How Irv WeissmanHow Irv learnedtofigurethingsout Volume 8, No.2 Volume 8, I By KristaConger Leroy Hood, MD,PhD. Earlierthatday, time friendsDavid Baltimore, PhD, and co-owns withfellow scientistsandlong- annual scientificretreat attheranchhe Judith Shizuru, MD,toMontana foran andthelabofhisformerstudent oratory invited more than30membersofhislab- search and Medicine at Stanford, had wig CenterforCancerStem CellRe- of the state. in parts from surrounding forest fires still raging ning they were obscured by thick smoke locally asthe Three Sisters. But thateve- stunning Comomountainpeaks,known ofthe afloor-to-ceilingview room sports the largelivingroom. Normally, the their research attablesinthecornerof of peoplesatoncouchesordiscussed cake by tomorrow? Inside, several groups on theranch’s patio. Couldtheymakea slow-cooking three largeprimeribroasts dashed outside to confer with caterers Cell Biology andRegenerative Medicine, rector oftheStanford Institute forStem California. are abitdifferent thanthoseinPalo Alto, Clearly, thein Hamilton,rules Montana, smile,afterbeingpolitelyrebuffed. a wry wants tomakeanymoney,” hesaid,with several dozen big enoughtoserve people. upacake torustle joling alocalbakery feet, hepickedupthephonetobeginca- andinstockinglong-sleeved beigeshirt Bitterroot River, cladinkhakisanda 22 thenextday. Fresh from fishingthe stat. His daughter, Rachel,wasturning man, MD, needed a birthday cake,man, MD,neededabirthday early September, andIrving Weiss - t CDX2 in their cancer cells. ter treatment, compared to74percent ofthosewith cells lacking CDX2 lived disease-free for five years af- colon cancer, only about41percent ofthosewith In an initial study of 466 patients with any stage of colon cancerhave tumorsthatdon’t express CDX2. researchers foundthatabout4percent ofpeoplewith other genesthatdrive coloncellspecialization. The these cells,CDX2helpstocontrol theexpression of CDX2, whichisfoundinmature coloncells.In based onthepresence orabsenceofaprotein called scribing its significance. land Journal to stage-2 patients had limited benefit. ous studieshave suggestedthatchemotherapygiven study by researchers attheSchoolof Medicine. Previ- motherapy aftersurgery, according toaretrospective proteina particular may benefit from the use of che- By KristaConger than othersfromchemo patients maybenefitmore Some stage-2coloncancer Weissman, who alsodirects theLud- Undaunted, Weissman, 76,thedi- “You’d thinknooneinthistown was 7:15ona Tuesday evening in But the researchers iden The researchers categorized coloncancerpatients The studywaspublishedJan. 21inTheNew Eng­ Stage-2 coloncancerpatientswhosetumorslack inside of Medicine alongwithtwoeditorialsde- Stanford medicine January 25, 2016 25, January - See colon, page4 tion since1992.But Weissman’s Mon- nity to commemorate their visit. - level-4 laboratories foraphotoopportu gear used by researchers at the biosafety given thechancetodonprotective are studied. The next day, they would be known Rocky Mountain spottedfever Ebola, influenza,plague andthelesser- ratories, where lethaldiseasessuchas at the nearby Rocky Mountain Labo- attendees had presented their research scientific discovery as a teenager working for the pathologist Ernst Eichwald. asateenagerworking forthepathologistErnst scientific discovery Irving Weissman was inGreat Falls, born Montana, where hefirstimmersedhimselfinthepursuitof The yearly gatheringhasbeenatradi- PublishedbytheOfficeofCommunication&PublicAffairs common human ancestors, said Justin Sonnenburg, take presumably mostcloselyresemble thoseofour in- populations, whose livingconditionsand dietary world’s dwindlinghunter-gatherer agrarian andrural That’s aslittleone-tenthoftheintake amongthe industrialized societiesofabout15 grams perday. resulted inaverage percapitafiber consumptionin hasconvenience foodssincethemid-20th century path. industrial societiesmayalready begoingdown that the study suggests. Those of us who live in advanced species tothegutsofindividualsinthatpopulation, right” may no longer be enough to restore these lost extinction of key bacterial species, simply “eating as threesystems in as few or four generations. cause an irreversible loss of diversity within those eco mammaliangut,butcan ecosystems residing inevery fiber dietsnotonlydepletethecomplexmicrobial cies that get passed along to future generations. industrialized societiesmayproduce internaldeficien- raises concernsthatthelower-fiber dietstypicalin By BruceGoldman gut bacteriapopulationsovergenerations Low-fiber dietmayirreversiblydeplete The proliferation ofnearlyfiber-free, processed Once anentire populationhasexperiencedthe The study, conductedinmice,indicatesthatlow- A study by School of Medicine investigators tana roots go much deeper. teacher gave himacopyofTheMicrobe Firstthe during World War. 1900s toavoid beingdraftedby theczar who emigratedfrom Russia in theearly owner andthegrandson ofafurtrader Weissman isthe sonofahardware store about 200 miles northeast of Hamilton, A scientistisborn When Weissman wasabout10,a A native of Great Falls, Montana, norbert v - on der gr zymes, is the main food zymes, isthemain food is thatfiber, whichcan’t bedigestedby humanen- ets are suboptimal. Probably thechiefreason forthis Suboptimal diets 13 in nology and senior author of the study, published Jan. PhD, associateprofessor ofmicrobiology andimmu- species inhabiting every healthy individual’sspecies inhabitingevery large intestine. High-fiber dietshelptosustainthethousandsofdistinctbacterial Virtually all health experts agreeVirtually allhealthexperts thatlow-fiber di- oeben Nature. Hunters a drug that a drug panies makebusinessdecisions.If there’s you do,” hesaid.“Pharmaceutical com- cause nobodyunderstandsthe field like don’t doit,nobodyisgoing todoitbe- many valuable lessons. ing to the field. George W. Bush restricted federalfund- researchers inthestateafterPresident to funnelabout $3 billion to stem cell nia Institute for Regenerative Medicine enacted in2004,creating theCalifor- California Proposition 71,whichwas organ rejection. treatments forcancer, blooddiseasesand that laidthefoundationforpossiblenew sible fortheimmunesystem,research human blood-formingstemcellsrespon- he wasthefirsttoidentifyandisolate patients. AsaStanford facultymember, ful skinandorgantransplantationsin experiments thatledtothefirstsuccess- high schoolstudent,hehelpedperform touchstone of Weissman’s career. As a into the clinic would prove to be the it to medicine.” what happened,butimmediatelyapplied tious disease. They notonlyworked out tofigure outwhatcausedinfec- trying Weissman. microbe hunterswere “The what alifeinsciencemightbelike,” said the pursuit of scientific discovery. Falls, where hefirstimmersedhimselfin McLaughlin Research Institute in Great ofthecelebrating the60thanniversary days beforea few the retreat ata talk nated him. He recounted the experience “I’ve found in my career that if you Along the way, Weissman learned He alsohelpeddeviseandpromote Shepherding scientificdiscoveries “From thatbook,Igotanideaof , by Paul de Kruif, which fasci See See c h o weissman, page6 mb bacteria, page7 Page 5 dure. novel proce- to undergo a the Westin first person in became the lung transplant awaiting heart- A teenager os a n / shutterst oc - k 5 questions Robert Cowan on treating, managing headaches an occasional feature in which an expert answers five questions on a science or policy topic Robert Cowan, MD, is the founding founded the headache clinic in 2011. He is board-certified in pain medicine, neurol­ director of the Headache and Facial Pain ogy and the neurological subspecialty of headache medicine. He holds several nationally Clinic at Stanford Health Care. Its doctors help patients prevent and manage their head­ elected positions, including chair of the section on chronic daily headache for the Ameri­ aches, working in collaboration with colleagues at the newly opened Stanford Neuro­ can Headache Society. Cowan brings a special motivation to his work: He has managed science Health Center. Cowan, a clinical professor of neurology and neurological sciences, his own migraines for decades. Recently, Cowan spoke with writer Sara Wykes.

