Tomas Lindahl

Tomas Lindahl
Lindahl in 2015
Tomas Lindahl
Born	Tomas Robert Lindahl 28 01, 1938
Birthplace	Stockholm, Sweden
Nationality	Swedish, British (dual nationality)
Occupation	Scientist, cancer researcher
Known for	Mechanistic studies of DNA repair, discovery of base excision repair
Education	Karolinska Institutet (MD, PhD)
Awards	Nobel Prize in Chemistry (2015) Royal Medal (2007) Copley Medal (2010)

Tomas Robert Lindahl (born 28 January 1938) is a Swedish-British scientist who has spent much of his career investigating the molecular mechanisms by which living cells repair damaged DNA. Born in Stockholm, Lindahl trained as a medical student at the Karolinska Institutet before turning to fundamental research in molecular biology and biochemistry. His groundbreaking discovery that DNA is an inherently unstable molecule — subject to constant decay and damage even under normal physiological conditions — overturned longstanding assumptions about the durability of the genetic code and opened an entirely new field of study. Lindahl identified and characterized the base excision repair pathway, one of the principal mechanisms by which cells correct lesions in DNA, and his work has had profound implications for understanding cancer, ageing, and hereditary disease. In 2015, he was awarded the Nobel Prize in Chemistry jointly with Paul L. Modrich and Aziz Sancar "for mechanistic studies of DNA repair." A Fellow of the Royal Society and the Academy of Medical Sciences, Lindahl has been associated with Cancer Research UK and the Francis Crick Institute, where he holds the status of emeritus scientist.

Early Life

Tomas Robert Lindahl was born on 28 January 1938 in Stockholm, Sweden. He grew up in the Swedish capital during the years of the Second World War and the postwar period. In a 2020 interview with the Nobel Prize organisation, Lindahl recalled that his early education played a formative role in directing him toward science, noting that he "started out as a medical student."

Lindahl's path to becoming one of the foremost researchers in DNA repair was not without its early setbacks. According to a 2025 report in The Times of India, accounts of Lindahl's educational journey have noted that he reportedly struggled with a chemistry examination during his student years — a biographical detail that has been cited as an example of how distinguished scientific careers do not always follow predictable trajectories. The anecdote has been used in educational contexts to illustrate that scientific achievement is shaped by persistence and curiosity rather than by unbroken academic success.

Growing up in Sweden, Lindahl was exposed to the country's strong tradition in the natural sciences. Stockholm, his home city, was itself a centre of scientific research and the seat of the Nobel institutions, though Lindahl has not publicly attributed his career choice to this proximity. His decision to pursue medicine initially, before turning to basic research, reflected a pattern common among Scandinavian scientists of his generation, many of whom moved from clinical training into laboratory investigation.

Education

Lindahl pursued his higher education at the Karolinska Institutet in Stockholm, one of Sweden's foremost medical universities and the institution responsible for awarding the Nobel Prize in Physiology or Medicine. He enrolled as a medical student and completed his medical degree at the Karolinska Institutet.

Continuing at the same institution, Lindahl undertook doctoral research and earned his PhD in 1967. His doctoral thesis, titled On the structure and stability of nucleic acids in solution, addressed fundamental questions about the chemical behaviour of DNA and RNA molecules under physiological conditions. This early work laid the intellectual foundation for his subsequent discoveries regarding the intrinsic instability of DNA, which would eventually reshape the field of molecular biology. The thesis was completed under the auspices of the Karolinska Institutet's research programmes in biochemistry and molecular biology.

Career

Early Research and the Instability of DNA

Lindahl's doctoral research on the structure and stability of nucleic acids in solution prompted him to question a prevailing assumption in molecular biology: that DNA was an essentially stable molecule. During the 1960s and 1970s, the dominant view held that the double-helical structure of DNA conferred a high degree of chemical robustness, ensuring that genetic information could be faithfully transmitted from one generation to the next. Lindahl, however, observed that DNA was subject to a surprising degree of spontaneous chemical decay.

Through a series of careful experiments, Lindahl demonstrated that DNA undergoes thousands of potentially damaging lesions each day in every human cell. These lesions include depurination (the loss of purine bases), deamination (the removal of amino groups from bases, converting cytosine to uracil, for example), and oxidative damage caused by reactive oxygen species. The sheer scale of this damage implied that cells must possess efficient repair mechanisms to maintain genomic integrity — otherwise, life as it exists would be impossible.

This insight was fundamental: it reframed DNA not as a static archive of genetic information but as a dynamic molecule requiring constant surveillance and maintenance. Lindahl's early work thus opened the door to decades of research into the enzymatic pathways responsible for DNA repair.

