Ellison Institute poisedfor preeminence

Matrix UC DavisSchool of Medicineand Medical Center

Volume 4 • Number 5 August 1997

Also in this issue:Page 3One-stop shopping

Page 5The mysteries of tissueregeneration

Page 6Cartilage implants forknee injuries

Page 7Cartilage transplants

Page 8New neurosurgery chair

Page 10Implantable pump forchronic spasticity

In the Silicon Valley, Lawrence J. Ellison foundeverything he needed to build a new software ideainto a Fortune 500 company. But when the self-made computer billionaire shattered his left elbow ina 1992 bicycle accident, he had to go to the CentralValley to find a surgeon with the skill to repair it.

At UC Davis Medical Center, Department ofOrthopaedics Chair Michael W. Chapman recon-structed Ellison’s elbow in a series of two operations,restoring the badly fractured joint to full function.When Ellison, 52, recently challenged world-classtriathlete Peter Kain, 32, to a “bar dip” contest tobenefit a charity, Ellison won. He did 49 of thepushup-like exercises to Kain’s 40.

“All the king’s horses and all the king’s mencouldn’t put Humpty together again,” a gratefulEllison said after his final operation. “But MikeChapman could. And did.”

Ellison, co-founder and chief executive officer ofOracle Corporation, expressed his thanks with a $5million gift to support musculoskeletal programs atthe UC Davis School of Medicine and Medical Center.The gift, matched by a $1.3 million UC Davis HealthSystem contribution, represents the largest single pri-vate bequest in the institution’s history.

“I wanted to make the art and science of MikeChapman and his colleagues generally available, in-stead of available only to the few,” Ellison said inannouncing his 1994 bequest. “I wanted more peopleto be able to benefit.”

They soon will. The Lawrence J. EllisonNeuromusculoskeletal Institute, a newly designatedUC Davis Health System Center of Excellence, is evolv-ing into one of the preeminent clinical and researchcenters for connective tissue disorders in the world.The Institute brings together under a single umbrellapatient care and research programs within severaldepartments, including orthopaedics, physical medi-cine and rehabilitation, neurology and neurosurgery,radiology and nuclear medicine. In addition, Institute

(continued on page 2)

clinicians and investigators will coordinate theirefforts with other departments that pursue muscu-loskeletal research, including the VeterinaryOrthopaedic Research Laboratory, the Otolaryngol-ogy Research Laboratory, the Division of MaterialsScience, the Biomedical Engineering GraduateGroup and the Departments of Physical Education,Civil Engineering and Mechanical and AeronauticalEngineering.

“Combined with the resources of the MedicalCenter, the new Shriners Hospital, the School ofMedicine, other centers on the Davis campus andthe UC Davis Orthopaedic Research Laboratories,

After a full recovery from a shattered elbow, computer billionaireLarry Ellison (far right) beat triathlete Peter Kain (middle) and JimMacLaren in a charity weight lifting contest.

UC Davis Matrix

2

Connective tissue research, repair a focus(from page 1)

the Institute should eventuallyprovide us with the biggestcritical mass of investigators inthe molecular and cellular biologyof connective tissues anywhere inthe world,” Chapman said.

The Institute will specialize notonly in orthopaedic problems likeEllison’s shattered elbow, but alsoin muscular and neurologic disor-ders stemming from such diseasesas cerebral palsy, multiple sclerosisand stroke.

“We’re excited about it,” saidRalph Johnson, acting chair of thenew Center of Excellence. “It willbring together the competence ofthose departments and specialistswho care for neuromuscular andmusculoskeletal disease, providecomprehensive care to patients andoffer both new research opportuni-ties and new opportunities for evalu-ation of treatment outcomes.”

Three new endowed chairs con-stitute the centerpiece of the Insti-tute. The Lawrence J. Ellison Chairin Musculoskeletal MolecularBiology, assumed April 1 by A. HariReddi, is endowed with $2.7million from the Ellison bequestand $500,000 in UC Davis HealthSystem matching funds.

The other chairs will beactivated when the ribbon is cutnext summer on The Lawrence J.Ellison Ambulatory Care Center. TheDavid Linn Chair in OrthopaedicSurgery, named for Ellisons brother-in-law,will support the Chair of the Department of Ortho-paedics. Its endowment includes $1.3 million fromthe Ellison gift and $300,000 in Health Systemmatching funds. The Doris Ellison Linn Chair inBone Biology, named for Ellisons sister, will supportresearch at the Orthopaedic Research Laboratories. Itcarries a $1 million endowment from the Ellison gift.

Rather than paying the salaries of incumbentfaculty who assume the chairs, the David Linn andDoris Ellison Linn endowments will be used tosupport additional post-doctoral fellows, graduatestudents, technicians, equipment and supplies inorthopaedic research.

R. Bruce Martin, director of the OrthopaedicResearch Laboratories, predicts the endowment

funds will elevate the lab “to thefirst rank of such laboratories inthe world.” The lab’s primaryfocus has been trying tounderstand how bone, cartilage,tendon and ligament cellscontinually renew and repairthemselves as they adapt to thechanging demands of dailyactivities.

Once this fundamentalmystery has been solved,investigators will have a means ofhealing and preventing connec-tive tissue diseases, from arthritisto osteoporosis. “Ultimately wemay learn to reconstruct theskeleton biologically rather thanwith carpentry,” Martin said.

It took master carpentry torepair Ellison’s bicycle injury.The software magnate suffered anintraarticular T-type supracondy-lar fracture of the humerus,complicated by loss of motion inthe elbow.

Ellison’s Bay Area orthopae-dist, a member of a prominentsports medicine practice thatprovides team physicians for theSan Francisco 49ers, promptlyreferred the complicated injuryto Chapman, an internationallyrenowned traumatologist.

