Nobel Prize in Physiology or Medicine 2009: Telomeres and the Enzyme Telomerase

This note covers the Nobel Prize in Physiology or Medicine 2009: who won it, how telomeres and the enzyme telomerase protect chromosome ends, how the discovery unfolded across two very different organisms, why it matters for ageing and cancer, and quick facts for exams.

What was the Nobel Prize in Physiology or Medicine 2009 awarded for?

The Nobel Assembly at Karolinska Institutet gave the prize jointly "for the discovery of how chromosomes are protected by telomeres and the enzyme telomerase".

In plain words, the three laureates found out what sits at the very ends of our chromosomes (the thread-like structures that carry DNA) and how that end-cap is maintained every time a cell divides.

Chromosomes must be copied completely each time a cell divides, or genetic information gets lost or damaged.

The scientists discovered that a special repeating DNA sequence, called the telomere, forms a protective cap at each chromosome end, and that an enzyme named telomerase rebuilds this cap so that it is not lost over repeated divisions.

The official name of the award is the Nobel Prize in Physiology or Medicine.

Who are the laureates?

Elizabeth H. Blackburn

Elizabeth H. Blackburn was born on 26 November 1948 in Hobart, Tasmania, Australia. At the time of the award she worked at the University of California, San Francisco, USA, and held one third of the prize.

She mapped the DNA sequence at the chromosome ends of the single-celled organism Tetrahymena and, with Jack Szostak, showed this sequence protects chromosomes from breaking down. With Carol Greider she went on to discover the enzyme telomerase.

Carol W. Greider

Carol W. Greider was born on 15 April 1961 in San Diego, California, USA. At the time of the award she worked at the Johns Hopkins University School of Medicine in Baltimore, USA, and held one third of the prize.

As a graduate student under Blackburn's supervision, she detected the enzyme activity that builds telomere DNA on Christmas Day 1984, and the pair later named and characterised this enzyme, telomerase.

Jack W. Szostak

Jack W. Szostak was born on 9 November 1952 in London, United Kingdom, and grew up in Canada.

At the time of the award he was affiliated with Harvard Medical School, Massachusetts General Hospital in Boston, and the Howard Hughes Medical Institute, USA, and held one third of the prize.

He showed that a linear DNA molecule introduced into yeast cells is rapidly degraded, a problem that led directly to the cross-species telomere experiment with Blackburn, who supplied the telomere sequence that solved it.

What problem in biology were the laureates trying to solve?

By the early twentieth century, scientists such as Thomas Hunt Morgan had shown that chromosomes carry genes.

Two later Nobel laureates, Hermann Muller and Barbara McClintock, noticed in the 1930s that broken chromosome ends behaved oddly, sticking to each other or rearranging, while the natural ends of chromosomes did not.

Muller coined the word "telomere" from the Greek for "end" and "part", but no one knew what made these ends special or how they resisted the fusing and breakage seen at accidental breaks elsewhere on a chromosome.

A second puzzle arose once scientists understood how DNA is copied. After James Watson, Francis Crick and Maurice Wilkins worked out the structure of DNA, and after DNA polymerase enzymes were identified as the machinery that copies DNA base by base, it became clear that this machinery always needs an existing starting point, called a primer, and copies in one direction only.

On a straight (linear) DNA molecule, one of the two strands, called the lagging strand, is copied in short separate stretches, each needing its own starting primer; at the very tip of the chromosome there is no room left for a further primer, so that last bit of sequence cannot be filled in.

Logically, chromosomes should get a little shorter every time a cell divides. Scientists including James Watson and the Russian researcher Alexei Olovnikov pointed this out independently, calling it the end-replication problem. Yet chromosomes in living cells generally keep their length.

Many simple organisms such as bacteria avoid the problem entirely because their DNA forms a closed loop with no ends to copy; but humans and most other complex organisms carry their genes on open, linear DNA strands, so the problem had to be solved some other way.

These were not abstract puzzles. If the end-replication problem were real and unsolved, cells would gradually lose genetic material with each division, which would eventually damage genes and threaten the cell's survival. Solving it mattered for understanding normal cell division, ageing and, eventually, cancer.

How does the telomere protect the chromosome end?