norbert von der groeben Are there different sorts of headaches? last more than one hour may be a sign of 1 other neurological problems and should Cowan: Headache is very common: Every year, more be brought to a physician’s attention. The than 90 percent of people in the United States expe- headache that follows the aura is similar to rience some type of headache. Tension-type headache a migraine headache without aura but of- is the most common, and 70 percent of people have ten milder in intensity. them at one time or another. The American Migraine Foundation estimates about 12 percent of people in Why do some people get headaches the United States — about 37 million — suffer from 3and others do not? migraines. Sinus problems only occasionally cause headache, cowan: Migraine seems to run in families, no matter what TV ads for decongestants and allergy very often on the mother’s side. Migraine and cold remedies may say. Studies show that most si- headache is three times more common in nus headaches are actually migraines. Headaches that women than in men. That increased risk do not respond to treatment of allergies are probably emerges in women when puberty begins migraine or tension-type headaches, or they are related and decreases after menopause. to overuse of pain medicines. Genetics can also hardwire us to get headaches. That we can’t control, but envi- What’s the difference between migraines and other ronment also plays a big role. A headache 2types of headaches? may come after intense exercise at high al- titude or with severe dehydration and high cowan: temperature. Some of us are just more Robert Cowan brings a special motivation to his work: He has managed his own A migraine is much more than a headache. It migraines for decades. occurs on average one to four times a month. Unlike sensitive to environmental changes, either a tension headache, it is often accompanied by nausea in the external environment — too much or vomiting. Its pain is intensified by physical activity sun, for example — or in our internal environment, rebound who have tried to stop overusing pain relievers and is so severe it interferes with daily activities. About from a drop in estrogen levels or a change in sleep pat- have found that their headaches got worse before they 30 percent of migraineurs — people with migraine tern. People who are not headache-prone do not usu- got better. Their headaches typically became more in- — have a warning that consists of neurologic signs, or ally get headaches under stressful conditions. However, tense within four to six hours after stopping the medi- auras, they experience before the migraine episode be- those who are prone to headache often experience cation and were at their worst within one to two days. gins. The most commonly experienced aura is visual, headache when under stress or during the letdown pe- This worst period may last for two to three weeks. If during which patients see small, colored dots, flashing riod, the time after a stressful period has passed. this describes you and you have not already consulted a bright lights or multicolored zigzag lines that may form physician, now is the time. a shimmering crescentlike shape. Sometimes there are How often can I take pain medicine for headache? blind spots in the visual field. 4 What can I do to avoid getting headaches? Aura symptoms last for 20 to 30 minutes. They are cowan: I chose to enter this field more than 25 5 followed within five to 60 minutes by the headache. years ago because people with migraines and other cowan: A good headache-management plan, espe- An aura shorter than five minutes may be something severe headaches know how disabling they are and cially if you experience migraines, starts with obser- else, so we do not diagnose a patient with short au- because I wanted to offer treatment that was multi- vation. We encourage our patients to take note and ras as having migraine with aura. Aura symptoms that disciplinary, that was more than stronger and stronger observe their own patterns of behavior and identify

Alliance / shutterstock medication. The vast majority of headaches should not the things that contribute to headaches. Patients may be treated with opioids or any other pain medications. notice they have certain symptoms that appear before It depends upon what kind of medicine you are taking, a headache begins. Irritability, lethargy, yawning, neck of course, but a good rule of thumb is not to take any stiffness and a food craving or aversion may be pre- pain medication more than two days in any week, and headache signals to note. no more frequently than recommended on the label or A great way for those patients who suffer from as prescribed. chronic headaches to get started is with a diary to If you need more medication to control pain, you record headache frequency and severity, time of on- should consult a physician. Overuse of acute medi- set and similar information for a month or three. You cations can actually increase the frequency of your may begin to see patterns that were not readily obvi- headaches. Headaches can be worsened by overusing ous when you relied on your memory to analyze your off-the-shelf and prescription medications: analgesics, headaches. Share your information with your doctor. barbiturates, caffeine and ergotamine tartrate. The There are several apps, computer programs and paper simple solution would be to stop overusing pain reliev- diaries available to document your headache history. ers. But it isn’t that easy. Most patients with analgesic ism

Medical school opens a new office to help faculty with grant applications

By Kris Newby The office’s director, Michael Helms, als and interfacing with sponsors and the amount of NIH funding it received While applying for a research grant PhD, MBA, is eager to assist faculty re- university liaisons. each year compared to other anesthesiol- may sometimes feel like buying a lottery searchers with a variety of grant-related Initially, the office will focus its efforts ogy departments nationwide. (In 2014, ticket, now faculty at the School of Medi- tasks. Services provided include identi- in three areas: the department’s ranking stood at No. cine can improve their odds by taking ad- fying funding opportunities, fostering • Large multi-investigator, multidis- 4.) vantage of resources provided by the new collaborative work, editing proposals, ciplinary grant applications that sup- He has also been a principal investiga- Stanford Research Development Office. managing the assembly of large propos- port School of Medicine centers and tor on his own NIH small-business grant programs. and has served as an ad hoc member of Inside Stanford Medicine is • Multi-investigator grants focused on an NIH study review section.

d e published monthly in July and the school’s priority initiatives, such as Helms said he feels his marketing ex- Stanford December and semi-monthly precision medicine and big data. perience has made a difference in the past n si

