation illegally on internet pirate site Sci-Hub, and publication processes to get validated, and ACS appears likely to succeed in a suit trusted material in a form that scientists against the site, according to a preliminary can access,” says James Milne, ACS’s se- finding released by a U.S. district court in nior vice president for publishing, speaking Alexandria, Va. on behalf of a group of publishers called Magistrate Judge John F. Anderson the Coalition for Responsible Sharing. “We agreed with ACS that Sci-Hub violated cannot allow ResearchGate to commer- ACS’s copyright and trademark protec- cialize that material without contributing tions when it provided free access to to the creation enterprise.” ResearchGate stolen journal articles. Anderson recom- also alters articles for its business purposes mended that the court take several actions and fails to update them when corrections requested by ACS, including ordering or retractions are issued, the coalition says. internet service providers with a legal re- After unsuccessful attempts to work lationship with Sci-Hub, such as domain with ResearchGate, the International Asso- name registries or web hosting services ciation of Scientific, Technical & Medical that Sci-Hub pays, to cease facilitating ac- Publishers, of which ACS and Elsevier are cess to Sci-Hub websites. members, issued a final proposal to the The filing is a recommendation to Judge company on Sept. 16. The agreement would Leonie M. Brinkema, who will likely issue a have allowed ResearchGate users to con- final ruling in the next few months.—JYL-

tinue uploading documents as they do now. LIAN KEMSLEY & ANDREA WIDENER RESEARCHGATE CREDIT:

22 C&EN | CEN.ACS.ORG | OCTOBER 9, 2017 CHEMICAL WEAPONS ▸▸Russia destroys last of its stockpile

Russia has destroyed the last of the massive chemical weapons stockpile it inherited from the Soviet Union at the end of the Cold War, the Organisation for the Prohi- bition of Chemical Weapons (OPCW) says. The final artillery projectiles filled with VX nerve agent were dismantled on Sept. 27 at a facility in Russia’s Udmurtia region, wrap- ping up an effort that spanned two decades. RENEWABLE ENERGY “The completion of the verified destruction of Russia’s chemical weapons program is a major milestone,” says Ahmet Üzümcü, Growth in global solar OPCW’s director general. OPCW oversees global efforts to eliminate stockpiles under energy capacity tops coal the Chemical Weapons Convention, which took effect in 1997. The group says that over In 2016, for the first time, global capacity for photovoltaic solar energy rose 96% of declared stockpiles have been elim- faster than that for any other fuel, exceeding even the net growth of coal, says inated by its 192 member nations. Russia the International declared an arsenal of 39,967 metric tons of Energy Agency. Coal ◼ Net additions chemical warfare agents, including mustard ◼ Retirements New solar projects agent, phosgene, and the nerve agents sa- Solar in China made up rin, soman, and VX. In 2012, the U.S. said it Wind nearly 50% of all had destroyed 90% of its declared chemical new international weapons, about 30,500 metric tons. But Natural gas capacity. China, the budget shortfalls have slowed the disposal Total renewables U.S., and India are program, and the last of the U.S. stock- 050 100 150 200 predicted to account pile is not scheduled for elimination until Additions, gigawatts for two-thirds of 2023.—GLENN HESS, special to C&EN future additions. Renewables overall provided two-thirds of global net energy capacity growth in 2016.—JEFF JOHNSON, special to C&EN ENDOCRINE DISRUPTORS Note: Renewables include solar, wind, hydropower, bioenergy, and geothermal. Source: International ▸▸EU Parliament Energy Agency

shuns limited that required regulation of endocrine head said last week. The agency will ex- definition of toxics disruptors based on hazards they pose. pedite the approval process for generic However, by 2015 the European Commis- alternatives to hard-to-make complex sion had failed to propose a definition for drugs, FDA Commissioner Scott Gottlieb The European Parliament last week reject- endocrine disruptors, which prompted the said in a blog post. “Any steps we can take ed a narrow definition of endocrine dis- European Court of Justice to condemn the to encourage the development of generic ruptors that would have allowed their use commission for not acting on its commit- competitors to complex drugs will have in some cases. The proposal—put forward ment. The commission is now expected an outsized impact on access, and prices,” by the European Commission, the EU’s to formulate a new proposal.—PAULA Gottlieb said. “If consumers are priced executive branch—would have exempted DOBIAS, special to C&EN out of the drugs they need, that’s a public some substances from scientific criteria health concern that FDA should address.” for identifying endocrine disruptors, such The new policy is significant because the as pesticides designed to attack parasites’ PHARMACEUTICALS agency has historically made its decisions endocrine systems. Environmental groups on the basis of safety and efficacy without lauded the vote. The proposal was an “un- ▸▸FDA acts to expand regard to cost. Complex drugs include med- fit definition because too many chemicals icines like metered-dose inhalers to treat would escape the regulatory net,” the access to complex asthma that have at least one feature that European Consumer Organisation said in generic drugs is difficult to replicate under current rules. a statement. The EU debate over defin- To help get more generic versions of these ing endocrine disruptors has long pitted drugs on the market, FDA will provide industry interests and agriculture against FDA will take steps to increase the avail- companies with guidance on how to win consumer and environmental groups. In ability of certain lower-cost generic med- approvals, including offering meetings with 2009 and 2012, the European Parliament icines in an attempt to address the rising agency staff early in the process.—GLENN

CREDIT: SHUTTERSTOCK CREDIT: approved laws on pesticides and biocides cost of prescription drugs, the agency’s HESS, special to C&EN

OCTOBER 9, 2017 | CEN.ACS.ORG | C&EN 23 Features

Resistance to roundworm- fighting drugs has been particularly problematic on sheep farms in New Zealand.

DRUG DISCOVERY Battling the worms Scientists hunt for new drugs as livestock- ago have already appeared on sheep farms. As drug resistance slowly creeps into the tormenting roundworms mount resistance U.S. cattle industry and arises in human infections around the world, farmers, against standard treatments veterinarians, doctors, and scientists are EMMA HIOLSKI, C&EN WASHINGTON seeking new treatment strategies. icture an open pasture with woolly sheep grazing on Ivermectin, the gold lush green grass. Idyllic, right? What’s not so idyllic is standard that inside some of these animals’ guts, deadly parasitic Out of the handful of anthelmintics worms could be thriving, sucking blood from the animals’ used against roundworms, otherwise P known as nematodes, one stands apart in stomachs and depriving them of nutrients. Researchers around the terms of potency and success: ivermectin. world have reported finding drug-resistant roundworms—some Not only does ivermectin kill roundworms resistant to multiple classes of standard treatments—in every type in infected plants, animals, and humans, leaving the host organisms unscathed, but of livestock host, including sheep, cattle, and goats. it also kills other types of parasitic worms. Outwardly, an animal may look healthy, you’ve had drug resistance for years.’ ” And it can treat infections caused by ar- leading a farmer to believe that regular Parasitic roundworms infect livestock, thropods, such as lice, ticks, and mites, treatment is keeping parasitic worms at crops, companion animals, and humans while causing limited side effects. bay. Inwardly, though, worms that have worldwide. The advent of modern anti- Although researchers are still working to mutated to shield themselves from com- worm drugs, or anthelmintics, starting fully understand ivermectin’s mechanism mon drugs are shedding eggs that will around the 1960s gave doctors, veteri- of action, they do know that it binds to hatch to create the next generation of re- narians, and farmers the tools an array of chemically OCH3 sistant worms. The sheep spread the eggs to effectively treat devastating HO through their feces, leaving behind infec- infections. For decades, anthel- (SHEEP) LEATHWICK OF DAVID COURTESY CREDIT: OCH3 tive larvae on the verdant pasture. mintics have kept livestock safe O

“The consequence is that a farmer from blood-sucking roundworms O H H O

will come to see a veterinarian because and helped halt the spread of parasit- O O O he has a whole lot of sick or even dead ic-roundworm-induced river blindness H animals lying around his paddock,” says among humans in developing countries. H David Leathwick, principal scientist for But the blanket use of these compounds Ivermectin is the New Zealand government research has contributed to a global rise in round- an anthelmintic O O group AgResearch. The farmer will ask, worms that exhibit drug resistance. that primarily OH H “What’s wrong with my animals?” Leath- The problem is especially bad in sheep contains the wick says. “The answer is, ‘Well, you just and goats. And roundworms that are resis- compound treated them, but it didn’t work, and tant to drugs developed less than a decade shown. O H OH 24 C&EN | CEN.ACS.ORG | OCTOBER 9, 2017 triggered ion channels, called ligand-gat- but it also eliminates important genetic stepped in to help fill gaps in basic re- ed ion channels, that are nestled into the refugia, or populations of worms lacking search and new drug development. A membranes of nerve and muscle cells in the gene mutations that confer drug resis- similar movement to aid in the search for roundworms. This “basket of tricks” likely tance. These susceptible worms help dilute novel anthelmintics is slowly taking shape explains how ivermectin can target mul- the effects of resistance-causing genes in today. tiple parasite species and life stages, says the overall worm gene pool, thereby keep- Given the challenges of working with Ray Kaplan, a veterinarian and professor of ing drug resistance at bay for longer. parasitic worms—their complex life cycle parasitology at the University of Georgia. Drug resistance is “widespread in cattle cannot be reproduced in the lab without The compound binds most strongly to in South America and in sheep and goats a host animal—many researchers have glutamate-gated chloride channels, which the world over,” says Timothy G. Geary, turned to Caenorhabditis elegans, a nonpar- regulate the passage of chloride ions into director of the Institute of Parasitology at asitic nematode and, thus, a model worm. and out of cells. By strongly activating the McGill University. It’s even showing up Their goal: Identify vulnerable proteins channel, ivermectin induces muscle paral- in horses, he adds. “There’s a legitimate and biochemical pathways in the worms ysis and death in roundworms. concern about our ability to manage these and then find compounds that target Debuted by Merck & Co. as a livestock things.” them. drug in 1981, ivermectin was the product Nearly all standard anthelmintics have Some researchers, like Laura L. of an international collaboration among stopped working against sheep parasites, Kiessling of Massachusetts Institute of public and private institutions. Satoshi according to Nick Sangster, a program Technology, focus on a protein target Ōmura at Kitasato University in Tokyo manager for Meat & Livestock Australia. already known to be essential to the first discovered avermectins, compounds Newly developed drugs are often the only produced by the soil bacterium Streptomy- treatment option, Sangster adds. And O ces avermitilis that have powerful activity resistance to the aminoacetonitrile deriv- R O against nematodes. William C. Campbell, S Cl Cl who worked for the Merck Institute for I –O O I –N O Therapeutic Research at the time, then S S studied the efficacy of the avermectins Cl Cl N N N N and their derivatives, including ivermec- H H tin, against parasites in animals. Ivermectin became a boon to livestock producers around the globe and was approved for use in humans starting in 1987. Since then, Merck has been donating ivermectin—“as much as needed, for as long as needed,” according to the company’s website—to help fight river blindness, a roundworm infection afflicting millions of Replacing a carboxylate (left top) with an people in the developing world. In 2015, acylsulfonamide (right top) helps novel anti- Ōmura and Campbell were jointly award- roundworm drugs evade detoxification enzymes ed one-half of the Nobel Prize in Physiol- ative monepantel has already ap- and disable or kill C. elegans (right bottom). Healthy ogy or Medicine for their discoveries and peared in worms, only seven to adult worms (left bottom) are about 1 mm in length. the impact they’ve had on society. eight years after the drug’s introduction. “It’s a ticking time bomb,” he says worms and search for novel chemicals to of the growing drug-resistance problem. disrupt its function. Kiessling, a professor Growing resistance Although there is definitely a need to of chemistry, had originally set out to The booming success of ivermectin for look for new drugs, Geary points out that target bacteria by attacking the enzymes livestock parasite control was so great “the bar has been set pretty high” by iver- that create key polysaccharide chains, or that it changed animal husbandry practic- mectin and similar drugs. New drugs must glycans, on their protective outer surface. es worldwide. Modified drug formulations be active against multiple parasite species Her team found that inhibiting the en- led to longer-lasting anthelmintics that yet adhere to stringent health and safety zyme uridine 5′-diphosphate galactopyra- were easier to administer, dramatically regulations. “Basically, we’ve evolved the nose mutase (UGM) in Mycobacterium mi- reducing labor costs. “When you talk market to think that one product gets all crobes slowed their growth. Because gly- about worm control to a producer,” Leath- worms,” Geary says. “It’s a very challeng- cans, including those produced by UGM, wick says, “their first, second, and third ing market.” are also crucial components of round- thoughts are all around the use of drugs.” worms’ protective sheaths, or cuticles, In the same way that overuse of antibiot- Kiessling thought these UGM inhibitors ics has led to antibiotic resistance, once New drugs could provide a novel, nonmammalian blanket anthelmintic treatment became After the rise of widespread antibiot- drug target. the norm among farmers, it was only a ic resistance, many academic scientists Unlike the drugs that treat roundworms matter of time before resistance to those drugs cropped up. Instead of treating only animals with ex- “We’re just blasting the worm with compounds ACS CHEM. BIOL. CHEM. ACS treme infections, livestock producers now and letting the worm tell us what it doesn’t like.” treat the entire flock. This practice helps