Working separately in the late 1970s, Elizabeth Blackburn studied the single-celled ciliate Tetrahymena, which happens to have tens of thousands of short, repeated minichromosomes with easily analysed ends. She found that the ends of these minichromosomes carried a short DNA sequence, CCCCAA, repeated between about twenty and seventy times.

At the same time, Jack Szostak, working with yeast, found that artificial linear DNA molecules (minichromosomes) he inserted into yeast cells broke down quickly, as if they lacked some protective feature present in real chromosomes.

The two met at a scientific conference in 1980 and designed an experiment that crossed the boundary between two very different species.

1. Blackburn isolated the repeated CCCCAA telomere sequence from Tetrahymena.
2. Szostak attached this sequence to both ends of his linear yeast minichromosomes.
3. These modified minichromosomes were introduced back into yeast cells.
4. Unlike before, the minichromosomes survived and were maintained stably, published in 1982.

Because telomere DNA from one organism protected chromosomes in an entirely different organism, this showed that telomeres use a fundamental mechanism conserved across very distant forms of life, later found in most plants and animals, from amoeba to humans.

Szostak then went further. He removed one of the Tetrahymena-derived ends from his artificial chromosome and replaced it with various fragments of ordinary yeast DNA, then watched which fragments kept the chromosome stable. Most fragments failed, but eventually he identified yeast's own natural telomere sequence, a short repeat closely resembling the Tetrahymena repeat. This confirmed that yeast chromosomes carry their own version of the same end-protecting mechanism, rather than simply borrowing one from Tetrahymena.

The researchers also noticed something unexpected: when they examined chromosomes that had spent time dividing inside yeast cells, some telomeres had grown longer rather than shorter. This observation, that telomere length could increase as well as decrease, suggested that some unknown process was actively building new telomere DNA onto the chromosome ends, rather than the ends simply being left alone once attached.

Draw a chromosome as a straight ladder-like DNA strand being copied by an enzyme labelled DNA polymerase, moving along in one direction on the top strand but working in short, separate patches on the bottom strand, leaving a short uncopied overhang at one end each time; label the overhang "lost each division without telomerase".

How was telomerase discovered and how does it work?

Once the telomere's protective sequence was known, a new question appeared: how is this repeated sequence actually built onto the chromosome end, since an ordinary DNA-copying enzyme needs an existing template strand to copy from? Carol Greider, then a graduate student in Blackburn's laboratory, searched for an unknown enzyme that could add this sequence without a normal template.

On Christmas Day 1984, Greider found the first sign of such an enzyme activity in a cell extract from Tetrahymena. She and Blackburn purified it and showed it contained both protein and RNA, and they named it telomerase.

1. Telomerase recognises the single-stranded overhang at the chromosome end.
2. Its RNA component, which carries a sequence matching the telomere repeat, acts as an internal template.
3. The protein component of telomerase uses this RNA template to add new telomere DNA bases one at a time.
4. The enzyme then repositions itself (translocates) along the newly made DNA to add further repeats.
5. The extended telomere then gives ordinary DNA polymerase a longer platform, letting it finish copying the chromosome right up to the tip without losing DNA.

In 1989 Greider and Blackburn confirmed that the RNA part of telomerase indeed contains a sequence matching the telomere repeat, and the following year further mutation experiments by Blackburn's group proved that this RNA genuinely serves as the template for building new telomere DNA.

Draw a short single DNA strand ending in repeated letters, with an oval labelled telomerase sitting on the end, containing a wavy RNA loop inside it as the template, and an arrow showing new repeated bases being added one at a time onto the strand's end.

How did telomere research reveal why cells grow old?

Once telomerase had been identified, scientists wanted to know what role, if any, telomeres played in the everyday life and ageing of a cell. Szostak's laboratory found a mutant strain of yeast, nicknamed EST1 for "ever shorter telomeres", in which telomeres became progressively shorter with each cell division.

These EST1 mutant cells lost chromosomes more often than normal and eventually stopped dividing altogether, entering a state called premature senescence. Blackburn's group produced a similar effect by mutating the RNA component of telomerase in Tetrahymena, again causing early senescence and defects inside the cell's nucleus.

Together, these yeast and Tetrahymena experiments showed that an intact, properly maintained telomere is needed to protect a chromosome from damage and to delay the point at which a cell stops dividing.