i the rest of the year. • Grants for early-career assistant proposals that he’s worked on. “I put on medicine professors who are writing proposals for my MBA hat and help investigators pres- is produced by Paul Costello their first independent research projects. ent their ideas in the best possible light,” Office of Communication & Public Affairs Chief communications officer Over time, Helms hopes to add he said. “My goal is to get grant reviewers Stanford University Susan Ipaktchian training programs on grant writing for excited about our research proposals.” School of Medicine Director of print & 3172 Porter Drive Web communications National Institutes of Health R01 and To begin the grant application pro- Palo Alto, CA 94304 John Sanford career development awards, team build- cess, contact Helms at mkhelms@ Mail code 5471 Editor ing and faculty development. These re- stanford.edu or 723-4526, or Sandra (650) 723-6911 Robin Weiss sources are funded through the office of Holden, PhD, grant development officer, http://med.stanford.edu/news/ Graphic designer the senior associate dean for research. at [email protected] or 724-5345. Helms previously worked in the De- To learn more about the grant sub- Send letters, comments and story ideas to John partment of Anesthesiology, Periopera- mission process at Stanford, visit https:// Sanford at 723-8309 or at [email protected]. tive and Pain Medicine, where he helped doresearch.stanford.edu/research-schol- Please also contact him to receive an e-mail version of Inside Stanford Medicine. the department move from No. 16 in arship/about-proposalapplication-and- 2009 to No. 2 in 2013, as measured by award-process. ISM 2 January 25, 2016 Inside Stanford Medicine vantage point We don’t just need precision medicine; one in an occasional series of essays written by faculty and staff we need precision health By Lloyd Minor their lives, from their genetics to their To be truly effective in building genetic and molecular information to We are coming up on one year environment. a culture of health and disease pre- create what will be the most complete since President Obama, in his State Bringing the promise of precision vention, physicians need to return to picture of a healthy human being. of the Union address, committed the health to patients will require a funda- some of the wisdom of our We’ve also launched nation to a $215 million investment mental shift in our view of medicine, predecessors. We need to Presence, a center to foster in precision medicine. Since then, we one which combines two seemingly recognize that through the research, dialogue, and col- have seen many breakthroughs in the different approaches — high tech and intimate bonds we form laboration across Stanford’s development of therapies tailored to high touch. with our patients when we seven schools to improve individual patients to treat the deadli- Start with data. Progress in health perform hands-on exami- the clinical experience for est of diseases. Recently we heard the care has always been based on a crude nations and listen to their our patients, providers, remarkable story of President Carter’s assessment of accumulated data. We concerns with empathy, we and families in our hospi- advanced cancer in remission from see that something works for one pa- enact a time-honored ritual tals and clinics. Led by Dr. a new immunotherapy treatment. tient, so we try it on a few more and and gain a different type of Abraham Verghese, Pres- Developments like these give us all observe what happens. That’s all the critical information than Lloyd Minor ence builds upon the Stan- hope that we can beat the most dif- clinical trials process is, really. But what we can garner from ford Medicine 25 program, ficult medical conditions facing in the past few years, the amount of lab tests and radiological scans. This which provides hands-on sessions humankind. available data about health care has kind of rich, nuanced data — what is to emphasize bedside physical exam I share those high hopes, but I can’t exploded, to the point where it can be important to our patients, what they skills to make sure all of our doctors help but think that we should aim overwhelming. fear, how their symptoms manifest and — from those just entering training to even higher. If the amazing scientific To take full advantage of these how they feel — must also factor into those who have been in practice for de- advances of recent years can help us breakthroughs, doctors must add a a truly holistic approach to health care. cades — maintain a strong bond with more effectively treat disease based on working knowledge of data science to Increasingly, medical schools are patients, make the obvious diagnoses individual factors, the natural sci- collaborating with engineering, com- when such signs are written on the shouldn’t we also “We really are on the ences that have puter science and business innovators body, and use technology judiciously put them to work traditionally throughout Silicon Valley to incorpo- to ensure patients get the care that is by helping us keep brink of an amazing been the focus of rate the latest developments in their right for them. people from get- transformation in how our professional respective fields into medical training We really are on the brink of an ting sick in the training. Doctors and practice. From detailing the hu- amazing transformation in how we ap- first place? we approach medicine.” must increasingly man immune system, to finding new proach medicine. But we can only go The vision be data special- applications for drugs, to decipher- as far as our vision allows us to. I hope would be to go beyond precision ists (and perhaps genomic specialists) ing autism in children or monitoring President Obama will use this year’s medicine: instead of a frantic race to and assess large pools of information pandemic strains with the help of so- State of the Union address to set our cure disease after the fact, we can in- through the lens of the individual cial networks — students are learning sights higher. Because when it comes creasingly focus on preventing dis- patient. how to harness data to improve human to health, we must think as big as we ease before it strikes. By focusing on However, understanding data is health. can — not just about treating disease, health and wellness, we can also have a not enough. With the advent of digi- Physicians are also partnering with but about making and keeping people meaningful impact in reducing health- tal health devices and online medical the top minds in Silicon Valley to not healthy. ISM care costs. At Stanford, we call this websites, more than ever, people have only gather data but to better under- idea precision health, where we focus become active managers of their own stand how to use it. Stanford, for in- Lloyd Minor, MD, is the dean of the on helping individuals thrive based health and demand a more consumer- stance, is collaborating with Google School of Medicine. This piece was origi­ on all the factors that are unique to friendly health-care experience. Life Sciences to collect anonymous nally published Jan. 6 in Forbes.

Conversations in Global Health to feature former What matters to scientist Lucy Shapiro NBC News chief medical editor Nancy Snyderman By Becky Bach Dante — interesting, Shapiro said, but “it Physician, author and former broadcast journalist Nancy Sny- didn’t make my heart sing.” derman, MD, will share insights from her Fasten your seatbelt: Developmental biol- When prompted to go back to school and storied career covering global health and ogy professor Lucy Shapiro, PhD, is driving, take an organic chemistry course, Shapiro dis- medicine in a conversation Jan. 27 with and we’re zooming through her achievement- covered her true love. Paul Costello, Stanford Medicine’s chief packed 40-year career in less than an hour. “It sounds corny, but it was like the sky communications officer. Speaking Jan. 13 as part of the “What cleared. [Chemistry] was the most beautiful The event, which is free and open to the Matters to Me and Why” series hosted by the thing I had ever seen. It was clear that was public, will begin at 5 p.m. in room 320 of Stanford Office for Religious Life, Shapiro, how my mind worked,” Shapiro said. the Li Ka Shing Center for Learning and who holds the Virginia She went on to Knowledge. and D. K. Ludwig Pro- “My love and passion make discoveries about Snyderman will soon join Stanford as a fessorship, said the topic the three-dimensional consulting professor in the School of Medi- Nancy Snyderman prompted her to ponder for the scientific world development of cells, cine. She is the former chief medical edi- why she was so passion- compounds called tor at NBC News and previously worked as a consumer education ate about the world of is spiritual.” RNA polymerases and executive at Johnson & Johnson and as a medical correspondent at molecules and cells, a many other aspects of ABC News. world invisible to most people. molecular biology that advanced She has reported on wide-ranging issues from all over the globe To figure it out, Shapiro said the field, along the way mentoring and has earned some of broadcast journalism’s most distinguished she had to think back to when she scores of students and budding honors, including Emmy Awards and Edward R. Murrow Awards. was 13, applying for high schools. scientists. Her awards are numer- She began her career as a head and neck surgeon, one of the first After consulting with her parents, ous and include the prestigious women in the United States to specialize in the field, and her medi- Shapiro decided to apply for one National Medal of Science. cal work has been published extensively in peer-reviewed journals. of New York City’s elite public Now, she’s particularly pas- Snyderman’s discussion is part of the Conversations in Global schools that focused on art and sionate about the threat posed by Health seminar series, organized by Stanford’s Center for Innova- music. Unbeknownst to her par- pathogens, which are rapidly out- tion in Global Health. ISM ents, however, she decided she evolving the drugs available to wasn’t going to take the exam in Lucy Shapiro rein them in. In response, she has music as planned. Instead, she helped found two pharmaceutical Memorial for Herbert Schwartz set for Feb. 5 checked out a book on drawing from the li- companies and is an active public speaker. brary, taught herself to draw and passed the During her talk she offered numerous Members of the Stanford community are invited to attend a entrance exam by producing a portfolio of words of wisdom, including: celebration of the life of Herbert Schwartz, MD, from 4:30-6:30 art. • On discoveries: “It’s just indescribable p.m. Feb. 5 at the Stanford Golf Course clubhouse. “That was really a defining moment. I when you discover something. It can be little, Schwartz, a professor emeritus and former chair of pediatrics, learned I could change the trajectory of my it doesn’t have to be earth-shattering. It is so died Nov. 13. He was 89. own life by some action,” she said. exciting.” Those planning to attend the event are encouraged to notify Discovering true love • On spirituality: “To me, science is reli- Sara Heller at [email protected]. gion. My love and passion for the scientific Donations in Schwartz’s memory can be made to Lucile Packard With that lesson firmly engrained — and world is spiritual.” Children’s Hospital Stanford at http://www.supportlpch.org. ISM with some well-timed assistance from men- • On her career: “These past 40 years have tors — Shapiro was off. There were detours, just been beautiful. I still can’t wait to get into of course. Her senior college thesis was on the lab each morning.” ISM Inside Stanford Medicine January 25, 2016 3 Colon norbert von der groeben continued from page 1 tified another important distinction between the two groups, particularly in those with stage-2 disease: Pa- tients whose tumor cells didn’t express CDX2 were much more likely to benefit from chemotherapy in ad- dition to surgery than were people with CDX2-positive tumors. About 91 percent of patients with CDX2- negative tumors treated with chemotherapy in addition to surgery lived disease-free for five years versus about 56 percent of those who did not receive chemother- apy. Previous studies that did not distinguish between CDX2-positive and CDX2-negative cancers suggested that chemotherapy provided little additional benefit to stage-2 colon cancer patients. “We’ve learned that a patient group that formerly was not known to need adjuvant chemotherapy may, in fact, benefit from this treatment. Conversely, it may be possible to identify those patients who could avoid the toxic side effects of chemotherapy,” said Michael Clarke, MD, professor of medicine and the Karel H. and Avice Beekhuis Professor in Cancer Biology. “This research is one of the first examples of how we can use our growing knowledge of stem cell biology to improve patient outcomes.” The retrospective study looked at gene expression in cancer cells and tissues from over 2,000 patients whose Michael Clarke and his colleagues found that stage-2 colon cancer patients with a particular gene-expression pattern may benefit from treatment courses and outcomes were known. The re- chemotherapy after surgery. searchers emphasize that a randomized, prospective clinical trial is necessary to further confirm the results before clinical changes are codified. Finally, to ensure their results would be useful to Gene Expression Omnibus database to identify CDX2. Clarke, who is also a member of the Stanford Cancer doctors, the researchers added another criterion: The Tissue samples were provided by the Cancer Diagnosis Institute and the associate director of the Stanford Insti- gene had to make a protein that was easily detectable by Program of the National Cancer Institute, the National tute for Stem Cell Biology and Regenerative Medicine, an existing, clinical-grade test. Surgical Adjuvant Breast and Bowel Project and the is the senior author of the study. Former instructors and The screening technique identified a promising can- Stanford Tissue Microarray Database. Siebel fellows Piero Dalerba, MD, and Debashis Sahoo, didate: the CDX2 protein. “We chose CDX2 because “A major question in the cancer field is whether the PhD, share lead authorship of the study. Dalerba is now it was the only candidate that was already used as a di- study of cancer stem cells can lead to increases in sur- an assistant professor of pathology and cell biology and agnostic biomarker in the clinic,” Dalerba said. “How- vival for cancer patients. This research is one of the first of medicine (Division of Digestive and Liver Diseases) ever, we were also intrigued by the fact that CDX2 is examples of how we can use our growing knowledge of at Columbia University, and Sahoo is an assistant pro- a master transcription factor controlling the expression stem cell biology to improve patient outcomes,” Clarke fessor of pediatrics and of computer science at the Uni- of many differentiation genes in colon epithelial cells.” said. versity of California-San Diego. When they separated colon cancer cases into those The work is an example of Stanford Medicine’s focus Stem cell, cancer connection with cells that either did or did not express CDX2, they on precision health, the goal of which is to anticipate found a marked difference in both five-year, disease-free and prevent disease in the healthy and precisely diag- Clarke and his colleagues have been studying the survival rates and in response to chemotherapy. nose and treat it in the ill. connection between stem cells and cancer for several Data sharing and collaboration Stanford co-authors of the study are former research years. For this study, Dalerba and Sahoo sought to assistant Pradeep Rajendran; former graduate student devise a way to identify colon cancers that were more “The CDX2 protein plays a role in the differentia- Stephen Miranda; former postdoctoral scholars Shigeo stem-cell-like, and thus likely to be more aggressive. tion of the intestinal epithelium,” said Clarke, who is Hisamori, MD, Tomer Kalisky, PhD, and Erna Forgo, They looked for a gene that was expressed in more ma- also deputy director of the Ludwig Center for Cancer MD; project coordinator Jacqueline Hutchison; lab ture cells but not in stem or progenitor cells. They did Stem Cell Research and Medicine at Stanford. “The manager Dalong Qian, MD; medical student Nate this by using a novel bioinformatics approach that drew novel bioinformatics analyses used in this paper links its Wilcox-Fogel; postdoctoral scholar Xiangqian Guo, on their knowledge of stem cell biology to identify de- expression to more differentiated cells in colon cancers. PhD; pathology professor Matt van de Rijn, MD, PhD; velopmentally regulated genes important in colon tissue We found that patients whose cancers lacked CDX2 ex- and professor of medicine George Fisher, MD, PhD. maturation. pression, which suggests that their tumors have a high The research was supported by the National Com- Because they knew from previous research by proportion of cancer stem and progenitor cells, had a prehensive Cancer Network, the National Institutes Dalerba in the Clarke laboratory that stem and im- much worse prognosis. However, their outcomes im- of Health, the Siebel Stem Cell Institute, the Thomas mature colon cells express a protein called ALCAM, proved significantly if they had received chemotherapy and Stacey Siebel Foundation, the Virginia and D.K. Dalerba and Sahoo looked for genes whose protein as part of their treatment.” Ludwig Fund for Cancer Research, the California In- product was negatively correlated with ALCAM expres- The study is hailed in an accompanying editorial stitute for Regenerative Medicine, the Department of sion. “We reasoned that those proteins would likely be in the journal as an endorsement of data sharing and Defense, the Bladder Cancer Advocacy Network and involved in the maturation of colon tissue and might collaboration among many different research groups. BD Biosciences. not be found in more aggressive, immature cancers,” The Stanford researchers used information stored in Stanford’s Department of Medicine also supported Sahoo said. the National Center for Biotechnology Information’s the work. ISM

