Wednesday, February 29, 2012

Ending a (somewhat) Anergic Winter HIbernation...

Hello Loyal Escaping Anergy Readers!!

I am writing to: 
1. thank you all for your continue support of helping to bridge the communication gap between scientists and the public by reading Escaping Anergy: The Immunology Research Blog 
2. to explain that I am finally emerging for my Winter Hibernation.  Ok so, I wasn't actually burrowed in the ground waiting desperately for the end of cool temperatures, but I was extremely busy with things that tied up my time to sit and write detailed analyses about the latest in amazing immunology research discoveries.  What was I doing that consumed all my time? 

There was everything from the Holidays and New Years' Celebrations to traveling to California for Research Conference...
Leafy Seahorse seen at the Seahorse Exhibit at the Monterey Bay Aquarium (seen during a very brief break from the conference).
to traveling to Jamaica for a wedding and much needed vacation...
Beautiful Montego Bay, Jamaica!
to preparing my own research manuscript for publication to preparing for the start of another semester where I teach a weekly Immunology Discussion section to applying for research grants and fellowships...

to beginning to train for a 10-mile race in April...
At the end of a half-marathon I ran last season with a few friends, goal this year: 8:30 min/mile for the 10-miler in April!
 to expanding our family to include our rescue dog, Ringo!! 
How could we NOT adopt him?! 
Whew!  So, you can say I've been pretty busy lately over these past few months and am happy to report that things are finally quieting down so that I can focus more on Escaping Anergy!  

Without adding to this blog, does that mean I've been anergic over Winter? Not completely because in addition to responding to your e-mails @ and teaching Immunology this semester I have been maintaining a very active Twitter account over these Winter months, so I encourage you to follow me on Twitter to get daily updates about the latest in immunology research!  Thank you to everyone currently following @escapinganergy and for your constant support!

There has been so much exciting research published in the fields of immunology, human health and disease that I can't wait to write about here. So please stay tuned here at Escaping Anergy: The Immunology Research Blog and on Twitter @escapinganergy


Monday, December 5, 2011

2011 Blogging Scholarship: Results and THANK YOUs


I want to sincerely thank everyone who voted and helped to spread the word in support of Escaping Anergy for the 2011 Blogging Scholarship! This year, Escaping Anergy competed against blogs about the NBA, baseball, religion, shark conservation, paleontology, tech gadgets and traveling at the chance to win the 2011 Blogging Scholarship awarded to full-time students who blog. Being relatively new to blogging, I was ecstatic to have such amazing support from my family and friends, The University of Maryland, fellow science bloggers and science enthusiasts! Although Escaping Anergy lost the ultimate prize (by only a few hundred votes!) I honestly believe that I wouldn’t have made it as far as I did without your amazing support! Being able to earn First Runner-Up has propelled Escaping Anergy into a bigger public arena, which I hope will enable it to be seen, discussed and further supported by more of the public. The greatest result of this scholarship adventure has been the chance to advocate for better public science and health education. Coming in a close second has revealed that much of the public (at least those who read blogs) craves to have a more in-depth understanding about the biology behind critical health concerns and disease. 

Throughout this scholarship process, I have received numerous e-mails, tweets and blog posts that not only positively acclaim the work I’ve done so far on Escaping Anergy, but also have asked for more information about particular aspects of immunology that may directly affect their lives. I am genuinely excited so many people have discovered their interest in immunology through Escaping Anergy! It was a truly amazing experience to receive so much positive feedback and messages describing your interest to learn more about immunology during this process and I hope to continue to hear from you!

For these reasons, I am so proud to see Escaping Anergy play a role in enhancing the public’s interest in immunology! Is there an immunology research paper you found that you’d like to see further explained? Are you an immunology/med student who has a question as you prepare for your immunology exam? Is there an immune-based therapy you’d like to know more about and the research behind it? Did you read a health news story that mentions the immune system and would like to learn more? I hope you continue to help spread the word about Escaping Anergy and I look forward to receiving more e-mails, tweets and posts about how understanding immunology affects your life and what you would like to see discussed on Escaping Anergy!

Lastly and Very Importantly: an extra special thanks to…

David Shiffman and Jacquelyn Gill who continuously advocated for improved science education as fellow finalists for the Blogging Scholarship. They are fantastic science bloggers and I hope with our combined effort, the public has greater appreciation and support for a variety of scientific issues! A recap of all the science bloggers who were selected as finalists for the scholarship can be found here.

Christie Wilcox of Science Sushi (and winner of the 2010 Blogging Scholarship) who promoted all the science bloggers up for the 2011 prize and offered generous words and support for Escaping Anergy on her Scientific American blog:
It’s not easy to make immunology engaging and interesting, but Heather does a fantastic job of it. She clearly has a passion for what she does, and loves to share it with others. She hopes that her blog will help connect the general public to a field that is often overhyped and misinterpreted – and I’d say she’s off to a damn good start.” 
Mike at for helping to spread the word and support for Escaping Anergy for the Blogging Scholarship: 
I've had the recent pleasure of exchanging email with Heather Cohen of The Escaping Anergy blog… Folks like Heather, Her interest in immunology and Her passion about these kinds of issues are the ones that can make a big difference in finding cures for so many diseases in my opinion.”
Aaron Broege of The Sensitive Scientist, who provided constant support for Escaping Anergy during the scholarship process and did a fantastic job at helping to spread the word:
"If you like your science served up awesome, vote for Heather's Blog!"
Tom McCaughtry, fellow immunologist who helped to rally votes and provided constant support for the need of a blog devoted to immunology research, commenting on PZ Meyers' post “A Poll with a Point”: 
Heather Cohen writes an extremely interesting blog that communicates scientific research to the public. She doesn’t dumb down the science like some of the other “news” sources, but she makes it simple enough for anybody to understand!”

