New Horizons in TreatingDisease

A Medical Revolution Begins

Getting Healthy GenesInto Cells

Vectors: Vehicles forTransferring Genes

Gene Therapy for Cancer andInfectious Disease

Should We Change Our Genes?

2

3

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

64

8101112

Gene Therapy OpensNew Horizons in Treating Disease

Getting New Genes into Cells

Profile

Mariann Grossman: A Pioneer inGene Therapy

The First Success in Gene Therapy:Helping a Woman Fight Deadly HighCholesterol

1415 Class Discussion

Ethical Problems in Genetics

Volume 4, Issue No. 2

Your World/Our World describes the application ofbiotechnology to problems facing our world. Wehope that you find it an interesting way to learnabout science and engineering.

Development by:The Pennsylvania Biotechnology Association,the PBA Education Committee, andSnavely Associates, Ltd.Editing and Writing by:The Writing CompanyCathryn M. DeludeKenneth W. Mirvis, Ed.D.Design by:Snavely Associates, Ltd.Educational Advisor:Keith Buckingham & Michael Canfield, FriendsCentral School

Scientific Advisor:Stephen Eck, M.D., Ph. D., The Institute for HumanGene Therapy, University of PennsylvaniaSpecial Thanks:The PBA is grateful to the members of theEducation Committee for their contributions oftime and energy:Anthony Guiseppi-Elie � AAI-ABTECH

Carolyn Townsend � BIOSIS

Richard Manzari � Boekel Industries, Inc.

Byron Long � Bristol-Meyers Squibb

Cynthia Gawron-Burke � Ecogen, Inc.

Grant Calder & Keith Buckingham �Friends' Central School

Barbara L. Handelin � Genovo, Inc.

Marion Guthrie � Guthrie Associates

Barbara McHale � Gwynedd-Mercy College

Stephen R. Collins � JRH Bioscience

Daniel Keller � Keller Broadcasting

Kodzo Gbewonyo, Althea Talento & Alan Shaw �Merck & Company

Jeff Davidson � Pennsylvania BiotechnologyAssociation

Kamal Rashid � Penn State Biotechnology Institute

Alan Gardner � SmithKline BeechamPharmaceuticals

J. Lawrence Snavely & Debbie Shephard �Snavely Associates, Ltd.

Mary Shields � TosoHaas

Laurence A. Weinberger, Esq.

Kenneth Mirvis & Cathryn Delude �The Writing Company

If you would like to make suggestions or commentsabout Your World /Our World, drop us a line at:CompuServe: 73150,1623Internet: 73150.1623 @ compuserve.com

Vectors: Vehicles for Transferring Genes

Gene Therapy for Cancer and InfectiousDiseases

Should We Change Our Genes?

Cover:Gene therapy has made the difference between a life of isolation in a sterile �bubble� and anactive life. Two of the children on the cover have a genetic disease of the immune system.With gene therapy, a new gene is inserted into a cell. The new gene�s DNA causes the cellto produce a protein that it would not otherwise make. That new protein helps treat or curethe disease.

Credits:Top right: Baylor College of MedicineTop left: March of Dimes Birth Defects FoundationCenter: The Institute for Human Gene Therapy, University of Pennsylvania

Pennsylvania Biotechnology Association1524 W. College Avenue, Suite 206State College, Pennsylvania 16801

Copyright © 1995. All rights reserved.

A Medical Revolution Begins

3

Since we humans have over 100,000genes you wouldn't think that one ortwo would make abig difference. Infact, though, evena single gene canmake the differ-ence between ahealthy body andone with a seriousgeneticdisease.

Scientists haveidentified morethan 4,000 ge-netic diseasescaused by singledefective or miss-ing genes, andthey are findingmore all the time.These diseasescan affect any part of the body, fromthe way we grow to the way our heartworks, and they can affect organsthroughout the body.

Many genetic diseases are inheritedfrom one or both parents. Others arecaused by changes in a person�s DNA.Most individual genetic diseases arerare by themselves, but there are somany diseases that taken all togetherthey are common, and they causetremendous suffering. Until recently,there was no way to treat mostgenetic diseases. Now we are learningto treat them by changing the genesthat cause them.

Gene therapy is the technique ofadding genes to certain cells tochange the way those cells work. Inaddition to treating genetic diseases,gene therapy may also help treatcancer, heart disease, AIDS, and otherconditions. In this issue of YourWorld/Our World, you will read

These two men both died of genetic diseases. Lou Gehrighad ALS (amyotrophic lateral sclerosis), now known as LouGehrig's disease, which destroys nerves in the spinal cord.Woody Guthrie had Huntington's disease, which destroysbrain cells.

Woody Guthrie, the folksinger who wrote “ThisLand is My Land.”