CREDIT: CREDIT: support animal health and boost growth, —Peter Roy, professor, University of Toronto

OCTOBER 9, 2017 | CEN.ACS.ORG | C&EN 25 Roundworm arsenal Parasitic roundworms have exhibited resistance to all these classes of drugs. Class discovery Drug class Drug examples date Cellular mode of action Drug effect Mechanism of resistance Impaired movement Worms substitute tyrosine for Benzimidazoles Albendazole, thiabendazole 1961 Attacks scaffolding protein -tubulin β and reproduction phenylalanine in β-tubulin Imidazothiazoles Levamisole, morantel, pyrantel 1970 Activates nicotinic acetylcholine receptor Paralysis Unknown Binds to glutamate-gated chloride and Potent, persistent Macrocyclic lactones Avermectin, ivermectin 1974 other ion channels paralysis and death Unknown Possibly binds to calcium-activated Cyclic octadepsipeptides Emodepside 2002 potassium channel Paralysis Unknown Aminoacetonitrile derivatives Monepantel 2008 Binds to some nicotinic receptor subunits Paralysis Unknown Sources: satoshi-omura.info, wormbook.org by binding ion channels and knocking functional group swap, replacing the car- mals do not possess the UGM enzyme. nerve and muscle cells out of commission, boxylate group with an acylsulfonamide, She is equally excited about the po- drugs targeting the cuticle would disrupt created “surrogate” compounds that tential to use carboxylate surrogates as a the organisms’ motion and potentially kill circumvented the detoxification enzymes general mechanism to activate other com- worms and larvae. Disrupting the cuticle and disabled and killed pounds. “I think it could could also help other drugs reach their tar- C. elegans (ACS Chem. “It’s a ticking be really useful for other get, Kiessling says. Biol. 2017, DOI: 10.1021/ people that are trying to Kiessling’s team identified 14 acschembio.7b00487). time bomb.” hit targets in nematodes small-molecule inhibitors of UGM. Al- The next steps in- and running up against though the compounds inhibited UGM clude testing these —Nick Sangster, program their detoxification activity when tested against the enzymes compounds against manager, Meat & Livestock mechanisms,” Kiessling directly, they were not effective against parasitic nematodes and Australia, on the growing drug- says. live C. elegans. The worms’ powerful ensuring their safety in resistance problem Another route to novel detoxification enzymes targeted the car- animals and humans, anthelmintics goes be- boxylate groups on the compounds and Kiessling says, although the side ef- yond screening compounds against pre- rendered them inactive. However, a single fects should be limited because mam- determined targets. “We’re not assuming

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26 C&EN | CEN.ACS.ORG | OCTOBER 9, 2017 that any one protein family in particular is cannot return to the first field they grazed AgResearch’s Leathwick and his team a good target,” says Peter Roy, a professor in for 60 days, he adds. have extensively studied the use of drug of molecular genetics and pharmacology Rather than treating all animals in a combinations—multiple drugs that target and toxicology at the University of To- flock, farmers should instead target ani- the same worm species—to manage para- ronto. “We’re just blasting the worm with mals with the worst infections for treat- site infections in sheep. Worms attacked compounds and letting the worm tell us ment, Kaplan says. In general, about 20% on multiple fronts are less likely to devel- what it doesn’t like.” of the animals will harbor roughly 80% op resistance to any one drug. Leathwick’s In a screen of more than 67,000 com- of the parasites. Comparing the mucus team is also beginning to delve into new pounds, Roy’s team homed in on a set of membranes of animals’ eyes to a special- gene-sequencing technology to find more 30 distinct compounds that killed C. ele- ized color chart can help farmers identify potential drug targets. Leathwick is excit- gans and two parasitic nematode species anemia, a telltale side effect of the most ed about the increasing feasibility of find- but did not harm zebrafish or a human cell important parasitic worm infection in ing such a physiological trigger and work- line (Nat. Commun. 2015, DOI: 10.1038/ sheep and goats. ing with a “clever chemist” to target it. ◾ ncomms8485). By exposing C. elegans to chemical mutagens, the team also generated 19 million genetic mutations in the worm and then exposed the organism to various compounds to observe how easily resistance could arise, a practice that also helps elucidate which proteins or pathways are targeted. The scientists zeroed in on one family of promising molecules to determine how it killed the nematodes. The compounds disrupted an essential SHARE CHEMISTRY. START A REACTION... component of the electron transport chain in mitochondria, cells’ energy factories. Only nanomolar concentrations were needed to achieve this effect, and the compounds showed limited risk of inducing resistance. One of the key areas for future drug Tell a friend development, according to Roy, is gaining why you love access to novel chemicals. “Most of the Mentor a stuff that’s commercially available that we chemistry. can get our hands on has been screened classroom for up the wazoo,” he says. A worldwide, open access library of new structures “would be National Lab a fantastic public effort.” Day. New philosophies Take As research into novel anthelmintics pushes forward, scientists and veterinar- Kids & Chemistry ians agree that dramatic changes in drug Explain the use practices are needed to help stem the to a scout spread of resistance. meeting. science behind a We need a “philosophical shift” away current event. from the blanket drug use model, one that includes a more holistic approach to parasite control and sustainable use of new drugs, Kaplan says. For example, although scientists have yet to uncover the mechanism behind it, adding certain tannin-rich plants to animals’ diets can naturally help control parasite infections, he says. Another nonchemical practice includes Chemistry labor-intensive field and grazing rotations Ambassadors to limit exposure to infective worm larvae. Eggs take about four to five days to reach the infective larval stage, so moving sheep www.acs.org/chemistryambassadors to a new pasture helps reduce the risk of Find everything you need to get started! infection, Meat & Livestock Australia’s Sangster says. This requires extra fencing and more field hands, however, and sheep

OCTOBER 9, 2017 | CEN.ACS.ORG | C&EN Chemistry Ambassadors Ad 1 3/17/10 27 2:14 PM OUTSOURCING Cambrex bucks the pharmaceutical service trend But the small-molecule stalwart may velopment and are concerned about their downstream production options. surprise with its next investment According to Chief Executive Officer Steven M. Klosk, Cambrex is stretching RICK MULLIN, C&EN NEW YORK CITY out a bit after focusing narrowly on late- stage, small-molecule pharmaceutical he world of pharmaceutical diversified services or a one-stop-shop chemicals for the past decade. The compa- contract manufacturing has approach combining API and final-dosage ny had a biologics business but sold it to been rocked by a number of manufacturing. Lonza in 2007. T jarring deals of late. Thermo But Cambrex’s latest investments are And Cambrex, one of the few publicly Fisher Scientific’s acquisition of Pathe- not a matter of simply doubling down on traded companies in the contract phar- on, valued at $7.2 billion, was a shock to small molecules. maceutical chemicals field, expects to many industry watchers earlier this year. In addition to adding preclinical and invest $70 million to $75 million in 2017 Lonza’s $5.5 billion purchase of Capsu- Phase I clinical trial capacity with the and is still on the lookout for acquisitions gel also made a stir, as did the merger North Carolina plant, Cambrex em- to increase capacity and perhaps broaden of Cambridge Major Laboratories and barked on an expansion in Charles City its offerings—even as far as bringing back AAIPharma Services to form Alcami. Even that includes a scale-up of high-potency biologics. smaller acquisitions, including Catalent’s API production capacity from 150 L to Yet Klosk, who became CEO in 2008 recent purchase of cell culture specialist 4,000 L—a $24 million investment. The and previously ran the company’s bio- Cook Pharmica for $950 million, made combined effect is a stronger pitch to pharma business, says he’s primarily in- waves. prospective drug industry customers that terested in further expanding Cambrex’s In all cases, the deals brought to light have molecules in the early stages of de- small-molecule production. evolving business models in “Biopharmaceuticals are an industry that is consoli- growing faster than small dating as its players diversify. Small molecules, big world molecules—it’s a smaller mar- Despite biologic drug encroachment, chemical-based therapies Firms are adding new service ket, but it’s growing faster,” continue to thrive. and manufacturing offerings Klosk acknowledges. Still, he to core businesses by combin- Small-molecule drug candidates is unmoved by estimates that ing final-dosage manufactur- 7,000 5-year compound the share of large-molecule ing with active pharmaceuti- biologic compounds in the cal ingredient (API) produc- annual growth rate current drug development tion, say, or adding biologics 6,000 Launched pipeline is approaching 50%. to a small-molecule services “There is still a very large business. 2.3% small-molecule market with a Cambrex’s acquisition whole lot of potential growth,” 5,000 Filed with FDA of High Point, N.C.-based he says. PharmaCore last October was 7.0% Klosk adds that the general worth noting for a different 4,000 shift of contract API produc- reason. The $25 million deal Pre-FDA filing tion from Asia to Europe and gave Cambrex manufacturing 7.1% the U.S. also puts Cambrex in assets for small-molecule 3,000 a good position. The company, APIs that are in the early Phase III which had sales of $492 mil- phases of human clinical tri- 7.3% lion in 2016, has facilities in als. The plan is for the new 2,000 Karlskoga, Sweden, where it facility to feed the firm’s larg- Phase II produces intermediates and er-scale API plant in Charles APIs, and in Paullo, Italy, City, Iowa. 1,000 2.9% where it makes intermediates The news, followed by Phase I and APIs for brand-name and announcements in the en- generic drugs. The firm has suing months regarding ex- 0 5.8% research sites in Tallinn, Esto- pansions at Charles City and 2011 12 13 14 15 16 Preclinical nia, and Wiesbaden, Germany. elsewhere, signaled that the ◼ Preclinical ◼ Phase I ◼ Phase II ◼ Phase III “The Cambrex brand stands small-molecule stalwart is ◼ Pre-FDA ﬁling ◼ Filed with FDA ◼ Launched 8.0% for something in terms of sticking to its guns as many of Note: Figures are for new chemical entities in the drug development pipeline or currently on the market. regulatory and quality excel- its competitors veer toward Sources: Cambrex, Citeline lence,” Klosk says. “Managing

28 C&EN | CEN.ACS.ORG | OCTOBER 9, 2017 in some of the areas outside the U.S. and contract can heavily impact a firm’s Europe, where we have a lot of experience, availability of manufacturing assets, and “If they bought comes with risk.” the lack of ready capacity could kill a And there are enough risks operating in major new contract. “Even with all the a dosage facility, the West, he says. Growth in small mole- investment we’ve been doing, there have cules is such that the firm is having a hard been capacity constraints at times,” he time keeping up with demand, even after acknowledges. I’d be shocked.” investing about $200 million over the past This dilemma is hardly unique to Cam- —James Bruno, president, Chemical & five years. brex, Klosk adds; the industry as a whole Pharmaceutical Solutions “You never quite get it right,” Klo- is suffering from capacity constraint. sk says, noting that it is just as easy “There are cycles, and we have been on at the plant. “Purchasing PharmaCore to overinvest as it is to underinvest in a very positive cycle. No doubt there will allows us to go back to preclinical and

CREDIT: CAMBREX CREDIT: contract manufacturing capacity. One be a dip.” increases our analytical bandwidth. There While many of the firm’s are 30 chemists down there,” he says, re- Cambrex CEO competitors claim that 2017 ferring to the North Carolina plant. “So we Steven M. Klosk. is a critical year for making have a lot more chemists available to do investments, Klosk contends the analytical and chemical development that getting it right is a matter work.” of the kind of steady invest- The new high-potency technology comment Cambrex has made. ing to the Charles City plant will expand Beyond the current project in Cambrex’s production capabilities to Charles City, the company re- what Nettleton calls the medium range in cently launched a large-scale terms of scale. High-potency capacity is a API plant in Karlskoga. key to growth in small molecules, he says, The acquisition of Pharma- given the number of potential customers, Core and the expansion proj- including start-ups, with oncology drugs ect under way significantly re- in development. “Folks expect it. It kind of calibrate the Charles City site, gets you a ticket to the dance,” he says. according to Joe Nettleton, James Bruno, president of the con- Cambrex’s vice president of sulting firm Chemical & Pharmaceutical U.S. operations, who is based Solutions, says Cambrex’s small-molecule