In one operation, Chapmanfixed the fracture with plates andscrews. In a second surgery, heremoved the hardware and

performed a soft tissue release that restored thejoint’s function.

“He got essentially a perfect result — an almostunheard-of outcome,” Chapman said, attributingEllison’s spectacular recovery in large measure toEllison himself. The same drive and determinationthat took Ellison to the top of the software businesscarried him through the painful, months’-longrehabilitation process. During that ordeal, Ellisonfirst proposed making a gift to the Department ofOrthopaedics.

Ellison has a history of backing winning ideas.Born in New York City and raised in a tenement onChicago’s South Side, the son of Russian Jewish

“Thanks to this gift,

we have the potential

within 10 years of

having a research

program in musculo-

skeletal and neuro-

muscular biology here

at Davis that will be

unmatched. It will

make available to the

citizens of our region a

level of care that is

unparalleled and

provide them with

access to the most

recent advances as they

come along.”

New clinicalprograms

TheNeuromusculoskeletalCenter of Excellence willencompass at least 16separate clinical programs.

The programs will behoused together in theLawrence J. EllisonAmbulatory Care Center, dueto open next summer. Theiraims will be to increasecommunication andcollaboration among thevaried specialists who treat aparticular disease or disorder;to streamline patientreferrals and care; and tofacilitate comprehensive,prospective outcomes studies.

“Patients now have togo to one place for one thingand another place for anotherthing, requiring multipleappointments and inhibitinginterdisciplinary communica-tion among treatingphysicians,” said center chairRalph Johnson.

“This can be resolved byhaving a program with acoordinator who can bring itall together, and by housingservices in a single buildingso that the patient comes toone place for a thoroughevaluation and treatment.”

The Spine Care Program,which opened May 1, wasthe first to begin seeingpatients under the aegis ofthe new Center of Excellence.Southern California spinesurgeon Munish Gupta hasbeen recruited to head theprogram. According toJohnson, the program willbring together surgical andnonsurgical health profes-sionals skilled in thediagnosis and treatment of abroad spectrum of spine

(continued on page 9)

3

August 1997

New building centralizes multispecialty careFor patients seeking care at UC Davis MedicalCenter, the Lawrence J. Ellison Ambulatory CareCenter will mean one-stop shopping for services thatnow require visits to multiple office sites alongStockton Boulevard. For physicians and researchers,the shared space will mean new opportunities forinterdisciplinary collaboration. And for the UCDavis Health System, the building will mean a morecost-effective alternative to expensive leased office space.

The four-story, 375,000-square-foot building isrising along 48th Street on the eastern edge of themedical center’s 140-acre Sacramento campus.When completed next July, the $81.2 millionbuilding and its 124 exam rooms will accommodateup to 806 patients a day — about 70 percent of allambulatory patients seen at the medical center.

The expansive facility will also house 250 facultyoffices, a visitors cafeteria and an employee food serviceoperation. A new freestanding parking structure, con-nected to the building by a landscaped breezeway, willprovide convenient parking for 800 cars.

“The Lawrence J. Ellison Ambulatory CareCenter is the culmination of the Neuro-musculoskeletal Center of Excellence,” said CenterDirector Ralph Johnson. “It will bring together allthose departments that deal with neuromuscularand musculoskeletal problems in the same buildingfor clinical evaluation, imaging studies andtreatment.”

Occupying the basement floor will be the neurol-ogy and neurosurgery clinics; the cardiac rehabilita-tion and car-diology clin-ics; and animaging cen-ter. On thefirst floor willbe ortho-p a e d i c s ;p h y s i c a lmedicine andrehabilitation;occupationaland physicaltherapy; in-door therapypools; anorthotics labo-ratory; familypractice; theremainder ofthe imagingcenter and apharmacy.

The sec-ond floor will

house special procedures and pain clinics; obstet-rics and gynecology; ophthalmology; dermatology;urology; plastic surgery; and academic offices forthe departments of obstetrics and gynecology,ophthalmology and family practice. The top floorwill be home to an Alzheimer’s disease clinic andacademic offices for faculty in orthopaedics,physical medicine and rehabilitation, neurology andneurosurgery, pain management, urology, derma-tology and radiology.

The building also will feature an outdoorwheelchair PAR course designed to teach patientsin wheelchairs to negotiate sand, gravel, smallbridges and other everyday obstacles.

Named for Oracle Corporation chairman andchief executive officer Lawrence J. Ellison, a formerpatient and major benefactor, the building is part ofa long-range development plan adopted by the UCRegents in 1989.

“The Ellison Ambulatory Care Center is goingto change the way we do business,” said RayGroom, manager of medical sciences planning. “Apatient will be able to see a physician, get an X-rayor other radiographic diagnostic procedure, fill aprescription and have lunch without ever leavingthe building. Literally everything they need will beright there.”UCD

problems, from fibromyalgiato workers’ compensationinjuries.

An arthritis and totaljoint replacement program willbe the Center’s second majorpriority, Johnson said. Othertop priorities are programs instroke treatment and sportsmedicine.

A trauma/vascularsurgery program will beheaded by Paul Muizelaar,new chair of the Departmentof Neurological Surgery and anationally recognized vascularsurgeon. Muizelaar is bringingUC Davis to the forefront ofresearch into ways to improvethe outcomes of people withtraumatic brain injury.

Plans are also underwayfor an anesthesiology/chronicpain management programand a spasticity managementprogram for patients whosuffer from chronic, debilitat-ing muscle spasms due tostroke, cerebral palsy,multiple sclerosis and a widerange of other injuries anddisorders. Available therapiesfor these patients includetendon-lengthening surgeryand use of an implantablepump to deliver baclofen, adrug that inhibits ungovernedmuscle reflexes.