Lou Gehrig, popular pro-fessional baseball player.

about several experiments � and onesuccessful treatment � using genetherapy. The experiments are called�clinical trials,� and we do not yetknow if they will be successful.

Many people are excited about thepotential of gene therapy to relievehuman suffering, but they are alsoconcerned about the potential tomisuse the technology. This issuewill help you understand the benefitsof gene therapy, and it will encourageyou to think about the challenges ofdefining its ethical use. n

OPENS NEW HORIZONSIN TREATING DISEASE

Phot

ogra

pher

: Lo

uis

Van

Oey

en

Nat

iona

l B

aseb

all

Libr

ary

& A

rchi

ve,

Coo

pers

tow

n, N

.Y.

These mice look different because theyhave different forms of the same genes.

Gene Therapy

You may have heard about genetherapy, and you may already havesome opinions about it. Write downyour thoughts on it before you readthis issue. After reading the issue,write down your thoughts again.Then compare your two essays. n

The human body has over100,000 different kinds of cells.

Every cell hasa nucleus.

Each nucleuscontains 23 pairsof chromosomes.

Each chromosomehas one strand fromthe mother and onefrom the father.

Each strand ismade of coils ofDNA.

A gene is a sectionof DNA that hasinstructions to makea certain protein.

4

In 1984,a twelve-year-

old boy known world-wide as the �boy in thebubble� (see above) died of a raregenetic disease that left him with noimmunity against even commongerms. He had a genetic diseasecalled severe combined immunodefi-ciency or SCID that completelycrippled his immune system. To keepfrom being exposed to germs, the boyspent his entire life in a sterile, air-tight �bubble� chamber. This bubblehelped him live longer than any otherchild with SCID had lived.

When the families of two baby girls,Ashanthi DeSilva and CynthiaCutshall, learned that their childrenhad a form of SCID, they sadly envi-sioned a short, protected life for theirdaughters. Both girls had a defectivegene that did not make an enzymecalled adenosine deaminase (ADA).Without this enzyme, the white bloodcells (or immune cells) die, and thebody cannot fight off infection.

Ashanthi and Cynthia were the first childrento receive gene therapy for the geneticdisease SCID. They work as “researchambassadors” for the March of Dimes,educating the public about potential benefitsof gene therapy.

Then in the early 1990s, these twogirls became the first children ever toreceive experimental gene therapy forSCID. The gene therapy added ahealthy gene for ADA to their im-mune cells in hopes that they coulddevelop a normal immune system.

In early 1994, magazines and newspa-pers covered the story of this appar-ently successful experiment.Ashanthi, then six years old, andCynthia, who was eleven, were at-tending school and leading normallives. (Researchers must still studywhether their healthy immune sys-tems are the result of the genetherapy or of other drugs they re-ceive.) You can read about themethod used for this gene therapy onpages 6 and 7 in this issue.

Children with SCID could not fightoff infection, so they had to live insterile bubbles such as this one.

Phot

o co

urte

sy o

f B

aylo

r C

olle

ge o

f M

edic

ine

Phot

os c

ourt

esy

of t

he M

arch

of

Dim

es B

irth

Def

ects

Fou

ndat

ion

In the past, people did not knowthey were carriers of a recessivegenetic disease until their childrendeveloped that disease. Today,genetic testing can tell us if wecarry certain recessive genes.Should everybody be tested forrare diseases? Would you want toknow if you carried a SCID, CF, orsickle cell gene? How would know-ing affect your life? nMedical

A

RevolutionBegins

5

INHERITING A DISEASECAUSED BY A

RECESSIVE GENE

Recessive InheritancePattern

Sickle Cell AnemiaSickle cell anemia is a commonrecessive disease among AfricanAmericans. It is related to anumber of other diseases of the redblood cells caused by defects on thebeta-hemoglobin gene. In this case,the gene produces a defective formof beta-hemoglobin protein. Thisdefective protein leads to misshapenred blood cells that cannot flowthrough the small blood vessels(capillaries) as easily as normalcells, resulting in pain and injury tovital tissues.

Developing a gene therapy forsickle cell anemia is particularlyimportant, since it affects so manypeople and since existing medicaltechnology cannot treat all of itssymptoms. However, this diseaseposes some unusual challenges for

Sickle cell anemia causes the red bloodcells, which are normally disc shaped,to develop a "sickle" shape. Thesemisshapen cells cannot flow through thesmall blood vessels (capillaries) as easilyas normal cells.

gene therapy. The amount ofreplacement beta-hemoglobin pro-duced by a transferred gene mustbe very carefully regulated. Too littleprovides no benefit, while too muchcauses other problems with red bloodcells. The ongoing research in sicklecell gene therapy may lead to bettertreatment of this and related blooddisorders. n