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alphoraresearch.com or [email protected] www.saltigo.com 4340 1/4 Page C+EN Ad Client: Alphora Research OCTOBER 9, 2017 | CEN.ACS.ORG | C&EN 29 905.403.0055 > [email protected] Issue: Oct. 9 2017 Dimensions: Quarter Page ad 3.4375”Wide x 4.625” no bleed focus is a savvy approach to the “I’d be shocked.” The technology pharmaceutical services market. and business of final-dose man- It’s a strategy that is paying off, ufacturing is fundamentally dif- especially given the company’s ferent from producing the drug recent moves, he says. active, he says. “The good thing is that they Klosk avows that Cambrex is have focused,” says Bruno, who open to adding either biologics is skeptical of the one-stop-shop or dosage services in a near-fu- approach. “They have not diluted ture acquisition, with a greater their efforts with things such likelihood that it would be a dos- as working on particle size or age facility. Large pharmaceutical engineering of salts. They’re not companies are investing in their looking at 50 different things.” own biologics capacity, he says, While the industry trend has adding that Cambrex is no longer been toward diversifying, Cam- involved in manufacturing tech- brex is locking in on the original nologies that are wholly different pharmaceutical service market Nettleton says high-potency technology is a “ticket to the from chemical production. and one that is still growing: dance” in small-molecule contract manufacturing. “It would be a very significant small-molecule APIs. investment, and we don’t have “There are a ton of small mol- Cambrex has a number of large con- the knowledge anymore since we ecules out there, and Cambrex is starting tracts, Bruno notes, notably with Gilead sold the biologics business,” he says. to capitalize on that, on their ability to Sciences, that have allowed it to expand. Still, it is most likely that Cambrex do smaller quantities, and on their being He speculates that the firm may fall in line will continue to invest in small-molecule a Western manufacturer,” Bruno says. “It with the competition and find an opportu- API production, Klosk acknowledges. “I points to them being in the right place at nity outside its small-molecule box. don’t feel an obligation or a need to do an the right time.” “If they were to buy a stand-alone fa- acquisition in what I’m calling tangential He adds that while pipelines are filling cility, even in biologics, I wouldn’t be in services,” he says, “meaning we feel good with large-molecule drug candidates, on- the least surprised,” he says. Biologics are about the small-molecule API business. cology drugs are a major drug-industry APIs and would be an extension of Cam- We need more capacity, and the market focus, and many of them are based on brex’s core business of API production. “If is strong. It makes sense for us to look to high-potency small molecules. they bought a dosage facility,” Bruno adds, grow in small-molecule APIs.” ◾ CAMBREX CREDIT:

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ENA.A1.0172.B.US-CEN.indd 1 Full page journal ad Chemical and Engineering News – CEN 9/8/2017 9:44:00 AM ELECTRONIC MATERIALS As chips shrink, cleaning needs grow Suppliers of electronic cleaning chemicals seek to remove even trace contaminants

MICHAEL MCCOY, C&EN NEW YORK CITY

ew materials deserve a lot of credit for helping minia- turize the computer chips that make our smartphones smart and keep our data centers humming. Hafni- N um-based dielectric materials, for example, are helping shrink transistors in Intel’s latest chips. Cobalt-containing Companies drogen peroxide with plants in Singapore, organometallic thin films are protecting delicate chip features. such as Intel, South Korea, Taiwan, and Mesa, Ariz. But credit should also go to the high-purity cleaning and par- whose Hillsboro, Scott Hancock, chief financial officer ticle-removal chemicals that underpin the chip-making process. Ore., chip of MGC Pure Chemicals America, a U.S. After every application of an exotic material to a silicon wafer, a manufacturing subsidiary, explains that the new plants meticulous cleaning step is needed to remove leftover particles plant is shown, are will use a homegrown purification process and other unwanted gunk. While new chip fabrication materials setting ever-higher to turn out hydrogen peroxide with trace get the headlines, ultra-high-purity cleaning chemicals are unsung cleaning-chemical contamination in the part-per-trillion lev- heroes making them possible. purity standards. el. “Our best advances and state-of-the-art They may not get respect, but these chemicals are profitable, technology will be incorporated into the and demand for them is growing. Manufacturers are investing in new plants,” he says. both new facilities and new technologies for making them as pure Hydrogen peroxide’s main use in the as possible so they don’t contribute unwanted gunk of their own. semiconductor industry is to create two As they get down to part-per-billion and part-per-trillion impurity “We are standard cleaning compounds known as levels, however, the purification task gets ever harder. SC1 and SC2. SC1, a mixture of hydrogen “We’re at a point now where we have to detect particles that effectively peroxide and ammonium hydroxide, re- are a similar challenge to finding a handful of quarters in the state operating moves organic matter and particles from of Massachusetts,” says James O’Neill, chief technology officer of silicon wafers. SC2, a mixture of hydrogen Entegris, a Massachusetts-based firm that makes high-purity pro- in a regime peroxide and hydrochloric acid, removes cess chemicals and systems for handling them. residual trace metals and metal hydroxides. High-purity cleaning chemicals for electronics are low profile where Gas Innovations, meanwhile, is target- in part because they constitute a modest-sized business. Global we can’t ing its anhydrous HCl at the dry-etching sales are about $1.5 billion annually out of an estimated $12 bil- process, in which unwanted material is lion market for semiconductor materials overall, says KMG directly selectively removed from a silicon wafer’s Chemicals, a U.S. firm that calls itself the world’s leading supplier surface using a mask. of high-purity process chemicals. see the Ashley Madray, president of Gas Inno- KMG built its business largely by acquiring high-purity chem- vations’ eHCL Innovations unit, explains ical lines from companies such as Air Products & Chemicals and stuff that his company got into the anhydrous OM Group. In its latest fiscal year, KMG had electronic chemicals we are HCl business in 2009 to supply high-puri- sales of $262 million; its largest customer is Intel. ty product to customers in the electronics Other firms are investing in new production with an eye to trying to and drug industries. But the increasing capturing growth in the business. Japan’s Mitsubishi Gas Chem- purity standards of the electronics indus- ical recently announced plans to spend $60 million by 2019 to remove.” try eventually caught up with Gas Innova- build two super-pure hydrogen peroxide plants in the U.S. The tions. “We had a product that was subpar,” facilities are set to open in Oregon and Texas, home to semicon- —James O’Neill, Madray acknowledges. ductor plants operated by Intel and Texas Instruments. chief technology When new purification equipment And in August, a U.S. company, Gas Innovations, said it will officer, Entegris is installed later this year, eHCL will be build a facility in La Porte, Texas, that upgrades industrial anhy- able to satisfy its customers’ heightened drous hydrogen chloride to a purity level of more than 99.999%. needs, Madray says. It will also install gas It expects to begin high-volume production early next year. chromatographs and inductively coupled

Mitsubishi Gas Chemical is already a leader in high-purity hy- plasma mass spectrometers to test all con- INTEL CREDIT:

32 C&EN | CEN.ACS.ORG | OCTOBER 9, 2017 taminants to part-per-billion levels and 20 become critical considerations in chemical media to match the specific chemicals that individual metals to part-per-trillion levels. performance,” he says. need to be purified. “No longer can you Hydrogen peroxide and HCl—both an- Entegris’s O’Neill points out that mere- take a filter off the shelf, throw it on your hydrous and hydrous—are two of the bulk ly manufacturing an ultra-high-purity favorite chemistry, and expect it to work,” high-purity chemicals used in semiconduc- chemical is no longer enough. Purity must O’Neill says. tor processing. Others, explains Michael be maintained along the chemical’s entire The introduction of new materials into Corbett of the electronic materials advisory supply chain by use of the right filtration, chips can cause big changes to long-stand- firm Linx Consulting, include isopropyl al- packaging, and fluid-handling equipment. ing cleaning formulas. For example, the cohol, ammonium hydroxide, and sulfuric, emerging use of cobalt in barrier films has hydrofluoric, nitric, and phosphoric acids. Cleaning up forced the reformulation of residue-remov- Together, Corbett says, these eight High-purity versions of standard acids ing solvents to avoid galvanic corrosion products represent 70% of the bulk wet and bases dominate the electronics between copper chip circuitry and cobalt, cleaning chemicals business. The rest con- cleaning market. O’Neill points out. New tungsten-based sists of formulated products that carry out barrier layers further complicate cleaning. Post-CMP Photoresist Environmental concerns can force niche residue removal and stripping tasks. cleaners strippers Corbett figures that the semiconductor 7% 6% change as well. Since 2013, Entegris has industry’s move from 28-nm to 16-nm requalified thousands of fluoropolymer Post-etch circuitry increased the number of clean- residue Acids, bases, materials-handling products to ensure ing steps required from 30 to 62. And removers and solvents they are free of the carcinogen perfluo- that shrinkage continues: The circuitry in 17% 70% rooctanoic acid. At the request of custom- today’s most advanced chips is single-dig- ers, Entegris has also been removing te- it-nanometers wide. tramethylammonium hydroxide, a solvent One source of the increased number 2017 market = $2.13 billion that poses neurotoxicity concerns, from of cleaning steps is multiple patterning, a post-etch residue removers, O’Neill says. CMP = chemical mechanical planarization. technique for doubling, tripling, or even Source: Linx Consulting These changes are taking place as En- quadrupling circuit line density by over- tegris and other companies are removing laying one lithographic pattern on top of “If I make it in Texas and ship it to cleaning chemical contaminants down another. Another is the introduction of Taiwan, it better be the same when it gets to sub-20-nm sizes that are extremely three-dimensional chip features that re- there,” he says. “There’s an enormous op- difficult to detect with current analytical quire more processing steps to implement. portunity to mess up this chemistry.” equipment. “We are effectively operating “Additional processing steps mean more As purity requirements ratchet up, new in a regime where we can’t directly see cleaning steps,” Corbett adds. technology is often required, O’Neill says. the stuff we are trying to remove,” O’Neill Moreover, as chip architecture shrinks, Take filtration. The strategy of reducing says. the purity demands on cleaning chemicals filter pore size is reaching the limits of During a presentation at the Semicon increase. Jeff Handelman, KMG’s senior its effectiveness because flow rates are West trade show in July, O’Neill warned vice president for electronic chemicals, getting too low. Increasingly, Entegris that the next generation of semiconductor explains that even the minutest particles and other firms are using a process that manufacturing will require purity levels can block or inhibit electrical connections O’Neill calls affiliative filtering in which measured in parts per quadrillion—like in modern chips. “Because line width in a membrane surface is functionalized to finding one minnow in San Francisco Bay. integrated circuits is so small now, particle remove a targeted contaminant. Maybe the cleaning chemicals industry filtration and process management have But that requires engineering filtration does deserve a little more respect. ◾

OCTOBER 9, 2017 | CEN.ACS.ORG | C&EN 33 REGULATION Perspectives: A new world for pharma contractors Trade association chief describes his move from the trenches of journalism to the front line on regulatory and legislative issues