 Thank you all a million times over,

Wednesday, November 16, 2011

Blogging Scholarship: On the importance of science research blogs and how YOU can vote to support students who blog about science!

"The academic research and teaching communities for science and related fields need to see blogging as more than a casual hobby, as core outreach for their science. It is an effective way for scientists to counter the misunderstandings, deliberate and otherwise, of popular culture...In this way, we can ensure that the quality of the science that is communicated to the public is high, while the personality of working scientists humanizes science." -John S. Wilkins "The roles, reasons and restrictions of science blogs. (2008).
I started Escaping Anergy because as a PhD Immunology student I wanted to get the public psyched up about the amazing role basic research plays in improving human health! Whether you have supported this blog since its beginning or if you recently stumbled across I hope you find this blog to be a unique place on the web where scientists and the public can discuss research and its impacts together. Your support and interest in Escaping Anergy is what motivated me to apply for a $10,000 scholarship for full-time students who blog and...

I JUST found out I was selected as a FINALIST! However, the winner will be chosen by the online community. Because my blog is still in its infancy, my chances of winning this scholarship are STRONGLY DEPENDENT on the great support of my family, friends and fellow science enthusiasts! 

Some of the other finalists have been blogging longer than I have and may have more followers on their blogs, so your vote is vital to my chances of winningNOTE: You can only vote once per device, therefore feel free to vote using your work, home computer(s) AND smart phones! Voting ends November 23rd. 

Please click here to vote for me!
It only takes a second!

Below is an excerpt from my submitted essay:
" Although I have taught microbiology and immunology to hundreds of undergrads and launched two newsletters that are distributed throughout my department to foster interdisciplinary communication, I yearned to discuss interesting research discoveries with the public at large. I continue to believe that blogging provides me with the unique opportunity to do exactly that, while giving me a forum to improve my writing skills.
  I soon began thinking of what kind of blog I would be proud to write. As an immunologist, I have noticed that although there are ample blogs, news columns, and television programs conveying general science and health issues, there wasn’t any public space devoted to discussing basic immunological research. To fill this important niche, I launched “Escaping Anergy: The Immunology Research Blog”. Anergy is an immunology term describing the state in which a T cell is inadequately stimulated and unable to actively participate in the immune response. Because of this, the anergic T cell is doomed to wander throughout the body quietly, doing essentially nothing. So how do individuals, like T cells, become active and prepared to take on whatever health challenges comes their way? The answer lies in the fundamental basis of my blog: to provide a second signal called co-stimulation. Co-stimulation refers to the guiding signal that T cells must receive to strengthen their ability to do all the things a powerful, active T cell can do. The purpose of my blog is to help reverse the process of anergy in our community by getting us psyched up about the biology behind human health issues so that we can become active members of society and engaged in furthering scientific discovery.
  I began this blog out of my genuine interest in both research and science communication. Although still in its infancy, I feel empowered with every new visitor who reads my blog, and I believe it is succeeding as I have received much praise from the online community for my in-depth analysis of the latest research articles in the fields of immunology, human health, and disease. I strongly believe that my experience as a blogger has strengthened my career, my research, my quality of teaching, and perhaps most importantly, my confidence in my ability to achieve my ultimate goals. I would be truly honored to receive this award and believe that it will provide me with significant resources to help publish my research findings, travel to conferences, attend writing seminars, and ultimately enrich my communication skills within both the scientific and public communities."
I hope you will help advocate science communication and can help spread the word! 

Thank you for support, it is truly appreciated!

Heather Wilkins JS (2008). The roles, reasons and restrictions of science blogs. Trends in ecology & evolution, 23 (8), 411-3 PMID: 18597888

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).

Monday, October 10, 2011

Silencing "The Silent Killer": Researchers reveal promising new strategy to prevent and diagnose osteoporosis

