lively lysosomes

CONTENTS

NEWS FEATURES PERSPECTIVES

2 18 32 PRESIDENT’S MESSAGE LIVELY LYSOSOMES EDUCATION e promise of BEST 4 25 ANNUAL MEETING MEET TIMOTHY KARR 35 Meeting up in San Diego COORDINATES 29 Continental shift 6 AN ARTIST NAMED CRICK NEWS FROM THE HILL 38 Better funding to weather public health crises 18 OUTREACH Lysosomes are Know your audience 7 appreciated to be more than just the MEMBER UPDATE cell’s trash cans. 40 IMAGE COURTESY OF CAREER INSIGHTS 8 DYLAN J. BRITT AND JUAN S. BONIFACINO AT THE Research spotlight IN MEMORIAM NATIONAL INSTITUTES OF HEALTH 38 10 RETROSPECTIVE 29 (1920 – 2015) 12 NEWS 12 Large donations fund new immunotherapy institutes 13 Fat mice lead researchers to new feeding control pathway 14 JOURNAL NEWS 14 Leukemia cells teach other cells not to self-destruct 15 Predicting pre-eclampsia 16 e Venus ytrap’s major protease 16 35

MAY 2016 ASBMB TODAY 1 PRESIDENT’S MESSAGE

THE MEMBER MAGAZINE OF THE AMERICAN SOCIETY FOR AND MOLECULAR Citation corruption By Steven McKnight OFFICERS COUNCIL MEMBERS Steven McKnight Squire J. Booker President Karen G. Fleming Gregory Gatto Jr. Natalie Ahn Rachel Green f I understand things right, jour- ingenious phenotypic assays that President-Elect Susan Marqusee nals get scored for citation impact allowed timing of both pupal eclo- Karen Allen Jared Rutter via a metric that considers only sion and locomotor activity, Konopka Brenda Schulman I Secretary Michael Summers two years subsequent to the publica- and Benzer found mutations that Toni Antalis tion of their papers. Papers that get lengthened, shortened or eliminated Treasurer ASBMB TODAY EDITORIAL cited after this two-year window do the 24-hour circadian clock of ies. ADVISORY BOARD not enhance the impact factor of the Remarkably, all three categories of EX-OFFICIO MEMBERS Charles Brenner Squire Booker Chair journal in which they were published. mutations mapped to the exact same Wei Yang Michael Bradley For journals, this is big business — — dubbed by the authors the Co-chairs, 2016 Annual Floyd “Ski” Chilton Meeting Program Cristy Gelling they live and die by citation impact. “Period” gene. Committee Peter J. Kennelly For scientists, this used to be e accompanying gure shows the Peter J. Kennelly Rajini Rao an afterthought. But boy do Bob citation history, according to the Web Chair, Education and Yolanda Sanchez Dylan’s famous words ring true in of , of the landmark paper Professional Development Shiladitya Sengupta Committee Carol Shoulders this instance: “ e times, they are a entitled “Clock mutants of Drosophila Daniel Raben changin’.” Whether we know it or not, melanogaster.” It was cited once in Chair, Meetings Committee ASBMB TODAY scientists are judged by the company 1971, once in 1972 and only 24 times Angela Hopp Takita Felder Sumter Executive Editor, we keep. If we publish our papers in in the decade after its publication. Chair, Minority Aairs [email protected] Committee journals that have high impact factors, ings sped up in the next decade, Lauren Dockett the benet rubs o in many ways. If during which the paper was cited omas Baldwin Managing Editor, Chair, Outreach Committee [email protected] we publish in journals that have mod- about seven times per year. Over Wes Sundquist Rajendrani Mukhopadhyay est citation impact numbers, we suer. the past two decades, since Michael Chair, Public Aairs Chief Science Correspondent, Advisory Committee [email protected] I see certain aws in the use of Rosbash, Jerey Hall and Michael Blake Hill Valery Masterson numerical scores to rank the value of Young cloned the Period gene (2) and Chair, Publications Designer, a scientist. Some of these aws have it became clear that the Konopka and Committee [email protected] Ciarán Finn been articulated by other critics of Benzer discovery was of watershed F. Peter Guengerich Web Editor, citation impact. Do a simple signicance, the paper has been cited Interim editor-in-chief, JBC c[email protected] search, and Wikipedia will give you roughly 40 to 50 times per year. Herbert Tabor Allison Frick Co-editor, JBC Media Specialist, plenty of input regarding the pros Few would doubt that the paper [email protected] A. L. Burlingame and cons of citation impact. Despite by Konopka and Benzer describes Editor, MCP Barbara Gordon Executive Director, obvious aws, I do not dispute the one of the most signicant discoveries Edward A. Dennis [email protected] general that there is a correla- ever achieved in the eld of circadian William L. Smith Co-editors, JLR tive relationship between the value of biology. By contrast, citation metrics a paper and the number of times it would have given reward neither to eventually is cited. PNAS nor to the authors. Publication I do choose to critique the two-year of this paper instead would have hurt For information on advertising, contact Pharmaceutical Media Inc. at 212-904-0374 or [email protected]. time window. both the journal and the authors. In Take the case of a paper published the two-year interval subsequent to in the Proceedings of the National publication of this paper, it was cited Academy of Sciences back in 1971 (1). only two times. It is hard to get a www.asbmb.org/asbmbtoday e report was authored by Ronald worse score than that! PRINT ISSN 2372-0409 Konopka and and e consequences of the insidious Articles published in ASBMB Today reect solely the authors’ views and not the ocial positions of described the results of a forward infection of citation impact, at least in the American Society for Biochemistry and Molecular genetic screen in search of that its current form, are huge. Both jour- Biology or the institutions with which the authors are aliated. Mentions of products or services are might tell us something about the nals and scientists want papers to have not endorsements. circadian rhythm of fruit ies. Using immediate impact. After the two-year ©2016 ASBMB

2 ASBMB TODAY MAY 2016 greatness? In its present form, this measure of citation impact conspires heavily in favor of what is trendy and fad- dish. Journals will die if they publish Konopka/Benzer-like science. Worse yet, scientists — if scored by these measures — will wither professionally if they fail to follow what is in fashion. It is hard to think of anything worse for our profession than this insidious form of citation corruption. We should desire and create a system The citation history, according to the Web of Science, of the landmark paper “Clock mutants of Drosophila that encourages scientists to take risks melanogaster” and work on new horizons. We should reward and encourage Konopka/ window, forget it — the stu is yester- immediate post-publication window Benzer-like creativity. What a pathetic day’s news. e corruptive inuences but having gained recognition later. mistake of unintended consequences of this awed system are obvious: We e journal that publishes these sorts we have created in allowing science to are forced to work on what is faddish of papers should be rewarded, not be led around by the lunacy of citation or trendy. penalized. Likewise, we all know that corruption. If anything, I think a paper should Konopka and Benzer were sage scien- be revered if blessed with the unusual tists. ey set the trend decades ahead Steven McKnight (steven. feature of having been ignored in the of others. Is this not the testament of [email protected]) is president of the American Society for Biochemistry and REFERENCES Molecular Biology and chairman 1. http://www.pnas.org/content/68/9/2112.full.pdf of the biochemistry department at the University of Texas-Southwestern Medical Center at Dallas. 2. http://www.nature.com/nature/journal/v312/n5996/pdf/312752a0.pdf

2017 Annual Aards

Nominations for the 2017 ASBMB awards are now being accepted. Nominate a colleague for a prestigious ASBMB award and recognition at the 2017 annual meeting in .

Deadline: June 1 To learn how to nominate, visit www.asbmb.org/awards.

MAY 2016 ASBMB TODAY 3 ANNUAL MEETING Meeting up in San Diego

Lila Gierasch, incoming editor-in-chief of the Journal of Biological Chemistry, and Fred Guengerich, the journal’s interim editor-in-chief, talk with a booth visitor.

University of Georgia Graduate School Dean Suzanne Barbour advises an attendee during ASBMB career hour. Marketing Director Jennifer Dean holds up a hot sale item in the ASBMB booth.

4 ASBMB TODAY MAY 2016 Plenary lecturer Xiaowei Zhang and opening lecturer A busy poster presenter describes her work Robert G. Roeder

From left, plenary lecturer , Federation of American Societies for Experiemental Biology President Parker Antin, FASEB Award lecturer Bonnie Bassler, incom- ing ASBMB President Natalie Ahn and current ASBMB President Steven McKnight

Attendees smiling through poster session time Experimental Biology attendees goof off.

MAY 2016 ASBMB TODAY 5 NEWS FROM THE HILL Better funding to weather public health crises By Benjamin Corb

ate in 2014, at the height of is year, one of those other, less pace with research needs for nearly the Ebola epidemic that took understood diseases is in the spotlight. a decade, and as a result, the NIH L the lives of more than 10,000 e Zika , currently wreaking hasn’t had the resources to research a people in western Africa, President havoc in Brazil, is predicted to spread multitude of diseases that are health requested more than to the U.S. mainland within the year. threats to many, such as heart disease, $6 billion in emergency funding. e To date, more than 300 American and Alzheimer’s disease. money was for research that would citizens have contracted the virus, Disease-focused translational research expedite understanding of the virus and globally more than 4,000 birth has moved slowly into the spotlight, and help speed approval of an Ebola defects are blamed on the mosquito- leaving basic discovery research — treatment that could bring the disease borne illness. Unlike Ebola, not a lot the type of research that may benet under control. A month after the is known about Zika, and at a press those focused on major diseases and president’s request and nine months conference led by the National Insti- minor diseases — a seemingly lower into the Ebola outbreak, the United tute of Allergy and Infectious Disease priority. NIH Director Francis Col- States Congress nally took action and director, , U.S. public lins published a letter in Science last earmarked more than $5 billion to the health ocials announced that they month rearming the NIH’s com- National Institutes of Health, Centers are nding the disease more dangerous mitment to basic research and the for Disease Control, Food and Drug with every new bit of research they important role it plays, but that he felt Administration, and other agencies to conduct. a need to write such a letter indicates fund a U.S.-led eort to combat Ebola Once again, the political response a recognition that basic researchers are that has proven to be a global health to a public health crisis is to provide a feeling heavy pressures resulting from success. bolus of funding to solve the problem. a decade of at funding. I wrote a blog post for the Ameri- e White House is requesting $2 bil- Understanding how specic can Society for Biochemistry and lion for Congress to combat Zika, and metastasize, guring out how the Molecular Biology’s Policy Blotter in predictably, Congress is not enthusias- brain works, and investigating the the fall of 2014 expressing my concern tic about releasing the funds. In 2014, underlying mechanistic makeup of that emergency requests for massive it took a month of debate in Wash- aviviruses like Zika are all equally ington, D.C., to provide the president important areas of research, and infusions of new funding to combat a with the Ebola funding he requested. only when the biomedical research disease can set a dangerous precedent Today, Appropriations Committee enterprise is funded appropriately can for biomedical research funding. I Chairman Rep. Hal Rogers (R-Ky.) we truly be prepared to respond to argued that funding “disease du jour” says that funding is likely to come but tomorrow’s unexpected public health research is not sustainable and that not for several months. crises. the NIH had limited resources and e reality is the need for these needed to choose areas of research for often politically charged funding Benjamin Corb (bcorb@asbmb. funding based on national priority. requests is a symptom of a larger issue. org) is director of public affairs Ebola was already a fairly well-under- at ASBMB. Federal investments in biomedical stood disease. In my post I argued that research at the NIH have not kept it was also not an existing threat to the American population and that the massive increase in funding to ght Interested in science policy? the disease might come at the expense Follow our blog for news, analysis and commentary on policy issues of research into other diseases that aecting scientists, research funding and society. Visit policy.asbmb.org. were less well understood.

