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1993 Outlook Magazine, Spring 1993

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~Ij\SHINGTO NIVERSITY SCHOOL OF l\IIEDJ I E SPRING 1993

o In support ofthe diabetes research of Paul E. Lacy, M.D., Ph.D., and David W. Scharp, M.D., the Barnes Hospital Islet Processing Lab was prepared for a March opening. The process, developed at the medical school, produces purified, vital islet cells from pancreata acquired from organ donors. The lab's technical supervisor, Dan Fraga, is shown at one of five isolators in which the organs are washed, dissected, broken down into cell aggregates, purified and cryofrozen for banking. The preparations are then pooled for transplantation to diabetic patients who have had kidney transplants or are taking immunosuppressive drugs. Volume XXX, Number I, Spring 1993 Bad To The Bone 8 Associate Vice Chancellor, Medical Public Affairs Is a virus the culprit in some cases Don Clayton of drastica ll y increased bone density? Editor Steve Kohler Design John Williams Photography Switching Good For Bad 12 Tom Heine Circulation Scientists explore gene therapies for Kathi Law delivering all they are leaming about genetics. Spring 1993 Volume XXX, Number I Outlook (ISSN 1042-2897) is published quarterly by the Washington University School of Medicine at 660 S. Euclid, Future Vision 17 Campus Box 8065, St. Louis, MO 63 I 10. Second-class postage paid at St. Spiral CT's capabilities put Louis, MO. a new spin on imaging.

POSTMASTER: Send address changes to Circulation, Outlook, 660 S. Euclid, Campus Box 8065, St. Louis, MO 63110. The Cori Continuum 20

© J993 Washington University Research inspired in one laboratory School of Medicine has flourished for nearly 50 years.

On The Cover: Newsbriefs 2 In pursuit of effective gene therapy, medical school research­ Personal Outlook 24 ers install genes in many types of Silhouette: Leopold Hofstatter, M.D. 26 cells. In the experiments recorded on the cover, David Leib, Ph.D., Alumni Report 28 and Jay Pepose, M.D., Ph.D., tested a particular gene promoter (the DNA sequence that instlllcts a gene to express the protein for which it encodes) to demonstrate its effectiveness in neurons. They were especially interested in res ults shown in the third ex­ amples from the left in the bottom two rows. The cells in those samples are retinal cells that clearly contain the active gene promoter, as shown by the blue il stain. Story on page 12. I,

Ii II Newsbriefs

according to Crane, in­ SlaltJ>~ Di.·( (~L~ creased clinician activity will benefit research by BiolllP.li(·al bringing in more patients to he votes have been way for physicians is being (~nlllpniing cast and certi fi ed by established that wi II better participate in studies. And T the university's serve the needs of th e School clinical revenues, he adds, Board of Trustees, and the of Medicine." will help support teaching avid 1. States, M.D., School of Medicine will of­ In awarding tenure, th e and research activities in Ph.D., has been fer a clinician track for doc­ university always has both the clinical and pre­ D named director of tors who spend more time stressed the importance of clinical departments. the Institute for Biomedical teaching and caring for pa­ research, explains James P. Professorial titles will be Computing at the School of tients than doing research. Crane, M.D., associate vice the same for faculty on ei­ Medicine. In a vote open to th e en­ chancellor and associate ther the investigator or clini­ tire faculty on November 6, dean for clinical affairs at ci an track. amendments to the tenure the School of Medicine. " In the past, we have lost policy to make a cJinician While excellence in research some excellent clinicians and track possible were approved will remain a critical part of teachers because we could by a four-to-one margin, ac­ the academic mission, he not promote them," Crane cording to John N . Drobak, points out that the demands says. "I believe the comple­ 1.0., professor of law and and complexity of medicine mentary nature of the clini­ chairman of the Senate make it essential that some cian and investigator Council, an elected body that individuals devote a major pathways should enhance the represents faculty interests in portion of their time to pa­ ability of our faculty to excel university policy decisions. tient care and teaching. in all aspects of our aca­ "This is a major change in The clinician track, Crane demic mission." tenure policy resulting from says, rewards physicians for The School of Medicine a year-and-a-half of dialogue excellence in patient care will join good company by between the medical school and teaching. It also should offering the clinician track. David J. States, M.D., Ph.D. administration and faculty," assure a stable patient load Of the nation's 126 medical Drobak says. "There was full to provide adequate learning schools, 1 12 offer tenure Formerly a senior staff and open discussion, and the opportunities for medical and, of those, 80 also have a fellow at the National Li­ end result is that a new students and clinician track. brary of Medicine's Nationa l career path­ house staff. In Crane and Drobak both Center for Biotechnology applaud Samuel A. Wells, Information (NCBl), States Jr., M.D., professor and head was responsible for the con­ of surgery, who chaired the struction and analysis of mo­ clinical pathway steering lecular sequence databases. committee, and William A. In conjunction with hi s Peck, M.D., executive vice position at the medical chancellor for medical school, States also directs a ffairs and dean of the program in biomedical the School of engineering in the School of Medicine, for their Engineering and Applied initiative to secure Science on the Hilltop cam­ the future for pus. States will oversee ex­ clinical pansion of the network facuity . • communication systems that will enable more researchers to have access to electronic data information. "My goal

2 is that network communica­ sol id foundation on which • Jewish Hospital to share its full- or part-time faculty tions use will become more Jewish Hospital, Barnes net revenues with the appointments at Washing­ widespread and routine at Hospital and the School of School of Medicine in or­ ton University School of Washington University, an Medicine will build the der to partially compensate Medicine. institution which already ha s health care system of the fu­ the school for the costs of The new agreement ex pertise in the area of elec­ ture. And Barnes Jewish, the medical direction and serves as a master document tronic communications," Inc. (BH) provides the ve­ teach ing services provided governing the broad terms of says States. "Electronic com­ hicle for Jewish and Barnes by the faculty, division the parties' affiliation. Addi­ munications are an impol1ant hospitals to deve lop this sys­ chiefs and department tional, subsequent negotia­ aspect of the research envi­ tem in ways that maintain heads; tions related to specific ronment, and we need to see th e highest quality patient • strong support of a medical facets of th e new a ffi Iiation that all of the university has care while reducing costs staff composed exclusively wi II be conducted in the access." and duplicative services," of clinicians who will have coming months. In addition, States will be says Wayne M. Lerner, principal investigator on the D.P.H., Jewish Hospital's Sohel HOllored rr)\~ if'e analysis component of the C president. e/egans Genome Sequencing William A Peck, M.D. , Center. His primary research executive vice chancellor for urton Sobel, M.D. , sc ientific ac hieve ments have interest is large-scal e mo­ medical affairs and dean of professor of medi­ contributed to the advance­ lecular sequencing and the the School of Medicine, B cine an d director of ment and practice of clinical analysis of genome sequence says, "This agreement final­ the cardiology division, re­ cardiology. Sobel accepted data . • izes the es tabl ishment of cently received two career partnerships between the honors: He was named presi­ medical school and its affili­ dent-elect of the American Afftliaiioll ated adult teaching hospitals Professors of Cardiology Renp"lvcfl - th e Jewish Hosp ital ofSt. (APC), a national organiza­ Louis and Barnes Hospital. tion devoted to exce llence in The platform now exists fulfillment of th e clinical, ewish Hospital and from which the Medical educational and investigative Washington Universi ty School and B1I can meet the responsibilities of academic have renewed their af­ hea lth care challenges of the cardiology programs, and he J future." was presented with the 1992 filiation with th e ap proval of a new IS-yea r agreement by The agreement between Herrick Award from th e the Jewi sh Hospital Board of the School of Medicine and American Heart Associa­ Directors. The Washington Jewish Hosp ital provides for: tion 's Council on Clinical University Board of Trustees • the parties to establ ish a Cardiology . had already approved th e new Joint Office of Clini­ Sobel was named presi­ agreement in principle and cal Affairs composed of dent-elect of the APC by the authorized officers of the senior mana gement from group's 118 members, all of School of Medicine to com­ both organizations that wi II whom are directors of aca­ plete the negotiations. work with the clinical demic cardiology programs The new contract aligns chiefs and hospital ex ecu­ around the country. He will responsibilities according to tives to set and reach joint hold th e post for one year Burton Sobel, M.D. the missions of both institu­ goals for clinical care, from January I, 1993 , then tions and positions them to teaching and research; will serve as president for the award on November 17 respond to challenges facin g • continuing Jewish one yea r, succeeding Yale at the American Heal1 medical education, resea rch Hosp ital 's independent re­ University'S Barry Zarut. Association's annual scien­ and patient care. search programs and its The prestigious Herrick ti fic meeting . • "This agreement is th e residency and nursing Award is given annually to final step in the creation of a teaching progra ms; recognize a physician whose

3 aspartate, can have toxic ef­ ders. Choi followed by pro­ Lane Deyoe, M.D., a radiol­ T"v() Shal'''' fects on cells in the brain and ducing glutamate excitotox­ ogy fellow. Wakenlan spinal cord, Injury from icity in cultured brain Currently, physicians di­ trauma or stroke and dis­ neurons and clarifying mech­ agnose possible urinary tract Aw ru-.1 eases such as Alzheimer's anisms by which glutamate obstructions by using a plain cause the release of large excitotoxicity can contribute abdominal X-ray to look for wo scientists here quantities of excitatory to neurological disorders. kidney stones and an intrave­ have been presented amino acids and destroy irre­ "The contributions are not in nous urogram (IVU) to as­ T with the Wakeman placeable brain and nerve competition with one an­ sess urine flow. For an IVU, Award for Research in the cells. other, but are rather separate patients are injected with a Neurosciences, John W, The Wakeman Award is aspects of the same th eme contrast material and ab­ Olney, M,D" professor of considered one of the most that complement one an­ dominal X-rays are made, psychiatry and neuropathol- prestigious in the neuro- other," Olney says, The contrast material pro­ The Wakeman Award is duces an image of the path presented every two years. urine takes as it leaves each It was established in 1972 by kidney and travels through Nancy D.W, Gardiner in the ureters to the bladder. Ifan memory of her husband, obstruction exists, an IVU William T. Wakeman. may show the contrast agent pooling up behind the block­ age, says Deyoe, LJltrasolllul The IVU is generally Spots Kl(ln(~y quite accurate and safe, Deyoe says, But in some pa­ ()],SIrlU'tiUJIS tients, the contrast material MOI~e Safel~ causes adverse reactions such as nausea, vomiting, irregular heart beat and, in esearchers here have extremely rare cases, death, John W. Olney, M.D. Dennis W. Choi, M.D., Ph.D. applied the latest ul­ Mild to moderate reactions trasound techniques affect two to eight percent of ogy, and Dennis W, Choi, sciences. "It is a special R to develop a safer method for pati ents; severe, life-threat­ M,D" Ph,D" Andrew B. and honor, for which I am very diagnosing kidney stones ening reactions occur in 0,0 I Gretchen p, Jones Professor grateful," Choi says. " I hope and other forms of urinary percent to 0, I percent of pa­ of Neurology and head of to join Drs. Watkins, Olney tract obstruction, ti ents, Deyoe says. In addi­ neurology, share thi s year's and others in continuing to Using color Doppler ul­ tion, the test is not ideal for award with Jeffrey C contribute to the excitotox­ trasound and conventional pregnant women because it Watkins, M,D., professor of icity field," X-rays, the investigators at exposes their fetuses to ra­ pharmacology at the Univer­ For Olney, the award rep­ Mallinckrodt Institute of Ra­ diation and to the contrast sity of Bristol in Bristol, En­ resents official recognition diology produced images of drug, he adds. gland. for the first three generations blood flow in the kidneys Deyoe and colleagues The three were recog­ of contributors to the field of and of urine entering the evaluated 32 patients sus­ nized for their work in the excitotoxicity, Watkins, he bladder to assess whether pected of having a urinary area of excitotoxicity, The says, provided the founda­ urine made the journey from tract obstruction using a word, coined by Olney, de­ tion by identifying how kidneys to bladder success­ plain abdominal X-ray and scribes the process by which amino acids alter the activity fully. The approach may three ultrasound techniques, brain and nerve cells are I it­ of neurons. Olney later dis­ help avoid the adverse drug They used IVU exams as the erally stimulated to death by covered the toxic effects of reactions that occasionally standard for comparison. the brain's neurotransmit­ the excitatory amino acids result from the current diag­ With a traditional ultrasound ters. Excitatory amino acids, and demonstrated their po­ nostic test of choice, says exam of the kidney, they particularly glutamate and tential role in brain disor­ looked for urine pooling in

