Reflectance Confocal Microscopy: An Elegant, Revolutionary Technique with Boundless Possibilities

by guest blogger Joshua Davyd Fox, University of Miami, MD class of 2016

 

At the 2015 American Academy of Dermatology Annual Meeting, I serendipitously discovered Reflectance Confocal Microscopy (RCM). I sat mesmerized, watching the presenters quickly flip through black-and-white mosaic images of in vivo skin at microscopic resolution in what may best be described as a fusion between radiology and dermatology. As a fly in a room filled with experts of a drastically underutilized technology, I felt as though I was witnessing something groundbreaking- the next evolution in dermatologic diagnosis since the revolutionary advent of dermoscopy.

 

Before I knew it, I was meeting a faculty member from my University to learn more about RCM and observe a case. The patient was a fair-skinned middle-aged woman with a dark brown macule on her buttock. The dermoscopic pattern was not diagnostic and would have required a biopsy.

 

RCM uses a laser as a source of monochromatic light. As the wavelength of the light increases in the near-infrared region (700-1400 nm), so does its depth of penetration into the skin; however, longer wavelengths have less lateral resolution.1 Thus, depending on the RCM application, the wavelength will vary based on the desired depth of penetration.

 

It is common to use an 830 nm diode laser on automatic image control, which adjusts the laser power to provide the best contrast (the range is 1-21mW and causes no tissue damage). A skin contact ring is affixed to the skin along with a drop of ultrasound jelly at the site of the lesion, and a small drop of a water-based gel is placed onto the objective lens that is in the housing of the skin-contact device.

 

The laser beam passes through a beam splitter, scanning and focusing optical lens, through the skin contact device and is focused on a couple of microns of skin. The light rays are refracted by various components of the skin such as membranes, melanosomes and keratohyalin granules based on their respective refractive indices. These refracted and reflected rays return to the direction of the detector (which is connected to the computer), though they are physically filtered by a small aperture that only allows the light rays originating from the focal point to strike the detector — hence, this is confocal microscopy. Similar to the contrast created by differing tissue radio-densities in x-ray imaging, in RCM the image depends upon the contrast that is created by the differing refractive indices of skin components. The water-based gel is used because it has a refractive index of 1.33, which is nearly equivalent to the 1.34 of the epidermis, thus eliminating artificial refraction.

 

One can choose how to display the captured images. For example, we captured 12 rows by 12 rows of 500-micron x 500-micron tiles that were combined to form a mosaic of a 6 mm x 6 mm field with resolution at the cellular level. We scanned multiple mosaic images of the lesion at various depths and magnifications and identified cells out of a tempestuous sea of black and white pixels.

 

Although confocal microscopy was developed in the 1950s it was not applied to skin imaging until the 1990s with Rajadhyaksha’s work.2 Today RCM is used clinically mainly in the diagnosis of skin cancer and corneal pathologies and in research in skin cancer, skin aging, laser treatment, pigment pathologies, melasma, UV-induced skin responses, wound healing, and conjunctival and corneal evaluation.3,4,5 In a recent study in the JAAD, handheld RCM was utilized in the evaluation of 47 eyelid tumors clinically suspicious of malignancy, and RCM had 100% sensitivity and 69.2% specificity in the diagnosis of malignant tumors of the eyelid.6 Even more impressive results were seen in a recent study in the American Journal of Ophthalmology, in which 30 patients with conjunctival tumors were correctly spared an excisional biopsy (based on at least 12 months of follow-up), and in all patients who did undergo excision (23), the authors found 100% RCM correlation to the histologic diagnosis.3

 

Our patient’s lesion that warranted a biopsy based on the physical exam and dermoscopy was found to be benign based on the RCM features. Nonetheless, the patient wished for the lesion to be excised, which was done in due time.