GIL ROTH, PHARMA & BIOPHARMA OUTSOURCING ASSOCIATION are less apt to speak with the press and seemed to move personnel in and out of ast month, I testified before the evolution in the drug industry’s business outsourcing management positions too U.S. House of Representatives’ model for manufacturing in which out- rapidly for me to get to know them. Energy & Commerce Commit- sourcing advanced to the point of some As a journalist, I witnessed the drug L tee’s Subcommittee on Health drug firms shuttering their small-molecule companies’ increased comfort with exter- about a proposed over-the-counter (OTC) production plants altogether. nal sourcing to dosage form manufacturers, monograph user fee. This fee would be Such a huge makeover inevitably led to which led CMOs to offer early-stage devel- paid to the U.S. Food & Drug Adminis- regulatory changes with staggering cost opment services, giving rise to a new enti- tration by manufacturers of OTC drugs implications for contract manufacturers. ty: the contract development and manufac- with an FDA-registered list of ingredients This diverse set of outsourcing companies, turing organization (CDMO). These CMOs to help fund staff to review changes to crucial to the contemporary pharmaceuti- and CDMOs, which are not necessarily API formulations of those products. I was the cal supply chain, needed a comprehensive makers but are focused primarily on mak- fifth of five industry representatives to definition and a unified voice, both of ing finished dosage forms of medicines, testify at that session. We each had five which were lacking in 2012 during the first became increasingly important both to minutes for our oral testimony, which authorization of the Generic Drug User the global pharma supply chain and to the meant I had 20 minutes or so to wait while Fee Amendments (GDUFA), which deter- growth of big pharma’s R&D pipelines. In sitting at a table facing elected House mine fees that industry pays to fund FDA’s essence, a new concept in contract services members and their staff. generic-drug review process in conjunc- had arrived, one that faced new challenges I found myself wondering how I, a long- tion with the FDA Safety & Innovation Act. in providing pharmaceutical services. time trade magazine editor with a liberal In 2013, a year after the act was signed The article I wrote about GDUFA fo- arts background, ended up in this particular into law, I was reporting on GDUFA for cused on important distinctions between hot seat. The simple answer is that I had Contract Pharma, a magazine about con- the dosage form interests of CMOs and recently switched careers and was testifying tract services on which I had been found- CDMOs and the interests of the API as the president of the Pharma & Biophar- ing editor since 1999. Over the years, I’d contract firms. The first round of annu- ma Outsourcing Association (PBOA), an or- built strong relationships with the dosage al finished dosage form facility fees, a ganization I helped start in order to repre- form contract manufacturing organiza- subset of the user fees paid by industry, sent the interests of the firms I’d covered— tions (CMOs) that I wrote about—stron- had been assessed months earlier, and contract manufacturers of pharmaceutical ger than those I’d developed with their dosage form contractors were undergo- products. The impetus for this move arose customers, which are drug companies that ing sticker shock. They’d never seen a from a fundamental and user fee program that defining change in the levied fees directly on field of contract services in manufacturing facilities. pharmaceuticals, one that Under the Prescription created the need for better Drug User Fee Act, fees representation on Capitol were assessed, but FDA Hill and beyond. sent invoices directly to In recent years, the the holders of new drug contract services sector, applications or biologics which converges on Frank- license applications—that furt on Oct. 24–26 for the is, to the drug companies annual CPhI Worldwide that outsourced manufac- conference and exposi- turing, not to the actual tion, has evolved from manufacturer. primarily supplying active CMOs were stunned by pharmaceutical ingredi- the size of the facility fees, ents (APIs) under contract about $175,000 in that with drug companies to- first year—they’d escalate ward manufacturing fully in future years—but they formulated drug products were just as amazed that for those companies. The PBOA’s Roth testified recently before a House subcommittee on setting these user fees could be

shift resulted from a major user fees for drug manufacturers. instituted without any in- GIL ROTH/C&EN CREDIT:

34 C&EN | CEN.ACS.ORG | OCTOBER 9, 2017 put from their industry. The article I wrote other industry stakeholders regarding GD- was brimming with anonymous quotes UFA, which requires reauthorization every from CMOs; the respondents were con- five years. We came out of the negotiation Why Mix cerned that attaching their names to these in August 2016 with a better deal for CMOs, comments could lead to trouble. one that reduced the fee burden by creating I recall thinking, “Man, these guys really a separate tier for CMO facilities. Just 1? need some sort of trade association to rep- When PBOA launched, I was naive resent them in front of FDA.” I filed that enough to think that its work could be When you thought away for a few months until the constrained to FDA relations, but I rapidly president of a CMO approached me at a learned that a presence on Capitol Hill is can Vortex trade show with the exact same idea. necessary for any trade association. Many Turns out this executive and some of issues are shaped there before they reach his peers were seeing new FDA, so I’ve had to register Mix all 26. regulatory requirements that I recall as a lobbyist and learn how they believed didn’t take into to negotiate the halls of Con- account the practical aspects thinking, gress (with the assistance of of a dosage form contractor, a D.C.-based advocacy firm). essentially treating them like “Man, these After our work on GDUFA a drug’s license holder in ways guys really reauthorization, PBOA has that created irreconcilable worked with FDA and other regulatory burdens. With his need some industry associations on qual- repeated prodding, I organized sort of trade ity metrics and serialization a symposium of 35 or so CMO implementation, the afore- and CDMO staffers that fall, association mentioned OTC monograph the evening before Contract to represent user fee, and inspection Pharma’s annual conference. issues, focusing on areas in There I debuted our unofficial them in front which the CMO/CDMO per- mantra, an adage popularized of FDA.” spective may differ from that by former Louisiana Sen. John of pharmaceutical license B. Breaux, now a health care industry con- holders and other service providers. sultant and lobbyist: “If you’re not at the This year, we conducted extensive lob- table, you’re probably on the menu.” bying efforts to educate Congress about That evening in September 2013, we the role PBOA members play, not just in reached consensus that a trade association producing quality, cost-effective, life-sav- was necessary for this sector and that con- ing medicines for their customers, but also tract firms were ready to take their seat at in providing development services that the table. The CMOs and CDMOs I worked enable start-ups to conserve capital and with over the years trusted that I would advance their innovative molecules. be able to organize them effectively. More All of which brought me to that panel importantly, they trusted me to not play fa- before the House subcommittee a few vorites. I never worked at any of their firms weeks ago. The proposed OTC monograph or any pharma company. Although that user fee relies on dosage form manufactur- was a negative in terms of developing an ing facilities for its revenues, and my mem- insider’s perspective on how the business bers were interested in making sure the fee worked, it meant I wasn’t in anyone’s pock- was fair, was equitable, and respected the et. By the same token, the contract firms economics of the CMO/CDMO sector. I believed I understood enough about the hadn’t covered OTC manufacturing during market distribution of the industry to build my editorial days, but PBOA achieved its a dues model that allowed smaller compa- goal through negotiations with FDA and nies to join without ceding too much of the other stakeholders, and I was able to sit finances to the largest members. beside my peers and testify about the value Multi Reax I resigned from Contract Pharma, and of OTC monograph reform and the key the new organization, PBOA, incorporated role CMOs and CDMOs can play in bring- in June 2014 with 15 member companies. ing new drug formulations to market. We filed for nonprofit status, nominated And no one questioned what I was do- trustees, approved bylaws, and got to work ing on the panel. demonstrating to FDA that we were an important stakeholder in GDUFA and many Gil Roth is the founder and president of the 224-265-9600 | [email protected] other topics. Pharma & Biopharma Outsourcing Associa- HeidolphNA.com By October 2015, I found myself in a new tion, a nonprofit trade association launched world, traveling up and down the Northeast in 2014 for contract manufacturing orga- Regional Amtrak line between Newark, N.J., nizations and contract development and and Washington, D.C., representing CMOs manufacturing organizations. It is based in and CDMOs in negotiations with FDA and Ringwood, N.J.

OCTOBER 9, 2017 | CEN.ACS.ORG | C&EN 35 Career ladder Michael Malaska Know a chemist with an Chemist turned a hobby into a job in space science interesting career path? Tell C&EN about it at cenm. ag/careerladder. TAYLOR C. HOOD, C&EN WASHINGTON

1965 1991 Young love for bugs From metallic to medicine Growing up in the Seattle area, Michael While getting his doctorate, Malaska developed an Malaska (left) was always intrigued by science interest in medicinal chemistry, so after graduation, and geology and often went to look at insects he did a postdoc with Alan P. Kozikowski at Mayo and rocks near the seashore. In high school, Clinic Jacksonville studying neurochemistry. After his Malaska became interested in physics and postdoc, Malaska was hired as a research scientist astronomy but decided to switch to chemistry at the French firm Rhône-Poulenc working on the after starting college at Massachusetts neurochemistry of insects. “It was kind of perfect for Institute of Technology in 1982. “The first me because it combined my love for bugs with my love class I took was organic chemistry, and I really for chemistry. I thought, ‘Are they really paying me for liked the way the shapes and the structures this?’ ” he remembers. He worked in France for three moved around. It was kind of like learning years as part of an effort in combinatorial chemistry. a different language,” he says. He became He returned to the company’s division in North Carolina interested in organometallic chemistry, which and later became a manager in medicinal chemistry as he pursued for his Ph.D. at the University of part of a spin-off company, Scynexis. California, Berkeley, under K. Peter C. Vollhardt.

2005 Today Hobby turned career Out-of-this-world Malaska was laid off in 2012 when Scynexis downsized its scientific volunteering staff. Almost immediately, he volunteered as a field geologist with the Malaska never lost his interest in geology and North Carolina Geological Survey to gain field geology experience. He astronomy. For fun, he started posting on successfully applied for a senior NASA postdoctoral position at JPL. unmannedspaceflight.com around 2005. “Initially, He’s now a scientist in JPL’s Planetary Ices Group, focused primarily I just started off lurking on it as a fan site, but over on the ocean worlds of the solar time, I got more and more interested and started system, especially those on digging into the literature,” he says. He was contacted the moons Titan, Europa, and by a team member of the National Aeronautics & Enceladus. “I’m kind of doing a Space Administration’s Cassini mission and was million things at once,” he says. invited to participate in workshops mapping Saturn’s He conducts research in the lab, moon Titan and talk with researchers from NASA’s such as simulating Titan’s cryo- Jet Propulsion Laboratory (JPL). genic hydrocarbon lakes, and he helps design future missions. He also travels around the world to conduct research in extreme environments. “I was dabbling in everything when I was younger and I’m still kind of dabbling in everything now.” CREDIT: COURTESY OF MICHAEL MALASKA (ALL) OF MICHAEL MALASKA COURTESY CREDIT:

36 C&EN | CEN.ACS.ORG | OCTOBER 9, 2017 Visit us at CPhI Worldwide VisitFrankfurt. us at HallCPhI 6.0 Worldwide Booth 60D53 Frankfurt. Hall 6.0 Booth 60D53

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NEW TECHNOLOGY PROMISES GREENER CHEMISTRY A simplified, standardized benchtop instrument for electrochemistry brings this powerful and clean synthetic method within reach of the broader organic chemistry community

BY MICHAEL EISENSTEIN C&EN BrandLab Contributing Writer

hil Baran’s message to the chemistry aluminum, polyvinyl chloride, and floral fragranc- community was clear: It’s time to clean up es for detergent. Pits act. When Baran, professor and Darlene Shiley Chair in Chemistry at Scripps Research But despite being robust and efficient, electro- Institute California, took the stage at an IKA- chemistry also remains a niche tool, relegated to sponsored keynote lecture at the ACS fall national either industrial production-scale or bench-based, meeting in Washington, D.C., he unveiled a secret analytical-scale use. “When you talk to people who weapon that would allow researchers to begin to do real chemistry, whether they’re in the medicinal truly deliver on the promise of sustainable, green chemistry environment or making agrochemicals chemistry. Although the technology presented that or materials, you’d be really hard-pressed to find morning was state of the art, it was rooted in a form people who do electrochemistry,” said Baran at the of chemistry that dates back more than 150 years. start of the event. Baran himself is only a recent convert. In 2014, his lab was struggling with a The use of electrical current to catalyze chemical stubborn natural product synthesis project. It fell reactions—known more generally as electrochem- into line only when he found that Ph.D. student istry—can be traced all the way back to Michael Brandon Rosen was willing to tackle it with an Faraday’s work in the 1830s and is widely used in electrochemical approach. “Desperation,” recalled the industrial manufacture of materials, including Baran. “That’s how we were brought to it.”