Healthy bone structure (left) vs Osteoporotic bone (right). From
Public Interest Note:
             Put two simple, innocuous words together and you get a longer word describing a disease that affects 200 million women worldwide: “Osteo” from the Greek word “osteon” meaning “bone” and “Porosis” meaning porous.  Porous bones.  Bone filled with cavities.  Bone loss.  Weak bones. Fractured bones. These phrases simply describe what having osteoporosis means.
         With such simplicity in describing the biological effects of this disease, it’s surprising that much of the public need celebrities like Sally Field to describe the importance of bone health to the public.  However, with an estimated 54% of postmenopausal women being osteopenic (lower than normal bone mass) and 30% exhibiting full-blown osteoporosis, the bone health industry and advocates for promoting bone health are trying everything they can think of to get people to pay attention this “silent killer”.
            Hold up!  Did I just go from the Greek word for “bone” to  “killer” in just over 100 words?  Unfortunately, it’s that easy to connect these two seemingly disparate terms. 
Osteoporosis is often called “the silent killer” because individuals who have the disease are usually unaware that they have it until a bone fractures.  Serious bone fractures often leave individuals with osteoporosis debilitated and can enhance susceptibility to infectious diseases, which can result in death.  In fact, according the International Osteoporosis Foundation, women over the age of 50 have “a 2.8% risk of death related to hip fracture…equivalent to her risk of death from breast cancer and 4 times higher than that from endometrial cancer”.  Importantly, the occurrence of bone loss is not limited to having two X chromosomes, as men over the age 50 have a 30% risk of experiencing an osteoporotic fracture,similar to the risk developing prostate cancer.
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) recommends that people “consider to talk to [their] doctor about osteoporosis” if you have broken a bone and are over the age of 45 (regardless of sex), if you are a 65+ year old woman, are taking certain medications that are known to cause bone loss,have developed poor posture, if you are a woman whose menstrual periods have stopped (or never started upon puberty), if you have anorexia, or have a chronic illness that is known to contribute to bone loss.  In most of these cases however, individuals at risk do not think of consulting their doctor until symptoms start to appear.  Scratch that. Symptom starts to appear.  The major symptom of osteoporosis is experiencing a bone fracture, which at that point the disease is so progressive that prevention of the disease no longer applies.  Furthermore, treatments may not be able to reverse the level of bone lost at this late stage in disease development, increasing the chance of repetitive bone fractures and risk of death in the future.
In addition to the need for more effective therapies on the market to treat osteoporosis, there are currently a limiting number of diagnostic tools that can be easily utilized in the clinic.  Currently, the main tests to assess a person for bone loss is to analyze his or her bone mineral density (BMD), bone strength, and bone turnover.  However, there are limitations to current diagnostic strategies including correlating data obtained from varying instruments, bone used for density and strength tests are not always uniform between testing clinics and techniques used, and in the case of assessing bone turnover in the blood and urine, these tests do not confidently correlate with disease progression.  Therefore in order to treat this disease effectively, the need for more precise diagnostics is urgent.
Notably, the loss of bone strength does not only inflict men and women with hormone imbalances, but is also caused by various drugs like glucocorticoids and chronic illnesses such as rheumatoid arthritis, periodontitis and cancer.  Additionally, bone loss has been observed in individuals who live with little to no bone mobilization as seen in individuals who are confined to a bed and in astronauts who live for long periods of time in zero-gravity environments.
Bone loss is becoming of greater importance to confront as a society as large portion of our population ages into their 50s and beyond.  Serious bone fractures can lead to chronic pain, reduced mobility, disability and an increasing degree of dependence, which not only negatively impacts our Nation’s workforce, but forcing the public to pay millions of dollars annually to cover bone-fracture-related costs.  In 2005, it was estimated that over 2 million fractures were treated costing $17 billion in healthcare costs.  The International Osteoporosis Foundation predicts the incidence rate to increase by 50% in 2025, costing upwards of $25 billion to cover medical treatments in the U.S.
Whether you care most about the pain people with osteoporosis endure, the deficiency of effective, accurate diagnostics, or the dismal economics associated with the disease, the scientists studying the disease need the public’s continuous support.  With such support, researchers will continue to enhance our understanding of the disease, discover new drug targets and design novel therapeutics to turn the trend of this debilitating disease around.
Our Bones and Our Immune System I: How Our Immune System Relies on Our Bones
Immune cell development occurs primarily in the bone marrow before cells. From
            The first thing that students in an Immunology 101 course learn is a process called hematopoiesis.  Hematopoiesis is a unnecessarily big word to describe how a stem cell becomes an immune cell.  It makes sense to start a course with learning this concept, however, it is usually briefly described and skimmed over by the lecturer.  Perhaps it is because most students are more interested in learning about things that they have heard of before like: antibody production, organ/tissue donation, infection, cancer and vaccine development.  At any rate, hematopoiesis probably represents about 1% of the material students will learn about immunology-which is unfortunate, because there is a lot of amazing things happening when an immune cell is “born”, that we need more research done to fully understand it all!
So, if we had to pick somewhere in the body for an immune cell to be born, we might think of the lymph nodes, spleen or the blood; after all these are the most popular organs associated with immune function, right?  However, surprisingly, the site where hematopoiesis occurs-where immune cells develop and mature is in the bone.  The bone marrow is where all immune cells, except T cells, spend all their time until they migrate throughout our blood and tissue ready to protect us from infection and injury.  In fact, the “B” in B cell comes from bursa of Fabricius, which was discovered in the late 1950’s as the organ where antibody-producing cells developed (compared to the thymic-derived T cells, hence what the “T” in T cell means).  If you are wondering why the “B” stands for some organ you probably have never heard of and not “bone marrow”, it is because those original 1950’s experiments were performed on birds, and a decade later it was discovered that mammals don’t have a bursa of Fabricius, but is analogous to mammalian bone marrow. 1
From birth to their “adolescence” most of our immune cells are intricately connected to the bone environment.  Since this revelation, much research has unveiled important factors of hematopoiesis and the mechanisms that explain how cells emigrate from the bone into tissue.  In addition, it is known the bone environment is a critical component of maintaining a constant supply of immune cell populations, which is important to clear infections as well as reconstituting the an immune system after exposure to radiation and chemotherapies.  With over 60 years of research in hematopoiesis, the medical field has greatly benefited from our understanding of how bone impacts immune cell development.  However, over this same period, little research has been devoted to understanding the other aspect of this bone-immune cell relationship: how immune cells impact to bone development and health.