Abnormal hemoglobin genes, likethe sickle cell gene, are common inparts of the world where malaria isalso common. Malaria is a dis-ease caused by a parasite thatinfects the red blood cells. Why doyou think that malaria and dis-eases of hemoglobin are found inthe same parts of the world? Couldthere be an advantage to being acarrier of an abnormal hemoglo-bin gene? n

carriercarrier

Each carrier has one healthy geneand one defective gene .

person with thedisease or condition

non carrier

SCID is a very rare genetic disease. Cysticfibrosis (see next article) and sickle cellanemia (see below), however, are relativelycommon. All three diseases follow arecessive inheritance pattern. Recessivediseases occur only if a child inherits twodefective genes, one from eachparent. If a child inherits only onedefective gene, the child is a carrier butdoes not have the disease. If both par-ents are carriers of a recessive gene (asshown in the illustration), what are thechances of a child:

� Not carrying the recessivegene?_____%

� Being a carrier (one recessivegene)?_____%

� Having the disease (two recessivegenes)?_____%

6

○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○

GENESGENES○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○

CELLS

GETTING

CELLS

How do we replace a disease-causinggene with a healthy gene? First, wemust find out where the gene be-comes active. For instance, thegene that makes the ADA enzyme isin every cell of the body. However,when it is missing only the whiteblood cells malfunction; the othercells in the body work normally.Next, we must insert the new geneinto the cells that need it. Justgetting the ADA gene into any cell,for example, will not treat SCID; thegene must get into the white bloodcells.

Removing Cells for GeneticTransferTo treat the two young girls withSCID, researchers first removedsome of their white blood cells andput a normal ADA gene into thosecells. In a laboratory they cultured(grew) millions of these engineeredcells. Then they injected them backinto the girls� blood in hopes thatthe altered immune cells wouldproduce the ADA enzyme and builda healthy immune system.

We call this kind of gene therapy exvivo or external, because the ge-netic transfer takes place outsidethe patient�s body. Other geneticdiseases may be treated in vivo orinside the body. In vivo methodsare used when the cells that needtreatment cannot be removed fromthe body.

Transferring Genes Insidethe BodyOne of the genetic diseases re-searchers are trying to treat with invivo methods is cystic fibrosis. TheCF gene leads to the build-up of avery thick mucus in the lungs,causing life-threatening infectionsand lung damage. To relieve theseproblems, experimental gene

The theory behind gene therapy for cystic fibrosis: A virus carries a good copy of the CF geneto the cells lining a patient’s airways. Each cell is shown as having two defective CF genes(that are crossed out) and one normal gene (green). Ideally, the normal gene would take overthe normal function of the cell.

therapy for CF is targeting the cellsin the lining of the lung. Sincethese cells cannot be removed,researchers put the healthy genedirectly into the airways of thelungs. They hope the cells in thelungs will take in the new gene andmake normal mucus.

You will read about how the healthygene gets transferred to the cells onpages 8 and 9. n

Illu

stra

tion

cou

rtes

y of

the

Cys

tic

Fibr

osis

Fou

ndat

ion

GETTINGNEW

INTO

Are there any conditions in yourfamily that might be inherited?Are there any illnesses that haveshown up in several genera-tions? Make a family tree of asmany generations as you can,and show these illnesses. Doyou think these illnesses arecaused by inherited genes? Bythe environment your familylives in? By your family�s life-style? Or a combination offactors? n

Monica Zepeda, a Ph.D. student at theUniversity of Pennsylvania, prepares humanairway cells for a gene therapy tissue cultureexperiment.

7

Career Tip:Nurse ResearchCoordinator

Nurse research coordinatorsare responsible for recruitingand organizing patients whovolunteer for a clinical trial.They make sure data on allpatients are collected properly,recorded, and kept confidential.These nurses are the lifeline ofany clinical trial because theyare the link between science andthe patient. They usually havean R.N. (registered nurse) de-gree, or an R.N. with M.S. (Mas-ters of Science) degree.

Career Tip:Research Doctor

Developing new treatmentsfor gene therapy requires acombination of very specializedskills � the technical knowledgeof a Ph.D. research scientist whoworks mainly in a laboratory,and the medical knowledge of anM.D. who deals directly withpatients. People working ongenetic therapies must under-stand both how to transfer genesto cells and how the human bodyresponds to disease and genetictreatment. Many research doctorshave a dual degree: M.D., Ph.D.

Career Tip:Genetic Counselor

Genetic counselors under-stand the science of inheriteddiseases, and they know how tocalculate the chances of youor your children inheriting adisease. They also help peopledeal with the emotional difficul-ties of discovering they have agenetic disease in their family.As our scientific knowledgeabout genetic diseases grows,our ability to understand how todeal with this information mustalso grow. For that reason,genetic counselors are becomingincreasingly important resources.