6 ASBMB TODAY MAY 2016 MEMBER UPDATE

Grossenbacher wins NCAA scholarship Max Grossenbacher, a biochemistry major at Colorado College, has received a National Col- legiate Athletic Association postgraduate scholarship for academic and athletic excellence. NCAA postgraduate scholarships are awarded to student athletes who have performed with distinction on the playing eld, are good citizens, possess a grade-point average of at least 3.2 and intend to continue their education. GROSSENBACHER A senior and a midelder on Colorado College’s Division III men’s soccer team, Grossenbacher will receive $7,500 from the NCAA. He plans to attend medical school in 2017. NCAA awards are bestowed three times a year, corresponding to the sports seasons of fall, winter and spring. Gros- senbacher is one of only 29 male and 29 female students to receive the award during soccer season. Grossenbacher is the Southern Collegiate Athletic Conference oensive player of the year, leading the conference with 27 points and nine assists. Additionally, he was one of 34 men’s soccer players to receive Academic All-America honors from the College Sports Information Directors of America in November and only the third player in the his- tory of his college to be named a Scholar All-American by the National Soccer Coaches Association of America. Written by Erik Chaulk

Charpentier and Doudna duPont and Virginijus Siksnys at the e prizes recognize achievements in Institute of Biotechnology of Vilnius the elds of agriculture, chemistry, share Alpert Prize University in Lithuania. mathematics, , physics and Emmanuel Charpentier and Doudna’s work the arts. Cantley is being honored for Charpentier at Umeå on CRISPR has been lauded widely. his discovery of the phos- University in Sweden In addition to their many individual phoinositide-3 kinase and its link to and honors, the two share the 2015 Break- cancer and other diseases. Kahn is at the University of through Prize in the Life Sciences, the being honored for his work on insulin CHARPENTIER California, Berke- Paul Janssen Award for Biomedical signaling and its contribution to the ley, have won the Research, the Gruber Prize in Genet- understanding of type 2 diabetes. e 2016 Warren Alpert ics, the and the L’Oreal- two winners will divide a $100,000 Foundation Prize. UNESCO International Prize for monetary award. Charpentier and . Cantley and Kahn have received Doudna share the Written by Lee D. Gibbs many of the highest honors in their prize with three oth- DOUDNA elds and both been elected to the ers. All ve recipients Cantley and Kahn win National Academy of Sciences and the are being recognized for their contri- Institute of Medicine. butions to the understanding of the Wolf Prize Written by Erik Chaulk CRISPR system and its potential for Lewis Cantley . at the Sandra and Established in 1987 by philan- Edward Meyer Garcia receives thropist Warren Alpert and awarded Cancer Center Science award in association with Harvard Medical at Weill Cornell Benjamin Garcia, School, the $500,000 prize recog- CANTLEY Medical College, presidential associ- nizes scientists and physicians whose and C. Ronald Kahn ate of research holds great promise in the at Joslin Diabetes biochemistry and prevention, treatment or cure of a Center and Harvard biophysics at the human disease or disorder. Medical School, have GARCIA University of Penn- Charpentier and Doudna won for won the 2016 Wolf sylvania Perelman School of Medicine, establishing that the CRISPR bacterial Prize in Medicine. has won the 2016 Protein Science KAHN could be used to alter Wolf Prizes, Young Investigator Award. or replace targeted DNA in a broad considered the Nobel Prizes of Israel, e award comes from the Protein array of , including humans. are bestowed annually by the Wolf Society and recognizes scientists in ey share the award with Rodol- Foundation, a nonprot organization the rst eight years of an indepen- phe Barrangou at North Carolina founded in 1976 by former Cuban dent career who have contributed State University, at ambassador to Israel Ricardo Wolf. CONTINUED ON PAGE 8

MAY 2016 ASBMB TODAY 7 IN MEMORIAM

CONTINUED FROM PAGE 7 , especially those involved in Garcia already has received the epigenetics, such as histones. His work Presidential Early Career Award, signicantly to the study of proteins. on the development of analytical and the National Science Foundation Garcia was chosen for developing computational tools to understand Early Career Award and the National and applying novel mass spectrom- better the importance of simultane- Institutes of Health Director’s New etry approaches to better study ously occurring histone modications Innovator Award. post-translational modications of also was noted. Written by Sarah Elkin

DAVID B. KNAFF (1941 – 2016) David Barry Kna, an expert on redox reactions in plant photosynthesis and professor at Texas Tech University, died in January in Lubbock, Texas. He was 74. Kna led Texas Tech’s biotechnology and genomics department and was a former editor-in-chief of the journal Photosynthesis Research. His research focused on the mechanistic details of redox reactions in plant photosynthesis with an emphasis on nitrate and sulfate assimilation and the redox KNAFF regulation of carbon metabolism. Born June 5, 1941, in the Bronx, N.Y., Kna attended the Bronx High School of Science before completing a bachelor’s degree in chemistry at the Massachusetts Institute of Technology. He received his master’s and Ph.D. in chemistry from , where he was a National Science Foundation predoctoral fellow. After his formal education, Kna transitioned to plant biochemistry — a eld he committed to for the next 50 years. He served as a National Institutes of Health postdoctoral fellow at the University of California, Berkeley, from 1964 to 1968 and stayed at UC Berkeley as a sta scientist in cell from 1968 to 1976. Kna joined the Chemistry Department at Texas Tech in 1976 and in 1987 received the university’s highest faculty rank, the Paul Whiteld Horn professorship. During his tenure, Kna chaired the school’s chemistry and biochemis- try department, co-established and served as director of the Center of Biotechnology and Genomics, and led eorts to create a biotechnology master’s program and dual degree M.S./J.D. program with the Texas Tech University School of Law. Along with the consecutive funding he received from federal agencies and private foundations for 43 years and his more than 220 refereed journal articles, Kna’s accolades included Texas Tech’s President’s Academic Achievement Award, the Barnie E. Rushing Jr. Faculty Distinguished Research Award and the Texas Academic Reward for College Scholars Scientist of the Year award. Kna leaves behind a wife, Joyce R. Kobb, a daughter and a granddaughter. Written by Jennifer A. Codding-Bui

Upcoming ASBMB events and deadlines

May 16: Application deadline for the Marion B. Sewer Distinguished Scholarship for Undergraduates MAY

July 14 – 16: ASBMB Grant Writing Workshop, Washington, D.C. JULAUGOCT

Aug. 1: Abstract and registration deadline for the ASBMB Transcriptional Regulation by Chromatin and RNA Polymerase II symposium

Oct. 6 – 9: ASBMB Special Symposia: Transcriptional Regulation by Chromatin and RNA Polymerase II, Snowbird, Utah

8 ASBMB TODAY MAY 2016 MAY 2016 ASBMB TODAY 9 RETROSPECTIVE Osamu Hayaishi (1920 – 2015) By Shuh Narumiya

samu Hayaishi, emeritus to cis,cis-muconic acid as the reaction ogy section of the National Institute professor of University, product. He named it pyrocatechase. of Arthritis and Metabolic Diseases O died in December at the age Using Warburg’s manometer, Hayaishi in 1954, Hayaishi led a team that of 95. A leading international gure found a concomitant consumption of tested his long-held hypothesis on in biochemistry, Hayaishi discovered equimolar molecular oxygen with the pyrocatechase. Using O-18 isotopes, oxygenase, ADP-ribosylation and the conversion. At this point he suspected he found that oxygen atoms incor- sleep-inducing action of prostaglandin that consumed molecular oxygen was porated in the product came entirely

D. incorporated directly to the substrate, from O2 and not at all from H2O. His Hayaishi was born on Jan 7, 1920, but experimental proof of his assump- discovery and a concurrent indepen- in Stockton, Calif., where his Japanese tion was years away. dent discovery by Howard Mason at father, who had studied medicine Hayaishi published his ndings the University of Oregon Medical in the U.S., ran a clinic. e family in 1949, attracting the attention of School of incorporation of an atom of moved from California to Germany David Green at the University of molecular oxygen into a substrate by and then settled in Osaka, , Wisconsin. Green invited Hayaishi to mushroom phenolase were milestones where Hayaishi grew up. He gradu- be a postdoctoral fellow, and Hayai- in the understanding of how oxygen ated from Medical shi crossed the Pacic to join him in is utilized in biological systems. Until School in 1942, served as a medical Madison. Hayaishi spent eight months then, scientists believed that biological ocer in the Japanese navy during the with Green before moving to the oxidation occurred exclusively through war and joined the lab of microbiolo- laboratory of Roger Stanier at the Uni- the dehydrogenation process that Ger- gist and virologist Tenji Taniguchi at versity of California, Berkeley. Stanier man Nobelist Henrich Wieland had Osaka University. also studied tryptophan metabolism discovered decades earlier. Hayaishi Living conditions in severely dam- in pseudomonas, and the two men named the group of catalyz- aged, postwar Osaka were miserable, struggled together in vain to extract ing incorporation of molecular oxygen and the university’s laboratory facilities tryptophan-metabolizing enzymes. into organic substrates “oxygenases.” were hopeless. Hayaishi spent much One rainy evening in Berkeley, Hayai- In 1958, Hayaishi returned to of his time in Taniguchi’s employ shi met National Medal of Science Japan and became a professor and reading scientic literature until the winner H. A. Barker, who advised him chairman of the Department of day he received an unexpected visit to use alumina to grind the . It Medical Chemistry at Kyoto Uni- from Yashiro Kotake, a biochemist worked. Hayaishi was able to extract versity Faculty of Medicine. He said known for his study of tryptophan enzymatic activities that reconstituted of the move, “My salary in Kyoto metabolism in mammals. Kotake metabolism of tryptophan to catechol was one-thirteenth of that (at) NIH. gave Hayaishi a bottle of tryptophan and consumed molecular oxygen con- More(over), the experimental facilities puried from casein lysates — a pre- comitantly. After four months with were miserably shabby.” cious gift at the time. Hayaishi had Stanier, Hayaishi joined the lab of As Hayaishi got to work recon- read about an enrichment culture -winner . structing the department, a ood of technique to isolate soil bacillus with Kornberg, whom Hayaishi had rst young people eager to learn modern adapted enzymes for added organic heard speak at a Federation of Ameri- biochemistry joined him. Hayaishi compounds and began culturing soil can Societies for Experimental Biology was as gifted a mentor as he was a samples with tryptophan. He enriched meeting, had oered him a position scientist. He organized a lunchtime a strain of pseudomonas, which before Hayaishi moved to Berkeley. seminar where all members in the degrades tryptophan completely to Hayaishi worked with Kornberg at laboratory gathered and critically carbon dioxide, water and ammo- the National Institutes of Health discussed papers. Hayaishi called the nia via kynurenine, anthranilic acid as a postdoctoral fellow and later at seminar a dojo and trained those in and catechol. He prepared bacterial Washington University as an assistant attendance through serious discussion. extracts and found in them an enzyme professor. He still loved being close to the bench that catalyzed conversion of catechol Appointed chief of the toxicol- and made a daily round in his labora-

10 ASBMB TODAY MAY 2016 tory. When writing a paper, Hayaishi invited the authors to his oce and carried out several rounds of review by examining the paper’s ndings and logical ow and correcting his researchers’ English word by word. Hayaishi inspired and trained sev- eral hundred people during his 25-year tenure in Kyoto and his several TAKAO SHIMIZO years of joint- Osamu Hayaishi gives a lecture at the in 2012. appointments Cancer Center of Japan. Hayaishi also discussing it with the lab members up at Osaka University and the Uni- discovered the diphtheria toxin-cata- until two years ago, when he fell ill. versity of Tokyo. More than 130 of lyzed ADP-ribosylation of aminoacyl Hayaishi retired from Kyoto them became university or transferase 2 and thus claried the University in 1983 and founded the department heads. toxin’s action mechanism. He was the Osaka Bioscience Institute. Hayaishi Hayaishi and his researchers rst to demonstrate that the bacterial served as the president of the Inter- extensively studied structures and toxin is an enzyme. Hayaishi also dis- national Union of Biochemistry from properties of oxygenases and came to covered indoleamine 2, 3-dioxygenase 1973 to 1976, received numerous a conclusion about the presence of and its induction by interferon, which awards and prizes and was a member the enzymatically activated form of is now known as one of the major of several academies, including the oxygen in the ternary complex of the immunosuppression mechanisms. U.S. National Academy of Sciences. enzyme heme—oxygen—substrate. e last area of Hayaishi’s research, e principles discovered by Hayai- e study of oxygenase initiated by sleep induction by PGD, began a few shi are known now to operate in many Hayaishi has developed enormously, years before his retirement from Kyoto physiologically important processes, and we now know that oxygenases are University. By characterizing enzymes and the science he created has inu- involved in the formation of various in PG biosynthesis, Hayaishi found enced nearly all areas of bioscience bioactive substances, cytochrome that PGD synthase and PGD are and medicine. P450-catalyzed xenobiotic disposition, enriched in the brain. He unexpect- A man of great charm, Hayaishi and the sensing of oxygen tension. edly found that intracerebroventricu- leaves behind his wife of 69 years, Hayaishi’s study on oxygenase lar injection of PGD induced sleep Takiko; their daughter, Mariko; two also led him to create new elds of in animals. His subsequent works grandsons and six great-grandchildren. research, including work on ADP- revealed that PGD acts on its recep- e academic community, his friends, ribose, a discovery derived from his tor in the leptomeninges surrounding colleagues and students, have lost an study on the oxygenase-driven tryp- the brain and transmits its signal from inspiring scientist who embodied the tophan metabolism to nicotinamide there to the sleep-regulation center in spirit of the eld. adenine dinucleotide, or NAD, and the hypothalamus. is mechanism of sleep induction by PGD fascinated made in parallel with Paul Mandel Shuh Narumiya ([email protected]) at the University of Strasbourg and Hayaishi. He maintained an active is a professor and the director of Medical Innova- Takashi Sugimura at the National group to pursue the topic and enjoyed tion Center of School of Medicine.