4 the kidney. They also ap­ Cullen Is Asso('ialt' Viee Cluuu't>llor Fur plied a technique called pulsed Doppler to look for Rt>sf~al"(~h: Lazarus l\anu!(l A.ssislanl [)~an decreases in blood flow to the kidney, which can indi­ cate a urinary tract blockage. usan E. Cullen, Ph.D., interface with other univer­ position of assistant dean. Third, the researchers used has been appointed the sityoffices. She assumed her new role color Doppler ultrasound to S uni versity's associate " Sue Cullen brings her December I. look for "ureteral jets," the vice chancellor for research, faculty and research experi­ " Dr. Lazarus is a fine regular spurts that normally and Cathy J. Lazarus, M.D., ence, as well as her knowl­ mentor and clinician, in­ send urine into the bladder. bas been named assistant edge of the research office, tensely interested in student Color Doppler, based on a dean for student affairs at the to this important part of the activities," says William A. principle similar to police School of Medicine. university's teaching, learn­ Peck, M.D., executive vice radar, uses sound waves to As the chief administra­ ing and research endeavors. chancellor for medical af­ measure the speed of moving tor, Cullen coordinates a ll She has outstanding creden­ fairs and dean of the School materials. activities of the research of- tials," says Edward S. of Medicine. " Her many The ultrasound approach talents will enhance our very correctly diagnosed all com­ impo11ant and already fine pletely obstructed patients student affairs program." and all patients who were In her new pos ition, completely unobstructed. Of Lazarus will assist Patricia 14 patients with partial ob­ L. Cole, M.D., associate structions, I I (79 percent) dean for student affairs, who were correctly di agnosed. will take on the added role of There was one false-positive director of the Cardiac Cath­ result in one completely ob­ eterization Laboratory at structed patient Overall, the Jewish Hospital, part of tests were accurate in 28 o f Washington Universi ty the 32 patients (88 percent). Medical Center. Lazarus and "We found that the ultra­ Cole will be respons ible for sound was very good at diag­ arranging all student affairs nosing these obstructions. Susan E. Cullen, Ph.D. Cathy J. Lazarus, M.D. activities at the medical The IVU is a good test, but school such as graduation, for patients who sbould not fice related to external sup­ Macias, university provost. orientation and other events. receive the contrast material, port for research, including Cullen is an immunologist Lazarus, who is an assis­ this gives us an option," funding from federal and who joined the faculty in tant professor of clinical Deyoe says. state agencies, voluntary 1976. In 1985, she was made medicine, will continue as Ultrasound, unlike the health organizations and the a fu II professor in both the director of student and em­ traditional X-ray exams, also corporate sector. Department of Molecular ployee health service, over­ gi ves physicians the capabil­ The office helps faculty Microbiology and the Oe­ seeing administration of the ity of looking for othe r find sources of supp011, pro­ pal1ment of Genetics. service and providing direct causes of abdominal pain, vides assistance in the pro­ Lazarus, who in 1990 was patient care to medical cam­ i' such as appendicitis or gall­ posal submission process, named director of the Wash­ pus students, including those bladder disease, he adds. The handles federal subcontract­ ington University Medical in the medical school, gradu­ ultrasound approach may be ing, establishes prime con­ Campus Student and Em­ ate school of biological sc i­ especially valuable for preg­ tracts with industrial ployee Health Services, will ences, occupational therapy, nant women, the elderly, sponsors, provides some of continue in that position in physical therapy and other I; peopIe who are allergic to the university's compliance addition to her responsibi li­ programs based at the the contrast material and functions and serves as an ties with the newly created School of Medicine. • people who have unhealthy kidneys, he says.

5 J\ll\.ill~nn A.I141 macology and professor of the title of dean of the Wash­ Washington University medicine, \vas named for his ington University School of Medical Center, which in­ (;(...duJI Nanl... ) studies on the cellular and Medicine as well. cludes Barnes, Jewish, 1"~\'A~ Ft-'lI()w~ molecular biology of cells Peck was named vice Cbildren's and Barnard hos­ .. that Iine the intestine and for chancellor for medical af­ pitals and the Central Insti­ analyses of the enzyme N­ fairs and dean of the School tute for the Deaf. ohn P. Atkinson, M.D., myristoyltransferase (NMT). of Medicine in 1989 and is "When the decision was and Jeffrey 1. Gordon, Gordon's laboratory has the first person to serve in made to combine the M.D., have been used a family of genes en­ the dual position. As dean, deanship and the vice J coding fatty acid binding Peck administers the aca­ chancellor's responsibilities elected to the rank of fellow proteins as models to study demic, research and patient into a single position, we by the American Association the atomic details of fatty care activities \vithin the knew we would need a for the Advancement of Sci- School of Medicine. As ex­ leader with exceptional tal­ ecutive vice chancellor, he ents in the areas of adminis­ guides and coordinates the tration, education and relationships between the biomedical research," says school and other organiza­ Danforth. "Bill Peck has cer­ tions and constituencies, tainly proven to have that such as the affiliated hospi­ mix of talents and has guided tals, the National Institutes the school extremely well of Health and corporations during a period of growing and foundations. Peck also expectations and chal­ serves as president of the lenges." •

IuYesligalors Lool~ }'Ol" Gcnclie Markers In Schizophrenia John P. Atkinson, M.D. Jeffrey I. Gordon, M.D.

ence (AAAS). The associa­ acid-protein interactions and, esearchers at the follow a moving object or tion bestows this honor on through the use of transgenic School of Medicine perform a task that requires members "whose efforts on mouse technology, to exam­ R have received a attention, they do poorly," behalfofthe advancement of ine the differentiation and $400,000 grant from the Na­ Moldin says. "Their rela­ science or its applications proliferation programs of tionallnstitute of Mental tives, who might not have are scientifically or socially intestinal epithelial cells. • Health to study the heritabil­ schizophrenia, also tend to distinguished." ity of schizophrenia. have impaired attention. Atkinson, professor and Steven O. Moldin, Ph.D., With this study we are trying chairman of the Department Pet,li Elevated assistant professor of psy­ to see how schizophrenia of Internal Medicine and . O.;Xf't·U lye chiatry, will evaluate 50 and attention together are professor of molecular mi­ rl' E' " schizophrenic patients and inherited through the fam­ crobiology, was named for Vice Chan('f·lIol· three family members to ily." his pioneering research in study biological traits com­ Moldin will gather data immunology, for exemplary mon in patients and their for the five-year grant from professional leadership in illiam A. Peck, relatives who are not suffer­ inpatients at Malcolm Bliss the field of rheumatology M.D., has been ing from the disease. All will Mental Health Center and and for inspiring contribu­ W named executive be tested for attention disor­ Barnes and Jewish Hospitals tions as a medical teacher. vice chancellor for medical ders. at the Washington University Gordon, professor and affairs, according to Chan­ "People with schizophre­ Medical Center, where he is head of the Department of cellor William H. Danforth. nia tend to have trouble with an attending staff psycholo­ Molecular Biology and Phar­ Peck will continue to carry attention. If you ask them to gist. •

6 P4~"."ZOI ;\yioli A,nti f:hrjlelli erate new approaches to They simulated a blood ves­ treating atherosclerosis sel blockage by apply ing (-l ..norerl F'OI' Cunl..ihllliulI~ among diabetics. pressure to decrease circula­ The findings provide the tion in an arm for 10 min­ arlos A. Perez, M.D., trol bone cell activity and best evidence to date I inking utes, then measured levels of director of the Radia­ biologica l function. insulin to the high rate of the natural clot dissolver tion Oncology Center The award is given annu­ card iovascular di sease in called ti ssue-type plasmino­ at Washington University's ally for outstanding resea rch people with non-insulin-de­ gen activator, or t-PA. Lean Ma llinckrodt Institute ofRa­ in the field oforthopedics and pendent diabetes (NlDDM) people responded appropri­ diology, has been awarded bone metabolism. Avioli is - a disease that affects 14 ately , by producing the the 1992 Gold Medal Award Shoen berg Professor of Medi­ millio n Americans, the re­ hi g her levels oft-PA re­ from the American Society cine, and Civitelli is assistant searchers say. quired to break up the clot, for Therapeutic Radiologists professor of medicine . • Clinical studies have had it been rea I. Diabetics, hinted that overabundance of however, had no such re­ insulin and its precursors­ sponse. The finding marks the substances from which the first time researchers insulin is formed - might have shown a direct link be­ accelerate atherosclero sis in tween PAI-l levels and an people with NlDDM, hyper­ impaired response to physi­ tension or obesity, says ologic stress in the same David Schneider, M.D. He group of people. and Janet McGill, M.D., in­ The studies suggest that structor of medicine, are lead diabetics may not respond authors of the study. properly to microscopic In th e first of two studies, blood clots th at may form on Schneider and his colleagues a regular basis, Schneider looked at in su lin's effect on says. "In each of us, a dy­ endothelial cells, the cells namic equilibrium exists be­ tha t line blood vessels. They tween making clots and Carlos A. Perez, 111.D. Louis V. Avioli, M.D. confirmed reports that insu­ dissolving them. If there is lin stimulates production of a too much PAI-I present, di s­ and Oncologists (ASTRO). Shu Iie~ l.Jink substance called plasmino­ solution of clots may be im­ ASTRO, the largest society gen activator inhibitor type I paired. The effect of that '( _1=­ of radiation oncologists, has n~lu.ul 'I'. H (PAl-I). PA I-I interferes may be persistence or recur­ given the award since 1977 with blood chemicals that rence of clotting, which can l)iaI U". ic'~ 'I to recognize outstanding prevent clot formation. exacerbate atherosclerosis," contributions to the field of AII ..·rosc' 1.-1'( ,~i!-l In th e second study, the he says. • radiation oncology. Perez is investigators measured PAL­ among th e youngest ever to I in 69 people: 34 with receive it. igh levels of in sulin NIDDM, 19 non-diabetic Louis V. Avioli, M .D., and insulin precur­ obese and 16 non-diabetic CO""fJoelioll sors may contribute I and Roberto Civitelli, M.D., H lean volunteers. They found n tbe legend accompa­ to atherosclerosis in non­ have received the Kappa that obese and diabetic nying th e photograph on insulin-dependent diabetics Delta A ward from th e people had abnorma lly hi g h th e inside front cover of by di srupting their bodics' TI American Academy of Or­ leve ls of PAL-I , findings that th e la st issue of Outlook built-in mechanism for dis­ thopedic Surgeons for their confirmed past studies. The (Winter, 1992), Carlton C. solving blood clots, accord­ outstanding contributions to researchers then went a step Hunt, M.D., and Albert Roos, in g to investigators here. A the fundamental understand­ further to see whether such M.D., were misidentified as ing of those factors that con­ better understanding of these PAI-I levels a ltered the abil­ !i Ph.D.s. " clotting disruptions may gen­ ity to respond to blood c lots. \I

II, 7 Investigators Search For A Virus That Is

ax Arens, Ph.D., got an unexpected phone call last year as he sat in his office. "Max," the unfamiliar voice said, "this is Michael Whyte at Jewish Hospital. Would you like to go fishing?" Arens had never met Whyte, but a virologist in an academic medical center with approximately 2,000 researchers becomes accustomed to calls from scientists needing help in tracking viruses. by Jim Keeley He accepted the invitation.

8 Rare and officially unnamed, a new disorder manifests itself in its victim's bones. Comparative X-rays (a normal left hip on the left) demonstrate the disease's dramatic effect on bone density.