 

This leads to the question: should we ask patients prior to performing RCM if they want the lesion to be excised regardless, in which case RCM would not be performed? Perhaps there is a benefit to conducting RCM even in these patients, as the tool is still developing and, with each case, more information is added to fine-tune the technique? Are there applications of RCM which we have not even thought of yet? I’m sure there are.

 

Cost and reimbursement issues will likely play a large role in the utility of RCM outside of the university setting. The average device costs between $70,000-$100,000, and each patient requires approximately 10-20 minutes to image.

 

To me, RCM’s ability to image in vivo skin, real-time, at microscopic resolution makes it a beautifully revolutionary technique. Only time will tell on which applications RCM will be most focused.

 

Anyone who would like to learn the technique of reflectance confocal microscopy may be interested in attending a weekend course in November 2015, at the University of Miami School of Medicine and can email umcme@med.miami.edu, or call 305-243-6716 for more information.

 

Acknowledgments:
Thanks to Robert S. Kirsner MD PhD and Theresa Cao DO of the University of Miami who critically reviewed this work.

 

References:

  1. Calzavara-Pinton P, Longo C, Venturini M, Sala R, Pellacani G. Reflectance confocal microscopy for in vivo skin imaging. Photochemistry and photobiology. Nov-Dec 2008;84(6):1421-1430.
  2. Rajadhyaksha M, Grossman M, Esterowitz D, Webb RH, Anderson RR. In vivo confocal scanning laser microscopy of human skin: melanin provides strong contrast. The Journal of investigative dermatology. Jun 1995;104(6):946-952.
  3. Cinotti E, Perrot JL, Labeille B, et al. Handheld reflectance confocal microscopy for the diagnosis of conjunctival tumors. American journal of ophthalmology. Feb 2015;159(2):324-333 e321.
  4. Ulrich M, Lange-Asschenfeldt S. In vivo confocal microscopy in dermatology: from research to clinical application. Journal of biomedical optics. Jun 2013;18(6):061212.
  5. Marchini G, Mastropasqua L, Pedrotti E, Nubile M, Ciancaglini M, Sbabo A. Deep lamellar keratoplasty by intracorneal dissection: a prospective clinical and confocal microscopic study. Ophthalmology. Aug 2006;113(8):1289-1300.
  6. Cinotti E, Perrot JL, Campolmi N, et al. The role of in vivo confocal microscopy in the diagnosis of eyelid margin tumors: 47 cases. Journal of the American Academy of Dermatology. Nov 2014;71(5):912-918 e912.

 

 

No Cell Sings Alone

An organism is  a chorus. Through an invisible song book its cells follow an omniscient conductor who directs them when to open their mouths and utter a note or a phase;  when the concert concludes, the effects suggest cosmic regulation. Ervin H. Epstein, Jr., MD and Anthony Eugene Oro, MD, PhD investigate how cells work and interact to make normal epithelial organs, such as skin and hair follicles: cells follow molecular conductors, pick up brief nuanced clues, nods, and signals, and they interact with other cells, hormones, and tissues. Sometimes a cell and its progeny follow discordant paths; then cacophony, discomforting rhythms, and disease occur, leaving the chorus a jumbled racket.

Epstein described how  small molecules could be used to correct these aberrant voices and make them rejoin the chorus; alternately, they could be made to abate their shouting and go away completely; or, perhaps, they could be made to wither away and allow other singers to continue on in tune. It can take decades to first identify the squeaky voice in a disease and then to develop an effective and safe means   for silencing it or training it.  Outstanding examples for new and effective treatment for the basal  cell nevus syndrome and the more common basal cell carcinomas of the skin were presented.

Oro discussed how cells could be returned to their youthful, pristine voices and directed to produce clear  tones in harmony with their sister cells.  Dermatologists in the audience perceived how drugs could take the place of surgery or ionizing radiation for treating of skin tumors, and how devastating genetic diseases could be ameliorated with a new set of an individual’s own cells.   Work in progress will focus on preventing resistant clones from growing in tumors undergoing treatment and developing drugs with fewer side effects, or maybe evolving completely new therapeutic modalities.