Johnson is meeting witha committee to identify otherclinical programs that may bedeveloped within the Centerof Excellence. Ultimately, theCenter may encompass asmany as 30 programs.

The Lawrence J. Ellison Institute will open in July 1998.

UC Davis Matrix

4

New Ellison Chair studies themysteries of tissue regenerationThis story begins with a mystery. In 1965, UCLAsurgeon Marshall Urist ground up rabbit bones anddemineralized them in acid so that only powderremained. When Urist sprinkled the powder into themuscle of a living rabbit, the unexpected happend:new bone started to grow in the muscle tissue.

What was it about the bone powder that couldcause muscle tissue to become new bone? Forscience to be able to take practical advantage of thiswonder, someone would have to isolate the specificfactor or factors that caused bone to grow.

Finding the answer would take nearly twentyyears. And it would deliver into the hands of sciencean unprecedented power: to regenerate bone andlearn the secrets of tissue formation.

The solution of this mystery story has A. HariReddi at its center. Reddi, the holder of the newLawrence J. Ellison Chair in Molecular Biology atthe UC Davis School of Medicine and MedicalCenter, is not the only one who helped solvethe mystery. Science is additive and collaborative.But the contributions of Reddi, who comes to UCDavis from an endowed chair at Johns Hopkins,were pivotal.

In his laboratory at Johns Hopkins, and beforethat at the National Institutes of Health, Reddistruggled with the implications of Urist’s results.Reddi persisted at a time in the 1970s and early1980s when most other scientists had lost interest inwhat they considered a hopeless quest.

“He kept the field alive,” said Vicky Rosen, abiochemist at Genetics Institute, a biotechnology

company based in Cambridge , Mass. Ultimately,the solution would come from the biotechnologyindustry, but not before Reddi and his colleagues hadsqueezed clues from the dry bones — clues thatwould later allow him to embark on an ambitiousprogram of tissue engineering.

In any mystery story, the person at the centerhas to find his way to the action . In Reddi’s case, thejourney was particularly long. It began in Madras, inthe dusty southern part of India, far to the south ofDelhi. Already as a student at Annamalai Universityin the isolated town of Annamalainagar, 100 milessouth of Madras, Reddi knew that he wanted to doresearch in the United States.

“There was very good research in Madras atthe time,” Reddi said. “But it wasn’t enough. So Idecided to travel 1,000 miles to pursue scientificstudies at the graduate level in Delhi. Such thingswere almost never done,” he said.

Reddi advanced by learning from a series ofsuccessful mentors. His graduate advisor, M.R.N.Prasad, had done research in Wisconsin. “Heencouraged me to work independently,” in contrastto the more hierarchical style then in vogue in Indianuniversities.

Reddi’s independent thinking paid off. One ofthe readers of Reddi’s dissertation, H.G. Williams-Ashman of Johns Hopkins University,recommended Reddi for the distinction of magna cumlaude. Soon Reddi was on the way to Williams-Ashman’s laboratory for post-doctoral work.

What came next was the move that put Reddi inthe right place at the right time for addressing themystery. In 1969, Williams-Ashman moved to theUniversity of Chicago and Reddi joined him. Downthe hall from their lab was Charles Huggins,a powerhouse of biochemistry, who was to winthe 1966 Nobel Prize for his work in understandingthe endocrine regulation of prostate cancer. Trained asa surgeon, Huggin’s rapacious intellect kept bringingnew questions and new collaborators into hislaboratory. Urist had been a student of Huggins’, backin the 1940s, and Reddi would join him.

“But I already have a firm offer to go to Harvardand to return to India after that,” Reddi recalledtelling him. But Huggins immediately picked up thephone and dialed Reddi’s erstwhile mentor atHarvard, saying, “He’s not coming!”

“It was a decision that changed my life and myfocus of research,” he said.

Huggins had planted the seed for Urist’s workmany years earlier, when he implanted a canine toothfragment into the abdomen of a dog and showed thatA. Hari Reddi, I

5

August 1997

The experience of

isolating bone induction

factors gave Reddi

unique insight into

tissue formation. In

some ways, bone is an

unusual tissue but in

other ways it is typical.

new bone formed there. But themystery was even more bafflingthen than it would become thirtyyears later.

Years passed. Reddi became aprofessor at University of Chicago,then accepted an offer to become avisiting scientist at NIH inBethesda. Reddi had successes inother areas, especially in character-izing the roles of specific proteinsin expanding bones that alreadyexisted.

But all along, he rememberedHuggins’ challenge: Whatproperty of the bone powder —or the dog’s tooth — was acting like an inducer,causing bone to grow in muscle or abdomen?

Night after night, month after month, Reddiwent after the elusive “bone induction factor.” Hisformer post-doctoral fellow Kuber Sampathremembers seeing all the notebooks in Reddi’s NIHlaboratory. “Reddi had spent a lot of time lookingfor these factors,” recalled Sampath, now a seniorresearch director at Creative Biomolecules, abiotechnology company inHopkinton, Massachusetts.

Part of the difficulty was in not knowing if asingle factor was there to be found. Looking for abone induction factor was “an orphan project” atthat time, said Rosen. “No one even believed thatthere was a factor. They thought it was a mixture ofthings.”

Another problem lay in the nature of bone.Reddi’s approach is what he calls classic “grind andfind” biochemistry. It involved taking the tissue inquestion , grinding it up and then sifting through itlooking for the activity, in this case, bone induc-tion. In the days before cloning and sequencing ofhuman genes, grind and find was about the onlyoption available.