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At his presentation on Aug. 22, it was obvious that Baran came as an elec- A POTENT PARTNERSHIP trochemical evangelist, armed with a powerful and simple new instrument that he believes will win over many more converts. This new system, called Baran’s collaboration with IKA began roughly three years ago, when ElectraSyn 2.0, was developed through close collaboration between Ba- the company’s owner and president, René Stiegelmann, visited Scripps. ran’s group and instrument manufacturer IKA. Baran offered an in-depth Stiegelmann was impressed by Baran’s passion and intellect. When the introduction, as well as live demonstrations, to show how ElectraSyn 2.0 concept of building a next-generation electrochemical tool came up, can make electrochemistry more readily accessible to chemists. Stiegelmann was concerned about doing right by the project. “I knew that to work with this guy, we would have to give everything,” says DIY DIFFICULTIES Stiegelmann. “We got our best engineers from all over the world, and three months later, we had a research center in San Diego.” This setup In principle, electrochemistry can make synthetic reactions faster and permitted routine cross-pollination between Baran’s chemists and IKA’s simpler. However, technology remains a critical hurdle to would-be engineers, and the company worked at a breakneck pace to complete electrochemists because simply the process of setting up the tech- the first instrument. The instrument Baran presented was designed and nique in the laboratory can be overwhelming. A typical produced within two and a half years of its original inception, laboratory setup comprises a jury-rigged amalgam of wires, after countless prototypes and more than 30,000 person-hours electrodes, potentiostats, voltammeters, glassware, and of engineering work. more that can devour most of the space in a typical fume hood. “Potentiostats and Baran praised the efforts of the engineers galvanostats have been available for the to bundle so many functions into a single specialists, but not general users,” says instrument that occupies minimal benchtop Shelley Minteer, an analytical chemist at space. “’No’ is simply not in their vocab- the University of Utah who routinely uses ulary,” he says. “The device incorporates a electrochemistry. “And even with the po- potentiostat and a stirring plate, and you tentiostat or galvanostat, you are plagued might think that would be easy. But there with trying to understand what electrodes is a thing called the electromagnetic effect and what cell geometry to use.” where it’s difficult to have a magnetic field and an electric current at the same time and This lack of robust standards or repro- have it be stable.” ducible instructions on how to design and perform an electrochemical synthesis He also highlighted the ElectraSyn interface, makes it a hard sell. “There’s definite- which uses software called Smart Assist to ly a stigma that’s grown up around the monitor the reaction conditions and offer technique,” says Patrick Harran, chair of suggestions to users on how to proceed. As organic chemistry at the University of Cal- an initial demonstration, Baran began an ifornia, Los Angeles. “I have a colleague electrochemical reaction on stage—the diflu- who jokingly cringes every time someone oromethylation of caffeine—and followed the mentions electrochemistry.” machine’s cues to select electrodes, solvent, power levels, and more. But at the same time, the community is aware of its potential. Baran recalls the In a second demonstration, he used the device response he got at a recent medicinal to take cyclic voltammetry readings of TEM- chemistry conference. “Everybody there PO, a commonly used catalyst. “Usually, you agreed that electrochemistry was exciting need a separate $5,000 instrument … to find but nobody had done it,” he says. “And then out the redox potential of your molecule,” he when they went and found out what the said. Finally, Baran moved into less well-chart- shopping list is—it’s like making a home- ed territory, programming the ElectraSyn made nuclear warhead!” This is especially to perform a newly invented, nickel-cata- problematic because the quicker solutions, lyzed aryl carbon-nitrogen bond-formation such as chemical catalysts, are also far dirtier. reaction. The reaction was described in an Chromium catalysis, for example, can exert The ElectraSyn 2.0 combines a potentiostat, Angewandte Chemie paper (DOI: 10.1002/ a toll on both the environment and human analytical tools, and a magnetic stirrer with a anie.201707906) that went live concurrently health. “Electrochemistry provides a more simple software interface intended to acceler- with his presentation. energy efficient and sustainable approach to ate the planning and execution of electro- synthesis,” Minteer says. chemical syntheses. Above all, Baran emphasized that the instrument was intended to enable consistent It was the combination of these factors that gave performance from experiments regardless rise to IKA’s ElectraSyn 2.0, an integrated and standardized instrument of where in the world they are being done. Earlier in his lecture, he for electrochemistry. In an instrument with the approximate footprint of recalled being confronted on Twitter about the reproducibility of his a laboratory balance, the ElectraSyn combines a potentiostat, analytical early electrochemistry work. This complaint was grounded primarily tools, and a magnetic stirrer with a simple software interface intended to in the inherent difficulties of successfully setting up an electrochemical accelerate the planning and execution of electrochemical syntheses. On experiment; this situation was rectified only after the online community stage, Baran noted that this instrument represents the first benchtop tool rallied to help the frustrated scientist reproduce Baran’s electrochemical of its kind in more than 70 years, since IKA released its original Electra- experiment. But if researchers can now obtain access to a standardized Syn instrument. collection of electrodes and experimental configurations, such complaints

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may become a thing of the past. Baran noted that the instrument’s price ment to expand these capabilities further, including a carousel system of $1,399—roughly the same as a magnetic stirring plate—makes it far that can be plugged into ElectraSyn to enable up to six reactions to be more accessible than a conventional electrochemistry apparatus, which performed in parallel. Minteer highlights this as a much-needed upgrade. can cost anywhere from $7,000 to $70,000. “The ability to multitask and have multiple electrochemical cells running simultaneously will be important,” she says. “Electrochemistry provides a more IKA has also developed and launched a higher-throughput version known as the ElectraSyn Flow, capable of performing energy efficient and sustainable reactions with output at the multikilo- approach to synthesis.” gram scale. The software will also be routinely up- SHELLEY MINTEER dated to include new reactions, including University of Utah contributions developed over time by the ElectraSyn user community.

Stiegelmann and Baran are proud of the ELECTROCHEMISTRY WITHIN REACH instrument that debuted at the ACS fall national meeting, but both men also recognize that IKA’s work is far In addition to Baran, 15 other research teams around the globe have got- from finished. Stiegelmann looks at each purchase of ElectraSyn as a ten hands-on experience with the ElectraSyn 2.0 as part of IKA’s pioneers long-term investment in a tool that will evolve over time in response to program. The feedback has been broadly positive. “We loved it,” says feedback from researchers. “If you buy products from IKA, you are buy- Minteer, who was part of the testing program. “It is very straightforward ing support and development for future products,” he says. “This is what and easy to use and priced extremely well.” gives us fuel for additional development.”

Other chemists, who did not participate in the IKA pioneers program, But finished or not, Baran sees ElectraSyn as an immediate opportunity were likewise impressed by the presentation and believe the instrument to directly test the organic chemistry world’s commitment to being envi- could be a powerful tool for winning over chemists reluctant to embrace ronmentally responsible. “Is it all talk, or is it real?” he asks. “Chemistry electrochemistry. “I think it’s an exciting development,” says Oana Luca of is often labeled as a dirty and polluting field, but if we think about what the University of Colorado, Boulder. “It will likely attract attention to some is the thermodynamic end point of the most sustainable chemistry that of the electrochemical methods currently utilized in the field and provide exists on Earth currently, it’s electrochemistry.” an accessible benchtop option for electrochemical reaction development.” She notes that it may not be able to perform the entire range of experiments that a high-end potentiometer would enable, but it should nevertheless be broadly enabling for synthetic chemists. Harran concurs, adding, “The lower the barrier for entry, the better.”

Although designed with professional chemists in mind, Baran made clear that he considers this an “everything instrument” that includes a user-friendly introduction to electrochemistry for undergraduate and graduate student, or even high school, classrooms. This accessibility will also be an important element of strengthening the field, from Luca’s perspective. “I think one of the barriers to adoption has been the lack of synthetic electrochemistry in any of the chemistry curricula,” she says.

This first iteration of the system is designed to enable individual reactions at the preparative Phil Baran of The Scripps Research Institute described in a lecture at the ACS national meeting how scale. However, other modules are in develop- he and his team collaborated with IKA engineers and scientists to develop the ElectraSyn 2.0.

ABOUT SPONSORED CONTENT Sponsored content is not written by and does not necessarily reflect the views of C&EN’s editorial staff. It is authored by writers approved by the C&EN BrandLab and held to C&EN’s editorial standards, with the intent of providing valuable information to C&EN readers. This sponsored content feature has been produced with funding support from IKA.

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ike the army of White Walkers beyond the brink who march haltingly across the tundra in the HBO Emboldened by real-world success and powered by CRISPR, a new wave series “Game of Thrones,” of biotech firms is revisiting the concept of synthetic lethality in cancer cancer cells trudge along in a menacing, but hobbled, state. LISA M. JARVIS, C&EN CHICAGO LThe same genetic defects that help them proliferate also render them vulnerable to attack. Find the right molecule for the right weak point, and it’s like charging the White Walkers with knives made of dragonglass: They’re done for. For several decades, small-molecule cancer drug researchers have dug In brief for dragonglass among the kinases. By designing small molecules that can “turn off” kinase enzymes stuck in the “on” position, they have managed to A new generation of can- ward off cancer’s attack. More recently, scientists have focused on ways to cer-focused biotech firms is help the body’s own immune cells seek and destroy cancer cells. reviving drug discovery driven But those approaches haven’t cured all cancers. Immunotherapy, while by synthetic lethality, the con- fantastically effective for some people, doesn’t work for everyone. And cept that specific combinations many of the best-known causes of cancer remain “undruggable”; chemists of mutations are deadly to cells. can’t come up with molecules that safely disrupt their activity. Newfound excitement about Take gastric cancer, for example. “Immunotherapy doesn’t work for the century-old idea is fueled by the majority of patients. There are no active targeted therapies, and real-world experience with PARP chemotherapy is only modestly effective,” points out Barbara Weber, inhibitors, which are the first chief executive officer of the oncology-focused start-up Tango Ther- class of drugs to work by the apeutics. Worse, most cancers feature at least one important gene mechanism, and by the potential that has lost its function. “The problem is that when gene function for companies to use the power- is lost or the gene is gone entirely, you can’t target them,” Weber ful gene-editing tool CRISPR to adds. find new and more reliable syn- Enter the concept known as synthetic lethality. Researchers have thetic lethal drug targets. long known that a cancer cell hobbling along with one broken gene is vulnerable. Knock out another key gene, they have discovered, and the cell will topple. The notion of killing cancer cells by damaging their already com- promised DNA should sound familiar. Chemotherapy agents do just that, but by using a sledgehammer to smash away at DNA. Because drugs that exploit synthetic lethality act with precision, they promise to be able to discriminate between healthy and diseased cells. Companies have already developed a class of drugs called PARP inhibitors that take advantage of a synthetic lethal interaction to treat certain types of ovarian cancer. Now, motivated in part by the real-world proof that the concept can work, a new wave of biotech firms is digging for dragonglass here. They are counting on the potential for the powerful gene-editing tool CRISPR to crack open the next generation of oncology drug targets.

42 C&EN | CEN.ACS.ORG | OCTOBER 9, 2017 OCTOBER 9, 2017 | CEN.ACS.ORG | C&EN 43 Sidetracked Geneticist Calvin Bridges first wrote “You’d burn through postdocs about synthetic lethality nearly a century ago, after noticing that fruit flies with certain combinations of genetic muta- very rapidly because the tions died, while their parents, which har- bored just one of the defects, survived. targets would not validate.” A colleague coined the term, using the original Greek meaning of the word “syn- —Barbara Weber, CEO, Tango Therapeutics thetic”: combining two things to form something new. DNA breaks would be enough to kill them. But iniparib’s failure continued to In the intervening years, other re- That led oncologists to think that PARP weigh on the field of synthetic lethality. searchers explored the concept and tried could work as a synthetic lethal drug tar- “It’s really very easy for a whole field to to exploit it in drug discovery. But many get and that PARP inhibitors might be ef- almost get stalled because of what is ef- decades passed before cancer drug devel- fective on their own. Indeed, early studies fectively an erroneous result,” says Chris- opers had a good test case. showed promise in using PARP inhibitors topher Lord, leader of the gene function Along came PARP, or poly(ADP-ribose) to treat ovarian and breast cancers marked team at the Institute of Cancer Research polymerase, a family of enzymes that re- by BRCA mutations. in London. pair single-strand breaks in DNA. Drug de- Enthusiasm evaporated in 2011 when Despite the approval of that first PARP velopers first tried combining PARP inhib- Sanofi’s PARP inhibitor iniparib failed to inhibitor, “the pharmaceutical communi- itors, which precisely inhibit DNA repair, show benefit in a Phase III study of wom- ty has just sort of held its breath a bit and with chemotherapy, the DNA sledgeham- en with triple-negative breast cancer. The not really pursued DNA repair,” says Niall mer. The combination proved too toxic. result didn’t drag down just the com- Martin, CEO of Artios Pharma, which But the drug class found new life in pound; the synthetic lethality concept as is pursuing the concept of DNA damage 2005, when researchers showed that mu- a whole was tarnished. response. Martin led the team that devel- tations in BRCA genes decreased cells’ There was a problem, though: Iniparib oped Lynparza at KuDOS Pharmaceuti- ability to undergo homologous repair, a turned out to not be a true PARP inhibi- cals, acquired in 2005 by AstraZeneca. way of patching up double-strand DNA tor. A few companies stuck with the drug Even without the iniparib red herring, breaks. The defect caused cells to rely on class, culminating in three PARP inhibitors the field had other problems. Notably, the PARP to fix damaged DNA. The scien- winning approval to treat ovarian cancer: process of finding synthetic lethal gene tists reasoned that putting those already AstraZeneca’s Lynparza (olaparib), Clovis pairs that could kill cancer cells was ardu- stressed cells under more pressure by pre- Oncology’s Rubraca (rucaparib), and Tesa- ous and riddled with technical challenges. venting them from repairing single-strand ro’s Zejula (niraparib). Until recently, big drug firms and aca- It takes two Cancer cells that have lost key gene functions become reliant on backup pathways. Synthetic lethality exploits that dependence to kill cancers while sparing normal cells.

Normal cell Normal cell Cell survival Genetic instability Drug prevents DNA repair Pathway B via pathway A inhibitor X

Cell with cancer-causing Cancer cell Cell death mutation Dependent on pathway B Synthetic lethality for repairing DNA DNA repair pathway A =

DNA repair pathway B = ASTRAZENECA/C&EN FROM ADAPATED CREDIT:

44 C&EN | CEN.ACS.ORG | OCTOBER 9, 2017 Lethal launches Since last year, a wave of biotech companies exploiting synthetic lethality have emerged.