MAY 2016 ASBMB TODAY 11 NEWS Large donations fund new immunotherapy institutes By Bree Yanagisawa

wo sizeable donations to fund and former presi- research in the area is increasing. the creation of immunotherapy dent of Facebook, Immunotherapies can help boost the T centers for cancer research were announced that he body’s immune system and train it to announced within weeks of each other will be putting $250 seek out and attack cancerous cells. in March and April. Both centers million behind the In a news release from UCSF, aim to encourage collaboration to PARKER Parker Institute for Parker expressed hope that his dona- speed up the generation of new cancer Cancer Immunotherapy. Parker’s tion will give the promising eld the therapies. institute will be led by Jerey Blue- push it needs to be successful for more First, Vice President Joe Biden and stone, an immune system researcher patients. “We believe that the creation former New York City Mayor Michael at the University of California, San of a new funding and research model Bloomberg announced $125 mil- Francisco, School of Medicine, and is can overcome many of the obstacles lion in funding to intended to bridge research between that currently prevent research break- the Johns Hopkins six major institutions: the University throughs,” he said. University for the of Pennsylvania; Memorial Sloan “Ending all cancer would rank Bloomberg–Kimmel Kettering Cancer Center; Stanford among humanity’s greatest achieve- Institute for Cancer University; the University of Texas ments, and immunotherapy is bring- Immunotherapy. MD Anderson Cancer Center; UCSF; ing that dream within reach,” said BLOOMBERG Financed largely by and the University of California, Los Bloomberg in a Johns Hopkins press Bloomberg and the Angeles. release. He added that the Bloom- philanthropist Sid- Both institutes will put an empha- berg–Kimmel Institute “will build on ney Kimmel, with sis on collaboration. e Bloomberg– the pioneering work that doctors and support from more Kimmel Institute wants to improve researchers at Johns Hopkins have than a dozen others, relationships between industry and done in immunotherapy and help fuel KIMMEL the institute aligns academic scientists. e Parker Insti- new advances and discoveries.” with the goals of the Obama admin- tute will manage separately the pat- istration’s Moonshot Initiative to cure enting and licensing of any discoveries cancer. Biden, who lost a son to brain among its six involved institutions to Bree Yanagisawa (byanagisawa@ asbmb.org) is a science writing cancer last year, is spearheading the streamline the therapeutic develop- intern at ASBMB Today and a initiative. ment process. Ph.D. candidate in pathobiology Second, Sean Parker, co-founder Immunotherapy is a promising at the Johns Hopkins School of of the music-sharing site Napster approach to cancer treatment, and Medicine.

12 ASBMB TODAY MAY 2016 NEWS Fat mice lead researchers to new feeding control pathway By Rajendrani Mukhopadhyay

hen their lab mice W unexpect- edly packed on weight, Richard Huganir at the Johns Hop- kins School of Medicine and his colleagues had to gure out why the mice OLOF LAGERLOF suddenly turned Researchers injected littermates with either a control virus or a virus that knocked out OGT in a part of the brain. The mouse missing OGT (left) ate twice as much as its normal sibling. The photo was taken about five weeks after the virus injection. obese. In a paper in the March of the proteins. modied mice. ese mice had OGT 11 issue of the journal Science, the As part of their project, Huganir missing only in the paraventricular investigators describe their discovery and colleagues genetically modied nucleus cells. “Knocking out OGT in of a protein-modication pathway in the brains of mice so that the research- only these cells inhibited their activity the brain that plays a surprising role in ers could turn o the expression of and produced the same overeating feeding control and satiety. OGT in the forebrain and hippocam- phenotype,” says Huganir. “ is was a serendipitous discov- pus. ese two regions of the brain are e investigators now know that ery,” says Huganir, a neuroscientist important for learning and memory. OGT plays an important role in the and member of the American Society “Much to our surprise, a couple of paraventricular nucleus cells in feeding for Biochemistry and Molecular Biol- weeks after we knocked out OGT, the control, but the molecular details are ogy. “We had to learn a whole new mice got very, very fat,” says Huganir. still unknown. For one, the investiga- area of biology — feeding control, “We stopped studying learning and tors don’t know what substrates OGT metabolism and obesity. Luckily, we started studying feeding control.” acts on in the paraventricular nucleus had great collaborators at Hopkins e parts of the brain the inves- cells to regulate their activity. who had the expertise to help us gure tigators had targeted in their mice And, as with any work done on out what was going on. We eventually usually are not associated with feeding mice, the implications for humans found out that the mice had impaired control. But the hypothalamus is. have to be worked out. “ is work in satiety and ate larger meals.” When the investigators looked at mice does suggest similar mechanisms e investigators originally were the hypothalamus, they discovered are important in human satiety,” says working on deciphering the role of that they inadvertently had removed Huganir. “However, much more work an enzyme called O-GlcNac trans- OGT in specic cells in a region of is needed to identify potential thera- ferase, known as OGT, in regulating the hypothalamus called the paraven- peutic targets to modify this pathway synaptic transmission and plasticity tricular nucleus. in humans to regulate food intake.” in the brain as well as its potential To make sure that OGT in the Rajendrani Mukhopadhyay role in learning and memory. OGT paraventricular nucleus cells was what ([email protected]) is catalyzes the attachment of a short was inuencing the feeding and satiety the chief science correspondent sugar molecule to proteins; the sugar of the mice, Huganir and colleagues for the ASBMB. Follow her on molecule then inuences the function created another set of genetically Twitter at twitter.com/rajmukhop.

MAY 2016 ASBMB TODAY 13 JOURNAL NEWS Leukemia cells teach other cells not to self-destruct By Bree Yanagisawa

n acute myeloid leukemia, or AML, relapses are a I major concern. About 65 percent of adult patients with AML go into remis- sion through chemotherapy, but more than half of those patients relapse. Residual AML cells are thought to cause these relapses. ese cells persist in the patient despite chemo- therapy and may expand and re-create the cancer. e cells survive chemotherapy using various mechanisms, including Acute myeloid leukemia cells use exosomes to transfer resistance to neighboring cells. avoiding the usual cell-death complex mechanisms. these secreted proteins are housed in pathways. In a recent paper published e researchers collected samples vesicles that originate from the AML in the journal Molecular and Cel- from patients with AML at the begin- cells. Jimenez says that these ndings lular Proteomics, Connie Jimenez at ning of disease and after remission. suggest that “by secreting vesicles, the VUmc Cancer Center Amsterdam When they examined the apoptotic leukemic cells may aect the global and her colleagues Anna Wojtuszkie- proles of residual AML cells and sur- expression proles of the recipient wicz and Jacqueline Cloos dissect the rounding normal lymphocytes within cells.” interplay between these residual AML the bone marrow, the researchers were In the future, the authors intend cells and their surrounding environ- surprised to nd that the two dierent to look into the ways in which these ment. cell types shared similar levels of pro- secreted proteins aect surrounding When things go wrong inside a teins typically involved in apoptosis. cells. cell, apoptotic mechanisms are in In addition, when cultured together, “Unraveling the mechanisms of place to serve as a self-destruct signal. AML cells that were especially communication between leukemic Cancer cells are capable of avoid- resistant to apoptosis were capable cells, including stem cells, and their ing these typical processes, making of making low-resistance cells more microenvironment is crucial to the them harder to kill. In the study, the likely to ignore self-destruct signals. ecacy of cancer treatment,” says researchers found that resistance to ese ndings suggest the apoptotic Jimenez. “Our work suggests that it self-destruction may be passed from proles of cells are being inuenced is a mutual interaction in which not AML cells to surrounding cells via by external factors. only the cells of the bone marrow secreted exosomes. e authors proled secreted pro- niche can promote survival of leuke- e extent to which cancer cells teins from AML cells with high and mic cells but leukemic cells themselves can ignore self-destruct signals uctu- low levels of resistance to apoptosis. are shedding vesicles, which can inu- ates over the course of the disease. Unexpectedly, the most prominent ence their neighboring cells.” Counter to what one might expect, types of proteins identied weren’t patients who carry AML cells that apoptotic proteins. Many of the are highly resistant to apoptosis at identied secreted proteins were those Bree Yanagisawa (byanagisawa@ asbmb.org) is a science writing diagnosis can have AML cells with usually involved in gene regulation, intern at ASBMB Today and a decreased levels of such resistance after hinting at a potential mechanism Ph.D. candidate in pathobiology chemotherapy. is suggests that the by which AML cells can inuence at the Johns Hopkins School of cell death pathways are governed by their surroundings. Furthermore, Medicine.

14 ASBMB TODAY MAY 2016 JOURNAL NEWS Predicting pre-eclampsia By Bree Yanagisawa

re-eclampsia aects failed to show an increase in roughly 3 percent of predictive value. When the P pregnant women in lipid test becomes publicly the U.S. and can lead to a available, Graves advises host of complications that using all 23 biomarkers can include premature birth together to account better for and even death for both individual patient factors. mother and child. Unfortu- ough the lipid biomark- nately, there is no eective ers are intriguing, Graves is diagnostic test to predict the careful to point out these onset of the disease, which is biomarkers aren’t ready for characterized by high blood the clinic just yet. A lipid- pressure that may not appear based test will be available until the second half of only after further study and pregnancy. approval by the U.S. Food In a recent paper pub- and Drug Administration. lished in the Journal of “What should happen now Lipid Research, Steven is one should establish a clear Graves of Brigham Young hypothesis that this set of University and colleagues markers would be useful and described a set of biomarkers then carry out studies,” he that could help in the early says. detection of pre-eclampsia. e research may not be Although proteins are con- of immediate clinical value, sidered a more conventional but knowledge of the bio- class of biomarker, Graves markers could help stream- and his colleagues decided line the research process. to look to lipids in the blood THE NATIONAL INSITUTES OF HEALTH Because the disease occurs Pre-eclampsia is a potentially dangerous complication in pregnancy infrequently, one of the big- because they tend to be characterized by high blood pressure. more forgiving subjects than gest issues with prospective their protein counterparts. the team compared the serum lipid studies for pre-eclampisa According to Graves, lipids “are not proles of women who went on to is the sheer number of women that particularly heat-sensitive compared develop pre-eclampsia and those who need to be enrolled in order to have to a protein or peptide, and they’re did not. After an initial analysis and adequate numbers of pre-eclamptic not degraded rapidly by proteolytic a second conrmatory run in another cases. However, if researchers rst can enzymes, which exist in the serum.” sample set, the team identied a set narrow the population using a set of Unlike invasive sampling proce- of 23 biomarkers in the form of mass predictive biomarkers such as the one dures, which may be risky, serum spectral proles that were able to pre- proposed in the paper, fewer women samples containing the lipids can be dict those women who would go on to would need to be enrolled. Accord- collected in the clinic relatively easily have a pre-eclamptic event. ing to Graves, this “could save time with blood draws. e researchers Any biomarker on its own can’t and allow for more things to be tested used samples that had been collected provide sucient predictive value, more eciently.” for a trial studying the early in utero but combining the markers together development of children with Down’s into sets increased predictability. For Bree Yanagisawa (byanagisawa@ syndrome. From the available samples, their sample population, the investiga- asbmb.org) is a science writing intern at ASBMB Today and a they selected those taken between 12 tors found that using six biomarkers Ph.D. candidate in pathobiology and 14 weeks of gestation. helped with predicting pre-eclampsia; at the Johns Hopkins School of Using mass spectrometry data, combining more than six markers Medicine.