3. Many copiesof the cell withthe new geneare grown.

2. In a laboratorya new gene isinserted intothe cell.

1. Cells are removed from the body.

The new gene is insertedinto the cells inside thebody.

EX VIVOGenetic transfer takes place outside the body

IN VIVOGenetic transfer takes place inside

the body

4. The engineered cellsare put back in the body.

8

Once we know which cells need to geta healthy gene, how do we get it there?We use a delivery vehicle called avector. In the world of transportation,a good delivery vehicle has to drive tothe right address (without accidents)and deliver its package (in good shape)to the right person. Likewise, in genetherapy a good vector has to get to itstarget cells without disturbing othercells along the way. Then it has totransfer its genetic package to the cell.There are different kinds of vectors fordifferent kinds of jobs.

Adenovirus for InternalTreatmentsIf you wanted to get a new gene to thecells of the lining of the lungs, whatvehicle might you use? Use one thatalready goes there! For example, theadenovirus (pronounced ad-no-virus)is a common cold virus that regularlyinfects the lungs. When it attacks thecells of the lungs, it naturally deliversits DNA to the cells.

Researchers are using these traits of

the adenovirus to develop an experi-mental gene therapy for cystic fibro-sis. They first deactivated theadenovirus so it can no longer causedisease or grow. Then they inserted acopy of the healthy CF gene into thevirus. When put into the lungs, thisaltered virus would �infect� the lungs.Instead of catching cold, though, thepatients would catch the healthygene!

No one knows yet if this treatmentwill work, or what kind of problemsthis viral delivery vehicle mightcause. After repeated doses, thebody�s immune system could build upa defense against the adenovirus andreject it. The new genes could beabsorbed by the wrong cells beforethey reach the lungs. They coulddisrupt the cells� other functions.

Retrovirus for ExternalTreatmentsBy working on cells outside the body,researchers can aviod the twin prob-lems of the immune system's inter-ference and misdirected deliveries.

Many experiments in external treat-ments use another kind of deactivatedvirus � called a retrovirus � as a vec-tor. Retroviruses are used for ex vivotreatments because they only infectcells that are dividing. When treatedoutside the body, the targeted cellsare grown in a culture, so they arerapidly dividing. The retrovirusquickly enters these dividing cells anddelivers the new gene.

Retroviruses would not have time towork in in vivo gene therapy becausethe body�s immune system rapidlyattacks most retroviruses. Even thefast-growing cells of a tumor are notdividing fast enough for theretrovirus to enter them before it getsoverwhelmed by the immune system.

Non-Viral VectorsBecause viruses and retroviruses bothhave limitations as vectors, research-ers are also working to build otherkinds of gene delivery vehicles. Someresearchers, for example, are puttinga gene inside a bubble of fat called a�liposome.� Other researchers arewrapping strands of DNA with analtered gene around microscopicpellets of gold or titanium. Then theyuse a gene gun to �shoot� the pelletsdirectly into the targeted cells. Sci-entists hope to use this method for invivo treatments of skin cancer, sincethe tumor cells are close to the sur-face. They also expect to use it forvarious ex vivo therapies. n

An adenovirus vector enters a cell.

The

Inst

itut

e fo

r H

uman

Gen

e Th

erap

y,U

nive

rsit

y of

Pen

nsyl

vani

a

9

Career Tip:Cell Libraries forGene TherapyResearch

To discover the genetic cause of adisease, researchers study cellsfrom people who have that dis-ease. Suppose you wanted to findthe genes responsible for theincurable Huntington�s disease,but didn�t know anyone with it.You might call a special kind ofresearch library that collectscells from people with differentdiseases. These libraries thenculture or grow the cells to cre-ate a �cell line.� You could ordera cell line from a patient withHuntington�s disease. Librariesfor cell lines have made it easierfor researchers to study differentdiseases. Without them, itwould have taken longer to dis-cover the genes responsible forcystic fibrosis, juvenile diabetes,Huntington�s disease, and others.

Cell line libraries are staffed byexperts in microbiology, molecu-lar biology, cytogenetics, cellbiology, and molecular genetics,as well as library science. n

Collections of living human cells, suchas the one stored here, serve the entirescientific community.

Cor

iell

Ins

titu

te f

or M

edic

al R

esea

rch

A gene gun is used to bombard cells with goldor titanium pellets that have been wrapped withstrands of DNA. The vector carrying the gene isput into an acceleration tube. Helium gascreates pressure. When the pressure reachesa precise point, a special disk breaks, sendingthe pellets hurtling to the cells fast enough tobreak through the cell membrane.

During the Trojan War in the 12th century B.C., Greek soldiers tried for ten years tobreak into the walled city of Troy. Finally they pretended to give up and left a largewooden horse as a gift for Troy. The Trojans opened their gates to let in thehorse, not realizing that Greek soldiers were hidden inside. A ferocious battlefollowed, and the Greeks conquered Troy.

