Jarle Breivik

Evolution of cancer

Cancer development is an evolutionary process within the body of an organism. These papers aim to explore and explain this process in an interdisciplinary perspective. A key aspect concerns the evolutionary relationship between environmental factors and rise of genetic instability in cancer cells. This model has been tested and confirmed by several experimental studies.

Selected science papers:

• Don't stop for repairs in a war zone: Darwinian evolution unites genes and environment in cancer development. Breivik, J. Proc. Natl. Acad. Sci. U. S. A. (2001) 98, 5379-5381.
• Unstable DNA Repair Genes Shaped by Their Own Sequence Modifying Phenotypes. Falster DS, Nakken S, Bergem-Ohr M, Rødland EA and Breivik J. J. Mol. Evo. (2010) 70, 266-274.
• Resolving the evolutionary paradox of genetic instability: a cost-benefit analysis of DNA repair in changing environments. Breivik, J. & Gaudernack, G. FEBS Lett. (2004) 563, 7-12.
• The evolutionary origin of genetic instability in cancer development. Breivik, J.Semin. Cancer Biol. (2005) 15, 51-60.
• Cancer - evolution within. Breivik, J. Int. J. Epidemiol. (2006) 35, 1161-1162.

Popularized articles concerning this research:

• The way we think about cancer must evolve,Wolverton M. Wired (2013) May 22.
• No solution to cancer? Science Daily (2007) April 17.
• Have our genes evolved to turn against us? PhysOrg.com(2007) April 16.
• Evolved for cancer? Zimmer C. Scientific American (2007) 296, 68-74.
• Untangling the roots of cancer Gibbs WW. Scientific American (2003) 289, 56-65.

Immunotherapy

For my PhD, I contributed to Gustav Gaudernack's pioneering work on immunotherapy and peptide-based cancer vaccines:

• Vaccination with mutant ras peptides and induction of T-cell responsiveness in pancreatic carcinoma patients carrying the corresponding RAS mutation. Gjertsen MK, Bakka A, Breivik J, Saeterdal I, Solheim BG, Søreide O, Thorsby E, Gaudernack G. Lancet (1995) 346:1399-400.

Science and Cancer Communication

Science is generally perceived as the objective search for facts and truths. Yet, how we perceive and understand the scientific truth is largely dependent on context. A gene, for example, may be presented as a molecular structure, a thing that determines our looks or behaviors, a risk factor for getting a disease, a unit that evolves over time, or a symbol of relationship. Each frame has different implications for the way we understand biology and medicine, as well as life in general, and it is important to be aware of these different modes of genetic communication:

• Frame that gene. Carver R, Waldahl R & Breivik J, EMBO Report (2008)
• Quantitative Frame Analysis of How the Gene Concept Is Presented in Tabloid and Elite Newspapers. Carver R, Rødland, EA & Breivik J, Science Communication (2012)
• Frame Analysis in Science Education: A Classroom Activity for Promoting Media Literacy and Learning about Genetic Causation. Carver RB, Wiese EF & Breivik J, International Journal of Science Education (2013).

Evolution and artificial reproduction

Evolution is a continuous process and humans are still subject to selection. Here we explore how recent medical advances may affect this process:

• Can IVF influence human evolution? Hanevik HA, Hessen DO, Sunde A & Breivik J, Human Reproduction (2016)

Education management

In order to do good research, we also need to take a research-based perspective to how we lead and organize our research organizations:

• Leadership and organizational change in biomedical PhD education: An instrumental case study of the development of a centralized organization for biomedical graduate studies at the University of Pennsylvania. Breivik J, Thesis (Ed.D. in Higher Education Management), University of Pennsylvania (2014).

• Evaluation of the medical student research programme in Norwegian medical schools. A survey of students and supervisors. Hunskaar S, Breivik J, Siebke M, Tømmerås K, Figenschau K and Hansen JB. BMC Medical Education (2009).

Self-replicating machines

In order to explore and illustrate the fundamental principles of biology, I have developed and patented the concept of making physical objects (e.g. robotic toys) that replicate like DNA molecules. Hopefully it will come to use one day:

• System which can reversibly reproduce itself. Breivik, J. (2001) US Patent 6,652,285.
• Self-organization of template-replicating polymers and the spontaneous rise of genetic information. Breivik J. Entropy (2001) 3, 273-279.

Magnetic DNA isolation

As a medical student, I developed a method for isolating DNA by magnetic separation. The patent is commercialized by Qiagen.

US Patent 6090935, Isolation of nucleic acid.