Children’s hospital physicians identify mysterious illness, deliver top-notch care

By Ali Koide first time she and her husband, Steven bumps and blisters covering Wyatt’s Stanford. Catalano, held their youngest son just body from head to toe. “I wanted to cry as I thought about “He was so handsome and so big! one year ago. “I immediately knew his “You can hold him for just a min- the fact that his first drive was in an He was a little tank,” Shannon Cata- name was Wyatt James.” ute,” a nurse told them. “But we need ambulance to another hospital, instead lano said, recalling the joy she felt the But then, she noticed the odd to take him to the neonatal intensive of home with us,” Shannon said. “As a

courtesy of the Catalano Family care unit.” mom, we always do whatever we have What should have been one of their to do in order to take care of our lit- family’s happiest moments quickly tles. I didn’t care that I had just given turned somber as they feared the seri- birth and was still healing — so long ousness of Wyatt’s condition. The der- as I could be with my sweet Wyatt.” matology team suspected it could be A special transport team came to a skin disease, but they couldn’t know bring the newborn to the children’s for sure. hospital, whose specialists quickly ‘I wanted to cry’ got to work. The next few days were excruciatingly slow as Wyatt endured Wyatt needed to be transferred to countless tests to rule out different Lucile Packard Children’s Hospital diseases. Rare disease

Wyatt James Catalano, who turned 1 in Finally, after six days of poking and October, was diagnosed with diffuse cutaneous prodding, the diagnosis came: diffuse mastocytosis, a disease of the white blood cells. cutaneous mastocytosis, a disease of