Our Bones and Our Immune System II: How Our Bones Rely on Our Immune System
 Cytokines associated with the chronic inflammatory disease, rheumatoid arthritis are used to model the complex nature of the immune system regulating bone development. From R&
The idea that immune cells impact bone development seemed to happen serendipitously in the 1990’s, beginning with the discovery that one of the major cell types that make up our bones was derived from a hemopoetic cell.  Soon, Udagawa and colleagues published their research findings that monoytes can turn into bone cells called osteoclasts.
 Monocytes are unique immune cells because unlike B cells, for example, which will always be B cells, monocytes can further differentiate into a variety of immune cells.  Monocytes are able to do this because they are acutely sensitive to changes in their microenvironment and highly responsive to a range of stimuli that instructs the monocyte to turn into a different kind of cell.  Osteoclasts, macrophages, dendritic cells, and microglial cells all derive from a monocyte precursor.  What makes each of these cells unique is what stimuli a monocyte senses.  For example, in vitro, to generate macrophages (which I do on a weekly basis), all you need to do is isolate bone-marrow cells or monocytes and throw in some macrophage-colony stimulator factor (M-CSF), wait a week and you’ve got macrophages!  If you want dendritic cells, do the same thing, but this time in addition to M-CSF add some IL-4.  Back when it was just learned that osteoclasts come from monocytes, a lot of research was done to figure out two major things: 1) what exactly an osteoclast was and 2) what a monocyte needed to become a bone cell. 
An osteoclast is a macrophage-like cell.  This seems to be post heavy with Greek terminology, so I’ll keep it up by describing a macrophage as a cell that is very big (aka “macro”).  An osteoclast is very similar in that they too are huge, in fact they are often referred to as (and I am not making this up): “giant cells”.  They are so big because are created when developing monocytes fuse into a single, giant cell.  One of the most distinguishing traits of an osteoclast is that they are multi-nucleated.  Osteoclasts differ from macrophages in many ways; however, including first and foremost-they stick specifically to bone instead of residing in tissue.  Moreover, unlike other monocyte-derived cells, osteoclasts are capable of resorption, the process of degrading bone by pumping large amounts of hydrogen ions into the bone.  Accumulation of these ions and other enzymes from the osteoclast into the bone causes the bone matrix to acidify and break down, which results in cavities in the bone.  Cavities typically have a negative feeling associated with them, but destruction of bone is not always a bad thing.   Think of what would happen if your bones just kept growing.  You might develop strange bone abnormalities or have problems acquiring enough nutrients to keep the excess of bone healthy.  So bone development, like everything in biology is a tightly regulated process.  In order to understand how errs in bone development lead to osteoporosis, it is important to appreciate how osteoclasts are generated, as they are the key to the pathology associated with bone disease.
Firstly, what a monocyte needed to turn into an osteoclast proved to be more complicated than anticipated.  Initially it was difficult because there were two groups of researchers working separately on something that unbeknownst to them at the time, was in fact the same thing.  There were the people studying bone trying to figure out more about how bone developed and there were the people working on the immune system trying to figure out how monocytes turned into osteoclasts.  For example, in the 1990’s, two important discoveries were made: First, the bone physiologists identified a protein, expressed by osteoblasts and stromal cells that was proven to be essential to osteoclast development- they called this protein osteoclast differentiation factor (ODF).  Secondly, the immunologists were please to announce the discovery of receptor activator of nuclear factor kappa-B ligand (RANKL), which is produced by T cells and was determined to be the second stimulus, in addition to M-CSF a monocyte needs to turn into an osteoclast.  It was later revealed that both groups of researches had actually discovered the same protein such that ODF is identical to RANKL!  2 Realizing this, Drs. Joseph R. Arron and Yongwon Cho quickly coined the term ‘osteoimmunology to be “used to describe the interface between these two disciplines”.  The authors of the article go on to explain, “Without a better understanding of this interface, it will be difficult to prevent or treat many common diseases that affect both bones and the immune system”. 3

Treatments for Osteoporosis: Why this research matters:

