Telomeres, Telomerase and Cancer

Often in nature things are notwhat they seem. A rock on theseaßoor may be a poisonous

Þsh; a beautiful ßower in a garden maybe a carnivorous insect lying in wait forprey. This misleading appearance ex-tends to certain components of cells, in-cluding chromosomesÑthe strings oflinear DNA that contain the genes. Atone time, the DNA at the ends of chro-mosomes seemed to be static. Yet inmost organisms that have been stud-ied, the tips, called telomeres, are actu-ally ever changing; they shorten andlengthen repeatedly.

During the past 15 years, investiga-tion of this unexpected ßux has pro-duced a number of surprising discover-ies. In particular, it has led to identiÞca-tion of an extraordinary enzyme namedtelomerase that acts on telomeres andis thought to be required for the main-tenance of many human cancers. Thislast Þnding has sparked much specula-tion that drugs able to inhibit the en-zyme might combat a wide array of ma-lignancies. The research also opens thepossibility that changes in telomerelength over time may sometimes play arole in the aging of human cells.

Modern interest in telomeres and telo-merase has its roots in experiments car-ried out in the 1930s by two remarkablegeneticists: Barbara McClintock, then atthe University of Missouri at Columbia,and Hermann J. Muller, then at the Uni-versity of Edinburgh. Working separate-ly and with diÝerent organisms, both in-vestigators realized that chromosomesbore a special component at their endsthat provided stability. Muller coinedthe term Òtelomere,Ó from the Greek forÒendÓ (telos) and ÒpartÓ (meros). McClin-tock noted that without these end caps,chromosomes stick to one another, un-dergo structural changes and misbehavein other ways. These activities threatenthe survival and faithful replication of

chromosomes and, consequently, of thecells housing them.

It was not until the 1970s, however,that the precise makeup of the telo-mere was determined. In 1978 one of us(Blackburn), then working with JosephG. Gall of Yale University, found thatthe telomeres in Tetrahymena, a ciliat-ed, single-cell pond dweller, containedan extremely short, simple sequence ofnucleotidesÑTTGGGGÑrepeated overand over. (Nucleotides are the buildingblocks of DNA; they are generally de-noted as single letters representing thechemical bases that distinguish one nu-cleotide from another. The base in T nu-cleotides is thymine; that in G nucleo-tides is guanine.)

Since then, scientists have character-ized the telomeres in a host of creatures,including animals, plants and microor-ganisms. As is true of Tetrahymena, vir-tually all telomeresÑincluding those ofmice, humans and other vertebratesÑcontain repeated short subunits oftenrich in T and G nucleotides [see ÒTheHuman Telomere,Ó by Robert K. Moyzis;SCIENTIFIC AMERICAN, August 1991]. Forinstance, human and mouse telomeresfeature the sequence TTAGGG; those ofroundworms feature TTAGGC. (A standsfor adenine, C for cytosine.)

In Search of Telomerase

The telomerase enzyme that is theobject of so much attention today

was found when comparisons of telo-mere length suggested such an enzymecould resolve a long-standing puzzle inbiology. By the early 1980s investiga-tions had revealed that, for some rea-son, the number of repeated subunitsin telomeres diÝers between organismsand even between diÝerent cells in thesame organism. Moreover, the numbercan ßuctuate in a given cell over time.(Every species, however, has a charac-

teristic average. In Tetrahymena, theaverage telomere has 70 repeats; in hu-mans, 2,000.) The observed heteroge-neity led Blackburn, who had moved tothe University of California at Berkeley,Jack W. Szostak of Harvard Universityand Janis Shampay of Berkeley to pro-pose a new solution to what has beencalled the end-replication problem.

The problem has to do with the factthat cells must replicate their genes ac-curately whenever they divide, so thateach so-called daughter cell receives acomplete set. Without a full set of genes,a daughter cell may malfunction anddie. (Genes are those sequences of nu-cleotides that give rise to proteins andRNA, the molecules that carry out mostcellular functions. The genes in a chro-mosome are scattered throughout thelarge expanse of DNA that is boundedby the chromosomeÕs two telomeres.)