4 January 25, 2016 Inside Stanford Medicine Teen awaiting heart-lung transplant first in West to undergo novel therapy

By Samantha Dorman is referred to as a “bridge-to-transplant” sustain patients’ lives for several weeks tin. “Once we arrived here, we knew we solution, one that would sustain Os- to six months, depending mostly on had the best and most experienced care 2016 is starting off a whole lot bet- waldo’s organs until transplant could be whether complications such as bleeding, possible.” ter than last year did for 14-year-old Os- done. blood clots or stroke arose. Added Carmen: “Now, the doctors waldo Jimenez of Salem, Oregon. “An integral element to success for On July 12, Oswaldo made history by can use this therapy to treat other pa- Oswaldo was diagnosed with pulmo- children awaiting lung transplants is to becoming the first child in the western tients. Maybe the next family faced with nary arterial hypertension at age 9. In keep them moving around,” said pediat- United States to undergo this treatment. this won’t have such a hard decision to early 2015, his heart and lungs were fail- ric pulmonologist Carol Conrad, MD, Then, just one week after receiving the make, because it certainly worked for ing, and a heart-lung transplant seemed director of the pediatric lung and heart- shunt, donor organs became available. Oswaldo.” to be his only real hope for survival. lung transplant program at the children’s Oswaldo received his heart and lung Conrad said the hospital team likely Oswaldo was referred to doctors at hospital and an associate professor of transplant on July 19. will use this bridge-to-transplant treat- Lucile Packard Children’s Hospital Stan- pediatrics. “Being in good shape helps “We are so, so thankful for organ do- ment again, adding yet another option ford and Stanford Children’s Health, one to make them good candidates for the nation,” Carmen said. “During another to the Stanford Medicine therapies and of America’s leading centers for pediatric transplant operation. Pre-operative de- family’s time of incredible grief, they innovations for kids with failing hearts organ transplant. There, physicians de- bilitation leads to prolonged recovery gave my son the ultimate gift of life.” and lungs. termined that Oswaldo would indeed period post-op and a poorer outcome in Looking ahead For Oswaldo, he is simply looking need a transplant, but that he could re- the long run.” forward to being a kid again. “I want to turn home to Oregon to await notifica- A novel procedure The post-operative period was com- run and play, and get my life back,” he tion of donor organs. But in the spring, plicated, but Oswaldo and his family said. As far as what the future holds? Oswaldo’s condition rapidly worsened. It was then that doctors decided to try returned home to Oregon in December. “I just know I want to do something He was admitted to a local hospital and a novel procedure, one that would enable “He’s steadily improving,” said Conrad. big in life,” he said. ISM emergency airlifted to Packard Children’s Oswaldo to be mobile. Called a pulmo- “There are no words to express our in May. nary artery to left atrial shunt, it was a gratitude, and we can’t say enough about Samantha Dorman is media relations What happened? The pulmonary surgery that had been used only a dozen our medical team,” said his dad, Mar- manager at Stanford Children’s Health. arterial hypertension made it hard for times in patients nationwide. It would blood to flow properly through Oswal- reduce the workload on his failing heart, Journal of Thoracic and Cardiovascular Surgery do’s lungs, where blood picks up oxy- and allow Oswaldo to stay mobile and gen for the rest of the body. “The high help oxygenate his blood while awaiting blood pressure in his lungs was requiring transplant. his heart to pump harder and harder,” “He was so critically ill, and it was explained pediatric cardiologist Jeffrey a very risky procedure; he was at high Feinstein, MD, director of the Vera risk of cardiac arrest when being put to Moulton Wall Center for Pulmonary sleep for the surgery,” said Katsuhide Vascular Disease and head of the hospi- Maeda, MD, surgical director of lung tal’s pediatric pulmonary hypertension and heart-lung transplant program and program. “This eventually caused his a clinical assistant professor of cardio- heart to fail.” thoracic surgery. “But essentially, this “When we initially evaluated him shunt established a ‘lung’ that served to a few months earlier, he had very few oxygenate his blood as it flowed through symptoms; when he returned, he could a box outside of his body. Since the de- only walk a short distance before getting vice was reasonably small, it allowed him breathless,” added Feinstein, who is also to stay awake and mobile while awaiting a professor of pediatrics in the School of transplant.” Medicine and the Dunlevie Family Pro- For parents Carmen Hernandez and fessor of Pulmonary Vascular Disease. Martin Jimenez, it was a difficult deci- “The pressure in his lungs also caused sion to go forward with this novel pro- two episodes of pulmonary hemorrhage. cedure, but there were no other options

This bleeding into the lungs can be fatal.” — and they trusted the team. samantha dorman Leader in multi-organ transplant “We weren’t given any hope until we came here,” said Oswaldo’s mother, Car- Combined heart and lung transplants men Hernandez, via a translator. “This are so rare that only 24 were performed seemed to give him the best chance to in the United States in 2014. Stanford live.” has long been a national leader in multi- How it’s done organ transplantation, performing the world’s first successful combined heart- The procedure involved the inser- lung transplant, on an adult, at Stanford tion of a tube that redirected blood away Hospital in 1981. from Oswaldo’s lungs into the oxygen- Listing Oswaldo for transplant was ator. This, in turn, provided oxygen to just the beginning. Care teams wanted to the blood and then returned it to his ensure his failing heart and lungs could body, with his own heart providing the keep going until donor organs were pump. available. They needed to perform what The shunt device has been shown to

Children’s hospital physicians identify mysterious illness, deliver top-notch care

the white blood cells. Wyatt is one Today, Wyatt, who celebrated of just 30 infant cases to have ever his first birthday in October, is been reported in the United States. a perfectly happy boy: He loves He is at risk of going into anaphy- to eat avocados, dance to coun- lactic shock at any time, and doc- try music, and play with his big tors are unsure of the effects an brother and big sister. Almost daily EpiPen — the last line of defense they’ll meet a stranger concerned — would have on an infant. The that Wyatt has chicken pox or that good news: The disease is some- he’s contagious (he’s not), and the An illustration (top) depicting the bridge-to-transplant system used by Oswaldo Jimenez (bottom, second what manageable with daily medi- family takes these opportunities to from right), who is shown here with his family and Carol Conrad, director of the pediatric heart-lung cation, a modified lifestyle (limited raise awareness of Wyatt’s disease transplant program at Lucile Packard Children’s Hospital Stanford. exercise, heat, cold, sunlight) and and share his story. frequent check-ups. “I love this hospital for a lot of “I feel incredibly blessed to live reasons. His doctors are the best,” Please give blood in the Bay Area and have access to Shannon wrote on a Facebook ad- Blood type needed: this world-class hospital,” Shannon vocacy page for her son. “They care O-, B-, AB- said, holding back tears. “They and each patient truly matters.” ISM have the expertise that other hos- To request an appointment, call 723-7831 or you can make an appointment online. pitals don’t. If it wasn’t for Lucile Ali Koide is the senior online com­ Packard Children’s Hospital we munity manager at the Lucile 3373 Hillview Ave., Palo Alto may still not know what was wrong Packard Foundation for Children’s 445 Burgess Drive, Menlo Park, with Wyatt and how to treat him.” Health. 515 South Dr., Mountain View http://bloodcenter.stanford.edu