But it did not work very well on bones. It wasdifficult both to find potential factors and then tosee what effects they had. Finding factors was hardbecause the scientists had to be so harsh inextracting them — how could they be sure that theacid bath that degradated the bone was not alsoirreversibly altering the factor?

Observing the effects was difficult because ofthe challenge involved in putting bone cells intissue culture. Most cells could be induced to growin a somewhat normal manner in a tissue culturedish, even though they were outside of their

normal environment. But successin bone tissue culture meant thatbone cells would begin to calcifyto the bottom of the dish,limiting their own growth. Thatmade it even more difficult todetermine what had caused thecells to grow.

Another obstacle, one thathad stymied Urist, was that hedid not have a reliable assay forquantifying bone growth. Thekey to “grind and find” layin knowing what one has found,said Reddi. But the assayproblem seemed insurmountable.

When Kuber Sampath told Reddi he wanted towork on finding “bone induction factor,” Reddi triedto dissuade him. “Maybe you’d like to think it over,”Reddi said. “You might not get any publications.”But Sampath persisted and ultimately succeeded atwinning Reddi’s support.

Sampath’s presence reinvigorated the search forthe mystery factor. He also brought new methodsand new ideas from his background as a proteinbiochemist. It was a true collaboration, Sampathrecalled, free of the usual hierarchy. “Hari neveracted as a senior person,” a superior, said Sampath.Instead, Sampath and Reddi would talk on theverandah outside Reddi’s NIH office.

Over the next five years, “we developed a bonafide assay that reflects bone formation,” recalledReddi with pride. The assay, which is still in wideuse, involves implanting a pellet with the mixture tobe tested beneath the skin of a rat. In a few days, ifthe test mixture is active, progenitor cells migrate tothe area and bone begins to form. Twelve days later,the implant is removed and the effect of the testmixture is quantified — the key to a scientific assay— by two different measures.

With the assay problem solved, it was time tofind the bone induction factor or factors. Unfortu-nately, the amounts of the active substances were sosmall that they could not be used to characterize themolecule. “It would have cost too much money,”said Sampath. “We would have had to extract thesubstances from twenty kilograms of bone everyweek, and the chemicals we used wereexpensive.” In the end, he recalled, it cost tens ofmillions of dollars to isolate the gene.

That’s where biotechnology companies stepped

A. Hari Reddi was recentlyawarded the Urist awardfrom the ....(more TK).

(continued on page 12)

UC Davis Matrix

6

Cartilage implants offer treatmentfor arthritic knee injuriesThe talk is generally called “The middle-agedarthritic knee.” It ‘s not exactly an award-winningtitle, but year after year, overflow crowds pack alecture on this topic at the American Academy ofOrthopedic Surgeons’ annual meeting to hear aboutthe latest treatment options.

“The problem is that we see arthritic kneesevery day, and there is no single treatment that is asgood as we would like it to be,” said Juan J. Rodrigo,professor of orthopaedics at UC Davis School ofMedicine and Medical Center.

Knee problems in the United States are reachingepidemic proportions. In 1994, the last year thatstatistics are available, orthopedic surgeons in theUnited States performed 311,000 knee surgeries, anincrease of nearly 50 percent from four years earlier.Hips and shoulders present similar problems and areresponsible for increases in the number of surgerieson the three joints, which totaled 649,000 in 1994.

Given that there is no “one-size-fits-all” treat-ment, a medical center like UC Davis does the bestfor its patients by offering every available option, saidRodrigo. “We treat patients who are experiencing theearly stages of arthritis as well as 90-year-olds whoneed end-stage treatment revisions.”

Most of the treatments involve cartilage becausewhile bone heals, cartilage doesn’t. Made up of longstrands of water-cushioned collagen protein,cartilage is a slippery shock absorber for the bangsand bumps of life. But sometimes it is torn off, as byan injury. Or it can rub away due to arthritis oreveryday wear and tear. A long, painful slide intoimmobility often results.

In an ideal world, physicians would augmentworn or missing cartilage with more cartilagethrough transplantation or regrowth. And that isjust the way the medical profession is moving. Thetrend is toward “true biological replacements,” saidRodrigo. “They offer the potential for remodelingand healing.”

But until recently, the treatment of choice formany patients — especially those 45 years old andup — has been to replace the entire joint with ametal or plastic prosthesis. With the appropriaterehabilitation program, recovery time is quick, saidRodrigo — in as little as three months, patients canresume many of their previous activities. Theprostheses can last as long as 20 years.

However, knee and hip replacements have theirdrawbacks as well. The joints can fail, they can wearout and they can wiggle loose from their moorings.Worse still, said Rodrigo, replacement joints almostinevitably destroy bone and often cause infection. A

second replacement has to be larger for surgeons tobe able to fuse it to healthy bone. And the largerimplant then reduces the patient’s mobility evenfurther.

When patients are younger than 45, andespecially if the problem is caused by a recent injury,Rodrigo typically turns to one of the “biological”treatments — a procedure known as debridementand microfracture (D&M), which could just as wellbe called “scrape and tap.”

The advantage of D&M is that it provides anopportunity for the patient’s own cartilage to fill inthe gaps. With the aid of a viewing device insertedthrough a periscope-like arthroscope, Rodrigoremoves any remnants of cartilage and debrides thebone with a sharp blade. He then uses a secondarthroscope to insert needle-like awls with adiameter no thicker than the width of a dime. Heuses the awls, which look like tiny ice picks, to pokeholes into the bone down to the marrow. Afterpunching 20 to 30 holes, he closes the incision andthe real work begins — by the patient throughrehabilitation.

But where does the cartilage come from? Itgrows by itself, said Rodrigo, from precursor cellsthat ooze from the bone marrow onto the scrapedbone surface. Over time, the precursor cells turninto “fibrocartilage,” a replacement tissue that is“not exactly the same as native cartilage but servesthe same purpose,” he said.