In 1972 James D. Watson, working atboth Harvard and Cold Spring HarborLaboratory, noted that DNA polymer-ases, the enzymes that replicate DNA,could not copy linear chromosomes allthe way to the tip. Hence, the replica-tion machinery had to leave a small re-gion at the end (a piece of the telomere)uncopied [see box on page 94]. In theo-ry, if cells had no way to compensate forthis quirk, chromosomes would shortenwith each round of cell division. Even-tually, the erosion would eliminate thetelomeres and critical genes in somegeneration of the cells. These cells wouldthus perish, spelling the end of that cel-lular lineage. Clearly, all single-cell spe-cies subject to such shortening manageto counteract it, or they would have van-ished long ago. So do germ-line cells(such as the precursors of sperm andeggs), which perpetuate the species inmulticellular organisms. But how dosuch cells protect their telomeres?

For Blackburn, Szostak and Shampay,the observed ßuctuations in telomere

92 SCIENTIFIC AMERICAN February 1996

Telomeres, Telomerase and Cancer

An unusual enzyme called telomerase acts on parts of chromosomesknown as telomeres. The enzyme has recently been found in manyhuman tumors and is being eyed as a new target for cancer therapy

by Carol W. Greider and Elizabeth H. Blackburn

Copyright 1996 Scientific American, Inc.

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SCIENTIFIC AMERICAN February 1996 93

TELOMERES, the end caps on chromosomes, preventchromosomes from sticking to one another and other-wise interacting in ways that threaten their stability.The telomeres in a human skin cell are highlighted bybright colors in the micrograph above. The image,made by confocal laser scanning microscopy, is a com-posite of optical sections through the nucleus; eachcolor represents a diÝerent depth.TO

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length were a sign that cells attempt tomaintain telomeres at a roughly con-stant size. Yes, telomeres do shortenduring cell division, but they are alsolengthened by the attachment of newlysynthesized telomeric subunits. The re-searchers suspected that the source ofthese additional repeats was some un-discovered enzyme capable of a trickthat standard DNA polymerases couldnot perform.

When cells replicate their chromo-somes, which consist of two strands ofDNA twisted around each other, theybegin by separating the double helix.The polymerases use each of these Òpar-entÓ strands as a template for construct-ing a new partner. The special enzymethe workers envisioned would be ableto build extensions to single strands ofDNA from scratch, without beneÞt ofan existing DNA template.

In 1984 the two of us, working inBlackburnÕs laboratory at Berkeley, setout to discover whether this putativetelomere-lengthening enzymeÑtelo-meraseÑactually existed. To our delight,we found it did. When we mixed syn-thetic telomeres with extracts of Tetra-

hymena cells, the telomeres gained add-ed subunits, just as would be expectedif the proposed enzyme were present.

Within the next several years we andour colleagues learned much about howtelomerase works. Like all polymerasesand virtually all enzymes, it consistsmainly of protein, and it requires thatprotein to function. Uniquely, though, italso includes a single molecule of RNA(close cousin to DNA) that contains thecritical nucleotide template for buildingtelomeric subunits. Telomerase placesthe tip of one strand of DNA on theRNA, positioning itself so that the tem-plate lies adjacent to that tip. Then theenzyme adds one DNA nucleotide at atime until a full telomeric subunit isformed. When the subunit is complete,telomerase can attach another by slid-ing to the new end of the chromosomeand repeating the synthetic process.

Telomerase and Human Aging

In 1988 Greider left Berkeley for ColdSpring Harbor Laboratory, and later

our groups and others found telomerasein ciliates distinct from Tetrahymena,

as well as in yeast, frogs and mice. In1989 Gregg B. Morin of Yale also discov-ered it, for the Þrst time, in a humancancer cell lineÑthat is, in malignantcells maintained for generations in cul-ture dishes. Today it is evident thattelomerase is synthesized by nearly allorganisms with nucleated cells. The pre-cise makeup of the enzyme can diÝerfrom species to species, but each ver-

sion possesses a species-speciÞc RNAtemplate for building telomeric repeats.