Bones are “Often thought of as a rigid, unchanging entity, skeletal bone is actually the result of a dynamic process” involving a balancing act between the activity of bone formation by osteoblasts and bone destruction by osteoclasts.  The harmony between these two processes is essential for maintaining strong bones.  It is when the rate of bone resorption exceeds the rate of bone formation that leads to osteoporosis.   Why does this happen? How can we slow the rate of resorption? What factors are present that promote osteoclast function to degrade bone? If we knew the answers to these questions we could better treat bone-loss related diseases or prevent the incidence of bone fractures! 
The “gold standard” for osteoporosis therapy is the use of bisphosphonates, which first entered the drug market in the late 1990’s by Merck [Fosamax aka alendronic acid] and Sonofi-Aventis/Proctor and Gamble [Actonel aka risedronic acid].  Currently drugs that are classified as bisphosphonates to treat bone loss represent more than 70% of the market with the expansion of generics and drugs that have improved dosage like Boniva [zoledronic acid, Novartis].  Another big reason for dominance of these drugs in the market is the history of 50 years of research detailing how how bisphosphonates regulate bone development. 4  
So what are bisphosphonates and how do they work?  They are simple, small chemicals that consist of two phosphonate groups (PO3-) linked together by a carbon atom.  These chemicals are particularly good at binding to calcium, so when they enter the body, bisphosphonates concentrate in the bone.  Drugs in the bisphosphonate class decrease bone resporption because once they enter a cell, they inhibit the cell’s ability to metabolize energy (ATP), which leads to a process called apoptosis or cell death.  Because osteoclasts are intimately bound to bone and have some macrophage-like properties like gobbling things up, bisphosphonates are particularly good at killing osteoclasts, thereby reducing bone resorption. 5
However, to no surprise, there are multiple risks and side effects associated with this class of drugs including: gastrointestinal irritation, oeophageal irritation, hypocalcaemia, renal irritation or more rarely: osteonecrosis of the jaw and atrial fibrillation.  There many reasons why there is a need for newer drugs on the osteoporosis market.  For one thing, bisphosphonates and other available drugs are not very specific to osteoclasts.  Any cell has the potential to take up a small chemical and be affected by it.  In addition, although the majority of the drug will work at its target site (bone), some amount of the drug is likely to influence the function of off-target sites as well.  Furthermore, these small chemicals are given orally introducing a high rate of non-compliance by patients, decreasing the potential efficacy of the drug. 4
Second to bisphophonates in populatrity is a class of drugs called selective estrogen receptor modulators (SERMs). 4   Although a decrease in estrogen tends to correlate with the onset of osteoporosis, which one reason why the prevalence of this disease is greater in post-menapausal women, there are a variety of reasons why SERMs are not the most effective treatment for bone loss.  For one, estrogen is not the only factor influencing the development of osteoporosis, and does not correlate in every case.  It is difficult to determine what, if any, is the threshold for estrogen that a women should have to prevent bone-loss.  Furthermore, SERMs are not as effective for women with sufficient estrogen levels or men that suffer from the disease.
Over the last few decades there has been strong developments made to generate drugs that have increased specificity, direction towards the target site, and effectiveness.  Furthermore, there is a great desire to not only treat bone loss, but to develop better diagnostic tools to diagnose bone loss, before the disease triggers a debilitating fracture. According to a recent review regarding the osteoporosis drug pipeline, “the osteoporosis market has not been a major target for innovation.  R&D activities are targeted at improving existing dosing regimens with the goal of reducing the pill burden in a highly medicated population”. At the top of the list for innovative, promising treatments for osteoporosis is an immunotherapy drug called Denosumab (Brand name(s):  Prolia®, Xgeva®).  Denosumab is an antibody that binds tightly to RANKL.  Denosumab is classified a blocking or neutralizing antibody because when it binds to its target, it attaches to the target very specifically and very tightly, blocking the function of the target.  Denosumab, binds tightly to RANKL, preventing RANK from activating it.   Because of this, the side effects can be potentially very limited, compared to chemical inhibitory drugs. 6  Furthermore, because it is injected subcutaneously 1-2/year it enhances patient compliance since patients would not be required to remember to take oral pills, like for bisphosphonates.  Moreover, in mice it has been shown to inhibit osteoclast development and bone resorption.  Just last month, Denosumab received U.S. FDA approval for human use to treat bone loss in patients with breast and nonmetastatic prostate cancer.  It is currently in clinical trials expand its use to other osteoporotic diseases. Amgen is developing Denosumab.
In order to enhance the number of promising therapies in the R&D pipeline, more research focusing on the basic immunological understanding of the disease is needed. By fully understanding the biological mechanisms behind disease development, we can then develop innovative, effective therapies and diagnostic tools to help answer these questions:

·      Is there a way to not only delay the onset of disease, but also prevent it? 
·      Is there a way to not only reduce the chance of bone fracture, but to prevent it? 
·      Is there a way to improve our method of detecting disease, as individuals with slightly low bone mass may go under-the-radar of current bone density measurements?

Without promoting our understanding of how disease develops, we are stuck, unable to move forward in a world where we have safe, available therapies to treat, cure and prevent diseases like osteoporosis

What the &*%$#! Does the Title Mean?!
Hsu, YH., et al. “Anti-IL-20 monoclonal antibody inhibits the differentiation of osteoclasts and protects against osteoporotic bone loss”. Journal of Experimental Medicine. 208:1849-1861. (2011).

      1.  IL-20 is a cytokine, a secreted molecule that regulates inflammation.  What exactly it does is a topic of current research, since it was only discovered 10 years ago.  We know that monocytes are potent secretors of IL-20 and that the cells that express the receptor for IL-20 include: keritonocytes (skin cells) and endothelial cells (line blood vessels).  Much of the work done to understand IL-20 biological function has been focused on what IL-20 does to cells expressing the IL-20 receptor.  For this reason, most of what we know about IL-20 is from a variety of skin and blood vessel-related diseases.  For example, one of the earliest studies revealed that keritonocytes rapidly divide and produce lots of potent pro-inflammatory cytokines including: monocyte chemotactic protein-1 (MCP-1) and TNF-alpha.7 In addition, generating mice that overexpress IL-20 results in skin abnormalities such as thickened epidermis and a wrinkled appearance.  These novel discoveries initiated scores of experiments evaluating the role of IL-20 in inflammatory diseases of the skin like psoriasis and are currently a top therapeutic target to suppress cutaneous inflammation. 8 In addition to psoriasis, a similar inflammatory, disease-promoting role of IL-20 has been established in rheumatoid arthritis9, athersclerosis10, and stroke 11. 