MAY 2016 ASBMB TODAY 15 JOURNAL NEWS

The Venus flytrap’s major protease By Indumathi Sridharan

enus ytraps grow in the nitro- gen-poor soil of the southeastern V . e lack of nutri- tion in the soil has turned these plants into sophisticated hunters. Two lobes of the ytrap produce sweet sap that lures small insects. If an insect brushes against a few microscopic, hair-like structures on the lobes’ surface in quick succession, the lobes spring shut instantaneously to trap the insect. en the plant secretes a uid that kills and digests the prey. e ytrap’s digestive uid is a rich concoction of enzymes includ- ing lipases, chitinases and proteases. In a recent paper in the Journal of Biological Chemistry, Jan Enghild and a team of researchers at the department of molecular biology and at Aarhus University in Denmark, characterized the function and structure of a 45 kDa cysteine protease, dionain-1, which is found abundantly in the digestive uid. e protein has a precursor form called pro-dionain-1. Pro-dionain-1 contains an N-linked glycan group, which is required for proper folding of the protein. e researchers used cDNA WIKIMEDIA COMMONS USER NOAH ELHARDT Carnivorous Venus flytrap plants secrete enzyme-rich fluid to mediate nutrient absorption from their prey. sequence analysis to demonstrate that pro-dionain-1 is similar to the precur- for maturation, dionain-1 must exert Enghild, who oversaw the work, sors of other plant cysteine proteases, its main proteolytic function at the says that the research on the digestive such as papain. acidic pH of 3.4 to 4.4 found in the uid oers insight not only into the Further analysis revealed that digestive sap of Venus ytraps. mechanisms of plant carnivory but pro-dionain-1 is also homologous e mature dionain-1 eciently also how those mechanisms dier to propapain at the structural level. digests lysine- and arginine-rich mus- from molecular strategies employed Despite the sequence and structural cle proteins to release nitrogen-rich by carnivorous animals. In the future, similarity, pro-dionain-1’s function is peptides. us, the authors conclude Enghild and his team plan to inves- better suited to acidic environments that dionain’s function is nely tuned tigate other enzymes in the ytrap’s than papain. Pro-dionain-1 undergoes to serve the plant’s need for nitrogen- digestive uid. rich sources. According to the study’s autoproteolysis at an acidic pH. e Indumathi Sridharan (Sridharan. autoproteolysis process leads to loss lead author, Michael Risør, dionain’s [email protected]) earned of the integrity of the prodomain and enhanced acid tolerance and its her bachelor’s degree in bioinfor- unravels the active site to produce the preferential digestion of nitrogen-rich matics in India. She holds a Ph.D. in molecular biochemistry from functional and mature dionain-1. e proteins is an important evolutionary Illinois Institute of Technology, authors highlight that, unlike other adaption that facilitated the ytrap’s Chicago. She did her postdoctoral work in proteases that require acidic pH only carnivorous lifestyle. bionanotechnology at Northwestern University.

16 ASBMB TODAY MAY 2016 MAY 2016 ASBMB TODAY 17 FEATURE lively lysosomes e organelles aren’t just trash cans. As researchers now appreciate, lysosomes do much more for the cell’s well-being. By Rajendrani Mukhopadhyay

DYLAN J. BRITT AND JUAN S. BONIFACINO AT THE NATIONAL INSTITUTES OF HEALTH A glial cell’s lysosomes, labeled in green, are distributed throughout the cytoplasm, which is in red, including cell protrusions. Lysosomes exhibit a variety of shapes, ranging from spherical to tubular.

18 ASBMB TODAY MAY 2016 ysosomes are having a Cinderella moment. Gone is the percep- L tion that lysosomes simply sit in a corner of a cell, mutely cleaning up whatever is sent their way. Lysosomes now are seen as critical signaling checkpoints that move around the cell and take part in important decisions about cellular biosynthesis and degra- dation. ey once were thought to be involved in only rare genetic disorders. But now researchers are beginning to appreciate that diseases as common as Alzheimer’s and certain cancers have roots in lysosomes too. Along with the reassessment of the capabilities of lysosomes comes THE NATIONAL INSTITUTES OF HEALTH the awareness that scientists have A typical drawing of an animal cell, sliced open to reveal cross-sections of organelles. The lysosomes are the more questions than answers about green spheres. The red dots within the green spheres signify cellular components that need to be broken down. exactly what the organelles are capable somes in vesicles known as autopha- of doing. Lysosomes, says Roberto gosomes. Botelho at Ryerson University in Once molecules are in a lysosome, Canada, “are much more fun than nucleases, proteases, lipases and other people thought.” hydrolytic molecules attack them. Exporters on the membrane carry out Trash can the bits and pieces of the degraded In 1955, at the molecules. e pieces go into the Catholic University of Louvain in Bel- cytoplasm either to provide energy gium and colleagues described a mem- or to be reused by the biosynthetic brane-bound organelle that housed pathways. at least ve enzymes. ese enzymes In 1963, Henri-Gery Hers, who degraded a variety of substrates in a had joined de Duve’s group, discov- pH around 5. In proposing that the ered that people missing a lysosomal organelle was involved in cellular glucosidase succumbed to a severe digestion, de Duve and colleagues glycogen storage disorder. at nd- called the organelle a “lysosome,” the ing introduced the idea that a host of Greek word for “digestive body.” diseases could be linked to the inabil- In subsequent years, researchers ity of the lysosome to produce specic found that there are at least two ways enzymes and thus degrade particular for molecules to wind up in one of molecules. Lysosomal research at that the hundreds of lysosomes in a cell. point became focused largely on the One way involves endocytosis, in clinical aspects of disorders associ- which molecules outside of the cell ated with the lysosomes and nding are brought inside the cell in pack- therapies for the disorders. ages. Some of the packages are fated Disorders related to the inability to become late endosomes, which are of the lysosome to break down and slightly acidic organelles that mature remove various types of molecules into lysosomes. became known as lysosomal storage Another way is autophagy. is disorders. ese included Gaucher, is a major housekeeping mechanism Fabry and Niemann–Pick diseases, within the cell, clearing away com- among others. ere are now more ponents that are about to expire. e cleared components arrive at lyso- CONTINUED ON PAGE 20

MAY 2016 ASBMB TODAY 19 CONTINUED FROM PAGE 19 is a cell biologist at New York Univer- Lysosome, not lysozyme sity. “When I rst identied mTOR as than 50 known lysosomal storage a graduate student, I remember I was In an article disorders, most of them rare genetic talking to (my dad) about it. He said, published in diseases. ‘David, one of the things you have to Nature Cell One of the notable breakthroughs do is you have to localize this within Biology on the in this area was enzyme-replacement the cell,’” recalls the younger Sabatini. 50th anni- therapy, during which certain missing “I was a typical obnoxious child, and DE DUVE versary of the or defective lysosomal enzymes are I was like, ‘You know, I don’t think lysosome’s discovery, Christian de replaced with functional enzymes, as that’s interesting. at’s old school.’ Duve was peeved with scientists Roscoe Brady’s team at the National e funny thing is that it turned who confused “lysosome” with Institutes of Health did with Gaucher out that the localization was the key “lysozyme,” a bacterial enzyme disease. thing.” discovered by By the 1980s, it seemed scientists In 2008, nearly a decade after of penicillin fame. “I trusted bio- knew what they needed to know about he began working with mTOR, the to be able to distinguish the basic workings of the lysosome. younger Sabatini, who also is with the between the Greek roots soma “Who wanted to work on lysosomes? Howard Hughes Medical Institute, and zyme,” he wrote in the 2005 It was more interesting to work on the led a team that made a surprising dis- perspective. “ is trust was sadly nucleus, where all the genetic informa- covery. When the team deprived cells misplaced. Even today, I am still tion is contained, or mitochondria of amino acids, mTORC1 was diuse sometimes given credit that is that make energy for the cell to func- throughout the cytoplasm. When the due to Fleming.” tion or the (endoplasmic reticulum), team added amino acids, the kinase where proteins are synthesized,” says quickly congregated on the surface of Juan Bonifacino at the NIH. “Lyso- lysosomes. somes were just involved in degrada- “I remember the rst few times I tion. ey were a trash can.” presented this nding, people would en came an unexpected nding. stand up and say that the lysosome was a trash can. Some people would ‘They didn’t like the idea’ be more charitable and say the David M. Sabatini at the White- lysosome was a recycling bin,” recalls head Institute is the rst to admit that Sabatini. “ ey didn’t like the idea. he should have listened to his father’s e nding was met with a bit of advice. When Sabatini was in graduate resistance because it was one of the school at Johns Hopkins University in rst that implicated there was some- the early to mid-1990s, he identied a thing dierent about lysosomes.” kinase that is targeted by an immu- e resistance turned to curiosity nosuppressant drug called rapamycin. when Sabatini’s group published the at serine-threonine kinase is the nding in the journal Science later in mammalian target of rapamycin, or 2008. A critical kinase that oversaw mTOR. Scientists soon found mTOR cell growth was making the lowly lyso- to be a critical player in cellular some its headquarters when activated. growth and implicated in a number of Sabatini “is single-handedly cancers. responsible for putting the mTORC1 mTOR comes in two complexes. signaling complex on the lysosomal One, mTORC1, is exquisitely tuned membrane,” says Michael Overholtzer to amino acid levels in the cell. at Memorial Sloan Kettering Cancer Researchers showed that the presence Center. “ at really brings the lyso- of amino acids triggered the activation some to the forefront.” of mTORC1. But how and where the kinase checked in on the amino acid Clearly not a dead end levels was a mystery. e next indication that the lyso- Sabatini is a second-generation sci- some wasn’t a mere refuse receptacle entist. His father, David D. Sabatini, came in 2009 from Andrea Ballabio’s

20 ASBMB TODAY MAY 2016 laboratory at Telethon Institute of Genetics and Medicine in Italy. His group published a paper in Science that showed that lysosomal genes are regulated by a single protein called transcription factor EB, or TFEB. Researchers knew that a single cell contains hundreds of lysosomes, enough to make up about 5 percent of the cell’s volume. But they thought the number stayed the same over the course of a cell’s lifetime. Ballabio and colleagues suspected otherwise. “We postulated that any cell needed to have a mechanism to modulate lysosomal function,” he says. “ is was actually a relatively new way of thinking, because the traditional view of the lysosome was of a static organelle not subject to regulation and adaptation. But we postulated that there was a network of genes encoding for lysosomal proteins that would be jointly regulated” by a common entity. Ballabio and colleagues analyzed the expression of genes encoding lyso- somal proteins under multiple condi- tions and situations. And they did so without picking up a pipette. ROBERTO ZONCU AT THE UNIVERSITY OF CALIFORNIA, BERKELEY “We didn’t even do the experiments Immunofluorescent pictures show mTOR in red and a lysosomal marker in green. The top two pictures are from ourselves because the experiments amino acid-starved cells. mTOR is dispersed and does not localize with lysosomes. The bottom two pictures are were out there in the databases,” says from cells that were starved and then given amino acids. There mTOR clusters on lysosomes. Ballabio. “We looked at microarray Deciding factor databases, where there are experiments en the worlds of TFEB and done under many dierent conditions, mTORC1 collided. In 2012, the and looked at all known genes encod- groups of Sabatini and Ballabio dem- ing lysosomal proteins.” onstrated that TFEB and mTORC1 Ballabio’s team discovered that show up on the same spot of the the expression levels of the lysosomal lysosomal membrane. When nutrients genes went up and down in a coordi- are abundant in the cell, mTORC1 nated fashion. When they looked at phosphorylates TFEB and keeps the promoter regions of the lysosomal it inactive on the lysosome. When genes, they found that there is a com- nutrients, such as amino acids, drop mon sequence, the CLEAR site, in in abundance, mTORC1 becomes many lysosomal gene promoters. is inactive and no longer phosphorylates site was a known target site for the TFEB. e unphosphorylated and transcription factor TFEB. Shortly active transcription factor takes o for thereafter, Ballabio’s group found that the nucleus to turn on lysosomal genes TFEB regulates autophagy, which and turn up the cell’s degradative implicated TFEB in controlling both capabilities to either reshue alloca- cargo delivery to the lysosome and tion of materials or provide energy. degradation. CONTINUED ON PAGE 22

