When I give presentation in journal club, I always select the kind of papers that tell a "fun" story- I believe we can learn more by discussing "how the author(s) come up with such idea?" question. Over the years, the topics of my selected papers have ranged from how bugs determine the color of laid eggs to whether getting cancer is just bad luck. Many people have told me that they like how the papers I selected arouse interest and discussion from the audience in journal club. Here I'd like to explain how we all can benefit our research by reading and interpreting research papers from a different perspective.

To begin with, we have to understand that the purpose of scientific research is very different from that of scientific publication, and the latter can facilitate but does not achieve the former. Therefore, it is important for a career scientist to be able to distinguish these from each other, get to know the structural elements of both, and identify what can be learned from them for her/his own research.   

First of all, we don’t only study cancer. We study the natural history of life. Ultimately, all biological studies address different perspectives of life. Keeping in mind the quote "Nothing in biology makes sense except in the light of evolution" (Theodosius Dobzhansky, 1973), any paper is relevant.   

Second, in most studies, the authors observe the world through the lens of the contemporary paradigm or prevailing models. Many papers in top-tier journals attempt to find the “last piece” of the puzzle in the established model (and many “elite” authors are very good at this). An idea that does not fit into any of the paradigms will have a hard time getting published. A good example is Carl Woese. He single-handedly redefined the history of life but was mostly ignored until his later years because people of his time did not know where his idea should be placed (if you don’t know who he is, please Google him).

Third, we have to understand how a paper is written. Running a study is like constructing a skyscraper. You dig ground to make a foundation, lift pillars, construct floor by floor. Finally, you reach the top and finish the roof. When the construction is completed, you remove all the scaffolds and auxiliaries, clean up all the garbage, and decorate the environment. Now a brand new, beautiful building stands in front of people. But when someone asks you how such a marvelous building is constructed, you say: "I started constructing it from the roof, followed by the top floor, and floor by floor built down until the first floor touched the ground. This is a perfect plan, isn’t it?” Unfortunately, this is often how a study is presented at publication nowadays. If you follow the authors’ plans, most papers are over-decorated in a similar fashion, making them quite indistinguishable, with everything arranged perfectly and logically, even though the study hadn’t truly evolved in that way, sacrificing many critical elements that may give implications or insights to the field. For example, a discovery made by chance is described as a process following a logical design without mentioning the accident, thus the critical elements involved in the discovering circumstances may be lost forever, resulting in low reproducibility. Alternatively, following a “perfect” plan, a paper may be over-decorated with mechanism studies, and the real drivers of the phenomenon are overlooked.    

The route out of these “conceptual traps”, I believe, comes from a genuine observation or curious question that can catch people by surprise. For example, one of my all-time favorite papers is “Genetic Variations Associated with Red Hair Color and Fear of Dental Pain, Anxiety Regarding Dental Care and Avoidance of Dental Care” - yes, this is the real title. The study was initiated by an urban legend circulating among dentists: redheads have a worse response to anesthesia and terrible tooth conditions. The author - a dentist - wanted to test if it was true. What would you think if you heard such a rumor as a dentist? As you can imagine, this study is not high-profile journal material (it was published in a dental house journal, J. Am. Dental Assoc., 2009, 140:896-905). Because I study pigment cells, the results gave me a “think-out-of-the-box” moment: pigment variation and neural response are intertwined together evolutionarily. 

With these thoughts in mind, I would like to share a few “tips” for selecting a paper and preparing a presentation for journal club:

● Select a paper with a subject that might interest both scientists and non-scientists. A genuine question out of curiosity is always intriguing. Studies in lifestyle and behavior are fun because the audience can connect with them personally.

● In many cases, why the researcher asked the question and how she/he solved it are more valuable - and interesting - than the discovery itself. Even a wrong question can lead to a good observation. 

● Discuss what led the authors to the current study in the historic and/or conceptual (paradigm) perspective. This is necessary, in my opinion. For example, Joan Masague copied the in vivo cycling methodology from Isaiah J. Fidler, who got the idea from Luria-Delbruck distribution in bacterial resistance to phage. From here, we can easily see how studies of bacterial resistance heavily impacted the concept of clonal selection in cancer research. It would be very interesting to discuss the extent/limit of this concept in cancer research. Digging into the history of the research field can bring implications beyond the imagination.  