      2.    Monoclonal antibodies are antibodies that are not only specific for the same antigen, but also recognize the exact same amino acid sequence on that antigen.  Normally when you mount an immune response against something like a bacterium, for example, your antigen presentation cells (APCs) will ingest the bacteria and chew up into tiny bits.  If the APCs stopped there, your B cells wouldn’t get effectively activated and you wouldn’t be able to make lots of antibodies to attack the bacteria and protect you from future infections.  In order to get these amazing antibody benefits, the APC must also present those chewed-up bits of bacteria on their cell surface so that your adaptive immune system (T and B cells) can wake-up and realize that there is an infection going on.  You have millions of T cells in your body, all expressing a unique T cell receptor to recognize a single stretch of amino acids of an antigen-those bits put on display by APCs.  Once a T cell recognizes its specific antigenic sequence, it becomes activated and ready to help B cells make loads of antibodies.  When a B cell receives T cell help, it rapidly proliferates generating hundreds of B cells all instructed by the T cells to make an antibody against that specific part of the bacterium that the T cell just saw.  With a little nudge from a T cell, a single B cell divides into thousands of B cells.  When a B cell divides, it is also going through a dramatic, incredibly unique process called affinity maturation.   With each division, a B cell is rapidly mutating the DNA that codes for the antibody’s specificity.  This process results in the production of thousands of B cells that are all able to recognize that specific bacterium, but with slightly different affinities.  But remember that T cells are not all the same and have a range of specificities to any particular antigen, so a variety of different T cells are doing this to different B cells, which quickly multiplies the number of different kinds of antibodies generated during an infection.  It’s like inviting a couple friends over for a drink, but then each of your friends decide to invite some of their friends and their friends invite some of their friends and so on.  Before you know it you have a house full of different people partying it up, having a great time.  This is essentially the same thing that happens in your body during an infection, so the next time you’re sick, remember that you have your partying B cells to thank for your swollen lymph nodes (and your ability to beat the infection)!
But what makes our immune system so amazingly effective is that these B cells must compete for available antigen to promote their survival and ability to secrete their antibodies they’ve just generated through affinity maturation.   This selection process weeds out the B cells that made ineffective, poorly binding antibodies, so that your body is left with the a handful of the most selective antibodies that bind the tightest to the pathogen.  This group of top-tier antibodies is the end result of a normal immune response and is collectively called, polyclonal antibodies, since there is still some variation among the specificity of antibodies generated, but they all derived from the same initial B cell.
Monoclonal antibody generation in the lab.
So how do you get from a variety of antibodies with varying specificity (polyclonal) to a variety of antibodies with the exact same specificity (monoclonal)?  You do it in the lab.  Monoclonal antibody production is not something your body does naturally, because when your body is at war with a pathogen, it’s best to have as many weapons as possible to use in the attack, right?  But, in research, scientists want to limit variables and find the most specific weapon to develop therapy.  In order to do this, all the antibodies have to be the same.  Exact same B cell.  Exact same affinity.  Exact same specificity.  Exact same antibody made.  You get the idea.  Ok, so in order to do this, you first find something you’re interested in making antibodies against, say that bacterium that infected us in the previous example.  In order to make antibodies against the bacterium, you need an infection, it doesn’t need to be robust or cause disease, but enough to stimulate B cells, like in a vaccination.
 In the lab, this is usually done in mice.  After a few weeks since the immunization with the bacterium, the mice will have hundreds of B cells activated with a polyclonal antibody repertoire.   The spleen is isolated since that’s where the majority of B cells reside.  The antibody-producing B cells are then isolated and cultured with an immortal cell line to create hybridomas.  B Cell Hybridomas are generated so that these B cells can live indefinitely so that monoclonal antibodies can be obtained, since natural B cells don’t live for very long in culture.  After selecting for the B cells that have successfully fused with the immortal cell, then scientists split the hybridomas into a culture plate so that there is only 1 B cell hybridoma per well.  Then, they stimulate each hybridoma with that same antigen you used to immunize the mice before.  Because there are no variability from T cells and the culture is in single-cell suspension, the single cell in culture dish will clonally expand, producing identical antibodies.  Specific antibodies based on affinity strength and specificity is further selected for using biochemical techniques, to result in the acquisition of purified monoclonal antibodies.  These monoclonal antibodies then can be used as reagents for experiments (FACS, Immunoprecipitation, Immunohistochemistry), blocking antibodies for therapies and experimental use, or immunotherapies for individuals who cannot mount their own immune response (i.e. Synagis to treat infant respiratory syncytial virus)

Now, with the information above, we can infer: 
Antibodies were generated to produce something that is highly specific for the pro-inflammatory cytokine, IL-20.  This paper is going to provide data revealing that when this anti-IL-20 antibody binds to IL-20 it blocks monocytes from developing into osteoclasts, thus preventing osteoporosis.