DATE NAME FUNDING INVESTORS FOCUS Arkin Holdings, MS Ventures, Boehringer Synthetic lethal drug discovery aimed at cancer metabolism April 2016 Metabomed $18 million Ingelheim Venture Fund, Pfizer, Pontifax Fund, targets and Technion R&D Foundation

5AM Ventures, Canaan Partners, Celgene, Personalized synthetic lethal medicines and immuno-oncolo- May 2016 Ideaya Biosciences 46 million WuXi Healthcare Ventures, Novartis, and gy treatments targeting the tumor microenvironment Alexandria Real Estate Equities

SV Life Sciences, Merck Ventures, Imperial In- September 2016 Artios Pharma 33 million novations, Arix Bioscience, CRT Pioneer Fund, DNA damage repair inhibitors, including Polθ inhibitors and AbbVie Ventures

Tango March 2017 55 million Third Rock Ventures CRISPR-enabled synthetic lethal drug discovery Therapeutics

Repare CRISPR-enabled synthetic lethal drug discovery, including June 2017 68 million Versant Ventures and MPM Capital Therapeutics Polθ inhibitors Flagship Pioneering, Polaris Partners, Arch CRISPR-based platform for immunology and oncology drugs, October 2017 KSQ Therapeutics 76 million Venture Partners, and Alexandria Real Estate including DNA damage repair inhibitors Equities

Polθ = DNA polymerase θ. Source: Companies demic researchers spent much time and were problematic. “You’d burn through lem: CRISPR, the powerful gene-editing energy screening for novel cancer targets postdocs very rapidly because the targets technology that in just a few years has using RNA interference (RNAi) tech- would not validate,” Weber adds. “There become a workhorse of industrial and nology. In order to generate clues about was no real threshold to separate the true academic labs. synthetic lethal drug targets, they filed positives from the noise.” Named for the “clustered regularly through giant libraries containing either interspaced short palindromic repeats” small interfering RNA (siRNA), which are seen in the bacterial immune system short oligonucleotides that can direct- New generation from which the technology was discov- ly silence genes, or short hairpin RNA, The new biotech companies have ered, CRISPR allows genes to be turned which use a viral vector to dampen gene been motivated largely by a possible on and off with exquisite precision. expression. solution to the signal-versus-noise prob- Meanwhile, new information about The RNAi technology was alluring cancer genetics has proliferated, as but unreliable. Off-target effects were O have cancer cell lines for testing that rampant, and validating targets was F information. “In the last five years, daunting. Big pharma researchers who N tens of thousands of genomes from lived through that period—many of N cancer patients have been sequenced, whom now populate the biotech firms so that now we have a much better O working on synthetic lethality—look N understanding of what the mutational back in frustration. NH spectrum looks like,” Repare’s Zinda “When you ran a screen, you came says. out with a massive number of false O In addition, academic researchers positives,” recalls Michael Zinda, who worked out how to use CRISPR RNA previously led oncology bioscience at AstraZeneca’s Lynparza libraries to find new synthetic lethal AstraZeneca’s Boston research site and H interactions, and these discoveries now heads R&D at synthetic lethali- N F have become the basis for several ty-focused Repare Therapeutics. “It was well-financed companies. inefficient to dig through the gene set H3C N The $68 million in first-round fund- to find one or two real hits.” H ing for Repare was the biotech indus- Weber, who before taking the helm N O try’s biggest early-stage financing in H at Tango was head of oncology trans- the first half of 2017. That figure was lational medicine at Novartis, agrees. Clovis Oncology’s Rubraca surpassed this month by the fundrais- Both the publicly available academic O– ing for KSQ Therapeutics, which got screens and the ones going on in- O NH O O $76 million to build a CRISPR-based side companies yielded long lists of 2 S discovery platform that will be used + potential synthetic lethal gene pairs • H2O in part to pursue synthetic lethal drug N NH2 that ran the gamut from strong possi- N targets. bilities to ones with limited effect, she Academic and industry scientists says. are taking varied approaches to their Even the seemingly strong hits Tesaro’s Zejula screens. One method uses CRISPR

OCTOBER 9, 2017 | CEN.ACS.ORG | C&EN 45 guide RNAs to screen two cell lines that using CRISPR, not everyone sees the repairing DNA breaks that becomes im- are identical except for the knockout of technology as a panacea. University of portant when more prominent repair one key gene, and look for places where Sussex structural biologist and DNA dam- mechanisms, including the homologous the cells are perturbed differently than age expert Laurence Pearl likes to point recombination used by BRCA, are lost. others. out that screens are still just cells, not Both Repare and Artios are pursuing Polθ Another strategy is to screen a CRISPR humans. Using siRNA to knock down ex- inhibitors. library against a panel of cancer cell lines pression of a protein in a cell or knocking that includes cells with and without a out its gene by CRISPR/Cas9, is a whole mutation of interest—BRCA, for example. lot different from using a small molecule The bigger picture Good targets should cause a perturbation to block the function of a protein in the As companies that are focused on syn- in only the mutated cell line. body. thetic lethality proliferate, they are also Both methods produce a more refined “In experiments, you have a perfectly contemplating how their drug candidates list of potential targets than what was happy cell, you remove one gene and will fit into the quickly evolving oncology found with earlier technology. “With challenge it with one stress, and it dies. landscape. Cancer immunotherapies have RNAi screens, you would have lists with You think, ‘Yeah, I’ve got a target now!’ ” become a prominent part of the drug hundreds of genes that looked like po- says Pearl, whose lab is working on drugs pipeline, and every new firm has to con- tential hits,” many of which might not be against synthetic lethal targets. “But sider how its DNA repair inhibitors might legitimate, Zinda says. A CRISPR screen that’s not a tumor.” combine with already approved immuno- yields a more focused list of genes, the Simon Powell, chair of the department therapies, like checkpoint inhibitors and vast majority of which are “real,” he adds. of radiation oncology at Memorial Sloan the new immuno-oncology drugs. “Five years ago, I was lucky to have Kettering Cancer Center, agrees. “Right Although pairing DNA repair inhibitors RNAi,” says Frank Stegmeier, who pre- now, the field is okay at the cellular lev- with immunotherapies makes sense on viously led oncology target discovery at el,” says Powell, who is on the advisory paper, studying combinations in the lab Novartis. Now, as chief scientific officer board of Artios. “But finding drugs and is a challenge. “At the moment, we’re suffering from a dearth of data,” says the Institute of Cancer Research’s Lord. Be- cause the immune system is difficult to “Right now, the field is okay at the model in cells and animals, “there’s a big research gap about whether DNA repair cellular level. But finding drugs and and immunotherapy work together.” Still, one appeal of combining checkpoint and DNA repair inhibitors is the making sure they actually work in a perceived safety of the approach. Unlike adding kinase inhibitors to immunothera- real tumor is where they need to go.” py, which has proved toxic in some cases, —Simon Powell, chair of radiation oncology, Memorial Sloan Kettering Cancer Center, early clinical data suggest side effects aren’t exacerbated by PARP inhibitor-immunotherapy combinations. of KSQ, he’s amazed at how precisely he making sure they actually work in a real Even as they contemplate blue-sky can interrogate gene functions. tumor is where they need to go.” questions like how to meld theoretical Each biotech firm is trying to add its Biotech companies counter that the DNA repair drugs with an evolving im- own twist to the screening process. Tan- technology is also helping them pressure muno-oncology pipeline, executives from go, for example, identifies a subset of test their targets. “There’s a convergence recently established biotech companies people with cancer it would like to treat of understanding patient tumors through remain focused on the major task ahead: and then uses cell lines that match their sequencing, new technology like CRISPR, getting cancer drugs to the people who genetic profiles. And rather than a full as well as a proliferation of novel mod- need them. Although Tango, Repare, and CRISPR library, Tango interrogates the els allowing us to ask really much more KSQ have secured significant funding and cell lines using a tailored “druggable” informed questions and identify patient quickly grown to several dozen employ- CRISPR library so that it can create small populations who would best respond to ees, they still have a lot more work to do. molecules against the hits that come out our drugs,” Repare’s Zinda says. All of them have selected their initial of its screens. The next phase for these young bio- drug targets, but none of them expects KSQ, on the other hand, is going broad tech firms will be proving that this con- to have a compound in the clinic before and deep. The biotech has already gener- vergence does indeed lead to cancer-kill- 2019. ated massive data sets by knocking out, ing drugs. Companies are already well That’s not to say this new generation one gene at a time, the entire genome of into winnowing the hits emerging from of biotech firms doesn’t have grand am- nearly 600 cell lines. The firm says the CRISPR screens using factors including bitions. Oncology drug developers have vast screening effort will help it under- whether drugs already exist against those never been able to get at the genetic stand whether targets can be safely inhib- targets and how easily the hits can be changes caused by a loss in gene function. ited with drugs. broached with small molecules. Synthetic lethality is “the only way” to do Ironically, today’s most prominent that, Tango’s Weber says. “What I hope, synthetic lethal drug target is one iden- and what our experiments are now show- Dose of reality tified before the CRISPR craze. DNA ing, is that if you could get that piece, Although companies are enthusiasti- polymerase θ, encoded by a gene called you open up a whole new target space in cally forging ahead with target validation POLQ, is a key player in a method for oncology.” ◾

46 C&EN | CEN.ACS.ORG | OCTOBER 9, 2017 ACS COMMENT NEWS Thirty years of National Chemistry Week MICHAEL MCGINNIS, CHAIR, ACS COMMITTEE ON COMMUNITY ACTIVITIES

his fall, we will celebrate istry” includes two activities on making Connect with or—better yet—volunteer 30 years of National Chemistry crystals: “Epsom Salt Needle Crystals” and to be your local section’s NCW or CCEW Week (NCW). In 1987, when “Borax Crystal Snowflakes.” These activ- coordinator. Coordinators receive addition- T then-ACS Immediate Past Pres- ities will teach and inspire the young and al materials from the ACS Office of Vol- ident George Pimentel launched National the young at heart. For an additional twist, unteer Support, and they can order up to Chemistry Day, only he appeared to imag- head over to the online archive of NCW ed- five complimentary boxes of “Celebrating ine the lasting impact that the outreach ucational resources at www.acs.org/NCW Chemistry” (a total of 1,250 copies) and one event would have on the American Chemi- and download the activity “Making Stalac- complimentary box of the Spanish-language cal Society and the greater chemistry com- tites and Stalagmites from Epsom Salt.” version (250 copies) from the ACS Store. munity. During that first For anyone who has vis- “Celebrating Chemistry” has been vetted celebration, Pimentel led ited a cave or gone spe- for safety concerns, and it contains arti- ACS members and staff lunking, this activity is for cles and activities that are appropriate for in a parade down 16th Street in Washington, D.C., past the ACS head- What can you do to share the quarters building. By 1989, more than excitement of chemistry? half of ACS’s local sections had expanded their you. With materials from fourth- through sixth-grade students. In ad- celebrations to a week, home, you can set the dition to activities on growing crystals, this and in 1993 National foundations for your own year’s edition of “Celebrating Chemistry” Chemistry Day was offi- stalactites and stalag- also includes activities titled “The Salt of cially renamed National mites within 30 minutes; the Earth: The Story of Sodium Chloride” Chemistry Week. This after leaving the materials and “Caught between a Rock and a Hard year’s 30th anniversary overnight, you will likely Place: Rocks, Minerals, and Gemstones.” In theme of “Chemistry Rocks!” calls on find a splendid display of magnificent crys- addition, Meg A. Mole interviews educator NCW coordinators and ACS volunteers to tals the next morning. Now there’s some and soil scientist Elizabeth Herndon about bring the excitement of geochemistry to chemistry you can see! her geochemistry explorations. children and adults across the U.S. and the Did you know that all NCW themes have Do you know an outstanding outreach world the week of Oct. 22–28. an associated community event? The 2017 volunteer? In an effort to recognize the NCW enables ACS members to par- NCW community event is taking a trip to immeasurable outreach efforts made by ticipate in two of ACS’s four strategic learn about rocks and minerals. What is local section volunteers, the Committee goals: support excellence in education the neatest rock you have ever seen? What on Community Activities established the and communicate chemistry’s value. Last features made that rock so interesting? Local Section Outreach Volunteers of the year, nearly 40,000 people attended local What did you learn about that rock? Year recognition program. Each year, local section outreach events, and more than A fabulous way to engage the public is sections can recognize one individual who 150,000 copies of the NCW publication to show people the stories behind rocks. has demonstrated extraordinary outreach “Celebrating Chemistry” and the Span- You can partner with a natural history volunteer service within the section. ish-language version, “Celebrando la museum, visit a state or national park, or ACS chemists are called to commu- Química,” were distributed in the U.S. involve a local geologist to host a “rocks nicate chemistry’s vital role through The 30th anniversary celebration kicked hike” in your hometown. outreach. The impact of public outreach off at a “Chemistry Rocks!” concert at the What can you do to share the excite- efforts on the community can be signifi- fall ACS national meeting in Washington, ment of chemistry? ACS is advancing sci- cant. Visit www.acs.org/outreach, or call D.C. More than 300 people celebrated the ence, advocating for chemistry, enabling (800) 227-5558 for more information on contributions of current and past NCW career development, educating the public, NCW, CCEW, and other ACS outreach coordinators and volunteers. Nearly all supporting future chemists, and promot- programs. You can also connect online ACS local sections have identified NCW ing diversity. The Committee on Com- through the ACS Network, Facebook, and coordinators and are planning NCW activ- munity Activities’ NCW and Chemists Twitter. And as we celebrate the 30th ities this year. Celebrate Earth Week (CCEW, previously anniversary of NCW this fall, engage the One of my favorite activities with kids is Chemists Celebrate Earth Day) provide public with the theme “Chemistry Rocks!” growing crystals. The awe and excitement the tools and resources to educate the of watching “magic crystals” form is price- public and promote the value of chemistry Views expressed are those of the author and

CREDIT: MARK COLLIER/NORWICH UNIVERSITY MARK COLLIER/NORWICH CREDIT: less. The publication “Celebrating Chem- through outreach. not necessarily those of C&EN or ACS.