The advantages of the procedure are simple.“We are just regrowing a tissue that would other-wise not grow,” he said. The success rate for thisprocedure, which is performed around the country,is about 80 percent. Success is defined as a return offunction to within 10 percent to 20 percent of whatit was before injury. Compared to the typical 50percent reduction of function in patients when theycome in for treatment, it is a significant improve-ment.

But D&M has some drawbacks too. The failurerate for regrown cartilage is high — 20 percent to 25percent in 10 years.

Consequently, many groups are attempting toimprove on cartilage regrowth. One of the mostadvanced efforts, which is being performed on anexperimental basis at UC Davis, takes the patient’sown cartilage cells and multiplies them in alaboratory before re-implanting as many as thirtymillion cells several weeks later.

The treatment, which was first used in Sweden10 years ago, has a reported success rate of 88percent in treating knee injuries involving cartilage

7

August 1997

damage. It is used only for injuries, not arthritis.Genzyme Corporation of Cambridge, Massachusetts,licensed the technique from its Swedish inventorand is in the process of training 1,500 U.S. surgeons— including Rodrigo — to do the procedure.

Despite the high cost — $30,000, which is morethan the price for knee replacement or for D&M —Rodrigo sees the procedure as “a major stepforward” that could ultimately replace D&M incertain patients. Currently, cartilage regrowth andreplacement are offered only if other treatments fail.But Rodrigo is involved in studies to see if it couldbecome the treatment of choice.

Ever since 1915, cartilage transplantation has beena tantalizing — and ultimately elusive — goal.

“Success rates have improved steadily,” saidorthopaedic surgeon Juan J. Rodrigo, “but theability to take cartilage from a recently deceasedyoung person and transplant it into a recipient —usually a trauma victim — is far from a standardprocedure. The current success rate is 75 percent to80 percent; but surgeons like to see 90 percent.”

Rodrigo has performed more than 20 cartilagetransplants since coming to UC Davis in 19XX.This is more than most of his colleagues at otheruniversities. But the real promise of his programlies in his research lab. There, Rodrigo and hiscolleagues have been working on breaking downthe barriers to routine transplantation and over-coming them one by one.

The initial hurdle facing cartilage transplantwas simple: a lack of antibiotics, which kept thefailure rate as high as 50 percent, primarily due toinfection. After World War II, antibiotic drugsappeared as did a reliable tissue bank — courtesyof the U.S. Navy. Success rates shot up close towhere they are now.

Since then, Rodrigo and his colleagues havebeen struggling with what may be the final barrier:an aggressive immune response. As happens whenother organs are implanted, the recipient’simmune system often puts up a spirited fightagainst the donated tissue, which it perceives as an“intruder.” In animal experiments, Rodrigoattempted to reduce this with immune-suppres-sant drugs. “They eliminated rejection, all right,”said Rodrigo. The problem was, they were also

toxic, sometimes fatally so. “You wouldn’t want todo a knee joint implantation and then have yourpatients die from complications from a drug.”

So he began working on other methods.Suspecting that cartilage itself is not the perceived“intruder,” but rather the bits of bone tissue thatcling to it, he began looking for ways to make thedonated tissue “invisible” to the recipient’s immunesystem.

Strangely enough, a cousin of ordinary house-hold detergent may be the answer. Using a labora-tory detergent called “Triton-X,” Rodrigo hassucceeded at shrinking the immune response of therecipient animals. The detergent partially digests thebone cells and makes them seem less of a threat;detergent damage. “The cartilage cells are hidden toa certain extent,” he said.

It will take a good two years before human trialscan begin. Before that, Rodrigo and his colleagueswill have to make sure that any detergent that clingsto the cartilage implants is not toxic to humanpatients. Furthermore, he will have to be careful thatthe implanted mixture of cartilage and partlydigested bone cells retains its desirable properties,such as their ability to bond to the existing bone andcartilage. “ Adding detergent might change thehealing properties of the implant,” said Rodrigo. Justlike toxic immune-suppressant drugs, “You mightget rid of one problem and give yourself another.”

Rodrigo likens his cartilage transplant project toa quest for a magic elixir that will help him createthe ideal transplant material.

“I’ve been looking for 25 years,” he adds with alaugh, “and I haven’t found it yet.” UCD

Despite 10 years of promising data, theGenzyme procedure remains controversial. Physi-cians at the last Academy meeting wonderedwhether cell reimplantation would survive the testof time. They wanted to see more evidence fromcontrolled studies demonstrating the procedure’susefulness. The Academy itself stated that thetechnique remains unproven and long-term resultsare unknown.

Still, Rodrigo is optimistic that the procedurewill find its place among the treatments UC Davis

Cartilage transplants remain a focus of research

(continued on page 12)

UC Davis Matrix

8

Jan Paul Muizelaar is infectiously enthusiastic. Hespeaks quickly and decisively about his plans for theDepartment of Neurological Surgery while sprinklinghis conversation with a generous amount of easy-goinghumor.

A nationally recognized expert in vascularsurgery, head injury and trauma, he was appointedprofessor and chair in May. He was attracted to UCDavis because the teaching hospital has such a highvolume of trauma patients.

Muizelaar has already initiated importantchanges. The ICU is being equipped with specialcomputers to monitor head injury patients and anew digital holography machine — one of only sixin the nation — is on order to help surgeons imageprocedures before operating. To improve theresidency training program, he plans to combineneurosurgery conferences with those at University ofCalifornia, San Francisco and Stanford, therebyincreasing the residents’ exposure to cases andtreatment plans and broadening their areas ofdiscussion.