A separate line of thinking had started decades earlier. In the 1970s, the Russian scientist Alexei Olovnikov noticed that human cells grown in laboratory dishes can only divide a limited number of times, a long-known limit sometimes linked to the work of Leonard Hayflick. Skin cells from a newborn baby could divide roughly 80 to 90 times, whereas cells taken from a 70-year-old could manage only about 20 to 30 divisions.

Olovnikov proposed that the end-replication problem might explain this limit: perhaps chromosomes shorten with every division until they fall below some critical length, at which point the cell can no longer safely divide and instead stops, as if a built-in tally had run out.

Carol Greider's laboratory later confirmed directly that telomeres in human cells do indeed shorten during repeated cell division in culture, lending support to this idea. For a time, many scientists speculated that telomere shortening alone might explain ageing of the whole organism, not just of individual cells, but this is now known to be an attractive but incomplete picture, since ageing was later found to depend on many different factors working together.

Why does telomere and telomerase research matter?

If telomeres shorten, cells age, a process called cellular senescence; but if telomerase activity stays high, telomere length is kept up and this ageing is delayed.

The Nobel Committee described cancer cells, which keep dividing almost without limit, as having "eternal life" in this sense, because most of them keep telomerase unusually active.

This has practical medical relevance in several directions. In cancer, scientists have proposed treatments that block telomerase activity or use vaccines that target cells with abnormally high telomerase activity, and clinical trials of such approaches were under way at the time of the award, though no therapy had yet proved conclusively effective.

Some cancer cells, however, can keep their telomeres long through an alternative route that does not rely on telomerase at all, sometimes called an alternative lengthening mechanism, which means simply blocking telomerase might not stop every tumour.

Normal body cells, by contrast, mostly divide infrequently, so their telomeres are rarely at risk of becoming dangerously short, and they therefore do not usually need strong telomerase activity; this difference between quiet normal cells and constantly dividing cancer cells is part of why telomerase looked like a promising target for new drugs.

In hereditary disease, some inherited conditions are caused by a defective telomerase. These include certain forms of congenital aplastic anaemia, where poor stem cell division in bone marrow leads to severe anaemia, as well as certain inherited diseases of the skin and lungs linked to telomerase defects.

On ageing in general, the picture is known to be incomplete: although telomere shortening was at first thought to explain organismal ageing, the process has turned out to be complex, with ageing depending on several different factors, of which telomere length is only one.

Research in this area remains intense, and the full significance of telomere biology for human health continues to be studied.

How does this connect to what you study?

This discovery sits at the heart of basic cell biology taught in school science: how chromosomes carry genetic information, how DNA copies itself before a cell divides, and how enzymes carry out specific jobs inside the cell. The puzzle of the end-replication problem gives a concrete, worked example of why ordinary DNA-copying machinery cannot simply be assumed to copy everything perfectly, and why living cells need a special extra mechanism at their chromosome ends.

It also links directly to the biology of cancer, since cancer cells are often described as dividing almost without limit, which connects to the high telomerase activity found in most cancer cells. A student studying cell division and cancer together can use telomerase as a single example that ties the two topics into one coherent story about how control of cell division can fail.

Understanding that telomerase uses an RNA template, not a DNA template, to build new DNA is also a useful example of how enzymes can work in unexpected ways. It extends the usual idea, taught for standard DNA polymerase, that an enzyme copying DNA always needs an existing DNA strand as its template; telomerase instead carries its own built-in RNA blueprint, which is an unusual and memorable exception worth remembering for exams on enzyme function and genetics.

Finally, the discovery illustrates how curiosity-driven research on simple organisms such as Tetrahymena and yeast can, over time, turn out to matter for human health, a theme useful for general-studies questions on the nature and value of scientific research.

Quick facts for exams

The Nobel Prize in Physiology or Medicine 2009 was announced on 5 October 2009 and awarded jointly to Elizabeth H. Blackburn, Carol W. Greider and Jack W. Szostak, each receiving one third of the prize, for working out how chromosome ends are protected by telomeres and the enzyme telomerase. The prize is given by the Nobel Assembly at Karolinska Institutet.