• Breivik, Jarle (2016). Reframing the "Cancer Moonshot". EMBO Reports.  ISSN 1469-221X.  17(12) . doi: 10.15252/embr.201643467 Show summary

  The way people understand cancer is essential to national policy making as well as individuals’ attitude and behavior toward the disease. Earlier this year, therefore, I wrote an Op‐Ed in The New York Times [1] that challenged the rationale of the Obama administration's initiative for a “Cancer Moonshot” [2]. Contrary to the President's call on America to “cure cancer once and for all” (State of the Union Address, 2016), I argued that we cannot treat ourselves out of the cancer epidemic. Cancer is a natural consequence of aging, and the better medical science gets at keeping people alive, the more cancer there will be in the population. Whether I am right or not is open to debate. What is just as interesting, however, is how people reacted to this message.

• Hanevik, Hans Ivar; Hessen, Dag Olav; Sunde, Arne & Breivik, Jarle (2016). Can IVF influence human evolution?. Human Reproduction.  ISSN 0268-1161.  31(7), s 1397- 1402 . doi: 10.1093/humrep/dew089
• Carver, Rebecca Bruu; Rødland, Einar Andreas & Breivik, Jarle (2013). Quantitative Frame Analysis of How the Gene Concept Is Presented in Tabloid and Elite Newspapers. Science communication.  ISSN 1075-5470.  35(4), s 449- 475 . doi: 10.1177/1075547012460525 Show summary

  Tabloid and elite newspapers differ in journalistic style and address different socioeconomic segments of society. Few studies have systematically investigated how these differences influence science communication, and the issue of genetics is particularly relevant. In this study, we performed a quantitative frame analysis of genetic discourse in 12 national newspapers that address different audiences. We found that tabloid and elite newspapers use different frames when communicating the gene concept. The differences were related to the use of expert writers and choice of topics, and we discuss how framing of the gene concept is related to the newspapers’ editorial profiles.

• Carver, Rebecca Bruu; Wiese, Eline Fatima & Breivik, Jarle (2013). Frame Analysis in Science Education: A Classroom Activity for Promoting Media Literacy and Learning about Genetic Causation. International Journal of Science Education.  ISSN 0950-0693.  4(3), s 211- 239 . doi: 10.1080/21548455.2013.797128
• Falster, DS; Nakken, S; Bergem-Ohr, M; Rødland, Einar Andreas & Breivik, J (2010). Unstable DNA Repair Genes Shaped by Their Own Sequence Modifying Phenotypes. Journal of Molecular Evolution.  ISSN 0022-2844.  70(3), s 266- 274 . doi: 10.1007/s00239-010-9328-0
• Hunskaar, Steinar; Breivik, Jarle; Siebke, Else-Marie; Tømmerås, Karin; Figenschau, Kristian & Hansen, John-Bjarne (2009). Evaluation of the medical student research programme in Norwegian medical schools. A survey of students and supervisors. BMC Medical Education.  ISSN 1472-6920.  9(43) . doi: 10.1186/1472-6920-9-43 Full text in Research Archive.
• Carver, Rebecca; Waldahl, Ragnar & Breivik, Jarle (2008). Frame that gene. A tool for analysing and classifying the communication of genetics to the public. EMBO Reports.  ISSN 1469-221X.  9(10), s 943- 947
• Breivik, Jarle (2006). Cancer - evolution within. International Journal of Epidemiology.  ISSN 0300-5771.  35(5), s 1161- 1162
• Breivik, Jarle (2005). The evolutionary origin of genetic instability in cancer development. Seminars in Cancer Biology.  ISSN 1044-579X.  15
• Breivik, Jarle & Gaudernack, Gustav (2004). Resolving the evolutionary paradox of genetic instability: a cost-benefit analysis of DNA repair in changing environments. FEBS Letters.  ISSN 0014-5793.  563, s 7- 12
• Andersen, Solveig Norheim; Løvig, Tone; Breivik, Jarle; Lund, Eiliv; Gaudernack, Gustav; Meling, Gunn Iren & Rognum, Torleiv Ole (1997). K-ras mutations and prognosis in large bowel carcinomas. Scandinavian Journal of Gastroenterology.  ISSN 0036-5521.  32, s 62- 69
• Breivik, Jarle; Lothe, Ragnhild A; Meling, Gunn Iren; Rognum, Torleiv Ole; Børresen-Dale, Anne-Lise & Gaudernack, Gustav (1997). Different genetic pathways to proximal and distal colorectal cancer influenced by sex related factors. International Journal of Cancer.  ISSN 0020-7136.  97, s 664- 669
• Andersen, Solveig Norheim; Breivik, Jarle; Løvig, Tone; Meling, Gunn Iren; Gaudernack, Gustav; Clausen, Ole Petter Fraas; Schölberg, A.; Fausa, Olav; Langmark, F.; Lund, Eivind & Rognum, Torleiv Ole (1996). K-ras mutations and HLA-DR expression in large bowel adenomas. British Journal of Cancer.  ISSN 0007-0920.  74, s 99- 108
• Gjertsen, Marianne Klemp; Bakka, Arne; Breivik, Jarle; Sæterdal, Ingvil; Gedde-Dahl jr, Tobias; Stokke, Kjell Torgeir; Solheim, Bjarte G.; Egge, Tor Schatvedt; Søreide, Odd; Thorsby, Erik & Gaudernack, Gustav (1996). Ex vivo ras peptide vaccination in patients with advanced pancreatic cancer: results of a phase I/II study. International Journal of Cancer.  ISSN 0020-7136.  65, s 450- 3
• Gjertsen, MK; Bakka, Arne Olav; Breivik, Jarle; Sæterdal, I; Solheim, Bjarte G.; Thorsby, Erik & Gaudernack, Gustav (1995). Vaccination with mutant ras peptides induces of T-cell responsiveness in pancreatic carcinoma patients carrying the corresponding RAS mutation. The Lancet.  ISSN 0140-6736.  (346), s 1399- 1400