“Resident training is my first priority,”Muizelaar said. “In many ways the combinedconferences will serve as mock oral boards. Forinstance, UCSF’s center would present their cases to

Neurosurgery chair specializes intreating traumatic brain injury

our residents who would then decide what kind ofX-rays should be made. X-rays taken previouslywould be shown and the residents would have toexplain what they see and then come up with atreatment plan and

an alternative plan. The process will help themthink through cases in an organized fashion underthe guidance of experienced people who will try totrip them up,” he quipped.

Under Muizelaar’s leadership, residents also willbe exposed to a number of clinical trials. He is onthe forefront of new treatments for stroke and headinjury.

He is the principal investigator for an interna-tional phase III clinical trial of a pre-synapticcalcium channel blocker in severe head injurypatients. The drug has shown promising preliminaryresults, appearing to protect against insufficientblood flow while normalizing metabolism in theinjured brain.

“I am working on a paper showing that theneuropsychological outcome after severe head injuryin rats is much improved with this drug,” Muizelaarsaid. “Motor function, memory and learningcapabilities are quite severely disturbed for 1 to 8weeks after experimental head injury in rats. But this

drug improves all of theseproblems considerably, and it isthe only drug that can be givenfairly late, up to 3 hours in rats,which equates to 20 hours afterinjury in humans.”

Muizelaar is planning amulticenter, placebo-controlledclinical trial of the drug incomatose patients with severetrauma to determine whetherCI1009 will improve outcomes.

He also is scientific advisorto a large, multicenter clinicaltrial of hypothermia in patientswith severe head injuries. Lednationally by the University ofTexas, Houston, UC Davis willbe one of only seven researchcenters participating once thestudy criteria gets approved bythe state senate.

“California law prohibitsenrolling patients in clinicaltrials in which the body tempera-ture is changed without informed con-

Jan Paul Muizelaar earned hismedical and doctorate degreesat the University of AmsterdamSchool of Medicine. In 1974 hecompleted a fellowship inneurophysiology at theNetherlands Central Institute ofBrain Research. He completedhis residency at the MilitaryHospital in Utrecht and theUniversity of Nymegen and theUniversity of Amsterdam. In1982 he completed afellowship in neurosurgery atthe Medical College of Virginiain Richmond joining the staff asassistant professor ofneurosurgery in 1982. He wasappointed the Lind LawrenceChair in 1987 becoming vicechair of the Division ofNeurosurgery in 1991. Threeyears later he accepted anappointment as professor ofneurosurgery and director ofthe Detroit NeurotraumaInstitute at Wayne StateUniversity. He joined thefaculty at UC Davis asdepartment chair in May1997. He can be reachedat (916) 734-3658.

About the source

Vascular surgeon Jan Paul Muizelaar joins medical center as new chair.

9

August 1997

“California law

prohibits enrolling

patients in clinical trials

in which the body

temperature is changed

without informed

consent. But the law is

contrary to federal law

and those in other

states. Hopefully, we

can change it because

many patients with

head injury who are

eligible for clinical trials

are deeply comatose.

Treatment needs to be

started right away, and

the family is not al-

ways available.”

sent,” Muizelaar said. “But the lawis contrary to federal law and thosein other states. Hopefully, we canchange it because many patientswith head injury who are eligiblefor clinical trials are deeply coma-tose. Treatment needs to be startedright away, and the family is notalways available.”

He has already sent a letter toGov. Pete Wilson outlining his con-cerns.

Muizelaar’s new plans for pa-tient care include some of the mosttechnically advanced equipment inthe world.

A new holographic digital im-aging device, which will convertCT or MRI scans, or even combinethe two, into holographic images,will enable surgeons to see the in-jury and everything around it inspace. “You can inject dye and seeexactly where all of the blood ves-sels are in the head and whetherthere is an aneurysm in any ofthem,” Muizelaar said.

“The device has special advan-tages for stroke patients because wecan image blood vessels withoutdoing angiography. Today strokesare being treated with clot bustingdrugs, but therapy must be admin-

istered within three hours to beeffective. It would be ideal to knowwhether a patient has an occludedblood vessel before you give themedication because the drug hasquite severe side effects.”

In the ICU, Muizelaar is in-stalling new computerized moni-toring equipment to record all ofthe patient’s physiological data,such as blood pressure, oxygen-ation of arterial blood, oxygenationof blood in the brain, cerebral bloodflow and intracranial pressure. Themonitoring system is so advancedthat UC Davis will be one of only afew major centers in the world withthis capability. Such systems areonly available at the Medical Col-lege of Virginia, Wayne State Uni-versity and Baylor College in theUnited States.

With so many new training,research and patient care effortsalready under way, Muizelaarspeaks rather modestly abouthis role.

“I feel UC Davis is a perfectfit for me,” he said. “Here theemphasis is on trauma, andthere is a real need for avascular surgeon who performsacute neurosurgery.” UCD

immigrants drifted into the computer business justout of college in the 1960s, according to a 1993Fortune magazine profile. He was working at Amdahlwhen he struck out on his own with an idea for asoftware database that could enable big companies tomanage corporate records on large mainframecomputers.

Oracle, founded in 1977, soon catapulted Ellisonto Forbes Magazine’s list of America’s 400 richestpeople. The company grew to become California’slargest software firm and the third largest indepen-dent global supplier of database software. Today itemploys more than 23,000 people in more than 100countries and generates annual revenues of more

than $4.2 billion.With his $5 million gift to UC Davis, the man

behind Oracle is investing in a new vision: anInstitute that will benefit patients with nerve, muscleand bone disorders for decades to come.