Blackburn was born in Australia and worked at the University of California, San Francisco; Greider was born in the United States and worked at Johns Hopkins University;

Szostak was born in the United Kingdom and worked at Harvard Medical School and related institutions in the United States.

Their work explained how telomere DNA caps chromosome ends and how telomerase rebuilds this cap, with implications for ageing, cancer and certain inherited diseases.

Note: Source. The prize facts in this note are from the Nobel Prize's official site, nobelprize.org.

Glossary

• Chromosome — a structure inside a cell nucleus made of DNA that carries genetic information.
• Telomere — a repeated DNA sequence that forms a protective cap at each end of a chromosome.
• Telomerase — an enzyme, made of protein and RNA, that builds new telomere DNA onto chromosome ends.
• DNA polymerase — an enzyme that copies an existing DNA strand base by base using it as a template.
• End-replication problem — the difficulty that DNA polymerase cannot fully copy the very end of a linear DNA strand.
• Senescence — the state in which a cell stops dividing, often linked to shortened telomeres.
• Tetrahymena — a single-celled freshwater ciliate organism used to study telomeres, with over 40,000 telomeres per cell.
• Minichromosome — a small, artificial or extra linear DNA molecule used in telomere experiments in yeast.
• RNA template — the part of telomerase's RNA component that specifies the sequence of DNA bases to be added.
• Dyskeratosis congenita — an inherited disease linked to telomerase gene mutations, which can cause premature ageing signs such as hair loss, nail changes and skin pigmentation.
• Aplastic anaemia — a condition with reduced blood cell production, in some forms caused by telomerase defects.
• Nobel Assembly — the body of 50 professors at Karolinska Institutet that awards the Nobel Prize in Physiology or Medicine.

Common errors and misconceptions

• Misconception: Telomerase is active and needed in every normal human cell all the time. Correct: most normal cells divide rarely and do not require much telomerase activity; it is cancer cells, which divide constantly, that most often show high telomerase activity.
• Misconception: Telomere shortening is the single, complete explanation for ageing. Correct: ageing is complex and depends on several different factors, of which telomere length is only one.
• Misconception: Telomerase was discovered by one scientist alone. Correct: Carol Greider detected the enzyme activity, but the discovery and naming of telomerase, and the proof that its RNA acts as a template, came from joint work with Elizabeth Blackburn.
• Misconception: The 1982 Blackburn-Szostak experiment used two similar organisms. Correct: it deliberately crossed very distant species, a single-celled ciliate (Tetrahymena) and yeast, to show the mechanism was general.
• Misconception: Blocking telomerase is already a proven cancer cure. Correct: clinical trials of telomerase-targeting therapies are ongoing, with no conclusive results reported.
• Misconception: Telomeres only shorten and never change otherwise. Correct: studies showed telomeres can both grow and shrink, depending on telomerase activity.

Exam-style questions with model answers

Q1. What is a telomere? [2 marks]

1. A telomere is a repeated DNA sequence that forms a protective cap at each end of a chromosome, preventing the chromosome from breaking down or fusing with others.

Q2. Name the three laureates of the Nobel Prize in Physiology or Medicine 2009 and state their shares. [2 marks]

1. Elizabeth H. Blackburn, Carol W. Greider and Jack W. Szostak each received one third of the prize.

Q3. Describe the 1982 experiment that first showed telomere DNA protects chromosomes. [4 marks]

1. Elizabeth Blackburn isolated the repeated CCCCAA telomere sequence from the single-celled organism Tetrahymena.
2. Jack Szostak attached this sequence to both ends of artificial linear minichromosomes he had built for use in yeast.
3. These modified minichromosomes were inserted into yeast cells, which had previously degraded unprotected linear DNA quickly.
4. The modified minichromosomes survived and were stably maintained, showing that telomere DNA from one organism could protect chromosomes in an entirely different organism, published in 1982.

Q4. Explain the end-replication problem and how telomerase solves it. [4 marks]

1. DNA polymerase, the enzyme that copies DNA, cannot fully copy the very end of one strand of a linear DNA molecule during cell division.
2. Without a solution, this would mean chromosomes get a little shorter each time a cell divides, a problem known as the end-replication problem.
3. Telomerase solves this by using its own built-in RNA template to add new repeated telomere DNA bases onto the chromosome end.
4. This extended telomere then gives ordinary DNA polymerase enough length to copy the rest of the chromosome without losing genetic material at the very end.

