Thursday, October 27, 2011

Discussion Forum: How Dogma Hinders the Advancement of Basic Research


from Dissemination of Research
           There is so much interesting aspects to the field of immunology in addition to the amazing research it offers, including historical and societal issues, that perhaps if discussed candidly would increase the public’s support and value towards basic research.  In addition to writing and discussing the latest published research in the fields of immunology, disease and human health, I would like to experiment with a few other forums to present on Escaping Anergy.  This is the first installment of Discussion Forum devoted to enhancing our ability to discuss immunology in an open, philosophical, communicative way.  After all…
Immunology is complicated.  It’s like a giant puzzle without a box depicting how the picture is supposed to look.  It becomes further complicated, because every few years a new puzzle piece drops into the pile.  The thing is, sometimes it feels as Sometimes that new piece in the “missing link” that can unify part of the puzzle, and other times it can’t seem to fit into the existing puzzle.  In research, the puzzle, in its entirety, is never complete, but people are working towards completing smaller chunks of the puzzle that can explain major biological processes.  Dogma represents a big chunk of the puzzle completed, but that can’t incorporate the remaining puzzle pieces.  It is much easier to accept the idea that at least a portion of the puzzle is completed, than to  re-examine the puzzle to ensure that the all the pieces in the completed section fit together smoothly and not forced into curves.   Fortunately, there are a number of scientists and educators who never lost their ability to question and whose curiosity has not waned. 
            Taking a few moments to describe how current dogmas evolve, one can begin to appreciate the challenges scientists encounter when trying to understand biological phenomena.  For example, in my specific field, macrophage biology, the dogma describing the function of these cells, has been under constant revision since their discovery at the turn of the 20th century. In the late 1890’s, Elie Metchnikoff (the “Father of Natural Immunity”) first described these cells merely based on what he could physically see: big tissue cells that were able to rapidly engulf dead cells.  For these reasons, he aptly called them “macrophages”. 1 Over the next 60 years, scientists around the world wanted to know more about what role these “big eaters” have in the immune system.  In the mid-20th century, a sentinel experiment by Mackaness and colleagues was performed using bacteria-infected macrophages. 2 In these experiments, they analyzed what the macrophages produced during infection and discovered that not only were these cells very good at eating and destroying bacteria, but produced huge amounts of pro-inflammatory cytokines as well.  These cytokines, TNFalpha and IL-12, are crucial mediators of the adaptive immune response and cellular recruitment to the site of infection.  This inflammatory, anti-microbial phenotype was then used to describe macrophage function for nearly 50 years.   Immunologists were largely content with relying on this new dogma of "classical macrophage activation".   This compelling description of macrophage function seemed to be etched into stone for decades, being unequivocally taught to future immunologists and so on.   It would be nearly half a century would pass before anyone proposed the notion of "alternatively activated macrophages".  This, to me, seems a bit surprising, after all in a field where people are trained to question their surroundings, be curious and ask questions, the idea of accepting dogma and moving on, should struggle to persist.   
             Before the millennium was over, numerous groups had discovered alternative activation macrophage states, including macrophages that were exactly the opposite of Mackaness’ classical macrophages.  Siamon Gordon, David Mosser and others discovered all sorts of abilities macrophages possessed that were previously thought of as impossible.  They had described macrophages that although were still very good at phagocytosis, were not able to control microbial infections and macrophages that were potent anti-inflammatory cytokine producers playing a significant role in regulating inflammation.3,4   Finally, we are beginning to appreciate that our previous understanding of macrophage function was over simplified and restricted; in fact we know believe there is a whole spectrum of macrophage diversity to explain how these cells work, behave and modulate immune responses.  It turns out that macrophage are capable of behaving in so many different ways depending on what they sense in their environment, and when and under what conditions.   However what factors regulate macrophage function and how and importantly, what other functions are these cells able to perform remain incomplete and elusive.  It is stunning to imagine what discoveries could have been made sooner if not for the 50-year lag in providing evidence for such an array macrophage activation states.  It is now known that such alternatively activated macrophages play significant roles in tumor development, microbial susceptibility, intestinal homeostasis and wound healing!
I believe that it is this fast-paced, dramatic evolution of understanding that provides the mystique that attracts people to the field, while simultaneously representing a major driving force to discourage people from taking an interest in research. However, the puzzle of understanding biological depends on the public’s support of basic research, which tackles essential questions that must be answered or expanded upon, in order to fully understand the mechanism behind disease.
As a doctorate student, I am supposed to devote most of my waking (and often, dreaming) hours to my research thesis, if I ever hope to successfully complete my PhD and move on to future endeavors.  Although, my time in the lab consumes 95-98% of the hours in a week, I desperately savor a few hours each week to “break” from the bench and take time to learn something new about immunology.  I treasure this time because, with all my course-work completed, I still yearn to learn new things.  I use this time to stay current with new discoveries and ideas and to further educate myself in immunology.  The time I spend reading the latest published research reminds me why I began investigating scientific research as a career in the first place: to always be in a position to challenge myself to learn new things. The field of immunological research is very challenging largely, because what we [think] we know about it is always morphing and expanding, new discoveries are always being made, and models of understanding are always in revision.
I understand this is exactly the aspect of science that often discourages people from wanting to learn more about it or why so many educators resort to using test-books that lump together decades of research to create main bullet points of understanding for students to memorize as facts.  But I think if we want to advance our scientific understanding of disease, we must be able to effectively and openly discuss how new research findings supports or changes current understanding.  
All children are curious beings, constantly trying to figure out the world around them and how it works.  Somewhere along the path to adulthood most of us, abandon our ability to do this.  We figure it’s easier to live in a world where other people figure things out; after-all our lives have become increasingly more hectic since we were kids.  For science to work the way we want it to-by providing insight into how our bodies work so that we can cure, prevent, and effectively treat diseases, all of us-scientists and non-scientists-must continue to think creatively and intelligently about the amazing physiological phenomena our bodies encounter everyday.  
Biological research is a very challenging field with limited immediate satisfaction.  These qualities tend to push the vast majority of would-be scientists away from the realm of research.  By assuming our current understanding of immunology is static and somehow set in stone, the field is doomed to lend itself in the development of drugs and treatments that work effectively and properly to treat disease.  