Inside Stanford Medicine January 25, 2016 5 Weissman because of the research papers I wrote. but was going to do research,” Weissman antibodies identified by Irv to give a pa- continued from page 1 One thing I learned right away from recounted in an oral history done by the tient a tumor-free graft of her own cells,” makes them more money, that’s the one Ernst is that what people teach you from American Association of Immunologists said Negrin, a professor of medicine at they will pursue. There’s no one out there textbooks has very little to do with sci- in 2013. Kaplan was alone in support- Stanford. “The initial results were re- looking for who will take the advances of ence. They’re trying to teach you the ing Weissman’s choice. “Everybody, in- markable. The women who received medicine to patients.” fundamentals, like the periodic table, cluding Saul Rosenberg, got on my case. about 1 milliliter of purified stem cells Learning how to think but not the experiences that lead to an courtesy of irving weissman understanding of where that information In the early 1950s, Great Falls was the comes from.” largest city in Montana, with a popula- Instead, Eichwald taught Weissman tion around 40,000. It was named for how to puzzle things out for himself. a series of waterfalls on the nearby Mis- Once Eichwald described the result of an souri River, around which Meriwether important experiment, but not what the Lewis and William Clark portaged in result likely meant to the field of trans- 1805. Low, rolling hills and buttes cov- plantation biology. “I had to guess what ered with prairie grasses surround the was going on, which I did fairly quickly,” city, topped by a vast expanse of sky. Weissman said. “I realized from that In school, Weissman was a good, but moment on that I might not be able to not exceptional, student. He struggled memorize the periodic table or chemistry with memorization, and didn’t particu- formulas, but I could think.” larly enjoy reading. His mother was a Conducting experiments classically trained pianist, and Weissman played the piccolo and flute. Weissman began to conduct his own When he was about 15 years old, a experiments in transplantation biol- friend of his mentioned a man named ogy aimed at working out why an adult Ernst Eichwald, MD, who had been re- mouse would reject tissue from a non- cruited in 1953 from the University of matching donor, but a fetal mouse ex- Utah to work as a pathologist at Mon- posed to blood-forming cells from an Weissman was a teenager when he first began working with mice in the lab of Ernst Eichwald. tana Deaconess Hospital in Great Falls. adult mouse of a different strain would Eichwald had made the move on the then accept tissue from that strain of condition that he be allowed to spend mice for the rest of its life. Work done They said, ‘You’re never going to be any- recovered as quickly and as well as those part of his time as a one-man research at that time by Eichwald and Weissman thing if you don’t do your internship.’” who received the traditional treatment of program, studying the biology of skin later provided the foundation for organ “I felt his decision was a mistake,” several hundred milliliters of unpurified transplantation in laboratory mice. transplants of all kinds. Rosenberg recalled. “He was talented peripheral blood.” “Instead of working at the scrapyard As Weissman’s scientific career blos- enough to do both clinical and research However, a series of pharmaceutical for my father’s hardware store, I went to somed, he began to mentor younger work. But on the other hand he wouldn’t mergers in the late 1990s left the trial, see Ernst, because my friend said it was students in Eichwald’s lab. As a high have had the time to dedicate to research and the rights to the antibodies neces- fun to be around mice and rats,” Weiss- school senior in 1956, he was intro- that he’s had. He chose his path and that sary to isolate pure blood-forming stem man said. “But the difficulty was that he duced to Leroy Hood — a fellow Mon- has worked out very well for him.” cells, in the hands of the pharmaceuti- was very hard of hearing, and he spoke tanan who was then attending his first The next two decades saw Weissman cal giant Novartis, which abruptly ter- in a thick German accent. So I couldn’t year at Caltech and is now the director doggedly identifying where the many minated support of the SyStemix stem understand anything that he was say- of the Institute for Systems Biology in cell types in the immune system were cell programs in 2000, after the trial ing, and I was pretty sure he couldn’t Seattle. Hood remembers Weissman as made and how they worked. In 1988, completed enrollment in 1998. The de- understand what I was saying. Finally, a confident researcher who was already he and his col- cision was likely in a moment of desperation, I said, ‘I’ll conducting seminal experiments in leagues identified a due, Weissman work for nothing!’ Suddenly he under- transplantation biology. panel of antibodies “It’s the people with the believes, to the fact stood and could talk to me. So I started “I was a little intimidated by Irv,” that could be used that Novartis was to work with him in the summer as Hood said. “I hadn’t done anything to isolate blood- common sense to work at the time pursu- mouse caretaker, autopsy assistant and like that yet at all. From day one it was forming stem cells things out for themselves ing small-molecule lab researcher.” clear that he was going to be a terrific from mice, a feat drugs like the anti- Weissman continued to work for researcher.” that had never be- who will really make a cancer medication Eichwald over several summers while he Weissman attended Dartmouth for a fore been achieved. difference in this world.” Gleevec that would finished high school. During that time, couple of years but then transferred to Three years later, give a higher re- Eichwald carried on his research in mice what is now Montana State University in they did the same turn on their in- and chaired the transplantation commit- Bozeman, where he graduated in 1961. with human tissue. vestment than the stem-cell treatment. tee of the National Academy of Sciences. By that time, he had already set his sights The purification of these cells sug- “So not only did we not learn the re- In 1954, he established the Laboratory on Stanford for medical school because gested the possibility of regenerating sults of the breast cancer trial, we didn’t for Experimental Medicine, which even- it was a five-year medical program that tissues, organs and cells damaged by dis- get to continue our planned studies into tually became the McLaughlin Research would allow him time for independent ease or trauma with a person’s own stem whether these blood-forming stem cells Institute. He also founded the journal research. cells, and eventually set the stage for the would allow us to also induce tolerance Transplantation. From him, Weissman At Stanford, he joined the lab of Len formation of the California Institute for transplanted organs like hearts or learned not just the fundamentals of sci- Herzenberg, PhD, and Lee Herzenberg, for Regenerative Medicine, a unique re- kidneys. Because they found other drugs entific research, but also how to think. D.Sc.-equivalent, a husband-wife team search funding mechanism designed to that would make them more money, of geneticists, before going to work avoid a repeat of a painful research epi- faster. It was simply a business decision. krista conger at the end of his first year with Henry sode Weissman would experience in the “So. That was part of my learning.” Kaplan, MD, a professor of radiology. 1990s. In a 2011 paper, Weissman and Shi- Kaplan gave Weissman his own lab and A transformative lesson zuru reported that five of the 15 women a research assistant he shared with Saul at Stanford who received the purified Rosenberg, MD, then an assistant pro- The traditional path that promising cells were still living compared to just fessor of radiology. research findings takes from laboratory seven of the 74 who received unpurified “It was unusual for a medical student to clinic requires the involvement of in- peripheral blood. to be given such resources,” Rosenberg vestors or pharmaceutical companies to Through the ‘valley of death’ said. “But I quickly learned that Irv was finance the expensive clinical trials and an extremely bright and experienced re- commercialization of a new drug or The experience soured Weissman on searcher. We got to know each other well technique. In the late 1980s, Weissman the involvement of for-profit compa- that year, and I was impressed with his and his colleagues formed a company, nies in the translation of research into early experience, his dedication and his SyStemix Inc., to explore the promise of clinical treatments that could help pa- self-confidence.” blood-forming stem cells. tients. It also highlighted a phase in Skipping residency At the time, women with advanced medical research known as the “valley of metastatic breast cancer were often death,”which refers to the fraught time By his junior year, Weissman had re- treated with high-dose chemotherapy in between the identification of a promis- cruited other medical students to work a last-ditch attempt to wipe out tumor ing finding in a laboratory and when it with him on researching how the im- cells throughout the body. But this treat- becomes standard clinical practice, dur- mune system develops to distinguish ment also killed stem cells in the bone ing which money, time and resources are “self” from “non-self.” In 1964 he spent marrow, and patients had to be rescued often scarce. nearly nine months in the laboratory of by a transplant of their own stem cells. “I realized that this was going to hap- Weissman helps prepare dinner for guests last immunologist Jim Gowans, at Oxford Weissman, together with Shizuru and pen again and again and again,” Weiss- September at the Montana ranch he co-owns with University, where he showed that im- Stanford physicians Karl Blume, MD, man said. two friends and fellow scientists. mune cells that induce tolerance are born and Robert Negrin, MD, realized that “We were always going to end up tak- in the thymus and then migrate through the unpurified blood cells traditionally ing our research to a certain point and the blood to the immune-response lym- used to reconstitute the immune system then either venture capitalists or big “Luckily, Ernst never asked me what phoid organs like the bone marrow and often also contained cancer cells. They pharmaceutical companies were going kind of grades I got in high school,” lymph nodes. believed that using purified blood-form- to get it because, unlike universities, they Weissman said. “Because I’ve never been “Once I knew that the thymus was ing stem cells could avoid disease recur- have the funds and the resources neces- in the top 10 percent of my class. Not the place that made T cells, and that I rence, and SyStemix began a clinical trial sary to support large clinical trials.” in high school, not in college and not could mark them, I decided I wasn’t go- to test the idea in 1996. In 2001, President George W. Bush in medical school. I’ve been successful ing to do an internship and residency, “The idea was that we could use the severely re- See weissman, page 7 6 January 25, 2016 Inside Stanford Medicine Bacteria bacterial species in their gut.” More than half of these of this group were indistinguishable from those of con- continued from page 1 bacterial species’ numbers had dwindled by over 75 per- trol mice. cent, and many seemed to have disappeared altogether. These findings hold major implications for humans, source for the commensal bacteria that colonize our co- After seven weeks, the mice that had consumed a said Erica Sonnenburg. “There are very few ecosystems lons, Sonnenburg said. low-fiber diet were switched back to a high-fiber diet where low species diversity is a good thing. There’s no Thousands of distinct bacterial species inhabit every for four weeks. Their gut-bacteria profiles partly re- reason to think our gut is any exception,” she said. healthy individual’s large intestine. “We would have covered — probably due to an uptick in abundance of Possible fixes difficulty living without them,” he said. “They fend some bacteria whose ranks had declined to undetectable off pathogens, train our immune levels during the low-fiber-intake “The extremely low-fiber intake in industrialized systems and even guide the devel- “There are very few period. Still, this restoration was countries has occurred relatively recently,” noted Justin opment of our tissues.” While we ecosystems where low only partial: One-third of the Sonnenburg. “Is it possible that over the next few gen- pick up these microscopic passen- original species never fully re- erations we’ll lose even more species in our gut? And gers in the course of routine ex- species diversity is a covered despite their return to a what will the ramifications be for our health?” posures throughout our lifetimes, good thing.” high-fiber diet. Simple tweaks in our cultural practices — for ex- one of the most significant sources No such changes were seen in ample, not washing our hands after gardening or pet- of our intestinal bacterial populations is our immedi- the control mice consistently fed a high-fiber diet. ting our dogs — could be a step in the right direction, ate family, especially our mothers during childbirth and Generational effects and steering away from overuse of antibiotics certainly infancy. is, he said. More extreme measures, such as mass fecal Surveys of humans’ gut-dwelling microbes have The real surprise came after mice on low-fiber diets transplants, would require large-scale testing to make shown that the diversity of bacterial species inhabiting had been bred and maintained on low-fiber diets for a sure they are both necessary and safe. the intestines of individual members of hunter-gatherer few generations. In their experimental confines, these The study was funded by the National Institutes of and rural agrarian populations greatly exceeds that of mice were exposed to microbes only through contact Health. individuals living in modern industrialized societies, with their parents. Each successive generation’s gut- Other Stanford authors of the study were graduate Sonnenburg said. In fact, these studies indicate the bacterial ecosystem declined in diversity. By generation student Samuel Smits and life-science research profes- complete absence, throughout industrialized popula- four, the depletion had reached a point where nearly sional Steven Higginbottom. tions, of numerous bacterial species that are shared three-quarters of the bacterial species resident in their Stanford’s Department of Microbiology and Immu- among many of the hunter-gatherer and rural agrar- great-grandparents’ guts appeared absent in their own. nology also supported the work. ISM ian populations surveyed, despite these groups’ being Even after these mice were dispersed across vast geographic expanses ranging from put back on a high-fiber steve fisch Africa to South America to Papua New Guinea. diet, more than two-thirds High- versus low-fiber diet of the bacterial species identified in the guts of “Numerous factors including widespread antibiotic their first-generation an- use, more-frequent cesarean sections and less-frequent cestors proved irretriev- breastfeeding have been proposed for why we see this able, indicating extinction depletion in industrialized populations,” said the study’s of those species by the lead author, Erica Sonnenburg, PhD, a senior research fourth generation of fiber scientist at Stanford (she and Justin Sonnenburg are deprivation. married). “We asked ourselves whether the huge dif- On the other hand, a ference in dietary fiber intake between traditional and somewhat more aggressive modern populations could, alone, account for it.” measure — fecal trans- The Stanford researchers employed young labora- plantation — did result tory mice that had been specially bred and raised in in these lost species’ re- aseptic environments so that, unlike ordinary mice trieval, the study found. (and ordinary humans), their intestines were devoid of Introducing fecal contents any microbial inhabitants. After populating the mice’s of fourth-generation high- guts with microbes from a human donor, the scientists fiber-diet mice into the divided them into two groups. One group was fed a intestines of fourth-gen- diet rich in plant-derived fiber. The other group’s diet, eration low-fiber mice, to- equivalent to the first with respect to protein, fat and gether with putting them calories, was practically devoid of fiber content. on the high-fiber diet for During the experimentation that followed, the re- two weeks, fully restored searchers analyzed fecal samples from the animals. their bacterial profiles. The two groups’ gut-bacteria profiles were initially in- Within 10 days of the distinguishable but soon diverged. “Within a couple procedure, the composi- of weeks, we saw a massive change,” said Justin Son- tion and diversity of the Justin and Erica Sonnenburg and their colleagues found greatly reduced microbial diversity in the guts of nenburg. “The low-fiber-intake mice harbored fewer bacteria in the intestines mice that had eaten low-fiber diets.