In a similar strategy, we use vectors to trick the cell into letting new genes throughthe cell "wall" or membrane. We hide the genes inside a virus or other vehicle thatalready has found a way to get into the cell.

Phot

o an

d il

lust

rati

on c

ourt

esy

of B

ioR

ad

10

and research. It is especially thrillingto work with patients who I mayactually be able to help.�

Mariann and her colleagues havemade some remarkable break-throughs. They were the first re-search team to treat successfully arare genetic disease called FamilialHypercholesterolemia (FH), whichyou can read about on the next page.When they began this research, everynew effort was a step into the un-known, and they had to invent newlaboratory strategies and techniquesat every turn. For example, to treatFH they wanted to add a healthycholesterol-related gene to the livercells. However, very few people hadever tried to isolate human liver cells.Mariann devised a way. Then shefound ways to keep the liver cells

alive and grow them in a culture.Finally, she helped develop a vectorto get new genes into the cells. Hercolleagues often say that Mariann hasa �green thumb� with cells, the waysome gardeners have a special knackwith plants.

Mariann�s work is completely absorb-ing, but she does find time to keepup with professional sports and withher own athletic loves, swimmingand dancing. She also collects CDsof every kind of music, from classicalto rock, jazz, and new age. Mariannis particularly excited because she isno longer the only scientist in herfamily. Her brother has enrolled inan M.D., Ph.D. program in genetherapy at Washington University inSt. Louis. Her enthusiasm is obvi-ously contagious. n

Mariann Grossman�s large Minnesotafamily considered her a pioneer,since no one in her family had evershown a strong interest in science.Now, she is on the cutting edge ofgene therapy research as director ofone of the laboratories at The HumanGene Therapy Institute at the Univer-sity of Pennsylvania.

Mariann went to college at the Uni-versity of Minnesota in the 1980s. Inher third year, she worked in thebone marrow transplant unit of theuniversity�s hospital where she sawmany patients with inherited geneticdiseases. She saw that bone marrowtransplant therapy did not alwayswork for these people, and she feltthere must be a better treatment forthem. Her research led her to hu-man gene therapy.

After college, Mariann accepted a jobin a lab at the Whitehead Institutefor Biomedical Research in Cam-bridge, Massachusetts. There shestarted working with a young re-search scientist in gene therapynamed James Wilson. Since then,she has conducted research andcollaborated on projects with Dr.Wilson at the Whitehead Institute,the University of Michigan, and nowthe Human Gene Therapy Institute atthe University of Pennsylvania. Shemight go to graduate school one day,but she�s not ready to leave her posi-tion. �I love what I am doing,� shesays. �I am learning both medicine

Mariann Grossman checks cultures of liver cells.

The

Inst

itut

e fo

r H

uman

Gen

e Th

erap

y, U

nive

rsit

y of

Pen

nsyl

vani

a

10

11

from highschool.� Since thenDr. Wilson�s team hastreated other patients withFH, including several youngchildren.

Each treatment requires a major,risky operation � and a lot of drama.Surgeons carefully remove part ofthe liver and rush it to MariannGrossman in her lab. She can�t losea second. She must keep the livercells alive while she loosens theminto separate cells. She dividesthem into 1,500 separate petridishes. For the next three days,these liver cells divide until thereare billions of them. Then they arebathed with a retrovirus that con-tains the gene for the LDL receptor.The treated cells are then injectedinto a vein in the patient that leadsto the liver. If every part of theoperation works, the liver will soonbegin to break down cholesterol inthe blood.

Dr. Wilson�s team is thrilled thatthis method may be helping to savelives, but they want to find otherways to get new genes into the liverthat do not require such difficultsurgery. They hope to find a vehicleto take the new gene directly to theliver cells. Then they could treatmore people with different kinds ofcholesterol problems and liver dis-orders. The work of gene therapy isonly just beginning. n

The First Successin Gene Therapy:

Helping aWoman FightDeadly HighCholesterol

The first proven successful treat-ment using gene therapy was on a29-year-old woman who had a raregenetic disease called familialhypercholesterolemia or FH. �Fa-milial� means that it is passedthrough one�s family, or is genetic.�Cholesterol� is a type of fat; if thebody does not break it down prop-erly, it will build up in blood ves-sels, clogging them and causingheart disease or heart attacks. Theprefix �hyper� means there is toomuch cholesterol; the suffix �emia�means "in the blood". So given thatinformation, how would you de-scribe the disease familialhypercholesterolemia?