Michael Whyte, M.D., hoped that similar symptoms. The man also had tan tal izing clues that these two patients Arens might help solve his puzzle. dense bones and complained of diffuse share a single, rare disease. Past X-ray Whyte's problem was that two patients skeletal pain that had plagued him for studies showed that years earlier, both with an unusual skeletal disease had two years. patients had normal skeletons. Studies been referred to him. Whyte proposed Whyte was perplexed. In the span of by musculoskeletal radiologist, William the fishing expedition to pursue the a year, two patients with dense bones A. Murphy, Jr., M.D., professor of disease's origin. had come to his office complaining of radiology, and bone pathologist, Steven In June 1990, Dennis Villareal, M.D., severe pain. Lab tests seemed nearly L. Teitelbaum, M.D., Wilma and a fellow in the division of bone and normal; they did not fit the standard Roswell Messing Professor of Pathol­ mineral diseases, had learned of a 27­ profile of any known bone malady, and ogy, showed that not only were the year-old woman who later appeared in previous doctors had been unable to patients' bones growing denser, but they Whyte's office complaining of severe diagnose the exact source of their pain. were being built up and broken down at pain in her legs. Her referring physician The patients had come to Whyte, a twice the normal rate. had taken X-rays that showed dense professor of medicine, hoping that he The studies didn ' t explain the cause bones. Her medical history was not and other bone experts at the School of of the abnormal bone growth, but they informative; almost everything appeared Medicine could find the cause of their did provide the reason for the patients' normal, leaving Whyte few clues on mysterious ailments. severe pain. Whyte surmised that as the which to base a diagnosis. At first, there was no hint that the two bones thickened and expanded, pain Eight months later, a second patient cases were even related. But after fibers anchored at the bone surface was referred to Whyte with remarkably persistent work, Whyte uncovered a few stretched and fired a pain signal. The

9 Michael Whyte, M.D., and William Murphy, M.D., are among collaborators tracking down the origin and cure for a newly identified disorder that accelerates bone growth. dramatic bone production probably Arens snagged no evidence of Whyte's diseases that can increase bone mass, but caused the pain fibers to fire often. prime suspect, a retrovirus that can none was similar to his patients' With the pain partially explained, incorporate its genetic information into a condition. Whyte began to consider the nature of host's DNA. As Arens had feared, they Osteopetrosis - the name means the prodigious bone formation. The had reeled in more questions than "petrified bones" - is a rare disorder patients' histories offered a clue: Both answers. But, like a good fish story, the that often has a genetic origin. Research­ patients had been intravenous drug tale was getting more interesting all the ers understand that this disorder is abusers who had shared needles with time. caused by defective bone-removing others. Whyte saw that their lifestyles Based on negative virology tests, cells. Bone is constructed in layers, each could have put them at risk of infection Whyte proposed a radical notion: layer radiating from the center outward from viruses that may have been passed Suppose hepatitis C virus or some like the rings of a tree. Construction is via contaminated needles. He decided to unknown virus accidentally tripped the well regulated by at least two different call Max Arens to see if Arens would bone growth switch in these patients. cell types: osteoblasts and osteoclasts. test his patients' blood for suspicious This rate of new bone growth and Osteoblasts add layers to bone. They are viruses. generalized skeletal thickening appeared in constant communication with osteo­ Whyte also recalled reports suggest­ to be a new syndrome associated with clasts, cells that chew away bone and ing that viruses may infect bone cells intravenous drug use. Uncovering the recycle some of its building blocks for and cause dramatic bone thickening in cause of the disorder, Whyte says, could future use. Osteopetrosis is caused by a other conditions. It occurred to him that conceivably help people with osteo­ cessation in the orderly breakdown of perhaps the tremendous bone growth in porosis who would benefit from reacti­ bone. The layers of bone continue to be his two patients also was caused by a vating the "on switch" for bone growth. stacked one on top of another with no virus. Before leaping to the concept of viral dismantling or recycling. The result is In fact, the laboratory tests showed transmission, Whyte had carefully ruled bones that increase in size and density. evidence of Epstein-Barr virus and out the possibility that these patients had Bone biopsies of the two patients hepatitis C virus in both patients. But the a known bone disease. His review of the excluded this disorder. fishing trip that Whyte proposed to medical literature turned up several

10 Paget's disease, another ailment that If the cause is viral, Arens suspects it patients will take time to percolate in the spurs dramatic bone thickening, is more will be a long time before that virus is medical community," he says. common than osteopetrosis, afflicting isolated and identified. "J think it's While writing on the subject, Whyte nearly 15 percent of the over-65 popula­ absolutely reasonable at this point to found what he thinks is a third case of tion. It is a "patchy" disorder, Whyte suspect an unknown virus," he explains, this syndrome. The published report says, affecting different bones in "but identifying the virus is not without details a young woman with a history of different people. Some people with the its problems." Arens speaks from intravenous drug abuse who developed disease may have an enlarging hat size, experience. Several years ago, while on the same type of painful diffuse bone because the bones in their skull become the faculty at St. Louis University thickening with increased skeletal thicker. Others may notice bowing of School of Medicine, he was asked by a turnover. Whyte writes: " It seems their legs, since the affected skeleton is local company to help identify a virus unlikely, but remains possible, that the actually soft. Neither of the patients intravenous drug abuse of our two showed classic signs of Paget's disease. patients and the similar previously These patients' bones were gaining reported patient is merely coincidental." mass fast. The average human receives a Whyte and Arens acknowledge that new skeleton once every eight years. His pinning down the cause of this enigmatic patients, Whyte says, could probably syndrome is going to take time. Whyte accomplish the same feat in half that believes it is a new syndrome and time. speculates that it is associated with Osteopetrosis and Paget's disease intravenous drug use. Arens remains less seemed to be excluded as the cause but convinced, preferring to let the science were not a dead end . The two disorders speak for itself. share more than their ability to increase Whatever the cause, the two patients the density of the skeleton. Reports in with this painful bone condition have medical journals provided evidence that benefited from their visits to the School Paget's disease and osteopetrosis may be of Medicine. Whyte and his colleagues caused by viruses. The evidence for were able to apply lessons learned from these disorders is preliminary, Whyte their research on bone metabolism and cautions, but there is speculation that Medical school virologist Max Arens, Paget's disease to stop the accelerated canine distemper virus could cause the Ph.D., investigates the possibility ofa bone growth and the attendant pain. "We dense bones of Paget's disease. viral origin for the disease. recognized that their dense bones were Osteopetrosis can be induced in chick­ caused by rapid bone formation and ens by certain strains ofavian leukosis that had run loose in its laboratories, rapid breakdown, much like Paget's virus. Whyte had these findings in mind contaminating hundreds of liters of cell disease," Whyte explains. when he asked Arens to be his fishing cultures. "We isolated the virus, ex­ The researchers knew from basic partner. tracted the DNA, and discovered it was research done at the School of Medicine Arens' virology report didn't support an adenovirus the likes of which no one that Paget's disease is probably caused the notion that a known virus was had ever seen before. But finding and by faulty communication between causing the problem, unless hepatitis C identifying the virus took a lot of work." osteoclasts and osteoblasts. Experimen­ is the culprit. Hepatitis C is capable of In August 1991, Whyte took his tal work showed that quieting the causing many symptoms, but no one has speculations on the road. He presented osteoclasts, or bone-breaking cells, with shown that the virus can switch on bone his findings concerning the two patients the hormone calcitonin would also quiet production, says Arens. at the 13th Annual Meeting of the the osteoblasts, the bone-forming cells. f I~ American Society for Bone and Mineral "We were hoping the same thing would I·; Arens admits that after Whyte'S I initial phone call he thought he would do Research in San Diego. "Those who happen in our two patients," Whyte says. the virology work and that would be the came by to see the poster were as­ There was danger involved in the end of it. Now, a little more than a year tounded by the density of the bones," he therapy. Whyte explains: "Say you're later, he and Whyte are still fishing for says. Despite the interest of researchers rapidly breaking bone and rapidly forming the cause of this mysterious disease. at the meeting, it didn't elicit the bone but the net effect is that more bone is "Dr. Whyte is very persistent," notes response Whyte had wanted. He'd hoped accumulating. Ifyou shut off the bone Arens. to hear that there were more cases like breakers and the bone formers keep going, Their discussion of the disorder is the two in St. Louis. "I would have these people could get worse." Fortunately qualified by "ifs" and "maybes." The thought that with the frequency of that hasn't happened, and now "both two scientists do not say the bone intravenous drug abuse, this disorder patients are feeling much, much better," growth is the work of a virus - they would be more common than just two Whyte says . • have no proof. But suspicions are that a patients who came to St. Louis. But I virus of some type is a prime candidate. think the publication describing these

II en years ago, medical scientists could identify some of the thousands of disorders that have their origins in limperfect genes, but they had no way of knowing where the responsible genes were, and they possessed little grasp of the protein products that genes are responsible for making.

Today, medical science is at ground zero in an explosion of knowledge about human genes, their products and the maddeningly complex ways in which they can go wrong. The leap into tomorrow requires bringing our deepening ken of genetics to patients whose genes malfunction. Gene therapy, as such science is called, proves to be even more daunting than unraveling DNA. In addition to locating and cloning the genes involved, re­ searchers must gain control over the Three Examples DNA sequences that signal genes to express their messages and other regulators of gene behavior that may be ofPotential spread out along the chromosome. Then they must devise delivery systems to get enough "good" genes into place so they Gene Therapy can do the work that "bad" genes fail to do. Recombinant theory is already being used to create medicines that can restore health when faulty genes don't produce a necessary protein. And investigations are rapidly advancing gene therapy's by Steve Kohler most ambitious vision, in which clini­ cians will replace genes inside specific

12 cells, complete with precise control. Three examples of gene therapy research being conducted at the School of Medicine show the possibilities:

01-gan •system: Eye Application: Retinitis pi gmentosa Researchers: David Leib, Ph.D., and Jay Pepose, M .D., Ph.D.

People who inherit the genetically transmitted disease retinitis pigmentosa (RP) frequently lea rn of their condition when th ey notice their ability to see the stars is dwindling. The disease - a slow degeneration of the eye's retinal cells­ begins at the periphery of the retina and most often affects the organ's more sensitive light receptors, th e rods, more than it does the cones, says ophthal­ mologist Jay Pepose, M.D., Ph.D. Those affected usually lose their peripheral vision first and lea rn just how dependent th ey are on the edges of their sight for navigating. The di sease progresses to take a ll but the 10 per cent of vision in the center - true tunnel vision - at which point a sufferer is lega lly blind. Central vision also may be affected in some forms or stages of the One ofthe gelle therapist's helpful tools, beta-galactosidase expressed by all disease. inserted gelle, reveals its presence ill telltale blue. Here, the gene was attached to a Not an uncommon problem, most is neuron-specific promoter and illstalled in nerve cells using the herpes virus as a known about the autosomal dominant vehicle. form, in which the degeneration ha s been identified as being a function of a Leib, Ph.D., have hit upon the herpes neural cells of the eye." Once th e altered defic iency in th e gene that carries the simplex virus, a vehicle well suited to virus infects a retinal cell , it may remain code for a protein named peripherin. the job. latent over time, expressing the thera­ For research purposes, a strain of " Herpes simplex will infect almost peutic protein th at its added gene mice called rds (for retinal degeneration, any cell type," Leib says, "but it only encodes. slow), has been bred, and both the persists in a neuron," or nerve cell. The The researchers use a crippled herpes defective rds gene and its correct reason is most likely that nerve cells are virus that is made safe by deleting a counterpart ha ve been cloned and post-mitotic; that is, they are no longer viral gene necessary for replication. The sequenced. Researchers at Southwestern di vi ding. The lack of neuronal cell viral particles remain infectious, but University have created transgenic rd s division allows the virus to persist in th ey cannot make more like themselves, mi ce that possess the correct form of the those cells for the Ii fe of the host. because the recipe is missing. Pepose rds gene. "The condition is reversed When herpes virus invades a neuron, and Leib go farth er still in manipulating complete ly in those mice; the degenera­ such as a retinal cell, it circularizes and the virus to do their work. They add a tion is rescued," Pepose says. enters a latent state. "But that's not a promoter from yet another gene - that But transgenic humans are not passive state," Leib points out. " It sti ll fo r rhodopsin , the protein that allows possible, "so we need a de livery system generates a lot of RNA." light to be converted into electrical for the correct genes," Pepose explains. "The herpes simplex virus makes a impulses in the eye. Common to retinal I n their search for a way to del i ver great Trojan horse," says Leib . "We tissue and powerful, the rhodopsin therapeutic genes into the cells of the incorporate our therapeutic gene into the promoter charges the th erapeutic gene eye, Pepose and his colleague, David virus' chromosome, then infect the with added activity.