The importance of telomerase inmany single-cell organisms is now in-disputable. Such organisms are immor-tal in that, barring accidents or geneti-cists meddling in their lives, they candivide indeÞnitely. As Guo-Liang Yu inBlackburnÕs research group demonstrat-ed in 1990, Tetrahymena needs telo-merase in order to retain this immortal-ity. When the enzyme is altered, telo-

meres shrink and cells die. BlackburnÕsteam and others have similarly demon-strated in yeasts that cells lacking telo-merase undergo telomere shorteningand perish. But what role does telo-merase play in the human body, whichconsists of a myriad of cell types and isconsiderably more complex than Tetra-

hymena or yeast?Surprisingly, many human cells lack

telomerase. Greider and others madethis discovery in the late 1980s, when


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4 But the enzymes cannot fillthe gap remaining at oneend (the 5′ tip) of each

1 Copying of chromosomal DNA, shown highly schematically, proceeds from regions known asorigins of replication, at which the parent strands separate. Synthesis of each daughter strand

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The End-Replication Problem

The so-called end-replication problem arises from the inability of standard mecha-nisms for replicating chromosomes to do a complete job. When enzymes known as

DNA polymerases copy the two original, or “parent,” DNA strands in a chromosome, theyleave each new “daughter” strand shortened at one tip (at the end traditionally labeled5′ ). If cells did not compensate for this flaw in the replication mechanism, chromosomeswould inexorably shrink. The existence of telomerase, the enzyme that elongates telo-meres, was proposed in the early 1980s as a solution to the end-replication problem.

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they pulled together the threads of re-search that investigators in Philadel-phia had initiated more than 25 yearsearlier. Before the 1960s, human cellsthat replicated in the body were thoughtto be capable of dividing endlessly. Butthen Leonard Hayßick and his co-work-ers at the Wistar Institute demonstrat-ed unequivocally that this notion wasincorrect. Today it is known that so-matic cells (those not part of the germline) derived from human newborns will

usually divide 80 to 90 timesin culture, whereas thosefrom a 70-year-old are likelyto divide only 20 to 30 times.When human cells that arenormally capable of dividingstop reproducingÑor, in Hay-ßickÕs words, become Òsene-scentÓÑthey look diÝerentand function less eÛcientlythan they did in youth, andafter a while they die.

In the 1970s a Soviet sci-entist named A. M. Olovni-kov linked this programmedcessation of cell division tothe end-replication problem.He proposed that human so-matic cells might not cor-rect the chromosomal short-ening that occurs when cellsreplicate their DNA. Perhapsdivision ceased when cellsdiscerned that their chromo-somes had become too short.

We were unaware of Olov-nikovÕs ideas until 1988,when Calvin B. Harley, thenat McMaster University,brought them to GreiderÕsattention. Intrigued, Greider,Harley and their collabora-tors decided to see if chro-mosomes do get shorter inhuman cells over time.

Sure enough, most normal somaticcells they examined lost segments oftheir telomeres as they divided in cul-ture, a sign that telomerase was not ac-tive. Similarly, they and Nicholas D.HastieÕs group at the Medical ResearchCouncil (MRC) in Edinburgh found thattelomeres in some normal human tis-sues shrink as people age. (Reassuring-ly, Howard J. Cooke, also at the MRC inEdinburgh, had shown that telomeresare kept intact in the germ line.) These

results indicated that human cells mightÒcountÓ divisions by tracking the num-ber of telomeric repeats they lose, andthey might stop dividing when telo-meres decline to some critical length.But deÞnitive proof for this possibilityhas not yet been obtained.

Could the reduction of telomeres andof proliferative capacity over time be acause of human aging? It is probablynot the main cause. After all, cells canusually divide more times than is re-quired in a human life span. Neverthe-less, the functioning of the older bodymay at times be compromised by thesenescence of a subset of cells. For in-stance, local wound healing could beimpaired by a reduction in the numberof cells available to build new skin at asite of injury, and a reduction in thenumber of certain white blood cellscould contribute to age-related declinesin immunity. Further, it is known thatatherosclerosis typically develops whereblood vessel walls have been damaged.It is conceivable that cells at repeatedlyinjured sites could Þnally Òuse upÓ theirreplicative capacity, so that the vesselsultimately fail to replace lost cells. Thendamage would persist, and atheroscle-rosis would set in.