Ready for an adventure? Read on for a guided-tour through the scientific data!
Using fluorescent microscopy and nuclear stains, such as DAPI  (blue) scientists can visualize multinucleated osteoclasts, how cool is this picture? From
          Although, IL-20 signaling has been associated with a variety of diseases that share bone-loss as a symptom, there was yet any data regarding the levels of IL-20 produced in osteoporotic patients.  Therefore, one of the first things that Hsu and colleagues wanted to assess was whether IL-20 cytokine levels were elevated in individuals suffering from bone-loss.  To do this, they compared IL-20 concentration in patient serum between 33 41-60 year-old healthy, 62 41-67 year-old osteopenic and 37 40-81 year-old osteoporotic women.  Indeed, circulating IL-20 was significantly increased in women who were clinically diagnosed with either osteopenia or osteoporosis.  Of note, this assessment was limited to Asian women (as the research group is based in Taiwan) and women with known metabolic bone diseases, diabetes, cancer, renal disease, athrosclerosis, using steroids or medications known to influence bone-loss were excluded in this study.

            To examine the role of IL-20 in bone-loss pathology, the researchers utilized a common mouse model that mimics the disease as seen in humans.  The osteoporosis mouse model is achieved via ovariectomy (OVX).  Similar to what was observed in osteoprotic women, IL-20 found in the serum of OVX mice was significantly greater compared to normal female mice, thereby suggesting that the OVX mouse model does, in fact, adequately represent osteoporosis disease symptoms (rise in IL-20) similar to the women clinically diagnosed with osteoporosis.
In a recent study, Hsu and colleagues studied the role of IL-20 in rheumatoid arthritis (RA).  For those experiments, they generated mouse anti-human IL-20 monoclonal antibodies and found that these antibodies inhibited IL-20 signaling in RA, which lessened the severity of the disease.  Now, Hsu, et al. wanted to know if this IL-20-specific antibody would have similar ability to reduce the severity of disease symptoms in osteoporosis.  They call this anti-IL-20 monoclonal antibody 7E.  In the OVX mouse model, they found that when they treated these mice for 2 months with 7E, the levels of IL-20 dropped to that of non-OVX females or OVX mice treated with estradiol, which serve as positive controls of healthy mice.  Furthermore, analysis of bone morphology and bone mass density (BMD) revealed that OVX mice treated with the anti-IL-20 antibody, 7E, exhibited less bone loss than mice that did not receive 7E. It is important to note, this research team was quite thorough in their experiments by including a number of positive and negative controls to justify that the observed effects with 7E was specific to IL-20. 
To show that these effects were specific to 7E and not to any injected antibody, the scientists also included a control group of OVX mice treated with non-specific antibody (mIgG), which did not attenuate IL-20 levels or bone-loss.  Moreover, by using ELISA in which they coat a culture plate with the 7E antibody to “capture” serum cytokines followed by a secondary antibody to detect a variety of cytokines with similar structure to IL-20, Hsu and colleagues demonstrated that the 7E monoclonal antibody they generated was specifically recognizing IL-20.  