Discovery of Base Excision Repair

Lindahl's most celebrated contribution to science was the discovery and characterization of the base excision repair (BER) pathway. In a landmark 1974 paper published in the Proceedings of the National Academy of Sciences (PNAS), Lindahl described the identification of an N-glycosidase enzyme from Escherichia coli that could liberate free uracil from DNA containing deaminated cytosine residues. This enzyme, later known as uracil-DNA glycosylase, was the first DNA glycosylase to be discovered and represented the initial step of the base excision repair pathway.

The significance of this discovery was profound. When cytosine in DNA undergoes spontaneous deamination, it is converted to uracil — a base that does not normally belong in DNA and that, if left unrepaired, would lead to mutations during subsequent rounds of DNA replication. By identifying the enzyme responsible for recognizing and excising this aberrant base, Lindahl provided the first molecular evidence of a dedicated cellular repair system for dealing with one of the most common forms of endogenous DNA damage.

Subsequent work by Lindahl and his colleagues elucidated the remaining steps of the BER pathway. After the damaged base is removed by a DNA glycosylase, the resulting abasic site is cleaved by an AP endonuclease, the gap is filled by a DNA polymerase, and the strand is sealed by a DNA ligase. Lindahl's research mapped each of these enzymatic steps, providing a comprehensive picture of how cells repair the most common forms of base damage in DNA.

The discovery of BER had wide-ranging implications. It demonstrated that cells possess a sophisticated molecular toolkit for maintaining genomic integrity and provided a mechanistic explanation for how organisms can survive despite the constant chemical assault on their DNA. The pathway has since been found to be conserved across all domains of life, from bacteria to humans, underscoring its fundamental importance.

Work at Cancer Research UK and Clare Hall Laboratory

After completing his doctoral work in Sweden, Lindahl pursued postdoctoral research and held positions at several institutions before settling in the United Kingdom. He became affiliated with the Imperial Cancer Research Fund (ICRF), which later became part of Cancer Research UK, one of the world's leading cancer research charities.

Lindahl served as the first Director of the Clare Hall Laboratories in South Mimms, Hertfordshire, a research facility associated with Cancer Research UK (originally ICRF). Under his leadership, Clare Hall became a centre of excellence for research into DNA repair, mutagenesis, and genome stability. The laboratory attracted researchers from around the world and produced a substantial body of work contributing to the understanding of how DNA damage leads to cancer and how repair mechanisms protect against malignancy.

Lindahl's research programme at Clare Hall continued to expand the understanding of DNA repair mechanisms. His group investigated not only base excision repair but also the cellular responses to alkylation damage, the role of DNA ligases, and the biochemistry of other repair enzymes. This body of work contributed to the broader understanding of how defects in DNA repair pathways can predispose individuals to cancer — a connection that has had direct implications for the development of cancer therapies.

The Francis Crick Institute

Following the reorganization of several London-based biomedical research institutions, Lindahl became associated with the Francis Crick Institute, a major biomedical research centre established in 2015 through a partnership involving Cancer Research UK, the Medical Research Council, the Wellcome Trust, and several London universities. Lindahl holds the position of emeritus scientist at the Francis Crick Institute, reflecting his continued involvement in the scientific community after the formal conclusion of his laboratory directorship.

Implications for Cancer Research

Lindahl's work on DNA repair has had substantial implications for the field of cancer research. Cancer Research UK has identified at least four major ways in which his Nobel Prize-winning research contributed to advances in cancer biology and treatment.

First, by demonstrating that DNA is inherently unstable and subject to constant damage, Lindahl's work helped explain why mutations — the driving force behind cancer — arise in cells. Understanding the sources and frequency of DNA damage provided a mechanistic basis for the study of mutagenesis and carcinogenesis.

Second, the identification of DNA repair pathways such as BER revealed that defects in these pathways can increase the risk of cancer. Individuals who inherit mutations in genes encoding repair enzymes may be more susceptible to accumulating the mutations that drive tumour formation. This insight has informed genetic screening and risk assessment strategies for various cancers.

Third, the understanding of DNA repair mechanisms has been exploited in the development of new cancer treatments. Several chemotherapy drugs work by damaging the DNA of cancer cells; knowledge of how cells repair such damage has enabled researchers to design strategies that block repair pathways, thereby enhancing the effectiveness of treatment. The concept of synthetic lethality, in which cancer cells with defects in one repair pathway are selectively killed by inhibiting a second pathway, owes much to the foundational work of Lindahl and others in the DNA repair field.