OCTOBER 9, 2017 | CEN.ACS.ORG | C&EN 47 ®

American Chemical Society NATIONAL CHEMISTRY WEEK (NCW) OCTOBER – ,

How to join the fun: Plan Discover resources to organize an NCW event in your area, free educational resources for K-12 teachers, and community event ideas. Participate Encourage students to participate in the Illustrated Poem Contest. Get Involved Find an NCW coordinator in your area to plan exciting community events. www.acs.org/NCW ACS PUBLISHING NEWS ACS launches two journals for applied materials research Titles aim to increase publication capacity, reduce publication time for energy and nanomaterials research

uilding on the success of ACS The deputy editor of ACS Applied Nano since its launch in 2009. The journal now Applied Materials & Interfaces Materials is T. Randall Lee, a chemistry declines to publish a majority of papers it (AMI), the American Chemical professor and associate dean for research receives, Schanze says. Schanze, Meyer, B Society in September launched in the College of Natural Sciences & Math- and Lee anticipate that the new journals two journals: ACS Applied Energy Materi- ematics at the University of Houston. “It’s will reduce time to publication and allow als and ACS Applied Nano Materials. a great opportunity to provide an avenue for publication of papers that would oth- The new journals fall under the purview for the rapid publication of interesting erwise have been rejected because AMI has of AMI and its editor-in-chief, reached capacity. Kirk Schanze, a chemistry AMI will continue to publish professor at the University of papers of broad and inter- Texas, San Antonio. Each new disciplinary interest. Energy journal has its own deputy Materials and Nano Materials editor and editorial advisory will be narrower in scope and board. likely allow more synthesis and The deputy editor of ACS characterization study than Applied Energy Materials is AMI, but they will still require Gerald J. Meyer, a chemistry a strong emphasis on applica- professor and his department’s tions, the editors say. vice chair of diversity at the “Applications in materials University of North Carolina, science is one of the most vi- Chapel Hill. “I think there’s brant areas of research globally a strong likelihood that this and has broad potential impact journal could be instrumental in solving critical problems in advancing energy research Gerald J. Meyer T. Randall Lee in energy, engineering, and and helping solve the world’s health and medicine,” says energy challenges,” Meyer says, noting and new nanoscale materials with an ap- James Milne, ACS’s senior vice president that although the journal’s topic is quite plications purpose,” Lee says, adding that for publishing. “We’ve been hearing from narrow, the range of chemistry involved is the journal will accept papers from a wide researchers on the need for high-quality broad. range of disciplines. titles that cater to their specific areas Meyer has served as an associate editor Lee has served as an associate editor of of applied materials science research to of AMI since 2012. His research focuses on AMI since 2010. His research centers on enhance the visibility and breadth of this excited-state transition-metal compounds the development of nanoscale materials work.” ACS plans to add other titles under that drive electron- or energy-transfer for applications in energy and medicine. AMI but has not disclosed specific topics. reactions in fluid solution and at semicon- The impetus for creating the two jour- ACS also publishes C&EN.—JYLLIAN ductor interfaces. nals was the exponential growth of AMI KEMSLEY

CAREERS SCI Scholars accepting applications The SCI Scholars Program is accepting Chemical Engineers to introduce chemis- teacher, who receives a certificate and applications for its 10-week industrial try and chemical engineering students to $1,000. internships. Up to 32 college sophomores careers in the chemical industry. Applicants must be U.S. citizens or per- and juniors will be selected for summer Participants receive a $6,000 to manent residents, college sophomores or 2018. $10,000 stipend and a certificate. An juniors, and chemistry or chemical engi- The SCI Scholars Internship Program additional $1,000 is provided to support neering majors and have at least a 3.5 GPA. was developed by the American Chemical further professional development. Partic- Applications will be accepted through Society, the Society of Chemical Indus- ipants also have the opportunity to rec- Nov. 30. For more information, visit www.

CREDIT: COURTESY OF GERALD J. MEYER; COURTESY OF T. RANDALL LEE RANDALL OF T. MEYER; COURTESY J. OF GERALD COURTESY CREDIT: try (SCI), and the American Institute of ognize an influential high school science acs.org/sci.— LINDA WANG

OCTOBER 9, 2017 | CEN.ACS.ORG | C&EN 49 Something new in peer-review education.

Announcing ACS Reviewer LabTM, a free online course from ACS Publications, designed to educate researchers on the fundamentals of peer review featuring six modules and interactive exercises.

SIGN UP FOR UPDATES AT acsreviewerlab.org ACS MEETINGS NEWS 69th Southeastern Regional Meeting LINDA WANG, C&EN WASHINGTON

he ACS Carolina-Piedmont Lo- cal Section will host the 69th Southeastern Regional Meeting T (SERMACS) at the Sheraton Charlotte Hotel in Charlotte, N.C., on Nov. 7–11. The general chair is Jordan Poler of the University of North Carolina, Charlotte. The program chairs are Dan Rabinovich, also of UNC Charlotte, and David Brown of Davidson College. The meeting theme is “Humans to Hybrids” and will feature five plenary lectures, Diversity Day, an exposition, a graduate school fair, K–12 programming, multiple poster sessions and workshops, and more than 30 invited symposia. SER- MACS 2017 is being held concurrently Charlotte, N.C. with the 2017 Solar Energy Research Cen- ter Conference and the North Carolina Photochemistry Symposium. ics such as résumé writing and how to as the keynote speaker. Later in the eve- identify your professional strengths and ning, meeting attendees can interact with Technical program. With more than 1,400 values. members of ACS governance during an submitted abstracts, the technical program On Saturday, Chemistry Educator ice cream social. Off-site events include will cover all the traditional areas of chem- Day will include an overview of the ACS the LGBTQ & Allies Social, and a Younger istry as well as bioinorganic chemistry, Project SEED program, activities for high Chemists Committee gathering at a local polymeric nanomaterials, biological mass school chemistry teachers, a plenary lec- brewery. spectrometry, organofluorine chemistry, ture by Eric Scerri of the University of The undergraduate program, with more analytical neurochemistry, microwave California, Los Angeles, on the periodic than 60 oral and 300 poster presentations, chemistry, heterocyclic carbenes, ionic table, and a live Chemistry Demonstration will kick off on Friday morning with a liquids, and the chemistry of fermentation. Extravaganza by Al Hazari of the Universi- breakfast and special lecture by Kathy The meeting will also highlight advances in ty of Tennessee, Knoxville. Reichs, a renowned forensic anthropolo- sustainability and energy conversion and gist and novelist. storage, with plenary lectures by Naomi Exposition. A reception on Wednesday af- The Graduate School & Recruiting Fair Halas of Rice University and Nathan Lewis ternoon will kick off the exposition, which will take place on Friday and Saturday af- of California Institute of Technology. will run through early afternoon on Friday. ternoon. Representatives from more than Other topical symposia include the The expo will offer meeting attendees an 25 graduate programs will be available to chemistry of art and artifacts, chemistry opportunity to learn about the latest prod- talk with meeting attendees at the fair. and the law, mechanochemistry, astro- ucts and equipment on the market. chemistry, the history of chemistry, and Awards. The following awards will be synthetic biology. A centennial symposium Social events. Diversity Day on Thursday presented during the awards luncheon on honoring R. B. Woodward will take place will feature a series of lectures addressing Saturday: the ACS CHED Southeastern Re- on Saturday morning. the challenges and opportunities faced by gional Award for Excellence in High School General oral and poster sessions will chemists from underrepresented minori- Teaching, the E. Ann Nalley Regional Award cover analytical, biological, inorganic, or- ties. The luncheon will feature Rigoberto for Volunteer Service to ACS, the Stanley C. ganic, physical, and polymer chemistry, as Hernandez of Johns Hopkins University Israel Regional Award for Advancing Diver- well as chemical education. Joe Schwarcz sity in the Chemical Sciences, and the Part- of McGill University will deliver a plenary SERMACS 2017 ners for Progress & Prosperity (P3) Award. lecture on science communication and pseudoscience. at a glance Registration and lodging. Advance registration for the meeting will close on Oct. 13; Workshops. There will be workshops ▸▸Dates: Nov. 7–11 registration at the on-site rate will be avail- on microwave-assisted chemistry, ▸▸Chairs: Jordan Poler, [email protected], able through the end of the meeting. Rooms electrochemistry, chemical safety, and general chair; Dan Rabinovich, drabinov@ can be reserved online at the Sheraton chemical entrepreneurship. Two ACS uncc.edu, program chair; David Brown, Charlotte Hotel, and special conference Career Pathways programs will focus on [email protected], assistant program rates will be available online until Oct. 17. professional development for new and chair To register for the meeting, or for more in-

CREDIT: SHUTTERSTOCK CREDIT: established chemists and include top- ▸▸Website: www.sermacs2017.org formation, visit www.sermacs2017.org. ◾

