Trial of Autologous Mesenchymal Stem Cells in Multiple Sclerosis

Randomized Placebo-Controlled Phase II Trial of Autologous Mesenchymal Stem Cells in Multiple Sclerosis Sara Llufriu,#1 María Sepúlveda,#1 Yolanda Blanco,1 Pedro Marín,2 Beatriz Moreno,1 Joan Berenguer,3 Iñigo Gabilondo,1 Eloy Martínez-Heras,1 Nuria Sola-Valls,1 Joan-Albert Arnaiz,4 Enrique J. Andreu,5 Begoña Fernández,1 Santi Bullich,1 Bernardo Sánchez-Dalmau,1,6 Francesc Graus,1 Pablo Villoslada,1 and Albert Saiz1,* Tim Friede, Editor

Slightly Modified from John W. Little and Roy Parker–University of Arizona

http://www.biochem.arizona.edu/classes/bioc568/papers.htm

The main purpose of a scientific paper is to report new results, usually experimental, and to relate these results to previous knowledge in the field. Papers are one of the most important ways that we communicate with one another.

In understanding how to read a paper, we need to start at the beginning with a few preliminaries. We then address the main questions that will enable you to understand and evaluate the paper.

Organization of a paper

In most scientific journals, scientific papers follow a standard format. They are divided into several sections, and each section serves a specific purpose in the paper. We first describe the standard format, then some variations on that format.

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A paper begins with a short Summary or Abstract. Generally, it gives a brief background to the topic; describes concisely the major findings of the paper; and relates these findings to the field of study. As will be seen, this logical order is also that of the paper as a whole.

The next section of the paper is the Introduction. In many journals this section is not given a title. As its name implies, this section presents the background knowledge necessary for the reader to understand why the findings of the paper are an advance on the knowledge in the field. Typically, the Introduction describes first the accepted state of knowledge in a specialized field; then it focuses more specifically on a particular aspect, usually describing a finding or set of findings that led directly to the work described in the paper. If the authors are testing a hypothesis, the source of that hypothesis is spelled out, findings are given with which it is consistent, and one or more predictions are given. In many papers, one or several major conclusions of the paper are presented at the end of this section, so that the reader knows the major answers to the questions just posed. Papers more descriptive or comparative in nature may begin with an introduction to an area which interests the authors, or the need for a broader database.

The next section of most papers is the Materials and Methods. In some journals this section is the last one. Its purpose is to describe the materials used in the experiments and the methods by which the experiments were carried out. In principle, this description should be detailed enough to allow other researchers to replicate the work. In practice, these descriptions are often highly compressed, and they often refer back to previous papers by the authors.

The third section is usually Results. This section describes the experiments and the reasons they were done. Generally, the logic of the Results section follows directly from that of the Introduction. That is, the Introduction poses the questions addressed in the early part of Results. Beyond this point, the organization of Results differs from one paper to another. In some papers, the results are presented without extensive discussion, which is reserved for the following section. This is appropriate when the data in the early parts do not need to be interpreted extensively to understand why the later experiments were done. In other papers, results are given, and then they are interpreted, perhaps taken together with other findings not in the paper, so as to give the logical basis for later experiments.

The fourth section is the Discussion. This section serves several purposes. First, the data in the paper are interpreted; that is, they are analyzed to show what the authors believe the data show. Any limitations to the interpretations should be acknowledged, and fact should clearly be separated from speculation. Second, the findings of the paper are related to other findings in the field. This serves to show how the findings contribute to knowledge, or correct the errors of previous work. As stated, some of these logical arguments are often found in the Results when it is necessary to clarify why later experiments were carried out. Although you might argue that in this case the discussion material should be presented in the Introduction, more often you cannot grasp its significance until the first part of Results is given.

Finally, papers usually have a short Acknowledgements section, in which various contributions of other workers are recognized, followed by a Reference list giving references to papers and other works cited in the text. Trial of Autologous Mesenchymal Stem Cells in Multiple Sclerosis

Papers also contain several Figures and Tables. These contain data described in the paper. The figures and tables also have legends, whose purpose is to give details of the particular experiment or experiments shown there. Typically, if a procedure is used only once in a paper, these details are described in Materials and Methods, and the Figure or Table legend refers back to that description. If a procedure is used repeatedly, however, a general description is given in Materials and Methods, and the details for a particular experiment are given in the Table or Figure legend.

Variations on the organization of a paper

In most scientific journals, the above format is followed. Occasionally, the Results and Discussion are combined, in cases in which the data need extensive discussion to allow the reader to follow the train of logic developed in the course of the research. As stated, in some journals, Materials and Methods follows the Discussion. In certain older papers, the Summary was given at the end of the paper.

The formats for two widely-read journals, Science and Nature, differ markedly from the above outline. These journals reach a wide audience, and many authors wish to publish in them; accordingly, the space limitations on the papers are severe, and the prose is usually highly compressed. In both journals, there are no discrete sections, except for a short abstract and a reference list. In Science, the abstract is self-contained; in Nature, the abstract also serves as a brief introduction to the paper. Experimental details are usually given either in endnotes (for Science) or Figure and Table legends and a short Methods section (in Nature). Authors often try to circumvent length limitations by putting as much material as possible in these places. In addition, an increasingly common practice is to put a substantial fraction of the less-important material, and much of the methodology, into Supplemental Data that can be accessed online.