13 Organ system:• Liver Application: Serum protein deficiencies Researcber: Katherine Parker Ponder, M.D.

Many genetic diseases involve proteins made in the liver: Most of the coagulation factors in the blood origi­ nate there; the apolipoproteins, deficien­ cies of which can lead to atherosclerosis, are expressed there, and the complement proteins of the immune system are produced in the liver. That wealth makes the system of particular interest to Katherine Parker Ponder, M.D., who concentrates her efforts on developing gene therapy there. In pm1icular, Ponder in vestigates the protein alpha-l antitrypsin, a genetic deficiency of which can result in emphy­ sema, and protein C, a blood coagulation factor. Working with crippled retrovirus to del iver correct genes to liver cells, Ponder is showing that it's possible to get long-term expression of serum proteins, but hurdles remain to be overcome. The retrovirus has several advantages as a delivery system to bring therapeutic genes to liver cells, Ponder says. First, it is relatively safe. By deleting the genetic information the virus needs to package copies of itsel f, Ponder takes away its ability to remain infectious. She then installs the same packaging information in a cell line. When the vector DNA is David Leib, Ph.D., (seated) and Jay Pepose, M.D., Ph.D., work to apply gene transferred into the cells that are making therapy to the treatment ofretinitis pigmen tosa, in which the eye's light-sensing empty retroviral particles, its RNA can cells degenerate as a result ofa gene flaw. be packaged into a virus capable of a single round of infection. In that way, And they delete the vims' vhs (for animals and inserted into the subretinal researchers make enough viral media for virion host shutoff) gene. Normally, that space. The "electric thumb," a device their purposes, yet mn no risk of gene slows a host cell's production of engineered for the purpose, gently multiple rounds of infection. protein so that the vims can subvert the delivers a microliter of virus in solution Second, a retrovirus has the capacity cellular machinery for its own use. "It each time a foot pedal is depressed. to integrate into the genetic material of shuts off the cell and kills it," Leib Pepose says the de Ii very system can the cells it infects. That means that it can explains. "By knocking out the vhs gene, treat 90 percent of the retina in an deliver its cargo gene directly to the we reduce damage to the very cells application. genetic machinery of those cells that we're wanting to fix ." Will the genes delivered via the require it. That DNA will be maintained How is the cocktail of altered herpes herpes virus produce the missing protein there for the long term. virus with its added therapeutic gene and rescue sensory cells in the eye? The size of the cargo, however, is delivered? Via direct application to the Experiments are in progress to answer limited; a certain amount of space is target cells. A tiny injector is inserted that question. required for the information that lets the through the clear cornea of experimental vims infect cells and integrate into

14 Ponder explores the possibility of getting each infected cell to overexpress the desired protein. Expression level is largely a function of the gene promoter installed with the desired gene. That promoter also affects the length of time for which the protein will be produced. "We now have used a gene promoter normally expressed in all cells, installed it upstream of our gene for alpha-I antitrypsin and achieved long-term expression of the therapeutic protein," Ponder adds. "We get reliable levels of protein A section ofliver from a laboratory animal demonstrates the ability ofresearchers production for six months," Ponder says. to deliver genetic payloads. The liver was treated in vivo with a retrovirus carrying "While we haven't reached therapeutic an inserted gene. The gene expresses a protein that enables a cell hosting the gene levels for alpha-I antitrypsin deficiency, to be stained; here, blue cells have been genetically modified. we've been using that serum protein primarily because we can check our cellular DNA. But Ponder is working to would like to achieve better penetration, results with a simple assay. The same find the smallest amount of viral infor­ and work proceeds to produce higher level of expression in other genetic mation necessary so that the genetic levels of infection. But with the in vivo disorders, such as hemophilia, would be payload she wants to deliver can be as method, investigators can treat 12 therapeutic. We're now working on large as possible. animals in two days instead ofjust the protein C deficiency, and we' re getting Using the retrovirus delivery system, one per week they could do using the ex close to the genetic disease ballpark," Ponder first explored an ex vivo method vivo approach. Ponder says. of gene therapy in which cells were removed and treated in tissue culture before being reintroduced. Several difficulties plague the approach. Cells must be manipulated to get them to repl icate, necessary before a retrovirus can infect them. Ponder says only about two percent of the total liver mass can be re-injected once it has been treated, "or you clog up the works." And the technique is time consuming. A second approach, done in vivo, addresses these limitations. Ponder explains that the liver is unusual because the structure of the blood vessels there a Ilows contact between large particles in the blood and liver cells. Thus, virus particles can be infused directly. Ponder and her colleagues remove a large pOl1ion of the liver in lab animals to stimulate cell growth and replication in what remains. When that replication peaks, about 24 hours after surgery, she injects the genetically altered retrovirus into the portal vein. The researchers then have only five minutes in which to work, after which time oxygen deprivation causes liver cells to die. "About one percent of the cells are infected by the virus," Ponder says. She Katherine Parker Ponder, M.D., explores the potential ofgene therapy in producing therapeutic levels ofserum proteins.

15 will safely re-activate fetal hemoglobin genes. Several have been tried, begin­ ning with 5-azacytidine about 10 years ago and continuing to recent, widely reported work with butyrate compounds. Some of these drugs insult the bone marrow so that it begins to make more fetal hemoglobin when it recovers. Others, origina lly cancer drugs, block the methylation of DNA on the theory that unmethylated fetal globin genes are more active. "But none of these agents wil I be the cure," Ley says candidly. "You can' t get comfortable using them in children when you don't know the effects 30 or 40 years down the road. What assurance do we have that we're not also activating an oncogene that causes cancer? If you Timothy J. Ley, M.D., (seated) directs research into the reactivation ofgenes that blindly manipulate blood cell ' programs ' normally are switched offat birth. Working with him are graduate students Bruce and you're wrong, you 're going to get Hug and Mike Ulrich (right). another problem, perhaps worse than the fetal hemoglobin, and th ey suffer no ill one you started with," he says . effects from what is called their Heredi­ A complicated alternative, Ley says, tary Persistence of Fetal Hemoglobin is first to remove some of the patient's Organ system: Blood (HPFH). bone marrow and purify the stem cells Application: Hemoglobinopathies• "There is good reason to push (from which aU blood cells are derived). Researcher: Timothy J. Ley, M.D. forward," Ley says. Sickle cell patients Stem cells account for perhaps one in in some parts of the U.S . experience every 10,000 cells in the bone marrow. The expression of genes is not annual health care costs that can average Into those cells, researchers would then constant; mechanisms exists to switch as much as $50,000 each. Patients suffer somehow deliver normally regulated genes on and off. Timothy Ley, M .D., is intermittent painful c ri ses when mis­ globin genes before destroying the working to understand one such mecha­ shapen hemoglobin molecules literally diseased marrow and installing the nism. His aim is to be able to open a get stuck in blood vessels and rob tissues corrected version. particular switch. of oxygen. The I ives of sickle cell Several major problems must be At about the time of birth, humans patients are shortened. confronted before that approach can normally change from producing one Thalassemia is widespread, particu­ work. Ley says that it is not yet possible form of hemoglobin, the fetal form, to larly in Mediterranean and Asian to fully identify stem cells, and the producing another, th e adult form, Ley countries. Its standard treatment in­ genetic therapy would have to treat explains. At the changeover, the gene for volves regular blood transfu sions every one to be effective. " Perhaps most fetal hemoglobin is switched off and the beginning shortly after birth. Iron difficult," he says, " is that the gene you gene for the adult version is switched removal therapy is the only way to lift transfer has to be perfectly regulated. If on. All too often, however, the adult the burden those transfusions bring, and it doesn't make enough globin, you version of the oxygen-carrying globin patients can expect to live only into their haven't solved the problem. If it makes protein is flawed - either misshapen or 30s or perhaps 40s. Bone marrow too much, you've created what's called so reduced in amount as to cause serious transplants have been used with success, alpha thalassemia, another destructive health problems, depending on the gene but must be done at an early age, and disease. So the regulation has to be flaw. Ley raises the ethical question of precise. And that's a tall order right When the adult hemoglobin is whether a preschooler can give truly now." malformed, one re sult can be sickle cell informed consent to a procedure that "Still," Ley says, " that would be the anemia. A defect that causes too little carries a five to 10 percent ri sk of very best method." And so researchers adult globin is called beta thalassemia. causing hi s or her death. continue to pursue means to overcome " An obvious strategy for treating these So gene therapy holds promise. But the hurdles that stand in the way of hemoglobinopathies," Ley says, "is to re-activating one pair of genes among replacing bad genes with good ones. • reactivate the fetal globin genes." The the body's 100,000 is easier to explain approach is especially attractive because than to do. Ley has been involved in a number of adults continue to express work to find a pharmacologic agent that

16 omputed tomography, or CT, has [ earned its place as a clinically valuable exam, but sometimes the bread-slice images it provides are not enough. Small abnormalities may lie between slices and remain undetected. Others may be obscured by the plane of view. And if the original slices do not meet diagnostic needs, the only option is to scan the patient again. Now a new twist on conventional CT, called spiral CT, is giving radiologists and their colleagues a clearer window into the human body. Hailed as a major advance in imaging, spiral CT reduces th e hit-or-miss problems of conventional CT, helps radiologists generate more diagnostically powerful images, and opens up new applications as well. For a conventional CT exam, a donut­ shaped structure called the gantry rotates an X-ray beam once around the patient for each slice. For the next slice, the gantry must be rotated back to its original position and the table moved forward in a carefully controlled increment. A computer assembles a cross-sectional image after each scan. Conventional CT has several draw­ backs, explains Jay Heiken, M.D., associate professor of radiology and co­ director of the body CT section at Washington University ' S Mallinckrodt Institute of Radiology. One of the biggest problems comes from respiratory motion. Patients must hold their breath during each scan to minimize motion; if breathing is inconsistent from one slice to the next, a small lung or liver lesion, for example, might be missed, he says. And, because the exams take several minutes to complete, it is sometimes impossibl e to collect all of the data during the limited time when contrast materia1 provides the best enhancement. Also, the computer only holds data for Spiral CT Improves Upon The Standard each slice; "If there is something in between that needs to be imaged, we by Juli Leistner have to rescan the patient," Heike n says.

17 they can do the entire scan when contrast enhancement is at its peak, Heiken says. In addition, they can often reduce the dose of expensive contrast material by approximately 50 percent in chest scans and 25 percent in abdominal scans without reducing image quality. After a scan, the computer can construct a set of slice images at any interval the radiologist chooses, typi­ cally from 2 to 10 mm. [fnecessary, the radiologist can go back to the com­ puter' s data set and generate thinner These bone scans were produced using slices even after the patient has gone spiral CTfrom data collected in jive home. It also is possible to compose minutes instead ofthe usual 20 min­ three-dimensional images and images in utes, with radiation dosage reduced by any plane; when a transaxial cross 60 percent. section is di fficult to interpret, an image reconstructed in a longitudinal plane Because we can reconstruct images at often provides more information, Heiken arbitrary intervals and we avoid respira­ says. Multiplanar and 3-D images were tory misregistration, we can pick up Stuart Sagel, M.D., and Jay Heiken, possible with conventional CT, but lesions that we might otherwise miss," M.D. inconsistencies from slice to slice he explains. limited their quality, he adds. Spiral CT also measures lesion Spiral CT eliminates many of these Although spiral CT is still considered density more accurately - important for problems, Heiken says. Mallinckrodt is investigational, clinical studies are deciding whether lesions are malignant, one of the first sites in the country to uncovering its practical benefits. Studies Heiken explains. Spiral CT's flexibility evaluate it. Investigators Michael show spiral CT finds more small lesions assures that radiologists can get slices Vannier, M.D., professor of radiology in the liver than conventional tech­ through a lesion's center for the most and chief of the clinical research niques, Heiken says. At Mallinckrodt, accurate density reading, he says. division; Stuart Sagel, M.D., professor spiral CT is used routinely for exams of Spiral CT also may provide a safer of radiology, chief of the chest radiology the pancreas and for many exams of the alternative to certain invasive imaging section and co-director of the body CT neck, chest and abdomen. "We are exams. A recent clinical study by Brink section; James Brink, M.D., assistant generating diagnostic images with spiral found that spiral CT rivals the gold­ professor of radiology, and others have CT that were not possible before. standard, cholangiography, for diagnos­ studied the technology for the past 18 months. The secret to its power is continuous scanning. An innovation called slip ring technology allows the X-ray tube and detectors within the gantry to spin around the patient continuously as the table glides forward. Because the table travels during the scanning process, the recorded X-rays plot a spiral course through the body instead of a circle. A computer stores raw X-ray data as one volume, a three-dimensional memory of On the left, a conventional, invasive the entire scanned area. The machine arteriogram. On the right. a 3-dimensional, speeds through a complete exam - of color-enhanced reconstruction produced via the chest, for example - in about 30 spiral CT. The spine is in green; the left seconds. carotid artery is in yellow, showing the Because spiral CT is so fast, scans are blockage ofthe internal carotid that should accomplished in a single breath-hold, supply oxygen to the brain. The right eliminating respiratory motion problems. carotid artery, in red and not blocked, shows The speed also means radiologists get to both branches. better diagnostic information, because