OCTOBER 9, 2017 | CEN.ACS.ORG | C&EN 51 DIRECTORY SECTION ACADEMIC POSITIONS 3e “BOND” OPTIONS THE DEPARTMENT OF CHEMISTRY AND BIO- www.oddelectronchemistry.com CHEMISTRY at the University of Colorado Boulder METAL (3d) COMPLEXES seeks to hire a tenure-track Assistant Professor in To advertise in the C&ENjobs section, the broad areas of Functional Materials and Complex please contact Heather McNeill via ACADEMIC POSITIONS Matter to begin in the Fall of 2018. Candidates in all e–mail at [email protected] or traditional and emerging sub-fields of chemistry telephone at (202) 452-8918. Please will be considered. Applicants should have a Ph.D. in see below for current advertising chemistry or a related field, and are expected to teach options and how to get started. graduate and undergraduate courses in chemistry. The successful candidate is expected to develop an active program focused on the synthesis and/or prop- Classifi ed Line Ads erties of materials with novel and/or useful optical, (best for posting a job): FACULTY POSITION IN BIOANALYTICAL CHEMISTRY electrical, magnetic, reactive, catalytic, thermal, and Want to appear within a section with mechanical properties, among others. headers that are classifi ed according The Department of Chemistry & Chemical Biology at IUPUI (http://chem.iupui.edu/) invites applications for a To ensure full consideration, complete applications, to your industry? Our Classifi ed Line tenure-track faculty position in bioanalytical chemistry to begin August 1, 2018. including letters of reference, should be received by Ad section gives you that opportunity. November 15, 2017. Review of applications will con- Your ad can appear with text only, or The position will be at the rank of Assistant or Associate Professor, with tenure status to be determined based on tinue until the position is filled. you may opt to include your logo in prior experiences and qualifications. While candidates with Applications will only be accepted electronically at color or black and white. Header posi- research interests in mass spectrometry of biomolecules are particularly encouraged to apply, we seek candidates that can https://www.jobsatcu.com, posting #11164. tion classifi cations include: Academic, support and expand the department’s efforts to complement The University of Colorado Boulder is an Equal Government, Pharmaceutical, and campus-wide interdisciplinary research programs in the life and health sciences. These include ongoing collaborative Opportunity Employer committed to building a di- Industry. Pricing starts at $75 gross efforts with the IUPUI School of Science, the IU School of verse workforce. We encourage applications from per line ($750 minimum). If your ad Medicine, and the Integrated Nanosystems Development Institute. Applicants must hold a Ph.D. in chemistry or a women, racial and ethnic minorities, individuals with is also posted online at chemistryjobs. related discipline along with relevant postdoctoral training. disabilities and veterans. Alternative formats of this acs.org, please ask about our print Candidates will be expected to establish an externally funded and rigorous research program, as well as effectively teach ad can be provided upon request for individuals with discount opportunities. undergraduate and graduate courses in chemistry. Applicants at the Associate Professor level must have a record of disabilities by contacting the ADA Coordinator at research excellence, current and ongoing external funding, [email protected]. See http://www.colorado. Display Ads (best for branding): and evidence of successful student mentoring. edu/ArtsSciences/overview/jobs/index.html for full Looking for a way to stand out from Applicants should submit a cover letter, curriculum vitae, job description. competitors and win the attention statements of research plans and teaching philosophy, and three reference letters. Interested candidates should review of potential candidates? Display ads the application requirements and submit their application to at Georgia State provide an excellent opportunity to https://indiana.peopleadmin.com/postings/4114. DEPARTMENT OF CHEMISTRY anticipates hiring one tenure-track fac- elevate your brand, highlight multi- Evaluation of applications will begin on November 1, 2017 and University will continue until the position is filled. ple open positions, or both. ulty member at the rank of Assistant Professor in IUPUI is an EEO/AA employer and is interested in candidates Organic/Medicinal Chem. pending budgetary ap- who will contribute to diversity and equal opportunity in higher Classifi ed Directory Ads education through their research and teaching. We encourage proval. Applicants for an Assoc. level position will be applications from women and members of minority groups. (best for announcements): considered if they have a well-established, funded Have something to sell? Announce? research program. Research area open but interests at the interface of chemistry and biology, in alignment Want to promote your graduate ACADEMIC POSITIONS program? 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52 C&EN | CEN.ACS.ORG | OCTOBER 9, 2017 ACADEMIC POSITIONS ACADEMIC POSITIONS TENURE–TRACK ASSISTANT/ASSOCIATE PROFESSOR POSITION MEDICINAL CHEMISTRY The Department of Chemistry at the University of Mis- souri is seeking to fill a tenure track position in medicinal chemistry beginning in Fall 2018. We anticipate that the position will be filled at the level of assistant professor, although appointment at the associate level may be considered. It is expected that the successful candidate will have the potential to build a funded, nationally recognized, research program focusing on the design of new medicinal agents within the framework of transla- tional precision medicine. The position requires the ability to work collaboratively with physicians and others in achieving goals that are aimed at the diagnosis and/or treatment of diseases at the molecular level, including, but not limited to, novel drugs, sensors, or radioactive probes. Finally, the candidate will demonstrate the promise of establishing a strong record of teaching at both the undergraduate and graduate levels. Review of applications will begin on November 15, 2017 and continue until the position is filled. The University of Missouri is fully committed to achieving the goal of a diverse and inclusive academic community of faculty, staff, and students. We seek individuals who are committed to this goal and our core campus values of respect, responsibility, discovery, and excellence. The University of Missouri is an equal Opportunity/Access/Affirmative Action/Pro Disabled & Veteran Employer. Please apply on-line at http://hrs.missouri.edu/ find-a-job/academic. Use the online application and be prepared to upload your CV, descriptions of research plans, and a statement of teaching philosophy. Three letters of recommendation are required and the applicant should arrange for the letters to be submitted. The letters should be submitted electronically to MUMed- [email protected]. Applicants may contact the Chair of the Search Committee (harmatam@missouri.edu) for any questions about the job duties. Con- Associate Professor and tact Human Resource Services ([email protected]) for any questions about the application process. The Department Chair of Chemistry University of Missouri is an equal Opportunity/Access/ The Department of Chemistry at the University of La Verne, CA Affirmative Action/Pro Disabled & Veteran Employer. invites applications for one tenure-track position in Analytical Chemistry starting Fall 2018. The position is open to applicants THE CHEMISTRY DEPARTMENT at Syracuse Uni- from all areas of analytical chemistry, but candidates with research versity invites applications for an Assistant Professor interest in Environmental Chemistry are particularly encouraged of organic chemistry with a leading interest in bioor- to apply. Candidates must have an earned PhD in Analytical ganic, medicinal, or polymer/materials in Fall 2018. Chemistry. This position will assume Department Chair duties Candidates are expected to establish funded research and will be filled at the Associate Professor level, commensurate and excellence in teaching. A Ph.D. in Chemistry and with experience. The department offers B.S. and B.A. degrees, and postdoc. experience is required. For details, and to promotes excellence in teaching and research at the undergraduate apply, go to www.sujobopps.com(job #073404). level. Teaching courses in area of specialty as well as lower Syracuse University is an equal-opportunity, affirma- division and G.E. courses, and research involving undergraduates tive-action institution. for completing their senior projects is required. Job requirements, application details, and Department of Chemistry info at http://apptrkr.com/1088610. Review of applications will begin immediately and continue until the position is filled. The University of La Verne is an equal opportunity employer committed to excellence through diversity; therefore, we encourage applications from historically underrepresented groups, veterans, and individuals with disabilities. EOE.

OCTOBER 9, 2017 | CEN.ACS.ORG | C&EN 53 ACADEMIC POSITIONS THE UNIVERSITY OF ILLINOIS at Chicago, De- TENURE–TRACK ASSISTANT PROFESSOR partment of Chemistry in the College of Liberal Arts POSITION THEORETICAL PHYSICAL and Sciences invites applications for a tenure-track CHEMISTRY ® assistant professor in the fields of BIOPHYSICAL The Department of Chemistry of the University of American Chemical Society OR BIOANALYTICAL CHEMISTRY. Areas of great- Missouri–Columbia invites applications for a tenure– est interest will emphasize high resolution biological track faculty position at the assistant professor level in imaging methods and research at the intersection of theoretical physical chemistry beginning in Fall 2018. nanoscale biophysics, biochemistry, chemical biology The successful candidate will establish an outstand- HOW and/or computational biology. ing, independent, externally funded research program The successful candidate will be expected to car- that complements current department strengths. DOES YOUR ry out a full and innovative program of experimental Candidates should also be committed to effective research and to teach graduate and undergraduate teaching at both the graduate and undergraduate lev- SALARY courses in biochemistry, analytical chemistry or phys- els. Minimum qualifications are a Ph.D. in chemistry or STACK UP? ical chemistry. A Ph.D. is required. Please submit an a related field with postdoctoral experience. Consider- on-line application, including the names and email ation of applications will begin on November 15, 2017 addresses of three references, and upload a cover and continue until the position is filled. The University Use the ACS Salary Calculator™ letter, curriculum vitae, list of publications, summary of Missouri is fully committed to achieving the goal of to see how your salary of past research, plans for future research, and state- a diverse and inclusive academic community of fac- compares to your peers’. ment of teaching philosophy at https://jobs.uic.edu/ ulty, staff and students. We seek individuals who are job-board/job-details?jobID=86323&job=assis- committed to this goal and our core campus values of Visit www.acs.org/StackUp tant-professor-chemistry by October 31, 2017. Final respect, responsibility, discovery and excellence. The to get started. authorization of the position is subject to availability University of Missouri is an equal Opportunity/Access/ of state funding. Affirmative Action/Pro Disabled & Veteran Employer. The University of Illinois at Chicago is an affirmative Please apply on-line at http://hrs.missouri.edu/ action/equal opportunity employer, dedicated to the find-a-job/academic. Use the online application goal of building a culturally diverse pluralistic faculty and be prepared to upload your CV, descriptions of and staff committed to teaching in a multicultural research plans, and a statement of teaching philos- environment. We strongly encourage applications ophy. Three letters of recommendation are required from women, minorities, individuals with disabilities and the applicant should arrange for the letters to be Brought to you by the ACS Career Navigator™ and covered veterans. The University of Illinois may submitted. The letters should be submitted electroni- www.acs.org/CareerNavigator ©2015 American Chemical Society. CN1531 conduct background checks on all job candidates upon cally to [email protected]. Applicants acceptance of contingent offer. Background checks may contact the Chair of the Search Committee will be performed in compliance with the Fair Credit ([email protected]) for any questions about Reporting Act. the job duties. Contact Human Resource Services ([email protected]) for any questions about the application process. The University of MissouriCN1531 is an - 2nd Round Evergreen Ads.1-6-V.indd 2 10/15/15 5:33 AM equal Opportunity/Access/Affirmative Action/Pro Disabled & Veteran Employer.

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54 C&EN | CEN.ACS.ORG | OCTOBER 9, 2017

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OCTOBER 9, 2017 | CEN.ACS.ORG | C&EN 55 Curating quirky Newscripts science since 1943 Pure Chemistry Since 1996

Catalog Products Isotope Synthesis The Spanish table runs through oganesson, The mother which has an atomic number of 118. So for Custom Synthesis/Manufacture GMP Compliance now, the Polish table wins on size, but the of all giant Spanish table wins on completeness. periodic tables Bacon to die for ack in June, the Newscripts gang heralded the installation he texture, the taste, and the VT1195 56726 of a giant periodic table of crunch of bacon don’t need an B the elements on the facade of update. But efforts to marry Spain’s University of Murcia chemistry T its good and bad attributes to building. Pedro Lozano Rodriguez, dean of unique taste sensations continue. the department of chemistry at the school, Another Newscripts reader, Dan Steible proudly proclaimed, “It could be the of Middletown, Del., saw the report in this 81312 84841 world’s largest permanent periodic table column on the recent Camp Bacon festival placed on a wall.” in Ann Arbor, Mich., celebrating all things Not so fast, says intrepid Newscripts bacon. He felt compelled to reader Michael Koberda of Northfield, Ill., share his sighting of an ar- an alumnus of the Warsaw University of tery-clogging delicacy at Technology. He recalls a student residence his local farmers’ market: 86297 27057 named the Riviera blessed with a unique chocolate-covered bacon. chemistry feature: Smacked broadside Delighted by his dis- against one street-facing exterior wall covery, the Newscripts gang was a large stone table of the elements installed in 1963. An adjacent exterior wall King of processed, high- was adorned with a mosaic representation sodium foods: Chocolate- 88566 80997 of a molecule. enrobed bacon. Alas, the mosaic is gone, victim of a building modernization project undertak- asked if he had sampled the en about six years ago. But the table of el- chocolate-enrobed savory ements survived—and it’s a whopper, says goody. He had not but gra- ciously went beyond the call of duty and purchased a 82812 P16557 sample of the $33-per-kg, sweet-and-savory indulgence and declared it “quite enjoyable, with some pleasant saltiness.” Many Camp Bacon attendees probably didn’t know or care about the latest Journal of the American Medical Association study HG1028 90219 (2017, DOI: 10.1001/jama.2017.0947) associ- ating processed high-sodium foods like bacon with deaths from heart disease, stroke, Writ in stone: The table of elements at and diabetes. Steible knew about the study 20 years track record Warsaw University of Technology. but took a philosophical perspective. 300 dedicated employees He wrote in an email that “anyone Paulina Król, a school press officer. could speculate forever on the nutritional 3000 bulk products for manufacture The Warsaw table stretches across good of chocolate defeating the nutritional 246 m2. Had the molecular mosaic sur- bad of bacon. Or they could speculate on 100,000 products (85% in stock) for R&D vived, the combined display would en- the bad of chocolate combining with the

2 (BUILDING); OF TECHNOLOGY UNIVERSITY L/WARSAW

compass 450 m of real estate. But who’s nutritional bad of bacon.” Like all things Ó quibbling? The University of Murcia table, food, the decision of what to eat comes www.astatechinc.com in contrast, spans 150 m2. down to a matter of taste. 2525 Pearl Buck Road, Bristol, PA, USA However, the Warsaw table could use an update. It stops at radium, element 88, Marc Reisch wrote this week’s column. 215-785-3197 coincidentally discovered by Polish native Please send comments and suggestions to CREDITS: PAULINA KR PAULINA CREDITS: Marie Curie and her husband Pierre in 1898. [email protected]. (BACON) SHUTTERSTOCK

56 C&EN | CEN.ACS.ORG | OCTOBER 9, 2017

CPhI Worldwide Frankfurt 24–26 October 2017

| Hello Frankfurt Let’s meet

Are you planning to be in Frankfurt for CPhI Worldwide? We’ll be there and happy to talk about all things API, from custom development and manufacturing to generics and controlled substances.

It’s a great opportunity to connect in person and meet the experts you’ll enjoy working with at Hall 8, Stand 80G40.

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