FH patients often die of heart at-tacks as young adults or even aschildren. These people have a de-fective gene that does not produce alow-density lipoprotein (LDL) re-ceptor in the liver. A receptor is aspecial cell part that combines withchemicals and allows them to entercells where they can be used ordisposed of. Without the LDL re-ceptor, the liver cannot break downcholesterol. To fight this disease,Dr. James Wilson and MariannGrossman (see previous page) founda way to insert a gene for the LDLreceptor into liver cells.

The first woman to receive thisgene began producing enough LDLreceptors to lower her cholesterolto a less dangerous level. After theoperation she said, �Now I hope tolive to see my daughter graduate

Gene Therapyfor FamilialHypercholesterolemia:

1) Doctors remove 15% of thepatient�s liver.

2) These liver cells have an abnor-mal LDL receptor gene. Theyare separated and cultured intobillions of liver cells in a labo-ratory. (Not shown in illustra-tion.)

3) A retrovirus vector is used totransfer the gene for the LDLreceptor to cultured liver cells.

4) The cultured cells now havenormal LDL receptor genes.

5) The cultured liver cells are in-jected into a vein that leads tothe liver. Liver cells begin tomake the LDL receptor, and thepatient�s level of harmful cho-lesterol drops.

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

○

LDL

LDL

Liver

Liver cell with

abnormal LDL

receptor gene

3

1

4Liver cell with normal

LDL Receptor gene

replaced in liver

2

Gene for normal LDL receptor

inserted into liver cells

5

12

Gene therapy may one day be used formuch more than adding a healthygene to treat inherited diseases. Itmight also be used to treat somecancers and infectious diseases. Inthese cases, scientists may add a genethat has nothing to do with whatcaused the disease. Instead, the newgene would change the way the dis-ease works.

Fighting Cancer...A common treatment for cancer ischemotherapy. With chemotherapy,patients receive a high dose of strongdrugs that kill the fast-growing can-cer cells. The proper dose for chemo-therapy is a delicate balance: toomuch and the healthy cells die; toolittle and the tumor cells survive.Gene therapy could help make thisbalance easier to achieve.

...by Strengthening theGuards...Chemotherapy can kill the bonemarrow cells and weaken the im-mune system. Researchers are look-ing for ways to keep the immune cellshealthy. In one experiment, theyremove some bone marrow cellsbefore chemotherapy. They give thecells a gene � called the Multiple

Drug Resistant Gene, or MDR � thatguards them against the toxic effectsof chemotherapy drugs. Then theyculture billions of these treated bonemarrow cells. After the patientreceives chemotherapy, researchersput the cells with the MDR gene backinto the patient. They hope thesecells with MDR will survive and pro-duce healthy immune cells, while thetumor cells die.

...and Weakening the TumorOther experiments use gene therapyto send in �suicide� genes to killtumor cells in patients with incurablebrain cancer. Researchers use a de-activated virus that carries the genefor an enzyme called thymidinekinase(TK). The virus makes thisenzyme inside the cell it has invaded.The enzyme kills cells that are divid-ing when they are exposed to ananti-viral drug called ganciclovir(gãn-sï-klõ-vear). The cell is said to�commit suicide� since, with the newgene, it makes a protein that leads toits own destruction. Researchersfirst give the patient the virus withthe suicide gene and then theganciclovir. Although some non-tumor cells may have taken up theTK gene and are exposed to

ganciclovir, only the tumor cells areactively dividing. Since theganciclovir only kills dividing cells,scientists hope the treatment willselectively kill the brain tumor, butnot the healthy cells.

A Dead End for the AIDS VirusThe retrovirus known as HIV (HumanImmunodeficiency Virus) causes thedeadly disease AIDS. So far, it hasout-tricked all the drugs and vaccinesthat we have thrown at it. Someresearchers now think that we may beable to treat AIDS by using genetherapy to interfere with the way HIVreproduces itself.

When HIV infects a cell, it makes aprotein called �rev.� The rev proteinhelps HIV reproduce; without it, theinfection cannot spread. Some re-searchers are putting a gene for analtered form of rev into HIV. Thisaltered rev keeps the normal revprotein from working, so the viruscannot reproduce. Other researchersare developing other ways to disruptHIV�s reproduction. n

13

Cancer and GeneticsSome forms of cancer seem to run infamilies. Why do some peopleinherit the tendency to develop aparticular cancer? Genetic re-searchers are discovering genes thatare linked to certain forms of coloncancer, breast cancer, skin cancer,and others.