Said Chapman: “Thanks to this gift, we have thepotential within 10 years of having a researchprogram in musculoskeletal and neuromuscularbiology here at Davis that will be unmatched. It willmake available to the citizens of our region a level ofcare that is unparalleled and provide them withaccess to the most recent advances as they comealong.”UCD

(from page 9)

Connective tissue

UC Davis Matrix

10

Implantable pump delivers optimaldosages to quell chronic spasticityJennifer Bandalan’s cheerful disposition seemsincompatible with her painful muscle spasms andrepetitive muscle contractions and relaxations. The11-year-old is a reminder to her parents, doctors andtherapists of cerebral palsy’s cruel oppression.

There is no cure for cerebral palsy, whichafflicts one of every 400 to 800 children born in thiscountry. About 75 percent of the 750,000 U.S.residents with cerebral palsy suffer from chronicspasticity, which interferes with everything fromstanding to smiling.

Spasticity originates when areas of the brain orspinal cord that produce descending inhibitoryimpulses are damaged. Sensory signals fromreceptors escalate uncontrollably while stretchreflexes are deprived of normal negative modulation.Chronic spasticity contorts young bodies. It can

lead to musculoskeletal deformities. To relieve thesymptoms, surgeons sometimes cut nerve fibers nearthe spinal cord that are involved in hyper-excitable reflex pathways. However, muscle flacidityoccasionally produced by such rhizotomies can be asdebilitating as the spasticity they are intendedto relieve.

Baclofen and other muscle relaxants blunt someof the symptoms. Baclofen, a structural analog of theinhibitory neurotransmitter gamma-aminobutyricacid (GABA), binds to GABA receptors, which arepresent primarily in the spinal cord and thalamus.The drug inhibits monosynaptic and polysynapticexcitatory transmissions, which thereby dampensungoverned reflexes. Unfortunately, baclofen doesn’tdiffuse into the area where it is needed the most —cerebrospinal fluid — so patients must be givenlarge doses orally to try to increase cerebrospinalconcentrations. The side effects can be sickening.Children often suffer nausea, headache andother side effects, and many also are too drowsy toread or listen attentively to a Dr. Seuss story.

In June 1996, Jennifer and hundreds otherchildren with cerebral palsy in Craig McDonald’spractice at UC Davis Medical Center could begin todream of swinging on a swing, eating with a fork orsitting up on the sofa with a book. That was whenthe Food and Drug Administration approvedintrathecal (within the spinal sheath) baclofentherapy to treat severe spasticity in childrenand adults with cerebral palsy, spinal cord injuriesand multiple sclerosis. Jennifer and 6-year-oldVincent Gonzales were among the first ofMcDonald’s patients to receive intrathecal baclofentherapy.

”Before, Vincent could stand on one leg,” saidhis mother, Shawn Reynolds. The baclofen therapyrelaxed his left leg enough so that Vincentcould stand on both legs. “Now, he can walk,” hismother said. “His dream is to run.”

McDonald hopes Vincent’s dream will come true.McDonald’s intrathecal baclofen therapy programinvolves implanting a programmable infusion system,made by Medtronic Inc., of Minneapolis, Minnesota,under the abdominal skin of patients. The devicecontinually pumps baclofen intopatients’ cerebrospinal fluid. (It can be programmedto increase the dosage at night to help patients sleepand lower the dosage during the day toimprove muscle strength.) UC Davis neurosurgeonJames Boggan has implanted the system in 20 ofMcDonald’s patients, including Jennifer and Vincent:That’s more than any medical center in the West.

Six-year old Vincent Gonzales can walk, but his dream is to run.

11

August 1997

Prospective intrathecal baclofen therapy patientsmust meet age, weight and other patient-selectioncriteria. They also must show a significant reductionin their spasticity symptoms after they are given oneinjection of baclofen by lumbar puncture. While asmall number of expected problems have croppedup with the baclofen pumps, the overall results havebeen stunning, McDonald said.

“The beauty of this treatment is we can bringthese children in and do a single test dose with abolus intrathecal injection and find out ifthe children respond without subjecting them to asurgery,” McDonald said. The patients who receivethe pump implants receive roughly one-100th of thedaily oral dose of baclofen. “It certainly doesn’t curethe cerebral palsy of patients who get the pump,” hesaid, “but the functional results are prettystaggering at times.”

In the surgery, Boggan inserts the tip of asilicone catheter into the fluid cavity of the anesthe-tized patient’s spine and sutures it in place. Hethreads the remainder of the tube under the patient’sskin, around their waist, to their abdominal area.Next, Boggan attaches the free end of the tube to thetitanium implant device, a programmable infusionsystem. The device, about the size and shape of ahockey puck, contains a collapsible 10- or 18-milliliter reservoir with a refill port, lithium battery,peristaltic pump and antenna.

The FDA cleared the infusion system forintrathecal baclofen treatment of severe spasticitydue to multiple sclerosis and spinal cord injury in1992, and for intrathecal delivery of morphine forpain in 1991. More than 30,000 Medtronic pumpshave been implanted worldwide, according to thecompany.

An integral part of the Medtronic pumps is anexternal device that looks like a laptop computer.Doctors use it to externally adjust the infusion rateof the pump with a radio telemetry signal. Withindays of the operation, parents are dumfounded.

“I couldn’t believe it,” said Barbara Keeler, whowith her husband Dave Keeler have been Jennifer’sguardians since 10 days after the girl’s birth.Jennifer, who previously couldn’t sit up on a sofa,suddenly could sit up, unaided, on a bar stool andspin on it. She also could now draw a straight linewith a pen and could easily transfer herself from herwheelchair to a chair or the toilet and into theseat of a swing in the back yard. Jennifer wasfunctionally transformed.