MAY 2016 ASBMB TODAY 21 cytoplasm. is lysosomal calcium signal- ing regulates TFEB. Ballabio’s group discovered that during starvation, lysosomal calcium release activates a phosphatase that dephosphory- lates TFEB. e dephosphorylated TFEB moves into the nucleus to kick o more lysosome biogenesis and autophagy. Taken together, mTORC1, TFEB and the calcium channels “constitute a signaling network to regulate when the degradation should occur and when degradation should be termi- nated,” says Xu. “It’s much more complicated than previously thought.” On the move It’s becoming abundantly clear that lysosomes are not one-trick ponies. For example, they are capable of ANDREA BALLABIO AT THE TELETHON INSTITUTE OF GENETICS AND MEDICINE repairing the plasma membrane. Lysosomes are seen as the red dots. The green dots show active TFEB in the nucleus. In 1997, Norma Andrews’ group, CONTINUED FROM PAGE 21 now at the University of Maryland, showed that lysosomes can function With the nding that TFEB and as calcium-regulated secretory vesicles. mTORC1 partner, says Overholtzer, ey don’t just take things in; they are it is obvious that “the lysosome is not capable of releasing molecules. e simply a dead end.” It directly com- nding was met with a lot of resis- municates with the nucleus, the cell’s tance at the time, since “conventional main control center, and partakes in lysosomes were not expected to do decisions about growth and degrada- that,” says Andrews. tion. In 2001, the group moved their ndings further along by demonstrat- ‘Much more complicated’ ing that the lysosome responds to e lysosome’s signaling roles calcium entering through tears in the appear to be even more sophisticated plasma membrane by fusing with the than rst thought. Haoxing Xu at the boundary to heal it. e calcium-con- , Ann Arbor, trolled process is known as lysosomal exocytosis. leads a research team studying a class But for exocytosis to happen, lyso- of calcium channels found spanning somes need to move. As researchers the lysosomal membrane. Mutations now appreciate, lysosomes don’t just in the channels, called mucolipin TRP sit in a spot. Depending on conditions proteins, cause a rare neurodegenera- in and surrounding a cell, lysosomes tive disease in children. move back and forth between the Xu says there is some evidence center and the periphery of the cell. that when the amino acid levels are ey do so by coupling to micro- low and mTORC1 is not active, the tubule motors, kinesin and dynein calcium channels kick into action, through an elaborate set of adaptor releasing calcium, an important sig- molecules, says Bonifacino, adding naling ion, from the lysosome into the that the attachment to motors “allows

22 ASBMB TODAY MAY 2016 the lysosomes to patrol the whole cytoplasm, looking for places where they can exert their activity.” But the movements and duties of the lysosome can be hijacked, explains Andrews. at’s exactly what the protozoan Trypanosoma cruzi, which causes Chagas disease, is capable of doing. e pathogen recruits lyso- somes to the plasma membrane, makes them fuse with the plasma membrane and tricks them into reforming with the parasite in them. When the lysosomes travel back to the cell interior, the parasite burrows out of the organelles and takes over the cell. Indeed, defects in lysosomal move- ment are implicated in disease. If lysosomes are forced to be immobile in a normal cell, “a lot of things go wrong in the cell,” notes Bonifacino. He gives the example of autophagy. HAOXING XU AT THE UNIVERSITY OF MICHIGAN If lysosomes are forced to hold still, Not much is known about the long, snakelike tubulated lysosomes. autophagosomes build up without destroy all kinds of unwanted matter, having lysosomes nearby to fuse with. the snake shape is thought to help is spells trouble for the cell. the lysosomes better pass on peptides Cell migration and adhesion also from unwanted matter to the plasma rely on moving lysosomes. “Late endo- membrane so that the immune system somes or lysosomes move to sites of knows which entities to search for. cell adhesion or migration, and they But, as Ryerson University’s Botelho bring adhesion molecules and signal- stresses, “Very, very little is known ing molecules like mTOR or MAP about tubular lysosomes.” kinases that remodel those adhesive Very little also is known about the structures,” says Bonifacino. “ at physical organization of the lysosome. allows the cell to move. If you inhibit Researchers estimate there are more lysosome motility specically then the than 50 types of enzymes inside the cells become less mobile.” lysosome. Do these enzymes it about like attendees at a cocktail party? Or New questions are they assigned to specic places like e renewed interest in lyso- workers in a factory? No one knows. somes brings with it new questions. Even for something as critical as For example, researchers know that mTORC1, the details are hazy. So lysosomes in certain cell types, such as far researchers know that there are the immune cell’s macrophages, can small GTPases that physically anchor be long and snakelike. In other cells, mTORC1 to the lysosome. e lysosomes tend to be round sacs, rang- GTPases have their own set of regula- ing from 100 to 1,000 nanometers in tors that in turn are controlled by a diameter. proton pump, the vacuolar ATPase, One tantalizing question: Is there which maintains the acidic pH of the a dierence between tubular and lysosome interior. But how exactly is round lysosomes? In the case of the mTORC1 detecting amino acid levels, macrophages, the cells that engulf and CONTINUED ON PAGE 24

MAY 2016 ASBMB TODAY 23 CONTINUED FROM PAGE 23 as growth and metabolism? Researchers also are now very inter- the job that it’s known for doing? ested in studying the lysosome’s roles Sabatini says his group has identi- in diseases such as neurodegeneration ed a protein that appears to trans- and cancer. “Some cancers upregulate mit information about amino acid their lysosomal complement mas- levels from the lysosome interior to sively,” says Zoncu. “ ere are several mTORC1. But, he adds, they are reports now showing that some cancer working on proving that what they types, especially Ras-based cancers, are have found is a bona de amino acid literally addicted to lysosomal func- sensor. tions. Whether this is a stress response pathway or if it’s a way for them to Extending the reach scavenge nutrients, I think this is a of lysosomes great direction of investigation.” For neurodegenerative diseases, It’s not just nit-picky molecular Bonifacino uses Alzheimer’s to illus- questions that are coming up about trate how researchers are starting to lysosomes. ere are some fundamen- think lysosomes may be involved. A tal questions too. For example, are all signature of Alzheimer’s disease is an lysosomes the same? accumulation of plaques in the brain. “It’s very likely that the composi- e plaques are aggregates of a peptide tion of the lysosome changes from called beta-amyloid, which is secreted organ to organ depending on the spe- from neurons and glial cells into the cic metabolic needs,” says Roberto areas around the cells. Zoncu at the University of California, Although this extracellular beta- Berkeley, who was the postdoctoral amyloid was long thought to be toxic fellow in Sabatini’s group when it to neurons, says Bonifacino, recent spearheaded the mTORC1 localiza- work suggests that beta-amyloid inside tion. “For example, in the liver, you the cells may be to blame for causing have a lot of glycogen production and neuronal damage. Here changes in storage. It’s possible that lysosomes lysosome function could lead to dam- might be specialized in handling aging accumulation of beta-amyloid sugars.” But, he adds, this aspect of inside cells. lysosomes is not well-explored. e element of surprise is the con- Researchers are wondering if, even tinuous thread in lysosome research. within a single cell, there are dier- Even the discovery of lysosomes hap- ences within the hundreds of lyso- pened as a tangent. De Duve’s group somes. Dierent groups of lysosomes actually was chasing the action of can be tasked with dierent jobs in insulin on the liver when it stumbled the cell. For example, Andrews says, across the acidic digestive body in cell- “my prediction would be there is a fraction studies. Surprise after surprise population specialized in associating came with associations with signal- with the plasma membrane and is ing molecules and other unexpected involved in plasma membrane repair.” features of lysosomes. Another big question is about So, these days, researchers no lon- the inuence of the lysosome on an ger relegate lysosomes to the corner. entire . “Just how far does ey put lysosomes on center stage this system go? If the lysosome is a and continue to be beguiled. signaling hub, what is the full range of actions that it can have on the body?” Rajendrani Mukhopadhyay says Zoncu. If the lysosome plays criti- ([email protected]) is cal roles in signaling cell growth and the chief science correspondent degradation, how do these roles play for the ASBMB. Follow her on out on whole-body parameters, such Twitter at twitter.com/rajmukhop.

24 ASBMB TODAY MAY 2016 FEATURE Meet Timothy Karr

By Rajendrani Mukhopadhyay

perm fascinate Timothy Karr. interested in sperm A postdoctoral stint with Bruce maturation? S Alberts in the early 1980s changed Karr’s interests from the bio- As an insect development biologist, chemistry and biophysics of polymers I learned that sperm are a central ele- to the developmental and genetic ment of all animal and plant organis- mal tness. As I started learning more contributions of sperm to the repro- about reproductive biology, it became duction and of a species. clear that the maturation process (of ese days, Karr, a visiting scientist sperm) is still a very mysterious one at the Kyoto Institute of Technology and complicated. e journey that in Japan and an adjunct professor at sperm make (through the male repro- Arizona State University, is analyzing ductive system) is essentially unknown the molecular changes that happen in terms of molecular details. e to mammalian sperm as they travel work has practical implications (for through the male reproductive system PHOTOS COURTESY OF TIM KARR fertility) along with the plain-old fact Karr studies how sperm changes on a molecular level and become capable of fertilizing an that I like to make biological discover- as it makes its way through the reproductive system. egg. ies. Karr recently became an associate editor for the journal Molecular & Why do proteomics? Cellular Proteomics, which is pub- lished by the American Society for What can it do that other Biochemistry and Molecular Biol- methodologies can’t? ogy. Rajendrani Mukhopadhyay, the ere are some systems you can ASBMB’s chief science correspondent, learn about only by doing proteomics spoke with Karr to learn about his because transcriptomics is a minor research interests and career trajec- player. Sperm are made by the testes, tory. e interview has been edited for which is a very complex organ that length and clarity. transcribes a very large number of genes, of which only a fraction end up in the sperm. Doing the transcriptome What is your research of the testes confuses you as to what’s about? actually in the sperm. Sperm are made We’re looking at using proteomics of predominantly proteins and lipids to follow the changes that occur in and other things, but, in terms of sperm composition during their transit transcription, they are mostly silent. People are starting to realize they can through the epididymis as they acquire leapfrog over the transcriptomic analy- fertilization competency. (Author’s sis and directly analyze the protein note: e epididymis is the duct components in sperm. through which sperm moves before We have begun trying to connect exiting the body. It’s present in male the dots between what is changing in mammals, birds and reptiles.) sperm and how they acquire the ability to fertilize at the proteomic level. e How did you become CONTINUED ON PAGE 26

MAY 2016 ASBMB TODAY 25 CONTINUED FROM PAGE 25 Between the time the sun went down and the time we went to bed, I read. hope is that it will lead us to a focus at also had a huge inuence on me. on important components of this I gravitated toward books about sci- system that could be used for further ence and scientists. studies of reproduction. Where did you go How did you become to college? interested in science? I had a scholarship to Stanford. But It was a natural consequence of when I got there, I couldn’t go because the way I grew up. I grew up in the I couldn’t aord it. I ended up going middle of central Arizona, about 60 to a junior college nearby, because I miles from Phoenix, near the Agua had to work to support myself for a Fria River, away from civilization. I couple of years before transferring to had exposure to a lot of desert nature. (the University of California), Santa A young child’s fascination with the Barbara. I did my undergraduate, creepy-crawlies, the noises at night and then I obtained my Ph.D. in the and the animals — I was immersed in chemistry department at UC Santa it. I didn’t have a choice. I naturally Barbara. gravitated toward curiosity-driven understanding of the world. Who was your adviser? e Arizona desert is quite hot. We His name is Daniel Purich. He’s at didn’t have electricity and air condi- the University of Florida now, and he’s tioning. In the summer, I remember still doing lots of wonderful things. there was a at rock. I would take He’s the reason I’m here. water out from the well, pour it on the rock and watch how fast it evaporated. I still remember how fascinated I was, What did he do? toying around with the conditions He was a fantastic mentor and under which (evaporation) would never let me believe, for one second, happen. I remember observing nature that I’d made a wrong decision for and trying to put rational thinking going into science. He’s so inclusive behind it. in his desire to bring people in and encourage them. What did your parents do? ey mined gold. It was a way to What happened after accumulate enough gold to go into your Ph.D.? town and trade it for food and stu. I did a postdoc with It wasn’t for money making or prot at (the University of California, San making. It was subsistence living. It Francisco) and also omas Kornberg was no-electricity, no-running-water at UCSF. I did two postdocs over the kind of existence. We grew some of course of about ve years before I took our own food. We had goats for milk. my rst academic position (at the We had donkeys to haul water. University of Illinois). When the sun went down, we were inside. e school that we went to was a one-room school with eight grades. How did you start working Once a month, the book mobile on sperm? would come by, a large, old-style I went to Bruce’s lab to work on T4 Winnebago lled with books. I would DNA replication. I had done my the- get a huge stack of books. I loved to sis work on microtubules but strictly read, and my sister loved to read also. from a biophysical and biochemical