Fourth, Lindahl's research contributed to the understanding of how environmental carcinogens — such as chemicals in tobacco smoke, ultraviolet radiation, and industrial pollutants — damage DNA. By characterizing the types of lesions these agents cause and the repair mechanisms that counteract them, his work helped clarify the cellular resistance to carcinogens, a topic for which he has been specifically recognized.

Personal Life

Lindahl holds dual Swedish and British nationality, having become a naturalized British citizen during his long career in the United Kingdom. In a 2018 interview with Chemistry World, Lindahl discussed aspects of his life and work in a feature titled "In situ with Tomas Lindahl," providing a glimpse into his personality and working habits.

At the Nobel Banquet held in Stockholm City Hall on 10 December 2015, Lindahl delivered his speech partly in Swedish, opening with greetings to the Swedish royal family and dignitaries: "Ers Majestäter, Ers Kungliga högheter, Excellenser, Kära pristagare." The occasion marked a return to his native city and the institution that awards the Nobel Prizes in Chemistry, having begun his scientific career at the Karolinska Institutet decades earlier.

Lindahl has maintained his connection to Sweden while residing in the United Kingdom, and his career exemplifies the international character of modern scientific research. He has been based in the UK for the majority of his professional life, working in London and Hertfordshire.

Recognition

Lindahl's contributions to molecular biology and cancer research have been recognized with numerous awards and honours over several decades.

He was elected a member of the European Molecular Biology Organization (EMBO) in 1974, early in his career, reflecting the significance of his emerging work on DNA repair.

In 1988, Lindahl was elected a Fellow of the Royal Society (FRS), one of the oldest and most distinguished scientific societies in the world. Election to the Royal Society is based on a candidate's contributions to the improvement of natural knowledge and is considered one of the highest honours available to scientists working in the United Kingdom.

In 1998, he was elected a Fellow of the Academy of Medical Sciences (FMedSci), recognizing his contributions to medical science.

Lindahl received the Royal Medal from the Royal Society in 2007 and the Copley Medal — the Royal Society's oldest and most prestigious award — in 2010, for his contributions to the understanding of DNA repair.

The culmination of Lindahl's recognition came on 7 October 2015, when the Royal Swedish Academy of Sciences announced that he would share the Nobel Prize in Chemistry with Paul L. Modrich of Duke University and Aziz Sancar of the University of North Carolina at Chapel Hill. The three laureates were cited "for mechanistic studies of DNA repair." Lindahl was recognized specifically for his work on base excision repair, Modrich for his studies of mismatch repair, and Sancar for his elucidation of nucleotide excision repair. Together, the three laureates had mapped, at a molecular level, how cells repair damaged DNA and safeguard genetic information.

The New York Times reported on the award, covering the announcement and the significance of the three laureates' contributions to understanding DNA repair mechanisms.

Legacy

Tomas Lindahl's scientific contributions have had a lasting impact on the fields of molecular biology, biochemistry, and cancer research. His fundamental insight — that DNA is not an immutable molecule but one that is constantly under threat from spontaneous chemical decay — transformed the study of genetics and genomics. Before Lindahl's work, the prevailing view of DNA emphasized its stability and fidelity; after his discoveries, the field recognized that the maintenance of genomic integrity requires an elaborate network of repair enzymes operating continuously in every living cell.

The base excision repair pathway, which Lindahl discovered and characterized, is now understood to be one of the most important and evolutionarily conserved mechanisms for maintaining DNA integrity. The pathway repairs an estimated 10,000 to 100,000 DNA lesions per cell per day in humans, and defects in BER components have been linked to cancer predisposition, neurodegeneration, and immunodeficiency. The discovery of uracil-DNA glycosylase, reported by Lindahl in 1974, initiated a new field of enzymology dedicated to the study of DNA glycosylases, of which more than a dozen distinct types have since been identified across various organisms.

Lindahl's work has also had practical consequences for medicine. The understanding of DNA repair mechanisms has informed the development of targeted cancer therapies, including PARP inhibitors, which exploit deficiencies in DNA repair pathways to selectively kill cancer cells. While PARP inhibitors were developed by multiple research groups, the foundational knowledge of repair pathways established by Lindahl and his contemporaries was essential to their conceptual underpinning.

As an emeritus scientist at the Francis Crick Institute, Lindahl remains a figure of significance in the British and international scientific community. His career, spanning more than five decades and two countries, exemplifies the cumulative and international nature of scientific progress. The Nobel Committee's decision to award the 2015 Chemistry Prize for DNA repair research affirmed the centrality of Lindahl's contributions to one of the fundamental processes of life.