In the future, scientists will probablydevelop genetic screening tests forthese genes. For people who have afamily history of certain cancers,these tests may either relieve theirfear by showing that they do notcarry the gene – or confirm that theyhave a high risk of developing can-cer. Learning that they carry a can-cer gene can encourage people totake better care of themselves and todetect their cancer at an early, moretreatable stage. ■

○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○

○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○

○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○

○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○

○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○

○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○

○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○

○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○

○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○

○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○

○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○

Genetic testing may one day identify genes associated withmany types of diseases. Many people are concerned that ge-netic test results could be misused. What would happen if healthinsurance companies required genetic tests for people applyingfor insurance? They might refuse to cover people with “suspi-cious” genes, or charge them higher premiums. What if em-ployers refused to hire these people? Do we have a right togenetic privacy? ■

13

Courtesy of the Washington Post Writer's Group

14

Should We Change Our Genes?Should We Change Our Genes?Uncharted Territory and Differing Viewpoints

Every advance in science presents society with choicesabout how we use the new knowledge we have gained.For example, think of how we use the computer. What ifsociety had decided that there should be no personalcomputers, or that computers could only be used forbusiness and that games were illegal? Similarly, societymust make choices about how we use biotechnology.

For example, should we use biotechnology to changesomething about ourselves that we do not like, such asour hair, our eyes, our size, our memory, or our athleticability? Have you ever said to yourself, �If only I couldchange my....�? Depending on how society guides the useof gene therapy, kids in the future may have that chance.

Gene therapy is already trying to treat previouslyuntreatable diseases. As we learn more about humangenetics, we may also be able to use gene therapy toselect what traits we will have. Should we?

Many people agree that we ought to use gene therapy totreat a fatal genetic disease. However, the line between agenetic disease and a genetic difference can be very hardto draw. Should we try to �cure� baldness, deafness,blindness, color blindness, dwarfism, or other non-fatalconditions? What differences should we try to change?Some people think we should only use gene therapy tochange things that affect our health, and not for �per-sonal enhancement� to improve our looks or abilities.They warn that using gene therapy to �improve� peoplecould lead to �social engineering� to encourage certaintraits and eliminate others. We might become followersof a �genetic fashion� and everyone would be the same.Others wonder whether there is any ethical differencebetween traditional plastic surgery to change a person�scheek bones and gene therapy to change a person�s eyecolor.

Some people fear that gene therapy may one day be usedto oppress certain groups. History has many examples ofpeople who tried to create a �master class� or to �cleanse�ethnic differences in their populations. What might theyhave done with gene therapy?

To safeguard against the potential abuse of gene therapy,some people want to limit gene therapy research to treat-ing disease. Others want to prohibit research into genetherapy on the reproductive cells that would carrygenetic changes into future generations. (At present,however, there is no technology even to begin such re-search; all genetic therapies now and for the foreseeablefuture are limited to the non-reproductive cells of asingle individual.) Is it appropriate to limit these areasof research? Is it possible?

The debate about the ethics of gene therapy will continuefor as long as people push the frontiers of knowledgeabout the human genetic code. During your lifetime,gene therapy may affect you in many ways. You canbecome an informed participant in the ongoing effort toset guidelines for this powerful new medical tool. n

GENETHERAPY

FLOWCHART

15

Ethical Problems in Genetics

The following cases give examples of dilemmas that might grow out of our use ofgenetics. What do you think is the ethical way to handle these situations?

It helps to use principles or guidelines when making ethical decisions. For example,should decisions be based on individual well-being? The prevention of harm toyourself or others? Fairness? Justice? Truth? Personal independence? Whatprinciples might you use to make an ethical decision?

There are many differing viewpoints on these questions. Our society has not yetdecided what direction to take. Read these cases, and reflect on what direction youthink we should take.

disease or through genetic testing.

She does not want to be tested becauseshe does not feel she could handle thepossible bad news. She also does notwant her future children to be tested,because if they should test positive, shewill know that she will come down withthe disease herself.

By not testing her children, she will denythem their only opportunity to be cured ofthe disease if they do carry the gene.

Do you think Cheri has an ethical obliga-tion to test her children? Do you think sheshould be tested before having children?

Case 4: Who Decides WhoReceives Gene Therapy?

The year is 2009. Scientists have devel-oped a low-cost, simple gene therapy totreat one form of hereditary deafness.However, the treatment must be donebefore a baby is four weeks old. Susan andJuan both have this form of deafness, andso does their newborn baby Eric.

Doctors encourage them to give Ericgene therapy so he will be able to hear.They refuse. They say deafness is not adefect, and that deaf people live fullyrewarding lives with a culture of theirown. They want Eric to grow up in thisculture of deafness, and they do not thinkmainstream culture should eliminatevaluable differences among people.

Is it ethical for Susan and Juan to refusegene therapy for Eric? n

Case 1: Treating FamilialHypercholesterolemia withGene Therapy

The year is 1997. Five-year-old Loresehas familial hypercholesterolemia (seepage 11). Gene therapy could give her amore normal cholesterol level and alonger life; however, it is very expensive.

Do you think Lorese should be able tohave gene therapy? Who should be in-volved in deciding? Parents? Doctors?Should cost or the question of who paysbe a factor?