“All I wanted to do was sit in my chair andwatch her,” said Barbara Keeler. “Even our care ofher is 100 percent easier. Before, both of us had tohold her arms up to shave her underarms. Now, sheholds her own arms up... Her voice is softer... Now,she is completely continent — we didn’t even dreamthat would happen.”

Parents like the Keelers predict that the baclofenpump will transform the lives and futures of otherchildren as well. But there also are risks.

About 250 medical centers have installedMedtronic’s baclofen pumps. Some of their patientshave developed infections after the surgery, and inthose cases surgeons removed the pumps. Also, thedevice’s silicone tubes have kinked and pulled awayfrom the spinal column in some cases, whichrequires a follow-up surgery to repair the problem.The pump must be replaced surgically every fiveyears or so when the battery wears down.

Most patients and their parents willingly acceptthe risks. “For a while, people would tease Jennifer:‘Can I have your pump?’” said Keeler. “She’d say,‘No way.’”

McDonald currently is “titrating” Jennifer’sbaclofen dosage high enough to control herspasticity and low enough to avoid drowsiness andmuscle weakness. Studies have shown that theintrathecal dosage of baclofen must be increased inmost adults and children during the first year ortwo. Those studies have shown that only 5 percentof intrathecal baclofen patients become refractory toincreased doses over time.

Because of the program’s success, correctiveorthopedic surgeries are no longer out of thequestion for McDonald’s patients.

“Before intrathecal baclofen, the deformitieswould likely recur after the surgical procedures,” hesaid. He recommended surgery for one ofhis patients, a 6-year-old girl with cerebral palsy,who couldn’t stand because her spasticity hadcaused permanent leg and hip muscle contractures.“We’ve been able to control the spasticity with thebaclofen pump, and she has had successful tendon-lengthening surgery to correct the deformities,” hesaid. ”She is standing in therapy now with braces onher legs.”

Doctors and their patients’ families interested ingetting more information about Dr. Craig McDonald’sIntrathecal Baclofen may call (916) 734-5293. UCD

UC Davis Matrix

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UC Davis Matrix

Matrix is published for physiciansand medical science researchers bythe Office of Medical Sciences PublicAffairs, (916) 734-2784.

Joseph SilvaDeanSchool of Medicine

Frank J. LogeDirectorHospital and Clinics

Bonnie HyattManagerMedical Sciences Public Affairs

Carole GanMatrix Editor

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Editorial Advisory BoardKent Erickson, Sarah Gray, FredMeyers, Thomas Nesbitt, EdithPerez, Fredrick Troy,Donal Walsh.

UC Davis Matrix

UC DAVISSCHOOL OF MEDICINE

MEDICAL CENTER

2315 Stockton BoulevardSacramento, CA 95817

In accordance with applicable State and Federal laws andUniversity policy, the University of California does notdiscriminate in any of its policies, procedures, or practiceson the basis of race, color, national origin, religion, sex,sexual orientation, handicap, age, veterans status,medical condition (cancer-related) as defined in Section12926 of the California Government Code, ancestry, ormarital status; nor does the University discriminate on thebasis of citizenship, within the limits imposed by law orUniversity policy. In conformance with applicable law andUniversity policy, the University of California is anaffirmative action/equal opportunity employer. Inquiriesregarding the University’s equal opportunity policies maybe directed to the Vice Chancellor of Academic Affairs —Affirmative Action Officer and Title IX Coordinator, 525Mrak Hall, (916) 752-2070. Speech or hearing impairedpersons may dial 752-7320 (TDD).

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(from page 3)

Ellison Chair

in. By 1987, Genetics Institute and CreativeBiomolecules had found the identity of the activesubstances, which most scientists started to call“bone morphogenic proteins.” Both companieshave BMP-based compounds in clinical trials torepair and heal bone. With the help of his assay, thebiotech companies “bottled the genie” of boneinduction factor, said Reddi. But even thoughbiotech companies took the prize, Rosen ofGenetics Institute gives Reddi “enormous credit forhaving the patience and fortitude to stick with apurification project for 20 years.”

The experience of isolating bone inductionfactors gave Reddi unique insight into tissueformation. In some ways, bone is an unusual tissuebut in other ways it is typical. Reddi began toformulate some general principles that haveturned out to be pivotal for other tissues as well:Three elements are necessary for successful engi-neering of human tissues: inductive signals, likeBMPs; responding cells; and the appropriatescaffolding or microenvironment.

These principles are just as useful in cartilage asthey are in bone. Articular cartilage regeneration hasbeen a difficult problem for science, Reddi is lookingfor ways to regenerate cartilage in patients who havehad an injury or severe arthritis. ”The structurewhere cartilage is replaced by bone is known as the

growth plate,” Reddi explained. At the growth plate,cartilage cells divide, then they die off and calcify,blood vessels come in and the cartilage is replaced bybone. “We’re asking what is responsible for theorganization of the growth plate. I’d like to learnhow this happens on a molecular level.”

But Reddi doesn’t want to stop at cartilage andbone. He is extending his work to ligaments as well,and like cartilage, no one knows how to regrow sothat it is just like new. He is even looking at kidneyregeneration, since kidney is a tissue that cannot beformed without the help of one of the BMPs.Scientists at Harvard University have shown thateliminating one of these BMPs in mice “completelyknocks out kidney development,” he said. BioGen,another biotech company, has put over $100 millioninto using BMP-7 to treat acute kidney disease.

“I want to let these factors lead me to otherorgan systems,” Reddi said, where he can applyprinciples he has learned so well from bone.

Ultimately Reddi’s work is leading him back tothe study of the developing embryo, where mostmysteries of the human body begin.“Cartilage begins to form in the embryo and is likelyto be maintained throughout one’s lifetime by thesame molecules. We need to isolate, maintain andpurify these factors,” he said. UCD