The Cancer Connection

Some investigators suspect that theloss of proliferative capacity ob-

served in human cells lacking telo-merase may have evolved not to makeus decrepit but to help us avoid cancer.Cancers arise when a cell acquires mul-tiple genetic mutations that togethercause the cell to escape from normalcontrols on replication and migration.As the cell and its oÝspring multiplyuncontrollably, they can invade anddamage nearby tissue. Some may alsobreak away and travel to parts of the


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How Telomerase Solves the Problem

One scheme for how telomerase solves the end-repli-cation problem proposes that the enzyme adds

DNA to chromosomes before replication begins. Theadded DNA consists of one or more telomeric subunits:the short sequences of nucleotides that are repeatedover and over in telomeres. The addition ensures that adaughter strand will be at least as long as its parent.

TELOMERASE carries its own tem-plate (purple) for synthesizing telo-meric DNA; here the enzyme is attach-ing the sequence TTGGGG (dark gold ) toa chromosome in Tetrahymena. Telomeraseadds nucleotides that are ÒcomplementaryÓ tothose in the templateÑthat is, it aligns T nucleo-tides with As, and G nucleotides with Cs.

1 Before replication begins, telomeraseadds some number of telomeric repeats(gold) to one end of each parent strand.

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body where they do not belong,establishing new malignancies(metastases) at distant sites. Intheory, a lack of telomerase wouldretard the growth of tumors bycausing continually dividing cellsto lose their telomeres and to suc-cumb before they did much dam-age. If cancer cells made telomer-ase, they would retain their telo-meres and would potentiallysurvive indeÞnitely.

The notion that telomerasemight be important to the main-tenance of human cancers wasdiscussed as early as 1990. Butthe evidence did not become com-pelling until recently. In 1994Christopher M. Counter, SilviaBacchetti, Harley and their col-leagues at McMaster showed thattelomerase was active not only incancer-cell lines maintained in thelaboratory but in ovarian tumors in thehuman body. Later that year groups ledby Harley, who had moved to GeronCorporation in Menlo Park, Calif., andby Jerry W. Shay of the University ofTexas Southwestern Medical Center atDallas detected telomerase in 90 of 101human tumor samples (representing 12tumor types) and in none of 50 samplesof normal somatic tissue (representingfour tissue types).

Even before such evidence was ob-tained, however, researchers had begunexploring some of the details of howtelomerase might contribute to cancer.That work suggests telomerase proba-bly becomes active after a cell has al-ready lost its brakes on proliferation.

The Þrst clue was an initially mysti-fying discovery made independently byTitia de Lange, now at the RockefellerUniversity, and by HastieÕs group. In1990 these investigators reported thattelomeres in human tumors were short-er than telomeres in the normal sur-rounding tissueÑsometimes dramati-cally so.

Studies by GreiderÕs, BacchettiÕs andHarleyÕs laboratories explained why thetelomeres were so small. The teams hadinduced normal cells from humans tomake a viral protein causing cells to ig-nore the alarm signals that usually warnthem to stop dividing. The treated cellscontinued to proliferate long after theywould normally enter senescence. Inmost of the cells, telomeres shorteneddrastically, and no telomerase was de-tected; eventually death ensued. Somecells, however, persisted after their sib-lings died and became immortal. Inthese immortal survivors, telomereswere maintained at a strikingly shortlength, and telomerase was present.

These outcomes imply that telomeres

in cancer cells are small because cellssynthesize telomerase only after theyhave already begun to replicate uncon-trollably; by then, the cells have pre-sumably lost a substantial number oftelomeric subunits. When the enzymeis Þnally activated, it stabilizes the se-verely clipped telomeres, allowing over-ly proliÞc cells to become immortal.

These Þndings and others have led toan attractive but still hypothetical mod-el for the normal and malignant activa-tion of telomerase by the human body.According to this model, telomerase ismade routinely by cells of the germ linein the developing embryo. Once thebody is fully formed, however, telomer-ase is repressed in many somatic cells,and telomeres shorten as such cells re-produce. When telomeres decline to athreshold level, a signal is emitted thatprevents the cells from dividing further.