Q5. Discuss the medical significance of the discovery of telomeres and telomerase. [6 marks]

1. The discovery explained a fundamental mechanism of the cell: how chromosome ends are protected and rebuilt, solving a long-standing biological puzzle about complete chromosome copying.
2. In ageing, telomere shortening was linked to cellular senescence, the state in which cells stop dividing, though overall organismal ageing is now known to depend on many factors beyond telomere length alone.
3. In cancer, most cancer cells keep dividing indefinitely because they maintain abnormally high telomerase activity, described by the Committee as giving them a kind of "eternal life".
4. This insight led to proposed cancer therapies that either inhibit telomerase activity or use vaccines targeting cells with excessive telomerase activity, with clinical trials under way though without conclusive results at the time of the award.
5. Certain inherited diseases, including some forms of congenital aplastic anaemia and certain skin and lung conditions, are now known to result from defective telomerase, aiding diagnosis.
6. Overall, the award recognised basic, curiosity-driven research that was not aimed at any immediate medical use but later proved important across multiple areas of biology and medicine.

Q6. Who first identified the enzyme telomerase, and when? [2 marks]

1. Carol Greider, working in Elizabeth Blackburn's laboratory, first detected signs of telomerase activity in a cell extract on Christmas Day 1984.

Q7. Explain the role of the RNA component of telomerase. [3 marks]

1. Telomerase is made of a protein part and an RNA part, unusually for an enzyme.
2. The RNA part contains a sequence matching the telomere repeat and acts as an internal template.
3. Greider and Blackburn found in 1989 that the RNA sequence matches the telomere repeat, and Blackburn's group confirmed the following year, through mutation experiments, that this RNA genuinely guides which DNA bases telomerase adds.

Q8. Which body awards the Nobel Prize in Physiology or Medicine? [2 marks]

1. The Nobel Prize in Physiology or Medicine is awarded by the Nobel Assembly at Karolinska Institutet, made up of fifty professors.

Key takeaways

• The 2009 medicine prize went jointly to Blackburn, Greider and Szostak for discovering telomeres and telomerase.
• Telomeres are repeated DNA sequences capping chromosome ends, protecting them from damage and fusion.
• The 1982 cross-species experiment with Tetrahymena telomere DNA in yeast proved telomeres work by a conserved mechanism.
• Telomerase, discovered on Christmas Day 1984, uses an RNA template to rebuild telomere DNA lost during replication.
• Telomere shortening contributes to cellular senescence, though overall ageing depends on many factors.
• Most cancer cells keep dividing because they maintain high telomerase activity, making telomerase a target for new cancer therapies.
• Certain inherited diseases, including some anaemias and skin and lung conditions, are caused by defective telomerase.
• The discoveries began as curiosity-driven basic research with no planned medical application at the time.

Test yourself

What does the word "telomere" mean, and who coined it?

Telomere comes from the Greek for "end" and "part"; the term was coined by Hermann Muller after observing special behaviour at chromosome ends.

Which organism did Elizabeth Blackburn first use to study telomere sequences?

Elizabeth Blackburn first studied telomere sequences in Tetrahymena, a single-celled ciliate organism with thousands of telomeres per cell.

What happened to Szostak's artificial minichromosomes in yeast before the 1982 experiment?

Before adding telomere sequence, Szostak's linear minichromosomes were rapidly degraded when introduced into yeast cells.

What two components make up the enzyme telomerase?

Telomerase consists of a protein component, which carries out the enzymatic work, and an RNA component, which serves as a template.

Why do most cancer cells avoid cellular senescence?

Most cancer cells show abnormally high telomerase activity, which keeps their telomeres from shortening despite constant division.

Name one inherited disease linked to defective telomerase.

Certain forms of congenital aplastic anaemia, caused by insufficient bone marrow stem cell division, are linked to defective telomerase.

Where did Jack W. Szostak work at the time of the award?

Jack W. Szostak was affiliated with Harvard Medical School, Massachusetts General Hospital and the Howard Hughes Medical Institute, all in the USA.