18 ing bile duct obstruction. Similar benefits are possible for imaging blood vessels that supply the kidneys, Heiken says. Preliminary work shows spiral CT may be valuable for im aging blockage and narrowing in the carotid arteries, the vessels that lead from the aorta to the head, says Christopher Moran, M.D., assistant professor of radiology. He uses scan data to generate 3-D color images. ~ "The information they provide is similar ;::::: to angiograms," he says. Spiral CT also .;:::. ~ shows promise for imaging aneurysms in the head, he adds. Kevin McEnery, M.D., instructor of radiology, is applying spiral CT to bone fractures. He and Anthony Wilson, M.B., Ch.B., associate professor of radiology, and William Murphy, M.D., professor of radiology, are among the few researchers anywhere studying this James A. Brink, M.D. application. "Conventional CT is used when complex fractures are difficult to Siemens Medical Systems, about future conventional method, and Mallinckrodt accurately assess on plain X-ray or when refinements. Studies by Brink and others is embarked on a long-term, cooperative clinicians need more detailed infonna­ are helping define the technical param­ development plan to refine and improve tion regarding the fracture," McEnery eters that generate the best results. And CT imaging. " Eventually, this will be says. " For musculoskeletal CT imaging, Vannier is developing better computer the way routine chest and abdominal CT when we want to create high quality, 3­ algorithms to turn raw scan data into is done. I would estimate that within five D images or multiplanar reconstructions, meaningful pictures. to 10 years, all major medical institu­ ma ny thin sections are necessary." With According to Vannier, in the future it tions will be using spiral CT routinely standard CT, the exam could take 20 is likely that spiral CT will replace the for body imaging," Heiken predicts. • minutes or longer. "A patient who is in pain usually can't be expected to hold still that long," he says. Even subtle movements cause misalignment of the slices and degrade the images. "We are excited about spiral CT. We can shorten examination times, reduce the radiation dose to the patient and obtain better data because there is much less chance of a patient moving during an examination that lasts only 30 seconds," he says. Another likely application will be helping surgeons zero in on targets with 3-D and multiplanar images. It also may benefit children, trauma patients and others who have difficulty following breathing instructions, Heiken says. And short scan times are a plus for unstable patients, McEnery adds. " As soon as the scan is done, the patient can go right Black arrows mark a leiomyosarcoma arisillg from the wall ofthe inferior vella back to intensive care, even though we cava (yellow arrows). The large organ is the liver. III the left image, reformed from still are working on the exam at the a stack ofcOIII'entional CT slices, the information is less thall clear because at least computer," he says. 100 seconds and several breaths were required to collect the data. In the spiral CT Washington University is one of five image 011 the right, spiral slices were gathered ill a single breath-hold, reducing schools advising spiral CT's developer, misregistratioll.

19 Photographs courte~y of Washington University School ofMedicine Archives

n October of 1992, Edwin Krebs, M.D. '43, shared the Nobel Prize in I Physiology or Medicine for research on reversible protein phosphoryla­ tion, a crucial process that regulates many enzymes and greatly affects cell growth and differentiation. This most recent laureate began his distinguished career 47 years ago in the laboratory ofCarl and Gerty Cori, who themselves shared the 194 7 Nobel Prize. The connecting link is a rare intellectual phenomenon: a generation of Cori-inspired research excellence that has flourished for nearly 50 years.

Krebs belonged to a group of brilliant from 1946 to 1948. Like Sutherland, their laboratory as, "a haven for ambi­ young scientists who launched their who won the 1971 Nobel Prize for tious, gi fted people from all over. .. right careers under the Coris' auspices. discovering cyclic AMP, Krebs followed after the war it was the liveliest enzy­ Among them, Krebs and the late Earl a line of inquiry clearly opened by the mology lab in the world." Yet, he notes Sutherland, M.D. '42, started research as Coris' research. regretfully, "My students are now totally medical students. While Sutherland Another alumnus of what might be unaware of the work and spirit of Carl assisted the Coris, Krebs worked in called "the Cori School," Arthur and Gerty Cori and of their guiding Philip Shaffer's laboratOlY and later held Kornberg, a 1969 Nobel laureate for influence on my generation of biochem­ a postdoctoral fellowship with tbe Coris research on DNA replication, described ists. "

20 Carl and Gerty Cori are pictured in their laboratory on October 4, 1947, at the time that they won tire Nobel Prize. Their tremendous illfluence cOlltinues to reverberate through tire scielltific community.

Krebs' 1992 prize is the most recent intellectual immortality - not only doctors' dilemma," they realized that sign of the Coris' guiding influence. through their own discoveries but post-war prospects for finding two good They generated future research excel­ through those of their students. By both positions in the same place were poor. lence by nurturing young scientists in an measures, the Coris' record is remark­ The years 1920-21 were a time of near extraordinary laboratory environment. able. starvation in Vienna; while working as a Though Gerty Cori died in 1957 and Their collaboration began when they pediatric intern, Gerty Cori developed I Carl Cori in 1984, their scienti fie legacy were medical students in Vienna, where symptoms of vitamin A deficiency. .~ remains vibrant. They are among those they received medical degrees in 1920. Although Carl Cori managed to get a job few scientists to achieve two kinds of In what Carl Cori later called "the in Graz, he later described the atmo- !;j 21 I -~ ------~~------

Nonetheless, they persisted in working proach: "Carl and Gerty had the experi­ together. mental gifts and wisdom to extend In 1931, their most fruitful years physiological studies of whole animals began in the Department of Pharmacol­ and organs to crude cell ex tracts and, ogy at the School of Medicine. Despite finally, to purified enzymes ... while nepotism rules then in force, Dean Philip teaching themselves and their students Shaffer was wise enough to welcome how to examine the molecular shapes them as a team. As head of pharmacol­ and operations of enzymes, they never ogy, Carl Cori carried major administra­ relinquished their devotion to under­ tive and teaching responsibilities. standing the function and hormonal Nonetheless, he continued research with control of enzymes in the intact animal." Gerty Cori (who received an appoint­ In 1947, the Coris shared the Nobel ment as research fellow). He was well Prize with Bernardo Houssay for aware that, as he later put it, "a most research on the catalytic conversion of exciting period in biochemistry had glycogen. At the Nobel dinner, Carl Cori begun to unfold ... all previous expecta­ referred to collaborating with his wife: tions about the rate of development of "Our efforts have been largely comple­ biochemistry were surpassed." mentary, and one without the other Edwin Krebs received the Nobel The Coris played a leading role in would not have gone so far as in Prize last year. He was a research that accelerated development. Between fellow in the Department of 1930 and 1935, they published a series Biochemistry from 1946 to 1948 < of papers analyzing what became known after receiving his medical degree Luis F. LeLoir, Nobelist in \ as "the Cori cycle" - elucidating the from the school in 1943. Chemistry in 1970, received the mechanism of blood glucose regulation. t prize for his discovery ofsugar While their work opened up several nucleotides and their role in the ! other areas of research, a decision to biosynthesis ofcarbohydrates. He sphere there as "very disturbing." To focus on glycogenolysis proved wise, for was a research assistant to the be hired, he had to prove Aryan descent. it was the most fruitful field of study. [I Coris in 1943. il Even experimental animals were hard to Arthur Kornberg has provided a ,I obtain. He recalled: "I was the only penetrating description of their ap­ person.. .in a position to do experimental work ... because my father...had been able to send me a shipment of frogs. These were kept in an aquarium under lock and key and were responsible for my coming to the United States." In 1922, an American laboratory director became interested in his studies and offered him a position at the New York State Institute for the Study of Malignant Disease. Gerty Cori arrived six months later and went to work in the pathology department. Carl and Gerty Cori's coUaboration on carbohydrate metabolism began shortly after their arrival, but they soon encountered institutional obstacles to working together. In a memoir, Carl Cori recalled that, at one point, his wife faced being fired "unless she stayed in her room and stopped working with me." Arthur Kornberg (left) and Severo Ochoa, Nobel Prize winners in 1959, When he decided to consider a job discovered the mechanisms in the biosynthesis ofribonucleic acid and elsewhere, Gerty Cori was taken aside deoxyribonucleic acid. Ochoa worked in the Coris' lab in 1941 and 1942; and told "she was standing in the way of Kornberg was a visiting investigator there in 1947. my career, and that it was un-American for a man to work with his wife."

,.f~· 22 i collaboration." In describing their laboratory work, a biographer noted, "The manual labor and tedium of these Christian de Duve won the Nobel Prize ill 1974for discov­ experiments were considerable. Collabo­ raWrs were few in number by prese-nt­ eries concerning the structure and functional organization of day standards, and automation was the cell. He worked in the Cori nonexistent." lab as a Rockefeller Foundation Despite these difficulties, the Coris Fellow and collaborated there always attracted young scientists to their with Earl Sutherland. laboratory. In his 1971 Nobel lecture, Earl Sutherland recalled: "When I returned to St. Louis after medical service in World War II, I was unde­ cided as to whether I should enter was no research factory with people medical practice or go into research. following detailed protocol laid out by Cori convinced me, not so much by others; it was a collection of extremely anything he said so much as by his talented individuals doing their own example, that research was the right work with their own hands. In that Earl Sutherland received the direction to take." In fact, Sutherland environment, sinking was unthinkable. I Nobel Prize in 1971 for his had co-authored a 1941 article (his first) felt privileged to be present...." discovery concerning the meclla­ with Carl Cori while still a medical What was the magic of the Coris' nisms ofhormones. He was a student. His retrospective view is telling, lab? Sutherland identified two crucial student laboratory assistant from for it reveals how the Cori-created ingredients: a critical mass of talented 1940 to 1942 and later an instruc­ laboratory environment shaped his young scientists and the free exchange tor, an assistant professor and an future: "I believe that kind of stimulat­ of ideas. By today's standards, their associate professor. ing environment, with the necessary laboratory was small and modest, but the critical mass of young and talented level of intellectual activity and scien­ investigators, with the opportunity for tific discourse was extraordinary. Severo highest praise for someone was to refer to him or her as a 'good worker.' ... The actual scientific contributions of the Coris served as the basis for what was to "{9-wc#whaO~ beell/!wyef!/ become my major life's work.... My own research was built on the foundation that they laid." comjJ!enzuuaJ':!/J andO/ll?/ {oitltotd t/zl?/ After the Coris' 1947 move to the Department of Biochemistry, their ~~{OOldd/ltK~8h/le-80-fo~ ~ a& research group grew considerably. Even so, the atmosphere of mutual collabora­ • -- //- /: - -._",-//l,..n. -'-' Ul/ COllllOOf-u.uAJTy. tion and collegial support remained. Enriched by the experience, former laboratory members would make independent contributions to knowledge in uoiversities across the country and the free exchange of ideas, is an impor­ Ochoa, a 1959 Nobel laureate who around the world. tant ingredient in the making of scien­ worked there in the early 1940s, noted Lo 1953, Gerty Cori wrote: "For a tific progress." This acknowledgment that "everyone was invited to comment research worker, the un forgotten meant enough for Cori to quote it in a on papers before publication." moments of h.is l.ife are those rare ones posthumous National Academy biogra­ As Krebs recently recalled: "The which come after years of plodding phy of his fOimer student. training I received in the Coris' labora­ work, when the veiJ over nature's secret Washington University Chancellor tory as a postdoctoral fellow provided seems suddenly to lift and what was William H. Danforth, M.D., also was me with the actual tools that I needed to dark and chaotic appears in a clear and among those who worked in the Cori lab get started.... By 'tools' I'm referring beautifui llight and pattern...." Thanks to and had the course of his life affected by not just to techniques but also to a host formative years in the Coris' research the association. At Carl Cori's memorial of other things that go into research ~ enterprise, many other scientists have service, on November 16, 1984, inquisitiveness, thoroughness, breadth of experienced those moments. • Danforth said, "The Cori department interests and hard work. Gerty Cori's

23 Personal Outlook

The tritieal Link: Health altd Human Rigltts

by Jonathan Mann, M.D.