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• Frich, Jan C; Breivik, Jarle; Lundin, Knut Erik Aslaksen; Rosvold, Elin Olaug & Os, Ingrid (2017). Valgfrie emner i medisinstudiet. Tidsskrift for Den norske legeforening.  ISSN 0029-2001.  137(20), s 1- 5 . doi: 10.4045/tidsskr.17.0549
• Breivik, Jarle (2016, 13. januar). Obama og kreft. [Radio].  https://radio.nrk.no/serie/dagsnytt-atten/nmag03000816/13-01.
• Breivik, Jarle (2016). Re: Insulinresistens - kroppens forsvar mot kaloriforgiftning?. Tidsskrift for Den norske legeforening.  ISSN 0029-2001.  136(14), s 1185
• Breivik, Jarle (2016). We won't cure cancer. New York Times, USA.  s A21
• Frich, Jan C; Wium, Kristin; Røine, Linda Kristin; Breivik, Jarle; Lundin, Knut Erik Aslaksen & Rosvold, Elin Olaug (2016). Implementing elective courses in the basic Medical curriculum at the University of Oslo.
• Breivik, Jarle (2015). Hvem har villedet Trond Mohn?. Tidsskrift for Den norske legeforening.  ISSN 0029-2001.  135(6), s 558- 560 Show summary

  Det medisinske fagmiljøet har gjennom flere tiår understøttet myten om at løsningen på «kreftgåten» ligger bak neste sving. Faktum er at dagens kreftepidemi ikke er et problem som moderne medisin er i ferd med å løse – den er et problem vi er i ferd med å skape. Det er derfor nødvendig å formidle en mer realistisk forståelse for kreft og kreftforskning.

• Breivik, Jarle (2015). Hvem har villedet Trond Mohn? :. Tidsskrift for Den norske legeforening.  ISSN 0029-2001.  135(6), s 558- 560 . doi: 10.4045/tidsskr.15.0053
• Breivik, Jarle (2015). J. Breivik svarer. Tidsskrift for Den norske legeforening.  ISSN 0029-2001.  135(17), s 1533- 1534 . doi: 10.4045/tidsskr.15.0919
• Breivik, Jarle (2015). J. Breivik svarer. Tidsskrift for Den norske legeforening.  ISSN 0029-2001.  135(22), s 2026- 2026 . doi: 10.4045/tidsskr.15.1197
• Breivik, Jarle (2014). Leadership and organization change in biomedical PhD education: An instrumental case study of the development of a centralized organization for biomedical graduate studies at the University of Pennsylvania.
• Breivik, Jarle (2014). Re: Brysomme studenter. Tidsskrift for Den norske legeforening.  ISSN 0029-2001.  134(21), s 2023
• Breivik, Jarle (2013). Sprikende forskerutdanning. Tidsskrift for Den norske legeforening.  ISSN 0029-2001.  133(9), s 617- 618
• Carver, Rebecca Bruu; Jorde, Doris; Breivik, Jarle & Klavenes, Eileen Holm (2010). Media Analysis in Biology Class.
• Carver, Rebecca Bruu; Klavenes, Eileen Holm & Breivik, Jarle (2010). Genes in the Media.
• Carver, Rebecca Bruu & Breivik, Jarle (2009). Gener i Media og Klasserommet: Genrammer. Naturfag.  ISSN 1504-4564.  (1), s 37- 37
• Carver, Rebecca & Breivik, Jarle (2009). Mediaanalyse i Biologitimen. Naturfag.  ISSN 1504-4564.  (1), s 34- 37
• Carver, Rebecca & Breivik, Jarle (2008). Frame that gene! How do journalists, scientists and the public talk about genes?. Show summary