Weissman for learning how tumor viruses interact let me come into his lab and, instead of last, unscheduled days of the Montana continued from page 6 with the DNA of the host cell. Weiss- telling me what something was, made trip. There’d be a bluegrass band at the man, Hood and Baltimore share time at me think it out for myself; from Jim ranch Wednesday. But what to do that stricted the use of federal funds for hu- the ranch, fishing and talking science. Gowans, who believed in purifying im- weekend? man embryonic stem cell research. In Or at least Baltimore and Weissman mune cells to find out what they could The buzz of talk subsided briefly as response, Weissman and real estate de- fish. In fact, after science, Weissman do in the body; and from Henry Kaplan, people ate. Then, around a large wooden veloper Robert Klein, who was associ- appears to prefer to talk about fishing who taught me how to translate discov- dining table, Weissman, Shizuru and ated with the Juvenile Diabetes Research above almost anything else. eries into patient therapies,” Weissman their lab members went back to doing Foundation, worked together to write Hood is another story. “Irv thinks I’m said. what they do best: figuring things out. a proposition to provide $3 billion for some kind of a mutant,” he said. “We’ve Now, Weissman and institute director Topics ranged from trouble-shooting ex- stem cell research in California. The spent many Christmases at the house George Carlson, PhD, along with Klein, periments and planning future collabora- proposition passed in 2004. together, and our families have grown have begun discussing the possibility of tions to how to ensure on the national “We put into that bill, called Proposi- quite close. But I’ve never enjoyed fly- introducing a bond initiative like Propo- stage that scientific research remains val- tion 71, that academics could keep doing fishing. What Irv and I do is we enjoy sition 71 to Montana, on a smaller scale. ued and supported by the public and its the research funded by the state agency drinks together — drinks, food and talk- “This could be one way for researchers in leaders. through the ‘valley of death,’ through ing about science.” the state to continue to conduct excep- One thing’s for sure: Weissman’s clinical trials,” Weissman said. Late last year, the McLaughlin Re- tional scientific research, particularly in never shied away from a challenge. In the 11 years since Proposition 71 search Institute, founded by Weissman’s the area of neurodegenerative and brain What’s more, he feels his unique brand was passed, the National Institutes of old mentor Ernst Eichwald, celebrated diseases, in the face of decreased federal of do-it-yourself problem solving, fos- Health has initiated four clinical trials its 60th anniversary with a symposium support,” Carlson said. tered by Eichwald and Kaplan, applies using stem cells. In contrast, the state featuring Weissman, one of its most no- Back at the ranch to all walks of life and every situation. stem cell agency has funded, or sup- table alumni. “Regardless of what career you chose, ported research that has led to, more “There’s a whole list of alumni of the On that September evening in his it’s the people with the common sense to than 20 clinic trials to study the ability institute who have done really well sci- low-ceilinged, well-appointed ranch work things out for themselves who will of the cells combat diseases from skin entifically,” Hood said, “including five kitchen, Weissman whipped out an really make a difference in this world,” cancer to blindness to spinal cord injury. or six like Irv who have made a real im- electric carving knife, donned a brown Weissman said. Montana ties pact.” Hood and Baltimore serve with “Montana Trout Unlimited” apron and Night fell. People trickled out on foot Weissman on the institute’s scientific ad- cut thick slabs of perfectly prepared to their various sleeping quarters while Through the years, Weissman always visory board. prime rib to serve the colleagues, lab the dark water of the river, full of fishy maintained his ties to Montana. In 1991, Weissman doesn’t hesitate to credit members and friends shooting pool in promise, slid by silently at the edge of he, Hood and Baltimore bought the the importance of the institute in his the large room next to the kitchen, sip- the lawn. ranch near Hamilton. Baltimore is a for- early scientific life. ping beer from a local brewery on the pa- A bat or an owl swooped low over- mer president of the California Institute “All of my research can be viewed as tio or wandering in damp and laughing head, and, due to Weissman’s persistence, of Technology. In 1975 he shared the a direct result of the lessons I learned after fishing in the ranch’s trout pond. someone, somewhere, was making plans Nobel Prize in Physiology or Medicine 60 years ago from Ernst Eichwald, who People discussed their plans for the to bake a last-minute birthday cake. ISM Inside Stanford Medicine January 25, 2016 7 p eo p le Expert in cancer immunotherapy joins Stanford Medicine faculty By Erin Digitale toward the clinic and toward novel therapies. She’s re- “We have entered the golden age of immunotherapy Cancer immunotherapy expert Crystal Mackall, ally a fantastic addition to our team.” for cancer,” Mackall said. “I think Stanford’s depth of MD, joined the School of Medicine on Jan. 1 as a pro- Mackall is an expert in the field of T cell homeosta- scientific excellence and innovation will play a funda- fessor of pediatrics and of medicine, as well as associate sis — the maintenance of a healthy number and level mental role in advancing this field. I’m excited to have director of the Stanford Cancer Institute and co-med- of diversity of these immune cells. She has worked at the chance to develop a vibrant translational research ical director of the Stanford Laboratory for Cell and the National Cancer Institute since 1989. After earn- program focused on cellular therapy for cancer, build- Gene Medicine. ing a medical degree from As part of her role in the Department of Pediatrics, the Northeastern Ohio norbert von der groeben Mackall is being appointed program leader in pediatric Universities Colleges of cancer immunotherapy. Medicine and Pharmacy Mackall, who previously headed the Immunology and completing a resi- Section at the National Cancer Institute in Bethesda, dency in pediatrics and Maryland, and served as chief of the Institute’s Pedi- internal medicine at Chil- atric Oncology Branch, will lead Stanford’s efforts to dren’s Hospital Medical advance clinical trials of immune therapies for cancer, Center of Akron/Akron with the ultimate goal of moving them to widespread General Medical Center clinical use. in Ohio, she moved to “We are very excited about Crystal’s arrival at Stan- the NCI for a fellowship ford,” said Hugh O’Brodovich, MD, professor and in pediatric hematology/ chair of pediatrics and director of the Child Health Re- oncology. She advanced search Institute at Stanford. “She will create an inno- through the ranks of NCI vative cancer immunotherapy program across Stanford investigators, earning the Medicine that will leverage and expand the academic title of tenured principal strengths of Stanford University and translate basic sci- investigator in 2003 and ence discoveries to treat cancers in children and adults becoming chief of the pe- using novel immunotherapy approaches.” O’Brodovich diatric oncology branch in is also the Adalyn Jay Physician-in-Chief at Lucile Pack- 2008. ard Children’s Hospital Stanford, a part of Stanford Advancing cancer Children’s Health. immunotherapy Translating discoveries into treatments In addition to her fun- Crystal Mackall will lead Stanford’s efforts to advance clinical trials of immune therapies for cancer. As associate director of the Stanford Cancer Insti- damental discoveries in tute, Mackall will oversee a multidisciplinary program the field of human T cell in cancer immunotherapy. “Cancer immunotherapy homeostasis, Mackall’s scientific achievements include ing upon all of the university’s existing strengths.” is one of the most promising areas in cancer research, conducting the first studies in humans of recombinant Mackall’s recruitment is in line with Stanford’s stra- showing remarkable results in several previously intrac- interleukin-7, a cytokine that can be used in cancer tegic decision to invest in research that aims to translate table cancers,” said Beverly Mitchell, MD, director of treatment. Her group was one of the first to demon- scientific discoveries into clinical treatments for several the Stanford Cancer Institute and the George E. Becker strate the success of a cancer therapy for pediatric acute categories of previously intractable disease, including a Professor in Medicine. “Dr. Mackall is at the forefront lymphoblastic leukemia that works by modifying the number of genetic diseases and cancers, Roncarolo said. of research in this critical area.” patient’s own immune cells. The cells are removed from Mackall joins experts in genetic diseases, tissue- “Crystal will be a key player in Stanford’s transla- the patient, engineered to express cancer-specific recep- specific diseases and complex diseases that could po- tional research program in stem cell and gene therapy,” tors and returned to the patient, where they attack the tentially be treated with stem cell, gene therapy and said Maria Grazia Roncarolo, MD, professor of pedi- cancer. immunotherapy techniques. To help the team imple- atrics and of medicine and co-director of the Stanford Mackall also serves as co-leader of Stand Up 2 ment these novel technologies, Stanford will open the Institute for Stem Cell Biology and Regenerative Medi- Cancer’s Pediatric Cancer Dream Team, a multi-insti- Laboratory for Cell and Gene Medicine this year, a cine. “Her expertise in the area of engineering T cells to tutional program focused on developing novel immu- Good Manufacturing Practice compliant facility. fight cancer is complementary to our existing ability to notherapies for childhood cancer. She holds patents “This program puts Stanford in a unique position engineer stem cells and T cells to cure genetic diseases. or has patents pending for nine advances in cancer im- to be a world leader in stem cell and gene therapies and She also knows how to move fundamental discoveries mune therapy. regenerative medicine,” Roncarolo said. ISM