he worldwide AIDS Rights. Briefly yet power­ vel oped and as tools such as The inferior role and low epidemic was the first fully, the universal declara­ the HIV serologic test be­ status accorded to women T epidemic to arise dur­ tion responded to the came available, direct con­ results in their inability to ing the modem era of human atrocities of Nazi Germany flicts arose between public say "no" to unwanted or un­ rights. As a result, it is not with a clear statement that health experts and human protected sexual intercourse. surprising that the dialogue all people are born with rights advocates. Health offi­ Thus, despite their knowl­ between public health and rights that adhere to them cials often acted as if health edge about HIV / AIDS and human rights perspectives simply because they are hu­ objectives (preventing HIV even despite the availability man and that governments spread) and human rights of condoms, these women cannot take away. Since the objectives (protecting the face a choice between refus­ adoption of the declaration rights and dignity of the in­ ing sex, with the likelihood in 1948, an important foun­ dividual) were at logger­ of physical violence and di­ dation of documents and in­ heads. vorce (leading basically to stitutions and a network of For example, some public civil and economic death), nongovernmental organiza­ health officials promoted and risking HIV infection. tions have been created to mandatory screening for In response to this situa­ explore the meaning and to HIV infection, while rights tion, women's organizations work to ensure respect for advocates resisted practices are working to reform the the entire range of human which threatened individual laws and customs governing rights. freedoms. In the end, the hu­ property distribution after I think my own experi­ man rights viewpoint gener­ divorce. If civil and eco­ Jonathan Mann, M.D., ence is somewhat typical. I ally prevailed, as health nomic survival following M.P.H. never encountered the idea officials came to the prag­ divorce can be assured, HIV of human rights in any for­ matic conclusion that if the prevention will be helped during the HIV pandemic mal sense during either my people they wanted to reach much more than it would be has been complex and some­ medical or public health with education about HIV by the distribution of addi­ times difficult. Yet, through training. Indeed, most physi­ were punished or threatened, tional condoms or brochures this experience, a clearer un­ cians are unfamiliar with the they would go underground on AIDS. The general mes­ derstanding of the inextri­ basic concepts, the docu­ and not participate in pre­ sage from this specific ex­ cable linkage between health ments, the institutions and vention programs. ample is clear: The fact of and human rights has led to the practices of modern hu­ However, as the pan­ being marginalized, stigma­ the creation of a new field of man rights. Yet, as I hope to demic intensi fied and spread tized or discriminated academic research, teaching demonstrate, there are practi­ to countries worldwide, an­ against in society is at the and practice - and to the cal and powerful reasons - other dimension in the rela­ basis of an increased risk of world's first center focusing beyond simply being an edu­ tionship between health and being exposed to HIV. on this critical relationship at cated person - for physi­ human rights emerged. Let Once it is clear that dis­ the Harvard School of Public cians and other health me explain using an ex­ crimination increases \rulner­ Health. workers to become literate in ample: In parts of Eastern ability to HIV - through The modern era of human human rights. Africa today, monogamous, having less access to infor­ rights started after World Back for a moment to the married women are becom­ mation, services and support, War II, with the approval by AIDS pandemic. During the ing infected with HIV. Their or by being less able to put the United Nations General early years, as policies and risk factor is their powerless­ into practice the practical Assembly of the Universal guidelines for preventing ness to influence their implications of prevention Declaration of Human HIV transmission were de- husband's sexual behavior. messages - the way for­

24 ward for public health A second dimension of of human rights as legitimate extent of global health-inter­ against ArDS is clear. Not the health-human rights rela­ concerns require that health dependence: An obscure only must existing programs tionship involves the ways in workers become human­ event somewhere rapidly of education, health and which health policies, pro­ rights Iiterate. became a health crisis here social services and social grams and practices can have The third dimension re­ and around the world. support continue to be devel­ adverse effects on human turns to the recognition that Thanks to the generosity oped and strengthened, but rights. For example, the social justice - or to put the of the Swiss-based Associa­ we must remove and prevent practices of quarantine and matter negatively, societal tion Francois-Xavier societal discrimination. isolation are part of the lexi­ discrimination - is critical Bagnoud, the first academic Thus, for example, promot­ con of public health re­ to efforts to promote hea lth. center to focus exclusively ing an equal role for women sponses to epidemic disease. While the general relation­ on health and human rights becomes a critical strategy But these practices violate ship between health and was established in January for improving public health. individual rights. How effec­ rights - such as the right to 1993 at Harvard. The Looking beyond AIDS, tive is isolation, and what are information, to education, to Francois-Xavier Bagnoud we can see at least three di­ its direct and hidden costs? recognition as a person be­ Center for Health and Hu­ mensions in a health and hu­ Is the evidence strong fore the law, to freedom of man Rights (named after the man rights relationship. enough to justify burdening movement, to the right to young Swiss helicopter pilot First, it is clear that abuses human rights? Before jump- marry and found a fami Iy, to who died on a rescue mis­ of human rights - - whether sion in West Africa in 1986) torture, or inhumane treat­ will link the academic ment during imprisonment, strengths of research and or rape or denial of the right teaching to field work that to information have im­ addresses real public health portant health impacts. Yet n1HtIerll tlu~ existence problems. In the wnrl(l./ even these impacts are often For me, the discovery of not well documented, or un­ and acknowledgnlcnt of (uIluan the inextricable relationships derstood. between health and human For example, we now rights as legititnate concerns rights has been a gradual know that prolonged impris­ process, based on my work onment under inhumane con­ require that health workers to fight epidemic disease and ditions creates lifelong to promote health. I believe threats to physical and men­ he(,(Hnp hLllnan-rights li tera te. that the pragmatic idealism tal health which require pre­ of physicians will add tre­ venti ve services and care. mendous strength to a grow­ Still another example in­ ing global capacity to volves rape during warfare prevent disease and promote ing to conclusions, we must freedom of opinion and ex­ or undeclared conflict. The health, as we seek to put reca 1I tha t medicaI leaders pression - is clear, the tragedy in Bosnia is particu­ health and human rights at actively participated in de­ mechanisms and interactions larly abhorrent because rape the center of our human veloping Nazi ideology and need to be better understood. has apparently been a sys­ commitment. • practices, under the guise of Finally, what is the mean­ tematic and deliberate the pseudo-science of racial ing of the right to health? policy. But how much is hygiene. By taking the con­ The right to health goes be­ known about the frequency Ed Nole: Jonathan Mann, M.D. cept that the "diseased" part yond access to quality health and incidence and conse­ is a 1974 graduate of the School of must be sacri ficed for the care, although this would be quences of rape during other Medicine. He is the former chief of health of the rest, Nazi doc­ a great achievement for conflict situations, including the World Health Organization'S tors promoted the practices American society. The pre­ insurgencies and various un­ AIDS programs, director of (starting with euthanasia and amble to the constitution of declared conflicts? It is im­ Harvard's Global AIDS Policy killing of the handicapped) the World Health Organiza­ portant to document the Coalition and chaired the 8th inter­ which led directly to the tion states that people have a health consequences of hu­ natIonal Conference on AiDS in death camps. What was right to the highest attainable man rights abuses, system­ Amsterdam. missing so desperately from standard of health, and that atically and carefully, in Nazi Germany was respect this is fundamental to world order to understand better for individual human rights. peace and security. At a how to prevent their occur­ In the modern world, the ex­ larger level, the ArDS rence and to ameliorate their istence and acknowledgment pandemic demonstrates the impact.

25 S.-'--oDette

SOIl ethillg Ext.-a

by Steve Kohler

he office of Leopold and been named a fe llow in Bible more appealing and " [ always have a project Hofstatter, M.D., is the American Association accessible to others. to work on," Hofstatter says. T simple and tidy, al­ for the Advancement of Sci­ During the hard days of He made a doorbell and th e most modest. When he's not ence in honor of his contri­ World War I, Hofstatter pre­ crude battery to power it for the re, two objects dominate butions. served food fo r his family the apartment building his the small space: a Webster's For almost a century no w, and applied a method by fa mily occupied in Vienna. unabridged dictionary on a his preference has been to which their meals could be The building was construct­ desk stand and a large paint­ stay busy, keeping out oftbe cooked, despite a shortage of ed before th e siege of Vienna ing on the wall op­ by Turk is h troops in posite. 1683 and had no The dictionary is provision fo r electri­ symbolic of cal w ires. But Ho fstatter's close Hofstatter knew his acquaintance with family would appre­ language and th e ciate the conve­ breadth of his inter­ nience of a doorbe ll , ests. The painting, so he created one. done by his first His projects were w ife, Lilli, is more done on the side intimately signifi­ while studying cant. The portra it's Latin , French and creator aside, it is English in school, the subject - a Italia n, Spanish, young man untms­ Russian and takably with a men­ Croatian on hi s own. ta I illness, his eyes A sense of inno­ closed and a pain­ vati on inspired by full y blank expres­ common sense a lso sion on his pal e face has in fused - that embodi es Hofstatter's profes­ Hofstatter's dedica­ sionallife and its LeopoLd Hofstatter, M.D. I ti on to serv ice to projects. He was others. steered toward medi­ ) At 91 and sincerely mod­ spotlight. "J have a lways gas for the stove. Young cine by its purpose o f serv­ est, he clearly is uncomfort­ lived in the service of my Leopold bu ilt a super-insu­ ing people directl y. A strong able being the subject of an fell ow man," Hofstatter says. .Iated chest that kept fo od sense of anti-militarism born interview. " [ am just an ordi­ The habit began in hi s birth­ cookin g for fo ur hours while of the horror of World W ar 1 nary huma n being, nothing place of Vienna, Austria, he was at waltz and ta ngo and his uncle ' s duty as com­ ex tra ," he says, though he when, as the oldest o f four class with hi s s isters. " We'd mander of a flame-thrower has in fluenced more th an a children, he often saw that come home to have rice un it bolstered that choice. hal f-c entury of psychiatry, his sisters were ca red fo r. As boiled in milk with chocolate Out of respect for his pa­ worked to improve the lot of a boy, he collected postcard s powder on top," he says, de­ tients as human beings, psychiatric patients, pio­ depicting religious paintings li ghted at th e memory o f Hofstatter years la ter was neered more restricted - not fo r personal g ratifica­ having done well in adver­ responsible for li m iting th e psychosurgica I tecbniq ues tion or gain but to make tbe s it y. extent of surgery to the fron­