Many other journals also have length limitations, which similarly lead to a need for conciseness. For example, the Proceedings of the National Academy of Sciences (PNAS) has a six-page limit; Cell severely edits many papers to shorten them, and has a short word limit in the abstract; and so on.

In response to the pressure to edit and make the paper concise, many authors choose to condense or, more typically, omit the logical connections that would make the flow of the paper easy. In addition, much of the background that would make the paper accessible to a wider audience is condensed or omitted, so that the less-informed reader has to consult a review article or previous papers to make sense of what the issues are and why they are important. Finally, again, authors often circumvent page limitations by putting crucial details into the Figure and Table legends, especially when (as in PNAS) these are set in smaller type.

Reading a scientific paper

Although it is tempting to read the paper straight through as you would do with most text, it is more efficient to organize the way you read. Generally, you first read the Abstract in order to understand the major points of the work. The extent of background assumed by different authors, and allowed by the journal, also varies as just discussed.

One extremely useful habit in reading a paper is to read the Title and the Abstract and, before going on, review in your mind what you know about the topic. This serves several purposes. First, it clarifies whether you in fact know enough background to appreciate the paper. If not, you might choose to read the background in a review or textbook, as appropriate.

Second, it refreshes your memory about the topic. Third, and perhaps most importantly, it helps you as the reader integrate the new information into your previous knowledge about the topic. That is, it is used as a part of the self-education process that any professional must continue throughout his/her career.

If you are very familiar with the field, the Introduction can be skimmed or even skipped. As stated above, the logical flow of most papers goes straight from the Introduction to Results; accordingly, the paper should be read in that way as well, skipping Materials and Methods and referring back to this section as needed to clarify what was actually done. A reader familiar with the field who is interested in a particular point given in the Abstract often skips directly to the relevant section of the Results, and from there to the Discussion for interpretation of the findings. This is only easy to do if the paper is organized properly.

Codewords

Many papers contain shorthand phrases that we might term ‘codewords’, since they have connotations that are generally not explicit. In many papers, not all the experimental data are shown, but referred to by “(data not shown)”. This is often for reasons of space; the practice is accepted when the authors have documented their competence to do the experiments properly (usually in previous papers). Two other codewords are “unpublished data” and “preliminary data”. The former can either mean that the data are not of publishable quality or that the work is part of a larger story that will one day be published. The latter means different things to different people, but one connotation is that the experiment was done only once. Trial of Autologous Mesenchymal Stem Cells in Multiple Sclerosis

Difficulties in reading a paper

Several difficulties confront the reader, particularly one who is not familiar with the field. As discussed above, it may be necessary to bring yourself up to speed before beginning a paper, no matter how well written it is. Be aware, however, that although some problems may lie in the reader, many are the fault of the writer.

One major problem is that many papers are poorly written. Some scientists are poor writers. Many others do not enjoy writing, and do not take the time or effort to ensure that the prose is clear and logical. Also, the author is typically so familiar with the material that it is difficult to step back and see it from the point of view of a reader not familiar with the topic and for whom the paper is just another of a large stack of papers that need to be read.

Bad writing has several consequences for the reader. First, the logical connections are often left out. Instead of saying why an experiment was done, or what ideas were being tested, the experiment is simply described. Second, papers are often cluttered with a great deal of jargon. Third, the authors often do not provide a clear road-map through the paper; side issues and fine points are given equal air time with the main logical thread, and the reader loses this thread. In better writing, these side issues are relegated to Figure legends or Materials and Methods or clearly identified as side issues, so as not to distract the reader.

Another major difficulty arises when the reader seeks to understand just what the experiment was. All too often, authors refer back to previous papers; these refer in turn to previous papers in a long chain. Often that chain ends in a paper that describes several methods, and it is unclear which was used. Or the chain ends in a journal with severe space limitations, and the description is so compressed as to be unclear. More often, the descriptions are simply not well-written, so that it is ambiguous what was done.

Other difficulties arise when the authors are uncritical about their experiments; if they firmly believe a particular model, they may not be open-minded about other possibilities. These may not be tested experimentally, and may even go unmentioned in the Discussion. Still another, related problem is that many authors do not clearly distinguish between fact and speculation, especially in the Discussion. This makes it difficult for the reader to know how well-established are the “facts” under discussion.

One final problem arises from the sociology of science. Many authors are ambitious and wish to publish in trendy journals. As a consequence, they overstate the importance of their findings, or put a speculation into the title in a way that makes it sound like a well-established finding. Another example of this approach is the “Assertive Sentence Title”, which presents a major conclusion of the paper as a declarative sentence (such as “LexA is a repressor of the recA and lexA genes“). This trend is becoming prevalent; look at recent issues of Cell for examples. It’s not so bad when the assertive sentence is well-documented (as it was in the example given), but all too often the assertive sentence is nothing more than a speculation, and the hasty reader may well conclude that the issue is settled when it isn’t.

These last factors represent the public relations side of a competitive field. This behavior is understandable, if not praiseworthy. But when the authors mislead the reader as to what is firmly established and what is speculation, it is hard, especially for the novice, to know what is settled and what is not. A careful evaluation is necessary, as we now discuss.

Evaluating a paper

A thorough understanding and evaluation of a paper involves answering several questions:

What questions does the paper address?
What are the main conclusions of the paper?
What evidence supports those conclusions?
Do the data actually support the conclusions?
What is the quality of the evidence?
Why are the conclusions important? Trial of Autologous Mesenchymal Stem Cells in Multiple Sclerosis