Case 2: I Want To Play

Basketball!The year is 2001. Harold is the shortestkid in his class. He makes good grades,has many friends, and is a superb athlete.His favorite sport is basketball, but heknows he could never pursue basketballprofessionally because he is too short.

Scientists have developed a gene therapythat causes people to grow taller.Harold�s personal physician believes thatgene therapy should be used only toimprove a person�s health, not just tohelp someone grow taller.

Harold knows people who have changedtheir hair color, the shape of their nose,and who have had surgical face lifts.Harold wants to be tall.

Is there an ethical difference betweenplastic surgery and gene therapy whenthey are performed for cosmetic ratherthan health reasons? Is it ethical forsociety to allow � or not allow � science tochange the genetic structure of an indi-vidual?

Case 3: Withholding InformationAbout A Genetic Condition

The year is 2005. Cheri is a recentlymarried 25-year-old eager to start a fam-ily. Her father recently died of a geneticdisease. This disease does not appearuntil people are in their thirties, and thenthey slowly lose their nerve function untilthey die ten or twenty years later.

Cheri has a 50% chance of carrying thisfatal gene, for which there is no treat-ment or cure for adults. (There is a curefor children, but only if they are treatedimmediately after birth.) If she does havethe gene, each of her children will alsohave a 50% chance of inheriting the gene.She can find out if she has this geneeither by waiting to get symptoms of the

Note to Teachers: See Teachers� Guidefor ideas and lesson plans for this activity.

16

Read more about it:

○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○

Moral Matters: Ethical Issues in Medi-cine and the Life Sciences, by ArthurCaplan (John Wiley and Sons, Inc.,

○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○

NY, 1995).

�Gene Experiment to Reverse InheritedDisease is Working,� by NatalieAngier, The New York Times, Friday,April 1, 1994. (Familial Hyper-

○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○

cholesterolemia.)

�Doctoring: Tinkering with the Stuff ofLife, Scientists are on the Edge of Engi-neering Cures for the Deadliest Dis-eases of Our Time,� by Mark Witten,Science, October, 1994. (Familial

○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○

Hypercholesterolemia.)

�Health: Getting New Genes. ARadical Treatment to Cure a Fatal LiverFlaw,� by Rick Weiss, The WashingtonPost, February 15, 1994. (Familial

○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○

Hypercholesterolemia.)

�Genetics: The Future is Now,� TimeMagazine Special Report, January 17,

○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○

1994.

�The Gene Doctors Roll Up TheirSleeves,� Business Week, March 30,1992. (Gene therapy and vectors for

○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○

SCID, CF, and cancers.)

�The First Kids With New Genes,� byLarry Thompson, Time Magazine, June

○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○

7, 1994. (Gene therapy for SCID.)

�Brave New Babies,� by Leon Jaroff,Time Magazine, May 31, 1993. (Dis-

○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○

cussion of clinical trials.)

�Gene Therapy: The Splice of Life,� byDarrel E. Ward, USA Today Maga-

○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○

zine, January 1993. (Ehical issues.)

�Beyond the Genome,� Science News,November 5, 1994, and its follow-up�DNA Dilemmas� December 17,

○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○

1994. (Ethical issues.)

�Genetic Clairvoyance,� by RichardSaltus, Boston Globe Sunday Maga-zine, January 8, 1995. (Genetic test

○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○

for Huntington�s disease.)

You can also read more about some ofthese topics in past issues of YourWorld/Our World: Vol. 2, No. 1features DNA profiling and forensicgenetics, cystic fibrosis, and geneticcounseling; Vol. 3, No. 2 features

○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○

vaccines, cancer, and AIDS.

Read more about it:

Dear Students:

The generosity and support ofthese sponsors have made theproduction of Your World/OurWorld possible. Please join usin thanking them:

SponsorsBiotechnology Industry OrganizationConnaught LaboratoriesDuPontHoffman-La Roche Inc.Life Sciences InternationalMerck Institute for Science EducationSmithKline Beecham, Inc.TosoHaas

Supporting OrganizationsOregon Biotechnology FoundationOregon Private Industry CouncilUtah State University Biotechnology Center

We are pleased to provide you with this issue ofYour World/Our World. We hope you find it aninteresting way to learn more about bio-technology. Biotechnology can be important toyou for two reasons:1. During your lifetime there will be tremendousdiscoveries in this field, and you'll want tounderstand what those discoveries mean foryou, your friends, and your family.

2. You can help make those discoveries if youdecide to continue to study science and math.

Either way, we hope you join us in discoveringthe promise of biotechnology for our world. Weare pleased to acknowledge the support of thecompanies listed. Their support makes thisproject possible.

Sincerely,

Jeff DavidsonExecutive DirectorPennsylvania Biotechnology Association