26 tal lobes when providing re­ When Albert Einstein ar­ therapy, which Hofstatter brain visualization tech­ lief from otherwise chronic rived in class, Hofstatter calls "a fraud from the be­ niques like positron emission and treatment-resistant men­ read the paper to the man he ginning," was for a while tomography (PET) and mag­ tal illness. His approach, came to regard as a hero, and accepted beyond anyone's netic resonance imaging based on the principle, the two were photographed imagination. And hydro­ (MRI). He is paliicularly "First, do no harm," became together with Professor therapy "has been given up, interested in applying them a milestone in the history of Schlenk, head of the although it is beneficial," he to the study of the effects of psyc hosurgery. university's chemistry de­ says. early childhood experiences That may have been his partment. "Some of the condi tions on myelination and on social greatest single contribution, After graduation, that used to be common are behavior. And he partici­ but smaller examples reflect Hofstatter intended to be­ almost unknown today," he pates in a project for the St. the same ethic. When he be­ come a surgeon, but Nobel says. "For example, take Louis Science Center that came assistant superinten­ Prize winner Konstantin von congenital syphilis. Now, we will include history's many dent at St. Louis State Economo saw his transparent treat syphilis early and effec­ great thinkers, writers, com­ Hospital in the '40s, he model of the human brain tively, so it no longer is posers and others who ha ve added a napkin, a glass of (made from urea, the first passed along. I saw many suffered from mental ill­ water, a fork and a knife to plastic) and encouraged him tragic instances of general nesses. the place settings at patient's to direct his attention to neu­ paresis of the insane, another He spends part of his time meals where previously only rology and psychiatry - a rare condition today. We caring for and playing the a spoon had been provided. single discipline in Europe at stopped its progression, but piano for his wife, Theresa, During World War II, he the time. we couldn't bring life back hersel f a pianist. On most made raisins a part of days, Hofstatter goes to most menus, improv­ his small office to work ing the patients' diets on his projects. He re­ with iron. And he in­ A.t every opportllnity~ hp in1IH'O\pd peatedly ponders one sisted on smaller ward question: "I've always sizes in the Missouri psyehiatric patients,) 1110rale by increasing wondered and been sur­ Institute of Psychiatry prised at the trust, con­ building to encourage the level of reRpeet shown to then1. fidence and respect socializing among pa­ shown me by my fam­ tients and staff. At ily, colleagues and su­ every opportunity, he periors. I was fortunate improved psychiatric to have the best teach­ patients' morale by increas­ In early 1938, Hitler's to the celts killed by invad­ ers and examples to learn ing the level of respect armies marched into Vienna. ing spirochetes," is his sad from and to be inspired by. I shown to them. The date was March II, observation. happened to stumble on a When Missouri's gover­ Hofstatter's birthday. He and When he met von few things. I keep myself nor came to review changes Lilli soon left and shortly Economo, the scientist had going. [just can't help being he had made as superinten­ therea fter settled in St. contracted with the Soviet interested," he says, shifting dent at the State School and Louis, where Hofstatter had government to preserve for the dictionary to sit squarely Hospital, Hofstatter turned obtained a research fellow­ future study the brains of on his desk. away the politician's con­ ship in neurosurgery with elite thinkers after their Hofstatter characteristi­ gratulations by telling the Ernest Sachs at the medical deaths. The plan was to ex­ cally has avoided honors and governor, "You don't have school. He taught applied amine the brain tissue micro­ awards, declining to join to be a doctor to understand neuroanatomy and, later, scopically to discover the even most professional soci­ this. Common sense tells psychiatry to med ica I stu­ source of their genius. eties. Other rewards have you. A tool is an extension dents. "Those people were com­ been more important. To il­ of the arm; all learning is an During his long involve­ pletely unaware of the lustrate, he tells the story of extension of common ment in psychiatry, chemical and electrical pro­ how, when Lilli's painting of sense." Hofstatter has witnessed cesses that occur in cerebral the mental patient had been During his medical train­ many changes. His early spe­ activity, and there was very hanging on his wall for some ing at the University of cia Ity of psychosurgery is little to be learned from his­ time, he encountered the Vienna, Hofstatter was asked little practiced since the ad­ tological studies," Hofstatter man in the portrait. Working to translate a chemistry pa­ vent of psychotropic drugs. says. as an elevator operator, the per on newly discovered iso­ The paternalistic attitude that Through it all, Hofstatter man had been treated suc­ topes from English into early psychiatrists some­ has kept pace with change. cessfully. "That's what gives German in preparation for a times adopted toward their Today, he follows the devel­ me satisfaction," he says. • visit from a famous scientist. patients is gone. Insulin opment and application of 27 II I Alumni

r_-::.-- ­

'\.- fit';,' , ~71 ,,~~{j•. " II -*~ t its January 25 J. Neal Middelkamp, i ':a.'iii' meeting, the Execu­ M.D., professor of pediat­ tf A tive Council of rics, has been on the faculty WUMCAA voted to name since 1953 . He was honored \ '\ Distinguished Alumni Schol­ with an Alumni/Faculty "~ arships in honor of Leonard A ward from WUMCAA in .,..... , .. '~ .­ Berg, M.D. '49; Robert C. 1988. ~~' Drews, M.D. '55; John Established in 1989 by -~ !4 Kissane, M.D. '52, and J. WUMCAA, the named ",1; .~r- '. Neal Middelkamp, M.D. '48. scholarships are not based on Sixteen such scholarships financial need but on aca­ had been established. The demic merit and the excep­ scholarships are the school's tional personal qualities The Coleman Foundation Symposium, presented Friday, major merit-bascd scholar­ required for the successful February 5, treated the subject "Molecular Oncology: Novel ship program funded by pri­ practice of medicine. • Approaches to Understanding and Treatment." Among the vate support. Funded dignitaries on hand were (left to right): Michael W. partially by annual gi fts from Hennessy, vice-president oIThe Coleman Foundation; John alumni, former residents and S ..ohaefer Trust E. Hughes, presidellt ofThe Coleman Foundation; Thomas other donors, they recognize F. Deuel, M.D., symposium organizer and moderator ofthe beloved teachers. Each DOl1ale~ $1.35 morning session; Jean D. Thorne, executive director ofthe named scholarship provides Million foundation, and William A. Peck, M.D., executive vice chan­ a first-year recipient with cellor and dean ofthe medical school. The Coleman Foun­ $10,000 toward tuition costs. dation Symposium, presented annually, rotates among six The medical school then he School of Medi­ midwestern medical schools andfocuses on recent discover­ matches the grant up to the cine has received a ies in basic cancer research. Located in Chicago, the founda­ full amount of tuition. The T $1.35 mi Ilion dona­ tion has been a continuous supporter ofthe mel/ical school. scholarships continue for the tion to fund research in the four years of medical educa­ division of pulmonary and tion. critical care medicine. The During his career, Hodges P 'ograul Leonard Berg, M .D. , donation comes from the organized radiology depart­ joined the faculty in 1955 as trust of Martin W. Schaefer, D dicat d To ments at the University of an instructor in clinical neu­ a Belleville IL native, who Chicago and the University rology and was named pro­ died in 1991 from emphy­ Paul IIoc ges of Florida, trained leaders in fessor in 1972. Today, he is sema, a common respiratory the field and developed inno­ director of the Alzheimer's disease that destroys the vative technological ad­ he Radiological So­ Disease Research Center. lungs by causing inflamma­ vancements, such as the ciety ofN011h Robert C. Drews, M.D., tion of the connective tissue phototimer. He taught physi­ America (RSNA) professor of ophthalmology, framework. Schaefer hoped ology and worked as a dedicated the printed pro­ has been on the clinical staff a tmst would fUl1her re­ Roentgenologist in China gram of its 78th Scientific since 1966. In 1979, he search and aid in the devel­ and returned to the Orient Assembly and Annual Meet­ served as the president of opment of new treatments. after his retirement. ing to Paul C. Hodges, M.D., WUMCAA. "Emphysema and other The RSNA meeting, con­ Ph.D., the oldest living John Kissane, M.D., associated severe respiratory vened each year in Chicago, is graduate of the School of joined the faculty in 1958 disorders constitute a group the single largest scientific Medicine. Hodges graduated and is professor of pathology of diseases affecting an in­ meeting held in the country . • in 1918, and he celebrated in pediatrics. In 1970, he creasing segment of our his 100th birthday on Janu­ was selected Teacher of the adult and aging population," ary 6, 1993. Year by the graduating class.

28 says David M. Kipnis, Chapter of Alpha Omega TI1e AOA chapter will host Danforth has called her one M.D., distinguished univer­ Alpha, held at the University visiting professor Al Tarlov, of hcr generation's great sity professor in the Depart­ Club on Wednesday, January M.D., on April 22 and 23. benefactors: "She showed us ment of Internal Medicine. 27. Tarlov, ofthe division of how to enjoy life's gifts "The ability to expand our Nearly 200 members and health improvement ofthe while sharing them with oth­ research activities in under­ guests of the chapter at­ Health Institute of the New ers. I am thankful that she standing the pathological tended the induction of 20 England Medical Center, Bos­ chose Washington Univer­ events leading to these disor­ members into the medical ton, is expected to speak on sity as a partner in doing ders and to devise mecha­ honor society, the president health care reform .• good for the generations nism-based therapeutic of which is Kenneth M . ahead." • strategies to treat them repre­ Ludmerer, M.D. sents an extraordinary oppor­ Fourth-year medical stu­ Bequest Will tunity for our scientists dents inducted were: Daniel CLAS, ~ engaged in this area ofclini­ E. Buerger, Douglas T. Can­ Fund Arthritis cal investigation." non, Lynne M. Champagne, R Schaefer was born July Paul 1. Cummings, Lora K. '20s and '30 16, 1923, and attended pub­ Eichner, Jodie A. Escobedo, lic school in Belleville. He Robert A. Fontes, Jr., ashington Univer­ was drafted into the U.S. Michele L. Francoeur, sity has received Army in 1942 and dis­ Patrick R. Gannon, Kirk P. W a $2 million be­ charged in 1946, after which Gasper, Cecilia M. quest from the estate of he joined the Army Reserve. Redmond, Theodora S. Ross, Audrey L. Levin, according He was called back into ser­ Dan G. Sewell, Vishwas R. to an announcement by vice during the Korean con­ Talwalkar and Robert J. Chancellor William H. flict and opted for a military Teaford. Also inducted were Danforth, M.D. career at the end of that war. three graduate trainees: John The bequest will establish He retired as a colonel in E. Frattini, James R. Howe an endowment in the Depart­ 1970. and Charles M. Kilo. ment of Medicine to fund The respiJatory and criti­ Each year, the chapter one, possibly two, chairs to cal care division is known elects one new faculty mem­ further research into arthritis. for its research in asthma ber and one new alumnus. Mrs. Levin and her husband, and pulmonary obstructive This year, the new faculty the late Sam 1. Levin, were disease and has the largest member is Patricia L. Cole, internationally recognized Gervais D. Smith, M.D. '22 lung transplant program in M.D., assistant professor of philanthropists and art col­ the world. The division di­ medicine and associate dean lectors. They contributed Gervais D. Smith, M.D. rector is Michael J. for student affairs. The new many works of art to muse­ '22, worked as a general Holtzman, M.D. • alumnus is Alan J. ums in Israel and the United practitioner in Bolivar MO Tiefenbrunn, M.D., associate States, including paintings for 66 years. Now 96, he professor of medicine. and sculptures to St. Louis lives in a healthcare faci lity AOA Holds AOA councilor John D. University, Washington Uni­ in Springfield where his wife Banquet Davidson, M.D., coordinated versity and the St. Louis Art of 52 years spends the day the banquet arrangements Museum. with him. She writes that he that included entertainment Mrs. Levin was the "has always been very proud eonard Slatkin, music by a string quartet composed founder of Audrey Levin to be a graduate of Washing­ director and conduc­ of school of medicine stu­ Realtors, a successful real ton University." L tor of the St. Louis dents Jacqueline Hoffman estate firm specializing in Joseph B. Kendis, M.D. Symphony Orchestra, was and Soham Roy from the commercial property. She '33, writes that he retired the featured speaker at the Class of 1995 and Nicole was a member of Washing­ about five years ago and is annual initiation banquet of Willeumier and Adam Eaton ton University's William " living the easy life now," the Washington University from the Class of 1996. Greenleaf Eliot Society. after many years working in