● Figure out if the question and the hypothesis are the “roof” or the “foundation” of the study. This will also arouse fun discussion.

● Examine whether the “mechanism” is required or decorative for the conclusion. Here is one of my favorite examples. In 1846, Hungarian clinician Ignaz Semmelweis published his findings in Vienna that washing deliverers’ hands with chlorinated lime solutions could effectively reduce maternal mortality in obstetrical clinics. Although the experimental data was solid, the idea was rejected by the most renowned doctors at the time, including Rudolf Virchow. The reason? Semmelweis could not offer an explanation fitting the contemporary scientific concept (i.e., “mechanism”) for his findings. The practice of hand disinfection did not prevail until Pasteur’s germ theory emerged in 1880, 15 years after Semmelweis had died in a mental institute. During this period, more women died unnecessarily because elite doctors demanded mechanisms in a scientific paper.

● Try to discuss how the findings can be applied to other fields. For example, after discovery of immune checkpoints, many immunologists tried to activate them to cure autoimmunity. Imagine this: if you read such a paper in those years, how would you think about its implication in cancer research?         

Actually, all the statements above involve only two factors: zooming out and then zooming in on the question. Believe me, doing this will easily facilitate many fun discussions.

Here are some more practical, step-by-step suggestions for the slides for journal club:

1. Start with a brief background of the field: a historic account to explain “how we got here”, and/or introduction to the current and alternative paradigms. Do these paradigms make sense in terms of biological evolution or life history? 

2. Summarize the model system and focused pathway/process being used and studied that is related to the paper. What is the scope of the model being used, and how relevant is it to the real world?

3. What is the author’s question? Why did she/he ask it? Is the question derived from the current model, or from an unexpected observation?  

4. What are the key claims in the paper? (We put this first so we can hang all the data against their claims. Ironically, the hypothesis in the paper may already give a good clue since it is often added after all the results were generated.)

5. A summary of the study design is helpful, especially for complicated projects.

6. Pick and choose key data that support the central conclusion, summarize everything else.

7. How much could the results answer the question? Alternatively, what is the paradigm-shifting discovery?

8. What is the implication of the results? How can we make use of the information in the paper in our own work? In what ways could the results impact other fields? What are the unanswered questions?

All the questions here can be asked during your presentation to arouse questions or discussion from the audience. 

Case Study: Ising C., et al. NLRP3 inflammasome activation drives tau pathology. Nature (2019).

Conclusion: 
1. fibrillar amyloid-beta -> NLRP3 inflammasome -> tau kinase/phosphatase -> tau pathology 
2. Neurofibrillary tangles develop downstream of amyloid-beta-induced microglial activation.

Historic context: What is the “driver” of Alzheimer disease (AD) identified by pathological and genetic studies in the history of research?

Evolutionary context: Why is there neurodegeneration disease? 
1. Do other animals get neurodegeneration disease? Are the genes involved in AD conserved in other animals? What are the functions of the conserved and divergent genes?
2. “Why would we have in our brains proteins such as α-synuclein or tau that, without substantive modification appears to be able to accumulate and cause some rather distressing diseases?” (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4662249/)
3. What is the common cause of microglia activation? Is neurodegeneration disease the price we pay to prevent parasite infection in brain?
4. Does the conclusion of this study fit in any evolutionary biology explanation? If so, is the explanation supported by any epidemiological data worldwide?

Results:
1. How much in pathology can the identified mechanism explain?
2. Can boundary condition of the model be mapped to human data?

Biomedical relevance:
1. Is there any study in diet and life style related to the conclusion, so a preventive/diagnostic measure can be suggested?
2. Disease of aging and cancer are two extreme ends in the same spectrum. Is the activation of microglia relevant to the occurrence or suppression of brain tumors?

The author would like to thank Dr. Sarah Spaeh for her editorial assistance.