Whether you are also a young scientist, or an older one, or someone who just wants to make more time in their busy life to learn something new, or a concerned citizen who wants to understand how their tax dollars lead to scientific advancement, I encourage you to ask more questions and to never take the easy route to scientific understanding!  Thanks for reading and I hope our discussion continues!

What makes you want to understand immunology and support the research behind it?

What motivates you to continue to be curious about science? 

Please feel free to comment below or shoot me an e-mail to discuss the philosophy of immunological research!

ResearchBlogging.orgMosser, D., & Edwards, J. (2008). Exploring the full spectrum of macrophage activation Nature Reviews Immunology, 8 (12), 958-969 DOI: 10.1038/nri2448






References and Further Reading:
1: Metschnikoff, E. Biol. Zentralblatt 3: 560–565 (1883).
2: Mackaness, G. B. "The immunological basis of acquired cellular resistance. "J. Exp. Med. 120:105-120(1964).
3: Stein, M., Keshav, S., Harris, N. & Gordon, S. “Interleukin 4 potently enhances murine macrophage mannose receptor activity: a marker of alternative immunologic macrophage activation”. J. Exp. Med. 176: 287–292 (1992).
4: Mosser, D. and Edwards, J. “Exploring the full spectrum of macrophage activation”. Nature Reviews Immunology. 8:958-969. (2008).

5 comments:

  1. Hey, I'm really glad I stumbled on to this blog, it's very interesting and some of the threads are thoroughly engaging.

    Can I ask if you have recently uncovered any recent (e.g. in the past few months) immunological discoveries which further illustrate a 'change in scientific dogma'?
    The point you raised is highly elucidating and well conveyed.

    Regards,

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  2. Thanks for checking out my blog Big Jabber! I'm glad you find the topics discussed her interesting and I hope you continue to read Escaping Anergy!

    In regards to recent immunological discoveries, there has been a number of published findings that have played a significant role in altering previously accepted dogma including:

    -Pelletier,N., et al. published that plasma cells (antibody producing B cells) have a significant role in regulating T follicular helper cells in the spleen, which is important in programing long-lasting immunity. Prior to this paper, activated B cells were thought of as strictly cells that contributed to the immune response by just making antibody. But what Pelletier, et al. discovered is that in addition to making antibody, these plasma cells also act as antigen presenting cells (APC) and are potent stimulators of T follicular help (TFH) cells and that in mice deficient for plasma cells, TFH cells proliferate like crazy which is associated with autoimmunity, as these T cells are no longer efficiently regulated. This finding has important implications in vaccine development and improving treatments for autoimmune disorders. "Plasma cells negatively regulate the follicular helper T cell program".Nature Immunology. Dec. 2010.