If, however, cancer-promoting geneticmutations block issuance of such safe-ty signals or allow cells to ignore them,cells will bypass normal senescence andcontinue to divide. They will also pre-sumably continue to lose telomeric se-quences and to undergo chromosomalalterations that allow further, possiblycarcinogenic mutations to arise. Whentelomeres are completely or almostcompletely lost, cells may reach a pointat which they crash and die.

But if the genetic derangements ofthe pre-crisis period lead to the manu-facture of telomerase, cells will not com-pletely lose their telomeres. Instead theshortened telomeres will be rescuedand maintained. In this way, the geneti-cally disturbed cells will gain the im-mortality characteristic of cancer.

This scenario has generally beenborne out by the evidence, although,once again, things may not be entirely

as they seem. Some advanced tumorslack telomerase, and some somaticcellsÑnotably the white blood cellsknown as macrophages and lympho-cytesÑhave recently been found tomake the enzyme. Nevertheless, on bal-ance, the collected evidence suggeststhat many tumor cells require telomer-ase in order to divide indeÞnitely.

Prospects for Cancer Therapy

The presence of telomerase in vari-ous human cancers and its absence

in many normal cells mean the enzymemight serve as a good target for anti-cancer drugs. Agents able to hobbletelomerase might kill tumor cells (byallowing telomeres to shrink and dis-appear) without disrupting the func-tioning of many normal cells. In con-trast, most existing anticancer therapiesdisturb normal cells as well as malig-nant ones and so are often quite toxic.Further, because telomerase occurs innumerous cancers, such agents mightwork against a broad array of tumors.

These exciting possibilities are nowbeing actively explored by pharmaceu-tical and biotechnology companies. Nev-ertheless, a number of questions mustbe answered. For instance, researchersneed to determine which normal cells(beyond the few already identiÞed)make telomerase, and they need to as-sess the importance of the enzyme tothose cells. If telomerase is crucial,drugs that interfere with it might in factprove unacceptably toxic. The shortnessof telomeres in certain tumor cells mayobviate this problem, however. Telo-merase-inhibiting agents might causecancer cells to lose their telomeres anddie well before normal cells, with theirmuch longer telomeres, lose enough of


GERM-LINE CELLSTelomerase is activeTelomeres are maintained

SOMATIC CELLSTelomerase is inactiveTelomeres shorten

ABNORMAL CELLS THAT IGNORE WARNINGS TO STOP DIVIDINGTelomerase is inactiveTelomeres shorten

IMMORTALIZED SOMATIC CELLS AND TUMOR CELLSTelomerase is activeTelomeres are maintained

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their telomeres to suÝer any ill eÝects.Investigators must also demonstrate

that inhibition of telomerase can de-stroy telomerase-producing tumors asexpected. Last September, Harley, Grei-der and their co-workers showed thatan inhibitory agent could cause the telo-meres of cultured tumor cells to shrink;the aÝected cells died after about 25cycles of cell division. Blackburn, nowat the University of California at SanFrancisco, and her group have found,however, that cells sometimes compen-sate for the loss of telomerase. They repair their shortened ends by othermeans, such as by a process called re-combination, in which one chromosomeobtains DNA from another. If activationof alternative, Òtelomere-salvagingÓ path-ways occurs frequently in human tu-mors, therapy targeted to telomerasewould fail.

Studies of animals should help re-solve such concerns. They should alsohelp reveal whether inhibitors of telo-merase will eliminate tumors in the liv-ing body and whether they will do soquickly enough to prevent cancers frominjuring critical tissue.

To develop agents that will block telo-merase in the human body, investiga-tors must also have a sharper picture ofexactly how the enzyme functions. Howdoes it attach to DNA? How does itÒdecideÓ on the number of telomericsubunits to add? DNA in the nucleus isstudded with all manner of proteins,including some that speciÞcally bind tothe telomere. What part do telomere-binding proteins play in controlling theactivity of telomerase? Would alteringtheir activity disrupt telomere elonga-tion? Within the next 10 years we ex-pect to learn a great deal about the in-teractions among the various moleculesthat inßuence telomere length.