26 ASBMB TODAY MAY 2016 While a visiting scientist at the Kyoto Institute of Technology in Japan, Karr takes in the scenery near Kyoto’s Ryozen Gokoku Shrine. standpoint. I wanted to continue three-dimensional reconstruction of working on systems that polymerized. sperm in a fertilized egg. Bruce had done unbelievable work in But the paternal product in the the area of (DNA replication), so I egg was (considered) an anomaly. I was fortunate enough to get into his had a bit of an uphill struggle, and, lab and start working on that for my until I went to England, I never rst year. en Bruce decided to work got funding for this work. It had a on Drosophila, so I was one of his negative impact on my career, because point people to get that jump-started nobody understood (paternal eects in his lab. in fertilization) and nobody wanted I knew nothing about develop- to hear about it. Because I couldn’t mental biology or genetics. It was get funding, I couldn’t make enough like doing another Ph.D. It was great progress to satisfy anybody. With the and wondrous, remaking myself as a new and emerging idea of epigenetics developmental biologist. During that of paternal products, I’ve been able process, I (learned) that Drosophila move forward. make very long sperm. Sperm gigan- I also became interested in Wolba- tism had been noted for 100 years … chia, because I was constantly trying ese sperm are as long as the male. to think of ways to show that the I discovered that this whole sperm father provides more to the fertilized entered the egg intact and formed a egg than just DNA. (Author’s note: structure in the egg. It was a rather Wolbachia is a genus of bacteria that stunning discovery. Using cell biologi- infects insects and some nematodes. cal techniques including 3-D micros- It is one of the world’s most com- copy, I published, in 1991, the rst CONTINUED ON PAGE 28

MAY 2016 ASBMB TODAY 27 CONTINUED FROM PAGE 27 University of Bath. I went back to Arizona and was fortunate enough mon parasitic reproductive microbes, to get a research position at (Arizona because it gets passed along from one State University) and continue to be generation to the next through insect productive. and nematode reproductive systems.) What do you think you Why did you go to England? ey gave me money to study bring to the table as sperm. ere was a person who had a MCP associate editor? taken notice of me when I published e eld of proteomics has been a couple of Nature papers on Wolba- highly technologically driven. MCP chia. He was a theoretical biologist is distinguished by the fact that it who had written part of his thesis also promotes cellular function. about Wolbachia, and he was fasci- Protein biology is so much more nated that somebody actually had complex than (that of) nucleic acids done experimental work on it. A at the chemical level that it’s been a couple years later, he contacted me huge challenge to get traction on the and said, “We have an opening here. technology. I really like the idea of Are you interested?” using the technology to discover new I was at the University of Chicago things about systems that are involved at the time. One of the evolutionary in evolution, development and biologists from Chicago had recently reproduction. We are garnering new moved to Edinburgh. He and a couple insights into aspects of human diseases others decided to support the (Univer- through the evolutionary lens. I think sity of Bath’s) application to get me a that angle is very important for the Royal Society Wolfson Research Merit journal, and it’s something I will try to Award. promote. People should be comfort- e Royal Society agreed. I had able with applying these powerful a ve-year window with a healthy technologies to fundamental questions chunk of money and a salary, because about evolution and development. the Royal Society also said they would match my salary at Chicago. It was What advice would you wonderful. I continued my Wolbachia and sperm work unabated for a few give younger scientists? years. I can only use myself as an example. I never wanted to do any- What brought you back thing else. I never would discourage anybody from wanting a life of discov- to the States? ery. e only mark I can leave is if I I wish I was still there. But it didn’t discovered something. e rest follows work out for the family for a number along. I’ve been bruised and battered of reasons. It was the worst possible by the academic system. I’ve had com- time (to move back) from a funding mensurate nancial complications. standpoint, because it was 2008. Our But I never, for a second, ever thought country was nancially bleeding to about not doing it. It’s the only reason death. It was very dicult to get a I’m still here. senior-level job. ey wouldn’t let me bring my money from the U.K. I was stuck. Rajendrani Mukhopadhyay ([email protected]) is But I had made a commitment to the chief science correspondent my family, which is far more impor- for the ASBMB. Follow her on tant than being a professor at the Twitter at twitter.com/rajmukhop.

28 ASBMB TODAY MAY 2016 STEAM STEM + ART

An artist named Crick By Bree Yanagisawa

he union of science and art is integral to who her family is rmly underway. Artists and and who she has become. T scientists are bonding over shared interests in discovery and experimen- A child of science tation, collaborating on shows and installations that ask fundamental and art questions about life processes and Crick was raised outside of new technologies, and exploiting art’s Seattle in Bellevue, Wash., in potential to help make science more what she calls “a very techie digestible. household.” For the artist Kindra Crick, this Both her parents and her coming together is nothing new. maternal grandmother were Crick’s paternal grandfather is programmers who encour- , co-discoverer of the aged experimentation, and the structure of DNA, and her step- objects of science were never grandmother, Odile Crick, is an artist far from her play space. As who drew the rst published images a young child she was given of DNA that accompanied Francis chemistry kits and space in the Crick’s original paper with James garage for experiments. KINDRA CRICK Watson. Time spent with her pater- Odile and Francis Crick attend a youth theater performance of As part of a 2015 fundraiser for a nal grandparents was forma- Hello Dolly featuring their granddaughter Kindra in the title role. new biomedical research center at the tive. “My grandad would Francis Crick Institute in England, always encourage my curiosity and the late Nobelist’s granddaughter instilled in me a great love of books, was invited to contribute a sculpture puzzles and learning,” she says. “He for auction. Provided with a blank, taught me to question assumptions.” double helical structure and the theme Crick remembers there being a “What’s in your DNA?” Crick chose plethora of artist’s resources on hand to give each helix its own form. One when she’d visit Francis and Odile. side she painted a vibrant blue to “My grandmother would give me full which she added seedlike structures access to watercolors, pastels, drawing, that twisted along the length of the and would even hire models,” she says. helix and were meant to represent art “I had a much enriched opportunity and the infectious nature of human to explore both disciplines.” ideas. e other side featured hand- When it came time to choose a written diagrams copied by Crick career, Crick opted for the science from pictures of her grandfather’s side of her interests, enrolling in the chalkboards. She titled the piece undergraduate program in molecular “What Mad Pursuit.” biology at Princeton. She enjoyed her To Crick, the merging of both coursework, but the actual research wasn’t all she’d hoped it would be. ALEX CRICK sides in the sculpture was not only Kindra Crick’s piece, What Mad Pursuit, is an homage complimentary, as DNA bases are, but CONTINUED ON PAGE 30 to her inherited love of science and art.

MAY 2016 ASBMB TODAY 29 CONTINUED FROM PAGE 29 always been separate,” she says. But in 2007 she gave birth to a daughter and “I always enjoyed lab work to some “became fascinated with the biological extent, but there was always some- mechanisms that could be involved thing missing for me,” says Crick. in the overwhelming sensation of love “I like making things and building that one feels for a newborn.” things.” e curiously intense emotions To meet her creative needs, Crick helped to mesh fully her love of sci- created posters and marquees for ence and her love of art and led to several theater groups on campus. the creation of pieces with scientic After graduation, she spent time in undertones. A new series of paintings a lab that studied the breast cancer- delivered abstract concepts through associated genes BRCA1 and BRCA2. schematic images resembling biology While there, she found herself as textbook diagrams. “I started using intrigued by the imagery she saw the concept of diagramming, but under the microscope as she was by instead of it being factual and based the work’s scientic questions. on measurements it was very emo- When it came time to decide about tive,” Crick says. graduate training, Crick felt tasked e rst piece in this science-art with arriving at her own research fusion is called “Mother, First Year II.” direction. But she stumbled. “When It features three brains, each represent- you’re in science you should pick a ing a dierent time after birth: day 12, question, and I wasn’t sure if I had my week 12 and month 12. An image of a question,” she says. fetus is shown in the rst brain, over- Instead of forcing herself into a life- whelming all aspects. As time goes on, style that wasn’t tting, she enrolled the fetus nestles inside the emotional at the School of the Art Institute of core of the brain. Chicago. Crick got a range of reactions to the piece based on whether the viewer The empathy molecule took the image literally or guratively. ough she enjoyed both disci- Many who immediately understood plines from an early age, Crick never the work tended to be parents them- thought to make science-informed art. selves, while others asked her if the “My art practice and my research had diagrams were backwards. “One of the things about art is that you’re speaking to a very specic audience some- times,” says Crick. “ e art isn’t sup- posed to be taken literally.” Art as outreach Crick’s methods for creating her art bear some relation- ship to the scientic KINDRA CRICK process. As she iden- Crick’s first piece to intentionally fuse science and art was inspired by her love for her newborn daughter. ties new questions

30 ASBMB TODAY MAY 2016 that interest her, she takes time to dig through research literature before get- ting started in the studio. Although she now works explicitly with scientic concepts, Crick insists she isn’t making art that’s meant to teach audiences about science. Dur- ing a recent partnership with NW Noggin, a group based in Portland, Ore., and founded by an artist and a neuroscientist who pair art with sci- ence outreach, Crick collaborated on a piece intended to inspire wonder. Working with postdoc John Hark- ness of Washington State University, Vancouver, Crick created a sculpture that represents an aspect of Harkness’s research on perineuronal nets, which are believed to support the preserva- tion of memory in neurons. Titled “Your joys, Sorrows, Mem- ory and Ambition” — a phrase taken from a larger quote by her grandfather — Crick’s piece is a towering spec- tacle. More than eight feet tall, it fea- tures neuron cables interspersed with glowing LED lights encased by wire mesh nets. e wire nets cradle the neurons, visually depicting the sup- portive relationship perineuronal nets provide neurons within the human brain. Crick purposely exaggerated KINDRA CRICK the net structures to draw attention to Postdoc researcher Josh Harkness and Crick with their collaborative piece inspired by perineuronal nets. their important role. In late April, 2016, as part of a Hood wilderness and diagrams of weeklong outreach trip by NW Nog- melting glaciers. e aged feel of the gin, the piece was installed at e pieces evokes a sense of the continuity Phillips Collection in Washington, of nature and of scientic mystery. D.C., for an event that showcased the Given her experience of mother- brain and our perceptions of beauty. hood, her formative time with her While there, the group also performed grandparents, and a life of separating, science outreach at local schools to connecting and nally combining bring its joint science and art curricu- science and art, Crick is mindful of lum from the Pacic Northwest to the continuity and of her inheritance. East Coast. She’s learned, she says, that “not only do we pass on our genetics. We Connecting comfortably pass on our ideas.” As Crick moves forward with her art, the inuence of science remains Bree Yanagisawa (byanagisawa@ asbmb.org) is a science writing prominent. Her most recent series, intern at ASBMB Today and a “Cerebral Wilderness,” features old Ph.D. candidate in pathobiology diagrams of brain anatomy overlaid at the Johns Hopkins School of with topographical maps of the Mt. Medicine.