  No single scientific concept is more fundamental to the understanding of life science than "the gene". As we shall no doubt see during the course of this conference, scientists and philosophers define "a gene" in many different ways, reflecting different perspectives. Likewise, journalists and the public also refer to genes in different ways, often without being aware of the type of meaning they are conveying. This huge variety of meaning can be bewildering, especially when trying to communicate important information connected to genetics. In my talk I shall attempt to make the whole complexity of gene-communication a little clearer; I will draw on the theoretical perspective of framing from sociology and science communication, and show five distinct ways of framing the gene in public discourse: materialistic, deterministic, relativistic, evolutionary and symbolic. These results are from a recently published study of how British and Norwegian newspapers frame the gene concept. Increased awareness of these five "gene frames" among scientists, philopsophers, journalists and the public may make communication about genetics easier, and may thus improve public understanding of life science. I shall discuss some examples of the implications this can have for health communication.

• Carver, Rebecca; Waldahl, Ragnar & Breivik, Jarle (2008). Frame that gene - A tool for analysing and classifying the communication of genetics to the public. EMBO Reports.  ISSN 1469-221X.  9, s 943- 947 . doi: 10.1038/embor.2008.176
• Breivik, Jarle & Aas, Harald (2007, 07. mars). Kreftgåten er uløselig.
• Breivik, Jarle (2005). Is there a solution to the cancer problem?.
• Breivik, Jarle (2005). Repeat protection, cancer suseptability and the evolution of selfish DNA repair genes.
• Breivik, Jarle (2005). Template replication: cancer development to magnetic toys.
• Breivik, Jarle (2005). The evolutionary origin of genetic instability in cancer development. Show summary

  Rise of genetic instability is a key factor in cancer development, and the underlying molecular basis is in principle understood: The unstable cellular phenotypes are caused by genetic and epigenetic deficiencies in mechanisms that maintain the integrity of DNA. A remaining and highly fundamental problem, however, concern the evolutionary origin of genetic instability: Why are the unstable phenotypes selected? Why is genetic instability a favorable trait in the somatic environment? The standard model for carcinogenesis explains this process by a linear pathway in which loss of genetic stability (caretaker genes) leads to loss of growth control (gatekeeper genes). This relationship is well documented and has lead to the apparently obvious conclusion that genetic instability is favored because it provides adaptive mutations. Taking a more fundamental perspective, however, genetic instability should be expected to have a negative effect. Each random mutation may be regarded as an unfavorable bet, and increasing the number of mutations within a cell will not increase the odds for a favorable outcome. On the contrary, basic statistics imply that more mutations will increase the overall probability of cellular breakdown. How then can genetic instability make cells grow faster and produce cancer? Intrigued by a curious relationship between unstable phenotypes and anatomical location of colorectal carcinomas, we have explored genetic instability in a different perspective. Somewhat paradoxically, we have shown that cancer cells lose specific DNA control and repair mechanisms in response to particular mutagenic environments. The underlying evolutionary logic may be expressed by the phrase “Don’t stop for repairs in a war zone”, and we have developed a theoretical and mathematical model that explains rise of unstable phenotypes in terms of costs and benefits of maintaining genome integrity. This model has been tested and confirmed by in vitro and in vivo experiments and has implications for the understanding of genetic instability, cancer development and evolution in general.

• Breivik, Jarle (2005). Whole genome analysis reveals high density of mononucleotide repeats within mismatch repair genes. Show summary

  In the absence of mismatch repair (MMR), simple repetitive sequences have increased mutation rates due to ‘slippage’ of the DNA polymerase enzyme during replication. Slippage can lead either to microsatellite expansion or contraction, depending on whether a loop arises on the template or nascent strands. In vivo and in vitro studies, however, indicate a strong bias towards contraction of repeat sequences in MMR deficient lineages, with the opposite observed for MMR proficient lineages, suggesting the MMR machinery preferentially protects against microsatellite contraction. Over evolutionary time and due to continuous shuffling of the gene pool via recombination, microsatellites are therefore expected to accumulate mostly in and around the functional MMR genes. We tested this hypothesis by comparing the density of mononucleotide repeat sequences found within coding and non-coding regions of all major MMR genes to that observed across the entire Homo sapiens genome. Repeat density was calculated as the fraction of nucleotides occurring within repeats longer than a threshold length (7bp). Statistical significance was assessed by comparing observed densities to those in 2000 randomly drawn sequences of equivalent length. All major MMR genes known to cause microsatellite instability (MSH2, MSH3, MSH6, MLH3, PMS2) except MLH1 were found to have significant repeat enrichment within coding or non-coding regions when compared to other genes within the genome. From an evolutionary perspective, these results may be interpreted as molecular adaptation to a MMR proficient intracellular environment which protects against microsatellite contraction.

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