At this point, there is data to suggest that IL-20 has a role in promoting bone-loss, since levels of this cytokine increase with disease and neutralizing the cytokine with an IL-20-specific antibody ameliorates disease symptoms.  However, HOW IL-20 is doing this and what cells are responsible for the IL-20-mediated effects are completely unknown.
Given what is currently understood about the cells involved in bone resorption, the research team started to focus on osteoclasts.  First, Hsu, et al. tested whether 7E affected the ability to generate osteoclasts from hematopoietic stem cells (HSCs).  As described above, these precursor cells require M-CSF and RANKL in order to differentiate into osteoclasts.  Regardless of when 7E was given to HSCs, prior to or at the same time as M-CSF/RANKL, 7E inhibited osteoclast formation (look for the giant cells!):
In addition to the defect in giant cell formation, treatment with 7E reduced the expression of a variety of osteoclast markers including: RANK, c-Fos, Cathepsin K, NFATc1 and TRAP.  These data show 7E can be used to block osteoclast formation in vitro, which for the antibody to have an effect, it needs to bind IL-20 present in the culture.  Because there were no other cells present in this culture, these data indicate that osteoclasts are capable of producing and sensing IL-20 themselves!
To determine if these precursor cells were capable of producing IL-20, Hsu and colleagues looked at IL-20 and IL-20 receptor expression in HSCs.  Only in the presence of M-CSF, did HSCs express IL-20 illustrating that in addition to giant-cell formation, M-CSF treatment induces IL-20 production in these cells.  Furthermore, when these M-CSF-derived osteoclast precursor cells (monocytes) were treated with exogenous IL-20, RANK expression significantly increased, suggesting that cells developing into osteoclasts produce IL-20, and respond to IL-20 by upregulating RANK on their cell surface.  Recall that RANK, is the receptor for RANKL and is required for osteoclast development and function.  The IL-20 neutralizing antibody, 7E, was able to greatly diminish RANK expression by osteoclast precursors, despite the presence of IL-20 in the culture.  These data provide compelling evidence that IL-20 promotes osteoclast development and that IL-20 may promote osteoporosis.
These cells may enhance RANK expression on their cell surface to enhance their ability to sense and bind available RANK ligand (RANKL) in the bone environment.  The idea is that the more RANK or RANKL available, the more monocytes are developing into osteoclasts that lead to degradation of bone. To further assess how IL-20 affects in bone development, the research team looked into how IL-20 affects osteoblast function.  In an osteoblastic cell line culture, IL-20 enhanced osteoblast signaling activity and RANKL expression. Currently, the understanding of the induction pathway of osteoclast development begins with RANKL stimulating RANK on M-CSF-stimulating osteoclast precursor cells.  But here, Hsu, et al. provide data showing that something upstream of RANK/RANKL is controlling RANK/RANKL function and therefore ultimately controlling osteoclast development--IL-20!  These are the first data indicating how RANK and RANKL expression is modulated by a soluble factor associated with bone disease! 
To further investigate the role of IL-20 signaling in promoting osteoporosis, the research team generated IL-20R1 knockout mice.  By removing the ability of IL-20 to stimulate signaling cascades responsible for osteoclast development, they observed that aging mice lacking IL-20R1 had increased BMD compared to wild-type counterparts.  In addition, mice lacking IL-20R1 had a defect in osteoclast development from monocytes and were unresponsive to IL-20 or 7E treatment, thus further accentuating the specificity of 7E for IL-20.  So perhaps, humans, like mice may lose the ability to maintain high levels of IL-20R1 thereby increasing the chance of developing more bone resorbing osteoclasts.  However, Hsu and colleagues did not investigate whether similar data regarding IL-20 receptor expression is observed in humans.
Lastly, Hsu, et al. went back to see if the IL-20R deficiency provided similar results as their IL-20 blocking antibody, 7E in the development of osteoporosis.  To do this, they performed ovariectomies (OVX) on IL-20R1 deficient (IL-20R1-/-) and IL-20R1 sufficient (IL-20R1+/+;+/-) mice.  Similar to what they observed in mice treated with 7E, OVX mice lacking IL-20R were protected from bone-loss!
This diagram depicts what was known about osteoclast function, what Hsu, et al. were able to add was data to answer the question: WHAT regulated RANK/RANKL expression? Hsu, et al. showed for the first time that IL-20 upregulated RANK/RANKL and that an IL-20-specific antibody could block this expression and IMPROVE osteoporosis symptoms! Importantly, they also demonstrated that IL-20 may be used as a potent diagnostic marker to indicate the presence of osteoporosis in humans!! Figure from
By utilizing a variety of methods including generating IL-20-specific blocking monoclonal antibodies and generating IL-20R-deficient mice, Hsu and colleagues convincingly provide data that are the first to describe the role and function of IL-20 in promoting osteoporosis.  Importantly, this is also the first report describing the positive correlation between IL-20 serum levels and bone-loss disease.  These findings lend insight and development of better diagnostic tools that may detect the onset of bone-loss earlier than current diagnostic methods.  More research is needed to elucidate the kinetics of IL-20 production in order for IL-20 to be effectively used as a biomarker to track the onset and progression of bone disease.
The current clinical treatments for bone-loss include drugs that largely target estrogen, calcium, or RANK/RANKL signaling.  The disadvantages to the former two are highlighted in the above section; however it is important to note that in mice, genetic deletion of either RANK or RANKL results in severe osteopetrosis (increased bone mass) and the utter loss of osteoclasts.  Which although may cure osteoporosis, it leads to poor bone homeostasis and may cause detriment to immune cell and bone development.  Because of these findings, there is potentially a danger in developing osteopetrosis with individuals with RANK/RANKL mutations or using drugs that completely block RANK/RANKL function.12 Because of this, it is imperative for researchers to continuously unveil new understandings in signaling pathways and be scavenging for new therapeutic targets in order to achieve the most effective drugs with the least amount of harmful side effects.  Studies, such as this one lead by Ming-Shi Chang at the National Cheng Kung University in Taiwain, is a testament to the encouraging role academic scientists play in developing promising, novel immunotherapies to help treat millions of people around the world. Hsu YH, Chen WY, Chan CH, Wu CH, Sun ZJ, & Chang MS (2011). Anti-IL-20 monoclonal antibody inhibits the differentiation of osteoclasts and protects against osteoporotic bone loss. The Journal of experimental medicine, 208 (9), 1849-61 PMID: 21844205 

References and Further Reading:
1. Glick,B. “Historical perspective: The bursa of Fabricius and its influence on B cell development, past and present”. Veterinary Immunology and Immunopathology. 30:3-12. (1991).
3. Arron, J. and Choi, Y. “Bone versus immune system”. Nature. 408:535-536. (2000).
4. Yasothan, U. and Kar, S. “Osteoporosis: overview and pipeline”. Nature Reviews Drug Discovery. 7:725-726. (2008).
6. Opar, A. “Late-stage osteoporosis drugs illustrate challenges in the field”. Nature Reviews Drug Discovery. 8: 757-758. (2009).
7. Sabat, R. “IL-19 and IL-20: two novel cytokines with importance in inflammatory diseases”. Expert Opin Ther Targets.  11:601-612. (2007).
8. Rich, BE. “IL-20: a new target for the treatment of inflammatory skin disease”. Expert Opin Ther Targets.  7:165-74. (2003).
9.Hsu, YH., et al. “Function of interleukin-20 as a proinflammatory molecule in rheumatoid and experimental arthritis”. Arthritis Rheum. 54:2722-2733. (2006).
10. Chen, WY. “IL-20 is expressed in atherosclerosis plaques and promotes atherosclerosis in apolipoprotein E-deficient mice”. Arterioscler Thromb Vasc Biol .26:2090-2095. (2006).
11. Chen, WY and Change, MS. “IL-20 is regulated by hypoxia-inducible factor and up-regulated after experimental ischemic stroke”. Journal of Immunology. 182:5003-5012. (2009).
12: Kong, YY, et al. “OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis”. Nature. 397:315-333. (1999).