Faculty members appointed to endowed professorships Six Stanford Medicine faculty mem- mechanisms of oncogene deregulation. the Shooter Family Professor, effective lished to honor the contributions of bers have been appointed to endowed This professorship is intended to Dec. 8. His research focuses on the de- the late Leonard Herzenberg, PhD, professorships. encourage and support women who velopment and functioning of nerve- and his wife, Leonore, who together Steven Artandi, MD, PhD, profes- are studying medicine, teaching medi- cell circuits. developed the first FACS, an instru- sor of medicine and of biochemistry, cine or conducting medical research. This professorship was created to mental tool in immunology, stem cell was appointed the Jerome and Daisy It was established with assets from support a faculty member in the Stan- research and proteomics. The funds Low Gilbert Professor, effective Dec. a bequest given in 1969 by the late ford Neurosciences Institute. It was came from a variety of sources, in- 8. His research focuses on the underly- Katharine McCormick to honor her established in January 2014 with gifts cluding friends and former students ing causes of cancer and degenerative husband, Stanley. from Eric and Elaine Shooter. Eric of the Herzenbergs. diseases, and new therapies to treat Anne Brunet, PhD, professor of ge- Shooter, PhD, is a professor emeritus Joseph Wu, MD, PhD, director of those conditions. netics, was appointed the Michele and of neurobiology. the Stanford Cardiovascular Institute This professorship was established Timothy Barakett Endowed Professor, Leonore Herzenberg, D.Sc.-equiv- and professor of medicine and of ra- to support a faculty member who effective Dec. 8. Her research focuses alent, was named the Department of diology, was appointed the Simon conducts basic science research that on the genetic mechanisms of aging Genetics Flow Cytometry Professor, H. Stertzer, MD, Professor, effective benefits humanity, with a focus on re- and longevity. effective April 14, 2015. Her research Oct. 6. His research focuses on cardio­ searchers using stem cells or regenera- This professorship was created by focuses on gene regulation in the im- vascular stem cell biology, genomics tive medicine. Michele and Timothy Barakett to sup- mune system, development and func- and imaging. Linda Boxer, MD, PhD, vice dean port work on computational biology, tion of B cells, and the development This professorship was created in of the School of Medicine, chief of he- inflammation, immunology and aller- of automated software for analyzing 1998 to encourage innovation in in- matology and professor of medicine, gies, with a focus on improving child research and clinical flow cytometry terventional cardiology and develop was appointed the Stanley McCormick health. data collected with the fluorescence- treatments for vascular disease. It was Memorial Professor, effective Oct. 6. Thomas Clandinin, PhD, profes- activated cell sorter, or FACS. established by Simon H. Stertzer, MD, Her research focuses on the molecular sor of neurobiology, was appointed This professorship was estab- professor emeritus of medicine. ISM

Steven Artandi Linda Boxer Anne Brunet Thomas Clandinin Leonore Herzenberg Joseph Wu

8 January 25, 2016 Inside Stanford Medicine