    -A long lasting paradigm in inflammation is that early in infection/injury monocytes are recruited to the site of damage where they then differentiate into tissue-resident macrophages, so if you assess the site of injury for macrophages over the course of inflammation and see that the number of macrophages increase, this is because of monocyte recruitment and subsequent differentiation. However, a few months ago, Jenkins, S and colleagues showed that during helminth (worm) infections, the expansion of macrophages is not due to monocyte differentiation, but rather to the proliferation of a certain kind of macrophage called M2 or regulatory macrophage. It turns out this kind of macrophage-intrinsic expansion is dependent on Th2 cytokines that are present during infections like that with worms, but not typically with bacterial infections. In this Th2 environment, are cytokines that promote wound-healing and immunosuppression, so these finding are exciting in the understanding that there are 2 ways to expand macrophage populations: an inflammatory type dependent on Th1 cytokines and monocyte recruitment and a second type dependent on Th1 cytokines and the self-expansion of macrophages in the absence of inflammatory mediators. This finding has many therapeutic applications in Th2-associated diseases that are regulated by macrophage including tumor development, tissue-repair and autoimmunity. "Local macrophage proliferation, rather than recruitment from the blood, is a signature of Th2 inflammation". Science. May 2011.

    Those are just a few off the top of my head, if you would like to know more I'd love to discuss this in more depth, so feel free to continue to post comments here or shoot me an e-mail at escapinganergy[at]gmail[dot]com and thanks again for reading!!!

    ReplyDelete
  3. I am concerned that our immune systems are overburdened and we should therefore not eat anything that causes ANY immune response.

    The general dogma is to eat freely of several items to which we are somewhat allergic (under ~600 on the ELISA scale).

    I am attempting to create an optimal diet to reverse my current illness, prevent anything more heinous from befalling me, and generally feel like a million bucks.

    I think I ought to focus on items on my ELISA score=0 list, but I want a second opinion because I also want the largest variety of nutrient-dense options from which to choose. I am concerned about sustained adherence as I am rebellious even to diets I myself am creating.

    Wheatgrass is a staple among vegans and raw foodists, so I would like to partake in wheatgrass cocktails at get-togethers, but my ELISA score for it is 128. Frankly I would like to have it daily, but I'm concerned about that score.

    Do you adhere to a particular viewpoint based on the latest research?

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  4. Thank you for reading Alice! First, I have to clarify that I am not a medical professional and therefore cannot offer you any medical or clinical advice.

    However, I do think you raise an interesting point about how the foods we consume interact with our immune system. Each person's gut environment is unique, so I would suspect various diets would affects each person differently, and what you may be allergic too may not cause food allergy to someone else because the immune environment in your gut may be slightly different than another person.

    Importantly, another major factor that influences our gut environment are the microbes that live there! Recently it was discovered that people can be categorized based on the groups of bacteria living in their gut (similar to blood types) and more recently researchers are investigating how these different microbial gut communities affect diet and vice versa (Gary Wu, et al. Science 2011)

    Lastly, although I have run hundreds of ELISAs, I am not familiar with what you call the "ELISA scale". I'm not sure if it refers to the level of inflammatory cytokine produced in response to a particular food, or the level of IgE allergy antibody produced-but either way, it's always necessary to take into consideration that different foods will produce different levels and kinds of antibody/cytokines, some may be more potent than others at instigating an inflammatory reaction. So, it may be important to evaluate each food separately.

    Importantly, some individuals may have greater/less tolerance to different foods so 300 may cause an allergic reaction in some people but not others depending on their immunological tolerance level, gut microbial communities, and their body's ability to control/prevent an allergic reaction.

    Also different foods are likely to yield varying levels of antibody produced. It's hard to imagine one strict scale to be used to define all these variables, so I can see your concern for the dogma described.

    I suggest you meet with a medical immunologist/allergist and nutritionist to effectively design a personal diet that works best for you.

    I hope these explanations helps and thanks again for checking out Escaping Anergy!

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  5. There are just so many variables! It seems like every doctor (with or without a book out) has a different opinion, so I was hoping to "jump the fence" straight to the scientists. Doctors can't know of all the latest concepts.

    I appreciate the concept of this blog.

    I will be looking up the gut microbial communities to see what I might discover there.

    Thank you for your response.

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