MAY 2016 ASBMB TODAY 31 EDUCATION The promise of BEST One school makes the most of an NIH-funded career-development program By Patrick Brandt

here is broad consensus among policy makers, career experts, T university administrators and others in the life sciences that the historical, apprentice-based model of graduate and postdoctoral training is no longer sustainable. In recent years, myriad recommendations have been advanced by the National Institutes of Health, scientic societies, university faculty members, thought leaders and trainees to overhaul the model and adapt training to the realities of today’s research environment (1–13). In 2012, the National Institutes of Health released the Biomedical Workforce Working Group Report, which suggested, among other things, that the number of Ph.D.s awarded to students interested in biomedical research careers was outstripping job openings in the eld. e report’s rst recommendation was the creation of a competitive grant program that would enable institutions to train graduate students for a wide variety of careers in science — not just tenure-track research positions. Within a year of the report’s

release, the NIH had committed more PATRICK BRANDT than $25 million to the funding of A UNC ImPACT student was funded for a clinical internship with a contract research and development organi- experimental career- and professional- zation. development programs through a new internships, career-focused peer postdoc interns each year. initiative called Broadening Experi- groups and improved alumni network e purpose of a UNC BEST ences in Scientic Training, or BEST. mapping. internship is to provide an immer- Ten BEST awards were announced in 2013 and another seven in 2014 (14, sive experience in a career path not 15). My institution, the University of Internships normally represented in an academic North Carolina at Chapel Hill, was In 2015, UNC started the Immer- setting. As interns learn about the pros one of the 2014 awardees. sion Program to Advance Career and cons of their desired career paths, Our experience with BEST has Training, or ImPACT, a 160-hour build their resumes, and hopefully get been enlightening and encouraging. paid internship program that sup- new letters of recommendation, they UNC’s version of the program consists ports 30 senior graduate student and also receive paychecks at their current of three interlocking components: stipend or salary levels and maintain

32 ASBMB TODAY MAY 2016 their health insurance benets. Fund- We will be tracking career satisfac- We anticipated that the research ing comes from university sources, tion, compensation and other metrics mentors (that is, the principle inves- an endowment from the Burroughs over the next several years to gauge the tigators) of the trainees would be the Wellcome Fund and matching funds success of the ImPACT program and least enthusiastic about the intern- provided by some of the internship already can report that satisfaction is ships. One could argue that they have hosts. Interns have worked in the fol- impressively high among interns, host the most to lose, at least in the short lowing areas: organizations, internship supervisors term, since the productivity of their • research and development at a and research mentors. laboratories are aected while the local biotech company, pairing whole Our survey results show that 93 interns are away. However, 86 percent genome sequencing and computa- percent of internship supervisors were of principal investigators surveyed tional computer programming; satised or very satised with hosting after the return of the interns reported • policy at the science policy divi- an intern, 73 percent said they would that the interns’ strengths across sion of a local NIH institute; be likely or very likely to oer the seven categories were about the same • outreach at a local science intern a position in the organization, or higher compared with before the museum engaging the public about and 100 percent said they were likely internship, 89 percent agreed that the the microbiome; or very likely to host an intern again. internship would have a positive eect • teaching at a local college, devel- e interns who responded to on the trainee’s competitiveness, and oping and delivering an undergradu- our post-internship survey agreed or all but one of the PIs reported that ate course; and strongly agreed that the internship the interns had met or exceeded their • business development with a new had made them more competitive for expectations. UNC startup company. the job market. CONTINUED ON PAGE 34

The gains of ImPACT trainees Leanna Gentry, a pharmacology experience from Parion, he was chosen for the highly doctoral student, worked part time at competitive postdoc program at in San Fran- Cato Research in Durham, N.C., a sisco. He will start his postdoc in July. Hagar says, “My contract research organization. Work- time at Parion solidied my interests in early-stage drug ing with senior regulatory scientists at development and business strategy. Insights I gained into GENTRY Cato on a regulatory aairs project, she these will be useful whether I pursue an industry career learned rsthand about regulatory legislation, Food and or academic career, the latter beneting from my being Drug Administration compliance, how to submit new better able to mentor trainees interested in industry and investigational drug applications, and regulatory report- tailor projects to have translational potential.” ing. Two months after completing her internship, Gentry Emilie Mainz, a chemistry doctoral graduated and was hired at Cato as a scientist without student, participated in a full-time the need for a postdoctoral training period. Her position internship at BD Technologies in allows her to contribute to both clinical and regulatory Research Triangle Park, N.C., work- strategy. Gentry says, “ e internship gave me experi- ing on a single-cell, next-generation ence in drug development that I could not have gained sequencing technology that will be otherwise in graduate school. anks in large part to the MAINZ released this year. Her supervisors at ImPACT award, I was able to secure a position in the BD were so impressed with Mainz that they encouraged competitive eld of clinical research without additional her to apply to BD’s competitive, rotational position postgraduate training.” known as the Technology Leadership Development Jon Hagar, a Ph.D. Program. e program, which Mainz will begin in candidate, worked part time at a mid- July, prepares high-potential Ph.D.s for leadership roles sized biotech company called Parion across all aspects of research and development innova- Sciences, also in Durham. His main tion within BD. Mainz says, “ImPACT supplied the goal was to evaluate the scientic and rare opportunity to develop new technical skills while HAGAR commercial merit of candidate pipeline building a valuable network within the medical device technologies. He was vigorously recruited for a full- industry. ese experiences solidied my career path and time position at Parion but instead pursued an industry undoubtedly made me a more competitive candidate.” postdoc. With great recommendations and his industry

MAY 2016 ASBMB TODAY 33 CONTINUED FROM PAGE 33 respond quickly to new career interests we invite alumni back to UNC for and multiply our programming in a career networking lunches, seminars Career cohorts sustainable way. and workshops. We also connect e career cohort model began as individual trainees with alumni for a grassroots eort led by trainees and Alumni network mapping informational interviews and, in some since has been fostered and expanded Trainees expect to have access to cases, actual job placements. by our oce. Led by graduate students graduate program training outcomes, If institutions are to continue attracting a diverse pool of new train- and postdocs who are all interested in and UNC is committed to report- ees and preparing them to aect posi- the same career path, UNC’s career ing complete and transparent alumni cohorts are organized around science tively the changing scientic work- placement data (16). e university policy, teaching-intensive careers, sci- force, the graduate and postdoctoral recently concluded a census of the ence and business, academic careers, training model will need to change. 1,100 alumni who have graduated and science communication. Each Universities, both those with and with a life science Ph.D. since 2000. group has a faculty leader and receives those without NIH BEST awards, are rough a variety of online and a modest program budget from the encouraging this process of change by personal contacts, we conrmed cur- university and from the BEST grant. devoting resources to career and pro- rent titles, employers, and city and Cohorts generally meet once a fessional development and implement- month to network, share information, state information for 91 percent of ing experimental training initiatives. work on individual development plans our alumni. Aggregate reports of this We intend to keep the pressure on and or attend events with invited speakers. information are publicly available to the dialogue going as we pull and prod Each career cohort maintains a listserv prospective students, current trainees the entrenched training model out of for distributing announcements, job and others. its historical rut toward a new track of opportunities and career-related infor- Institutions that openly report these success for all stakeholders. mation, and each year we work with sorts of outcomes are at a competitive two or three cohorts to develop and advantage when it comes to recruiting fund a workshop series related to their the best trainees — many of whom Where to go for more careers of interest. For example, this enter training with dened career aspi- BEST information academic year we held workshop series rations. Presenting these data to our on science policy, pedagogy skills and faculty also helps to create a training e approaches taken by science communication. e career environment where career success is participating BEST institutions; cohort model empowers trainees to measured by many dierent outcomes how the results of various BEST take control of their own career learn- and not just tenure-track attainment. programs will be shared with the ing, provides leadership opportunities Current trainees benet from this research community; and a blog, for trainees, and enables our oce to expanded alumni network map when news feed and discussion forum on best practices can be found at REFERENCES the consortium website: 1. http://www.rackham.umich.edu/downloads/2012%20NIH%20Workforce%20Report.pdf. www.NIHBEST.org. 2. https://loop.nigms.nih.gov/2015/11/catalyzing-the-modernization-of-graduate-education/. More information about 3. Gould, J. Nature 528, 22–25 (2015). UNC’s career cohorts model is 4. Fix the PhD. Nature 472, 259–260 (2011). available at tibbs.unc.edu/career- 5. Leshner, A. Science 349, 349 (2015). cohort/. 6. Alberts, B., et al. PNAS, 112, (2015). UNC maps its alumni network 7. http://bit.ly/1T08Ci9 and makes aggregate reports of 8. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4304227/. alumni information publicly 9. Polka, J., et al. Science 346, 1422 (2014). available at tibbs.unc.edu/unc- 10. http://www.rackham.umich.edu/downloads/alberts-et-al-pnas.pdf impact-program/unc-life-science- 11. Pickett, C., et. al. PNAS 112, 10832–10836 (2015). phd-placement-data/. 12. Daniels, R. PNAS 112, 313–318 (2015). 13. http://www.fasebj.org/content/early/2016/04/12/.201500067R.full.pdf+html Patrick Brandt (Patrick_brandt@ 14. http://www.nihbest.org/wp-content/uploads/2015/10/FASEB2015.pdf med.unc.edu) is the director of 15. Mathur, A., et al. Science Translational Medicine 7, 285 (2015). career development and training 16. http://www.molbiolcell.org/content/26/8/1413.full.pdf+html. at the University of North Carolina 17. http://bit.ly/1VUbtzJ at Chapel Hill and a co-PI on UNC’s NIH BEST award. 18. Muindi, F., and Keller, J. Nature Biotechnology 33, 775–778 (2015).

34 ASBMB TODAY MAY 2016 Continental shift A young Indian scientist’s journey to the United States By Soma Chowdhury

was not the most focused kid in school. I After nishing my pri- mary studies, I more or less stumbled into an under- graduate zoology program with a vague sense that I liked biology and found botany boring. In the same unthinking way, I rode the science-student tide to a zoology master’s degree at the University of Calcutta in India. It was around this time that I met my future hus- band, Shurjo, who was my classmate at the university. He had been more strategic with his academic life and helped me bring a similar, if belated, focus to my academic career. PHOTOS COURTESY OF SOMA CHOWDHURY The author with her parents and husband on her wedding day. A few months into our relationship, Shurjo started decided to start studying. high school, nervous as he was for me preparing for the American Graduate I told my parents that I wanted to to leave the safety and security of our Record Exam so that he could go to go to America for graduate school. As small town and incur the nancial the United States and get a Ph.D. in small-town folks from the Indian state burdens of big-city living. But, to my primate genomics. We didn’t really of West Bengal who had spent almost surprise, he eagerly agreed. know what him pursuing that Ph.D. all their lives within a 20-mile radius Shurjo soon left India for Baton meant for our relationship until the of where they were born, they didn’t Rouge, La. I had no idea where that moment he was oered a graduate know how to react. America! My was. All I knew about America was assistantship from Louisiana State mom didn’t even know where it was what I’d heard about New York City, University. It immediately became and had to be told I’d be going to the Las Vegas and Niagara Falls. I chan- clear that, if we wanted to be together, other side of the globe. I thought that neled the sadness I felt when he left I would need to be willing to move to the real hurdle would be convincing into studying even harder for the the U.S. and to take the GRE myself. my father that this was a good thing. GRE. I worked so hard, in fact, that I Without stopping to think about the He hadn’t even wanted me to apply didn’t recognize myself. Never in my life-changing nature of this decision, I to colleges in Calcutta after I nished CONTINUED ON PAGE 36