29 ; ,I

r-­I Ii

11 alcoholism and drug abuse Harry E. Lichtwardt, member of the medical staff '60s lind -70s both in private practice and M.D. '43 (December), re­ at Memorial Community ~ at the Hyland Center at St. tired from active practice in Hospital, served on the utili­ Mary Ann Reynolds, Anthony's Hospital in St. urology nine years ago when zation review committee and M.D. '62, retired from pri­ Louis. he was working as chairman the board of trustees. He is a vate practice on December Kenneth M. Amlin, of the Department of Urol­ life member of the hospital's 31 , 1992, Harry Reynolds, M.D. '35, has moved to San ogy at William Beaumont board of governors and has M.D. '60, continues to work Mateo CA after living in Hospital in Royal Oak MI, served as president, vice­ part-time as a locum tenens Arnold CA, at an altitude of one of the 10 largest admit­ president and secretary/trea­ general surgeon. They write 4,000 feet in the Sierra Ne­ ting hospitals in the nation. surer of the medical staffs at that they hope to travel both vada, for 21 years. He writes He serves on the Executive Memorial and St. Marys in the U.S. and abroad. The that he was "tired of being Committee of the American Health Center. couple resides in Turlock snowbound after heavy Urological Association and Lowell A. Gess, M.D. CA. storms." He would like to divides his time between Or­ '51, reports that he "emerged Jim Murdock, M.D. '63, hear from his classmates at chard Lake MI, and Naples unscathed from a military and his wife (Marilyn) and 75 W. 5th Ave., San Mateo FL. He and his wife, coup in Sierra Leone, West children live in Eugene OR CA 94402. Genevieve, also visit their Africa," and planned to do on a small mountain with E. Norris Robertson, three grandchi Idren and two more eye surgery at the Arabian horses, German M.D. '37, sends word that he sons in California and Mon­ Kissy UMC Eye Hospital in shepherd dogs and Siamese and his wife, Mary, have tana. Freetown during January, cats. Jim is active in the sur­ been married for 56 years, James O. Davis, M.D. February and March of this gical community at Sacred residing in Oklahoma since '45, Ph. D., received the Dis­ year. Heart General Hospital and the end of World War II. The tinguished Alumni Award Marvin E. Levin, M.D. keeps up his music, having couple has one son and one from the College of Arts and '51, and Lawrence \V. performed with the Eugene daughter, two grandsons and Sciences at the University of O'Neal, M.D. '46, have just Symphony. The couple has two granddaughters. Missouri on February 19. published the fifth edition of three daughters: Lynn re­ Robertson is engaged in the Davis, who retired in 1982, the text The Diabetic Foot. cently graduated from private practice of ophthal­ worked for many years at the The third editor is John H. Carleton, Elizabeth is a j un­ mology and holds the rank of National Heart Institute and Bowker, M.D., ofthe Uni­ ior at Yale, and Katie is in clinical professor of ophthal­ did research that led to the versity of Miami School of her first year at Sewanee. mology at the University of development of enzyme in­ Medicine. Recently, Levin David L. Dunner, M.D. Oklahoma Health Center. hibitors used in the treatment was a visiting professor in '65, is president of the Soci­ of heart disease. He served Cairo as a guest of the Egyp­ ety of Biological Psychiatry as chainnan of the Depart­ tian Diabetes Care Associa­ 40 and '.50s for 1992-'93. Dunner is pro­ ment of Physiology at the tion. fessor and vice chairman for University of Missouri be­ Philip S. Crossen, M.D. William S. Curtis, M.D. clinical services in the De­ ginning in 1966, and a pro­ '54, has retired from active '40, received the University partment of Psychiatry and fessorship in cardiovascular practice but continues as of Colorado medal at winter Behavioral Sciences at the research is established in his medical director at Planned commencement exercises at University of Washington. name there. Parenthood of Lexington the University of Colorado­ He edited the recent publ ica­ Robert H. Tanner, M.D. KY. He writes, "Doesn't pay Boulder. Curtis is a longtime tion, Current Psychiatric '47, has received the special too well, but it is very satis­ member of the student health Therapy (W.B. Saunders, service award from Memo­ fying, and they don't fire me center medical staff. Co., 1993). His wife; Peggy rial Community Hospital in when we are away for ex­ Roland R. Cross, Jr., Zolbert Dunner, OT '64, Jefferson City MO. The tended time to Michigan in M.D. '40, in November re­ operates an antique jewelry award is presented for out­ summer and Florida in win­ ceived the Stritch Medal business near Seattle. standing service to the hospi­ ter." from Loyola University for David C. Bisno, M.D. tal, the community and the his contributions that include '66, sold his Atlanta ophthal­ surrounding area. A family 23 years on the admissions mology practice in the spring practitioner, Tanner is a committee.

30 of 1992 and has since been the Department of Otolaryn­ Larry L. Mathis, RA aged care at Corona Medical enjoying studying the history gology at Jewish Hospital in '72, is president and chief Center in Corona CA. of science at Dartmouth Col­ Cincinnati. He also was executive officer of The Rose J. (Catron) Flynn, lege and Harvard University. elected recently to the Coun­ Methodist Hospital System NU '51, retired at the end of He reports that his daughter cil of the Cincinnati Acad­ and its 10 member corpora­ January fr0111 the Baptist is an "aspiring, although un­ emy of Medicine. tions, including The Method­ Memorial Hospital System employed," actress, and his John S. Spratt, M.D., ist Hospital, a 1,527-bed in San Antonio TX, after son is a third-year rabbinical FHS in surgery, is a Naval tertiary care, education and working there for 21 years. student. Reserve captain and a clini­ research facility located in She says her plans are in­ Steven B. Raffin, M.D. cal professor of surgery at the Texas Medical Center in definite, but that she and her '68, wrote a chapter for the the Uniformed Services Uni­ Houston. He is chairman­ husband have lots to keep 16th edition of the Merck versity for the Health Sci­ elect of the board of trustees them busy, including enjoy­ Manual. ences in Bethesda MD. He of the American Hospital ing their grandchildren. Charles L. Rich, M.D. recently attended the annual Association. Healtlzweek Martha Sue Sublette '69, has assumed the posi­ meeting and luncheon of tile magazine named him one of Birk, OT '33, has lived and tion of chairperson of the editorial advisory board and 25 top multi, alLiance and worked in Decatur lL since Department of Psychiatry at reviewers for the joumal buying group executives in she married Carl P. Birk, the Univcrsity of South Ala­ Military Medicine. the nation, and Business M.D. '34, who practiced bama. His previous position Fremont P. Wirth, M.D., Week named him one of the medicine there for 51 years. was with the State Univer­ FRS in neurosurgery, has five best managers in non­ The couple raised three chil­ sity of New York at Stony been appointed a director of profit health services in the dren and repOits that many Brook. He also is editor-in­ the American Board ofNeu­ U.S. members of their extended chief of the Annals ofClini­ rological Surgcons. The 14­ family are Washington Uni­ cal Psychiatf)' and was listed member board, organized in versity alumni. recently in the book, The 1940, is the certifying board Anne Rothstein Ander­ Best Doctors in America. for neurosurgeons in the son, OT '77, her husband, United States. Wirth prac­ Jim, and her son, Paul, live '80s tices in Savannah GA, where in the shadow of Yosemite's he currently serves as secre­ high peaks in Sonora CA. tary of the Georgia Medical Anne owns and operates a Wilfred G. Ellis, M.D. Society. small therapy practice spe­ '82, has been awarded the cializing in geriatric rehabili­ AIDS Service A ward from tation. the State of Ohio for 1992. o T H E R Mrs. George Basinger, Ellis has been an advocate PT '53, has completed 15 for his patients and commit­ years as the director of ted to the local AIDS Task physical therapy at the East Force, as well as being an Calvin R. Robinson, HA '76 Texas Medical Center ­ early supporter of the Ryan Pittsburg. She continues to White initiative. He is chair­ Calvin R. Robinson, HA serve the East Texas Re­ man of infectious diseases at '76, has been appointed to gional Healthcare System by the St. Rita 's Medical Center the position of vice president extending its physical in Lima OH. of operations for Meridia therapy service to many Huron Hospital in Cleve­ other northeast Texas medi­ FORMEH HOUSE land. He resides in Cleveland cal facilities. T A F F Heights. Jim Humphrey, RA '87, Robert Maltz, M.D., and his wife, Loraine, are FRS in otolaryngology, has expecting their first child in Larry L. Mathis, HA '72 been appointed director of May. Jim is director of man­ :I

31 ~ IN ME~fORIAM ciety of CI inical Investiga­ Melson was a member of vivors are his wife, Brenda, tion. Later, he moved to the the medical school faculty one daughter, two sons, his William J. Harrington, University of Miami, where for 20 years. He was highly mother, and a sister. M.D., former director of the he founded the Center for respected for his work as a Jack R. Rhodes, M.D. division of hematology here Blood Diseases, became the teacher and clinician, as well '45, died November 2 of and an internationally re­ chairman of the Department as for his research on ab­ natural causes in Sheridan nowned blood specialist who of Medicine and founded the dominal ultrasound imaging. WY, while he was attending made major discoverics Ph.D.IM.D. program. For 25 Melson received his a building dedication at the about the mechanisms of years, he worked to improve medical degree from Wash­ Sheridan Veterans Affairs blood disorders from experi­ medical education in Latin ington University in 1965 Medical Center. He was 71. ments he performed on him­ America, and he made house and joined the faculty in Rhodes began his general self, died at his home in calls for as long as he prac­ 1972 as an instructor at the surgery practice in Sheridan Miami in October. He was ticcd. Harrington earned one School of Medicine's in 1953 and served 30 years 68 years old. of 70 Mastership awards Mallinckrodt Institute of Ra­ on the staff of Memorial Harrington apparently ever granted among the diology. He became chief of Hospital there, including died while repairing a gen­ 60,000 members of the the clinical ultrasound divi­ holding the post of chief of erator outside his home that American College of Physi­ sion in 1977 and a full pro­ staff. Rhodes closed his had been without electricity clans. fessor in 1983. practice in 1983, joining the and running water since Hur­ He is survived by his He received several hon­ staff at Sheridan V A Medi­ ricane Andrew hit the area wife, Mary, a daughter, three ors during his career, includ­ cal Center. He retired earlier the week before. sons and four grandchildren. ing being named a member in 1992. M.K. King, M.D., Robert A. Huckstep, of the medical honorary so­ Rhodes was active in Boy Danforth Professor of Pre­ M.D. '48, died on November ciety Alpha Omega Alpha Scouts, his church and fra­ ventive Medicine and former 28, 1992, at his home in and a fellow of the American temal and professional orga­ dean of the medical school, Farmington MO. He was 71 College of Radiology. In nizations. He was an avid says Harrington "was Carl years old. A community 1989, he was recognized by fisherman and traveler and Moore's greatest pupil." leader in Farmington, the St. Louis Metro Area had just retumed from a trip Both men performed experi­ Huckstep had been commit­ Sonographers for his contri­ to England, Scotland and ments on themselves in the ted to education and had butions to the field of ultra­ Ireland. H is sudden death interest of advancing medi­ served on the local board of sound. came as a shock. Survivors cal knowledge. In 1950, education and the board of He published more than include his wife, Mary Eliza­ Harrington discovered that a trustees of Mineral Area 50 scientific journal and beth, two daughters, five substance in the blood of ColJege for 15 years. He had textbook articles and was an sons, a sister and 13 grand­ individuals with idiopathic been instrumental in the active member of several children . • thrombocytopenia purpura building of Farmington professional societies. He (ITP) destroyed their plate­ Community Hospital. served on the Missouri Ra­ Cal FOI' ~' ~ lets. He made the discovery Though he had ofticially re­ diological Society board of Nt by injecting a pint of an lTP tired, he continued to work directors, as vice president part-time at Medical Arts of Alpha Omega Alpha's M embNS of the patient's blood into himself. medical school Clinic in Farmington. local chapter at Washington Almost immediately, his community with Among his survivors are University and as a past own platelet count dropped. news for their colleagues are his wife, Mary, two sons, president of the Greater St. He was admitted to Barnes invited to send a note to one daughter, one brother Louis Society of Radiolo­ Hospital where, within a Ruth Bebermeyer, Medical and three grandchildren. gists. He also served on a week, his platelet count re­ Alumni and Development G. Leland Melson, M.D. consensus-development turned to normal, showing Office, Box 8049, 660 S. '65, professor of radiology, panel for the National Insti­ that the factor that caused Euclid, St. Louis MO 631 10. died of cancer on November tutes of Health. ITP was in the blood. Please include mention of 10 at his home in Glendale A memorial service was At age 28, he became the the variety and date of your MO. He was 53. held November 13 at Salem youngest member ever affiliation . • elected to the American So­ United Methodist Church in Ladue. Among Melson's SUf­

32 -[ All awards IUllcheoll was held in the King Center on December 8, 1992, to recognize out­ standing achievements by students in the 1991-'92 academic year. Nancy E. MacDonald received the CIBA-Geigy Award for Community Service and was presented with the complete CIBA Collection of Medical Illustrations prepared by Frank H. Netter, M.D. CIBA's Kevin Clark made the presentation. Honored along with MacDonald were medical students Michele L. Francoeur, Timothy J. McCulley, Lawrence S. KaskO\,vitz, Michael E. Ohl, William L. Lyons, Jennifer L. Paterson, Scott M. Pinter, Corina Jo Norrbom, Catherine Bradley, Stephanie B. Cox, Ryland E. Melford, Korwyn L. Williams, Marianne Ingels, Martha S. Terry, Mathias J. Kill, Lynne M. Champagne, Mark A. Koler and Tamara L. Densmore. School of Medicine

Campus Box 8065 660 S. Euclid Ave. St. Louis, MO 63110-1093

The birth ofRaja at the St. Louis Zoo on Sunday, December 27, was assisted by staff in the endocrine laboratory of the Department of Obstetrits and Gynecol­ ogy. Several elephant births in recent years have been complicated because zoo staff could not know exactly when the calf was due. But Janet Willand, Alice Hightower and Tonj Broeker of the lab tested the serum progesterone levels of Pearl, the mother elephant, regularly. And on Saturday, the 26th, when Pearl's progesterone level dropped from the 500-600 picograms per milliliter it had averaged to I! 9 picograms, Hightower alerted zoo veterinarians that the birth was imminent. Pearl was then monitored closely, and her early signs of labor were detected. Raja has captured the city's affection.