Research into the regulation of telo-mere size could also yield beneÞts be-yond new therapies for cancer. A popu-lar approach to gene therapy for vari-ous diseases involves extracting cellsfrom a patient, inserting the desiredgene and then returning the geneticallycorrected cells to the patient. Frequent-ly, though, the extracted cells proliferatepoorly in the laboratory. Perhaps inser-tion of telomerase alone or in combina-tion with other factors would temporar-

ily enhance replication capacity, so thatlarger numbers of therapeutic cellscould be delivered to the patient.

Modern research into telomeres hascome a long way from the initial identi-Þcation of repetitive DNA on the endsof chromosomes in a unicellular ponddweller. Elongation of telomeres by telo-merase, initially considered to be mere-ly a ÒcuteÓ mechanism by which somesingle-cell creatures maintain their chro-mosomes, has proved, as ever, to beother than it seemed. Telomerase is, infact, the predominant means by whichnucleated cells of most animals protecttheir chromosomal end segments. And,now, study of this once obscure pro-cess may lead to innovative strategiesfor Þghting a range of cancers.

In the early 1980s scientists wouldnot have set out to identify potentialanticancer therapies by studying chro-mosome maintenance in Tetrahymena.

The research on telomerase reminds usthat in studies of nature one can neverpredict when and where fundamentalprocesses will be uncovered. You neverknow when a rock you Þnd will turnout to be a gem.


Further Reading

IDENTIFICATION OF A SPECIFIC TELOMERE TERMINAL TRANSFERASE ACTIVITY IN TETRAHY-MENA EXTRACTS. Carol W. Greider and Elizabeth H. Blackburn in Cell, Vol. 43, Part 1,pages 405Ð413; December 1985.

IN VIVO ALTERATION OF TELOMERE SEQUENCES AND SENESCENCE CAUSED BY MUTATEDTETRAHYMENA TELOMERASE RNAS. G.-L. Yu, J. D. Bradley, L. D. Attardi and E. H. Black-burn in Nature, Vol. 344, pages 126Ð132; March 8, 1990.

TELOMERASE, CELL IMMORTALITY AND CANCER. C. B. Harley, N. W. Kim, K. R. Prowse, S. L.Weinrich, K. S. Hirsch, M. D. West, S. Bacchetti, H. W. Hirte, C. W. Greider, W. E. Wrightand J. W. Shay in Cold Spring Harbor Symposia in Quantitative Biology, Vol. LVIX, pages307Ð315; 1994.

TELOMERES. Edited by E. H. Blackburn and C. W. Greider. Cold Spring Harbor LaboratoryPress, 1995.

The Authors

CAROL W. GREIDER and ELIZABETH H.BLACKBURN began collaborating in 1983,when Greider joined BlackburnÕs laboratory atthe University of California, Berkeley. Greider,who earned her Ph.D. in molecular biologyfrom Berkeley in 1987, is senior staÝ scientistat Cold Spring Harbor Laboratory. Blackburnholds a 1975 doctorate in molecular biologyfrom the University of Cambridge. She has beena professor of microbiology and immunologyat the University of California, San Francisco,since 1990 and department chair since 1993.

YOUNG CELLS SENESCENT CELLS TUMOR CELLS

MODEL OF TELOMERE LENGTH REGULATION in humanssuggests that germ-line cells (blue line in graph at left ) maketelomerase and maintain telomeres at a long length. In con-trast, many somatic, or nongerm, cells (dark gold curve) pre-sumably lack telomerase, and so their telomeres shrink overtime. Eventually, most somatic cells enter senescence: theystop dividing and undergo other changes. Aberrant cells

(light gold curve) might continue to divide, however. Manywill lose telomeric repeats until they reach a crisis point anddie. But if the deranged cells begin to make telomerase, theymay replicate indeÞnitely (green curve). This property,found in many tumor cells, is known as cellular immortality.The micrographs above show young somatic cells (left ),senescent cells (center) and immortal tumor cells (right ).

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Telomeres, Telomerase and Cancer

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