MAY 2016 ASBMB TODAY 35 CONTINUED FROM PAGE 35 be such a challenge. convince the embassy ocials that I At the U.S. embassy in Kolkata, I had roots in India. My future father- life had I been so motivated. was told by a consular ocial that my in-law notarized a document saying My GRE score was decent, and I parents’ nances were inadequate for that he would help me if I needed any managed to land a graduate assistant- me to have any true ties to my own nancial help while in the U.S. I was ship at LSU. It was a great relief. But country. e fact that I already had incredibly grateful for all the help I soon the next dose of reality hit. I was funding from a U.S. university did not was getting from those around me. It going to need money — money for an matter. In an instant, my passport was all felt so surreal. air ticket, clothes, a visa and parapher- pushed back at me through the narrow After 14 agonizing days ooded nalia related to the trip. slit in the thick glass window. I was with anxiety, I appeared at the U.S. Given my nances at the time, the crying like a baby when I called Shurjo embassy for the second time. A dier- total amount of money was enormous. from a local phone booth next to the ent ocer asked one or two questions I felt desperate but still determined embassy. I’d had no clue that a student and approved the visa. He didn’t even to join Shurjo. He had saved some visa could be denied in the blink of look at all the documents I had so money from his graduate stipend, an eye by a consular ocial who was painstakingly gathered. which would cover a few things. A ocially mandated by her government At rst, I was in shock. I couldn’t couple of weeks after I was accepted at to treat me as a possible immigrant. come to terms with the arbitrary LSU, I applied for a travel scholarship nature of the whole process. I told my oered by the University of Calcutta, I felt helpless. I had only a month before the fall semester started at LSU, father, who had been waiting appre- never thinking that I would get it. hensively outside the embassy, what I did get it, and it covered my air but I couldn’t get a new interview at the embassy for another two weeks. had transpired. ere were no more ticket. So that I could shop for the hurdles. basics of starting a new life, my father Desperate, I took the rst possible interview slot. My father went to e next two weeks were a blur of took a loan out against his retirement preparations, and I didn’t get a chance account. work gathering everything he could to prove that he was nancially stable to contemplate the gravity of what As overwhelming as coming up was happening. ere were a million with the money felt, it was easy com- and would not be dependent on my other things to worry about. I almost pared to the next and most dicult earnings in the U.S. He also made a never had spoken to anyone in English hurdle: getting a U.S. student visa. At will in which he left all his property before, never had own in an airplane, the time I didn’t realize that this would to me in the hopes that this would hadn’t been to an airport, never had cooked anything edible, and never had lived without my parents for more than a month. On the day of my ight, I checked my packing list one last time, taking special care to note the pressure cooker and the spices, and hurriedly jotted down a few recipes from my mother. I was the rst person from my extended family to step outside of India. Many of my friends, neighbors and relatives came to celebrate that moment and to bid me adieu. I looked through the back window of the rented SUV that would take me to the airport and saw everyone waving. As we drove o, my friends and relatives gradually grew smaller, and I realized I was leaving everything I knew behind. I felt simultaneously blank, numb, thrilled and nervous. As The author’s husband on a brief visit home. She left India and joined him at Louisiana State University a few I boarded the ight to Chicago, I was months later. struck by a great sadness and began to

36 ASBMB TODAY MAY 2016 sob uncontrollably. what it meant to be homesick. After 36 hours in a dystopian world It’s been 10 long years since I of airports and airplane interiors, I arrived in the U.S. Shurjo and I are landed in Baton Rouge. While I was still facing the two-body problem on the ight, I had thought a lot while looking for jobs (thankfully, about what I would be doing when I this time, on the same continent). I rst saw Shurjo again. He was waiting survived grad school with a master’s for me with two of his friends, in degree, discovered a air for cooking almost as much shock as I was. Where and moved from Baton Rouge to the I come from, displays of aection in Washington, D.C. area with Shurjo. public are frowned upon, so I could After many years of fooling myself not even give him a hug. e moment that I wanted to do research, I took we saw each other, both of us ner- a leap of faith and became a science vously smiled, equally unsure if we writer. Our U.S. visa issues nally got were indeed in the same baggage claim resolved. area, actually together, or if the whole I can’t say that I’ve sorted out every- thing was a cruel and stress-induced thing in my life. But, for now, I think hallucination. I’ve stopped meandering and found I remember it took quite some time the right direction, both personally for our happy new reality to sink in. and professionally. Another chapter of my life was soon underway, and I found myself surviv- ing grad school, dealing with endless Soma Chowdhury ([email protected]. visa issues, understanding Southern Chowdury’s parents on their first visit to the United com) is the communications accents, learning how to cook and States. They’d never before flown on an airplane or editor at the National Institute of feeling for the rst time in my life seen snow. General Medical Sciences.

MAY 2016 ASBMB TODAY 37 OUTREACH Know your audience A blueprint for successful science outreach By Jeanne Garbarino

cience outreach can mean many things, and the eectiveness of S any particular outreach endeavor can vary just as much as the array of activities that fall under the science outreach umbrella. As director of the Science Outreach Program at e in New York City, a full-time program aimed at establishing equitable access to science research opportunities for urban K – 12 communities, I have learned that being eective at science outreach has little to do with fancy equipment, elaborate presentations or expensive reagents. Instead, eective- ness really comes down to one simple question: How well do you connect with your target audience? By presenting science in contexts that are familiar to our audiences, we PHOTOS COURTESY OF THE ROCKEFELLER UNIVERSITY have been able to grow our program, Kids at Rockefeller’s annual Science Saturday festival watch a liquid nitrogen demonstration. establish partnerships, and engage and support local students and teachers. networks. When the students map doing outreach should be equipped Here’s how we do it. out how dierent conditions, such as with a roadmap of relevant goals and leaks from heavy rains or track res talking points for every outreach We try to understand who from too much garbage, can aect project. Without this kind of dening the entire subway system, it opens framework, we can ramble and our our audience is and where up conversations about ecosystem message can lack purpose. they come from connectedness. Once basic, familiar Science Saturday, our annual sci- frameworks are established through At Rockefeller, we serve K – 12 ence festival for 5- to 13-year-olds, the subway example, I can then move students and teachers from communi- features more than 35 unique, hands- on and talk about the variety of the on learning stations. With just a few ties within New York City. If, in this planet’s ecosystems. urban context, I am going to center minutes to engage kids at each station, outreach activities on, say, ecosystems, we work ahead of time to dene a few I will avoid introducing the topic We map out goals and core elements of the communication using unfamiliar examples, such as relevant talking points strategy for each station. salt marshes or microbiomes. Instead, rough much trial and error, we First, we identify the ultimate goal I might ask the students to highlight have learned that less is often more of the station. Is it meant to educate, all of the things that exist at a subway when it comes to communicating raise awareness, dispel misconceptions station, and use their daily experi- science. Because science encompasses or perhaps promote specic ideas? ences riding the train as an entry point such an amazing breadth of informa- Once we’re clear on the goal, we arrive for teaching about relationships and tion about our world, those of us at the three most important talking

38 ASBMB TODAY MAY 2016 points we need to cover average, much older than to get to that goal. our typical high school For instance, our classes. I started teaching “Sweet hide and seek” our normal curriculum, learning station, facili- but the students were not tated by Rockefeller’s engaged at all and were bionutrition depart- saying things like “I don’t ment, aims to educate trust scientists” and “I’m young kids about the too dumb for science.” I link between obesity realized that, in order to and sugar and promote make an impact, I had to healthy eating habits. Students learn about ethics and the genetics of disease in Rockefeller’s toss our planned agenda is learning station is LAB Experience program. and do something totally designed as a game, and dierent. So I took them wonder how digestion works?” kids have to guess how many grams of to the cafeteria for coee, and then we is strategy has been really help- sugar are in common drinks like juice set out on a walk around campus. ful for our Learning at the Bench and soda. e conversations about To keep things relaxed while After School Program, which aims to this activity name three main talking building their trust, I invited them teach New York high school students points: many common drinks have to bring up any ideas or questions about metagenomics and microbial sugar in them; when you drink them, they had about science. Letting them community formation. ese topics sugar gets into your body; when there lead the conversation as we strolled, I by themselves could be daunting to is too much sugar in your body, it can periodically pointed out some of our any teenager. To make them more aect your health. interesting lab spaces or cool equip- accessible, we tell this particular story ment, which opened the door for through food. Our program has deeper conversations about scientic We try to tell a good story teamed with New York’s iconic store, issues that were relevant to them, Murray’s Cheese. Murray’s has its own that is relatable such as vaccinations, the development cheese caves, and our students are able Once we’ve identied our goals and treatment of cancer, and how to to visit and observe the microbiome and talking points, we think about become a scientist. how to weave them into a narrative of the caves and learn how microbial that includes relatable elements. ese communities aect the aging process narratives can take the form of a few and avors of cheese. We emphasize connection sentences or a series of interrelated We have had thousands of stu- and fun activities that convey real- We stay flexible dents and teachers come through our program in the past few years, and world application. We might even do While it is important to plan your successful execution of our events something as simple as ask the audi- outreach strategy, it is also important always comes down to how relevant ence a question, such as, “Do you ever to be able to go where your audience we’ve made them for our audiences. takes you. ere are times when I We’ve learned that being able to have spent ages planning an outreach relate to, understand, prepare for and event or curriculum, keeping in mind respond with exibility to our audi- every possible detail and direction that ences is often the dierence between could interest my audience, just to an outreach project that engages and have to throw it all out the window. one that zzles. For more about doing I’ve learned that, no matter how pre- successful outreach, please check out pared I think I am, when my material the outreach miniseries on our blog, is not connecting, I need to switch it up. e Incubator (http://incubator. A few weeks ago, about 20 students rockefeller.edu/). from a specialized high school came on a school eld trip to our learn- ing lab through our LAB Experi- Jeanne Garbarino (jgarbarino@ rockefeller.edu) directs the ence program. ese students had science outreach program at The A Rockefeller LAB student swabs the floor a history of truancy, were behind in Rockefeller University in New of a cheese cave for microbes. their academic credits, and were, on York City.

MAY 2016 ASBMB TODAY 39 CAREER INSIGHTS Research spotlight A Q&A with Kathy Goodson By Andrew Macintyre

athy Goodson is a research fellow Focus, great note taking, persever- and the director of communica- ance and patience. My analytical, K tions at the Potomac Institute for organizational and scientic writing Policy Studies. e Potomac Institute skill sets as well as my skills in coor- is an independent public policy insti- dinating people and resources came tute located in Arlington, Virginia, from my graduate education. and is focused on the role of science and technology in society. Goodson What is the biggest also works on a variety of Secretary of Defense and naval science and challenge that you have technology projects related to commu- faced in pursuing your nications and education. I asked her about the skills she learned during her career? What have you scientic training that prepared her for done to overcome it? a career in science policy research. Coordinating with graduate research advisers from separate aca- What are the key demic institutions and dierent scien- tic disciplines. Never underestimate experiences and decisions the power of developing people skills. that have enabled you Working with scientists from varying to reach your current disciplines has given me keen per- Kathy Goodson spective on conducting research and position? led me to take a more collaborative and Washington, D.C., area list events Attending Virginia State University approach. Ultimately, I believe that a that are open for attendance. e best was vital to determining some of the collaborative approach is fundamen- way to learn about something can be decisions that led to my current career. tal to the practice and promotion of to immerse yourself in the environ- As an undergraduate at Virginia education in science, engineering and ment. Join a group for an event and see what it is all about rsthand. State University, I received invaluable technology. experience and exposure to amazing scientic, medical and pharmaceuti- What advice would you What are your hobbies? cal research. I developed relationships Jogging, reading and oristry. with mentors that have been key give to young people to some of the insights I have been who want to pursue What was the last book aorded. I didn’t know or think it at the time, but Virginia State University a career similar to yours? you read? was the rst key stop on a lifelong Literally talk with someone who is One of the last books I read was journey. doing what you want to do. I rmly “Seveneves” by Neal Stephenson. It believe exposure is a powerful com- is a science ction novel depicting What skills did you learn modity that often is lost at all ages. post-survival awareness and challenges What can young scientists do to as humans move on from an unin- during your scientific learn more about careers in your eld? habitable earth. I love science ction training that prepared Attend events and network. ere is a because it’s not always ction. Some you for your current role? great resource called Linktank where of the best everyday inventions are the think tanks in the Maryland, Virginia spawn of great science and technol-

40 ASBMB TODAY MAY 2016 ogy endeavors that were at one time varying levels of scientic expertise. you motivated? thought of as ction. I have been fortunate to have many I absolutely love science. ere is such individuals in my life and even something new to learn every day. My Do you have any heroes, more fortunate to be able to do the (work has) allowed me to see amazing same for others. A mentor can be any- research being undertaken, and I am heroines, mentors or role one who does something that you’re excited for the opportunity to assist in models? If so, how they interested in doing yourself. If you the translation of those research eorts nd someone who is willing to share through science policy. have they influenced you? their time, enjoy and soak up informa- Science communication involves an tion like a sponge. And don’t forget to Andrew Macintyre (amacintyre@ individual who can interpret scientic return the favor with someone else. asbmb.org) is an education and professional development information and present it in a way manager at the ASBMB. that is accessible to individuals with What is it that keeps

The Marion B. Sewer Distinguished Scholarship for Undergraduates

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Applications open: Spring 2016 Application deadline: May 16, 2016

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MAY 2016 ASBMB TODAY 41 The American Society for Biochemistry And Molecular Biology

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