The final song will be worth the effort.

 

Epstein, EE Jr:  Twacking the Hedgehog

Oro, AE:  Heal Thyself: Using Stem Cell Biology for Skin Disease

 

Presented at the Plenary session of the 75th Annual Meeting of the American Academy of Dermatology, Sunday March 23, 2014, Denver CO, USA.

Pattern Recognition: Stick with the “Ugly Duckling” Rule?

By Guest Blogger Abrar Qureshi, MD, MPH
Brigham and Women’s Hospital, Boston, MA

In their recent study, Wazaefi at al asked dermatologists and non-dermatologists to cluster images of pigmented lesions from a series of patients and found that dermatologists did a better job at pattern recognition.  Boy, does that makes all dermatologists feel good!  We should be able to spot the difference between a black-capped chickadee and a white breasted nut-hatch in flight!  Maybe training our residents to recognize nature’s patterns outside the clinic will further embellish their clinical skills, with outings such as ‘astronomy night’ or ‘bird watching in the marshes’.

White breasted nut hatch by Mdf, via a creative commons attribution share-alike license on Wikipedia
White breasted nut hatch by Mdf, via a creative commons attribution share-alike license on Wikipedia

There are more layers to all this talk of ‘patterns’ – for example, are we looking too closely at pigmented lesions nowadays?  In the era of cross-polarization and spectroscopic gizmos, fortunately there are still some dermatologists who walk around clinic with a jeweler’s loupe in-hand.  Even more basic, there are other clinicians who use naked-eye inspections to examine their patients:  no loupes, forget fancy dermoscopes.  Is there a rationale to this variation among dermatologists when faced with a questionable pigmented lesion?  Are we looking for the ugly duckling through a scope?  Does the approach matter when seeing the whole patient versus looking at images of specific pigmented lesions?  Could the results of this study be different if dermatologists and non-dermatologists were asked to actually examine patients rather than work with images?

 

REFERENCES:

Wazaefi Y, Gaudy-Marqueste C, Avril M-F et al.  (2013) Evidence of a Limited Intra-Individual Diversity of Nevi: Intuitive Perception of Dominant Clusters Is a Crucial Step in the Analysis of Nevi by Dermatologists.  J Invest Dermatol doi:10.1038/jid.2013.183

These Eyelashes Are Not Eyelashes

The title suggests Magritte has escaped from his exhibition  at the Museum of Modern Art in New York and is writing this week’s post. Recently, in the Bali Bird Park near Ubud, Indonesia I saw a remarkable hornbill bird from Africa with what looked like eyelashes; really looked like eyelashes.  Yes, of course I know that eyelashes are limited to mammals and that they are hairs made up of alpha keratins, and that birds do not have alpha keratins, and that feathers have beta keratins. I have known that since I was a resident in Howard Baden’s laboratory at Massachusetts General Hospital. Howard is interested in many aspects of skin biology and chemistry, and I was a junior researcher there, dodging the X-ray diffraction beams and studying  the patterns of human epidermal keratins and their associated lipids. Howard had hundreds of grams of desquamated snake skin in the  laboratory for his comparative keratin research.

Ground Hornbill "Eyelash" photo ©iStock.com/EcoPic
Ground Hornbill “Eyelash” photo ©iStock.com/EcoPic

Many hornbill species have tiny cylindrical eyelid feathers that mimic eyelashes and serve the function of eyelashes  — keeping foreign material from the eyes.  In hornbills it is suggested that they may also serve as mini-hats, shielding the eyes from sunlight.

It is unknown, but unlikely, whether many of our readers have seen the “Hunger Games,” in which Effie Trinket, who escorts  the female tributes, has feather-like eyelashes.  This has started  a fashion trend in those many generations younger than this blogger, and Effie, her clothes, and the eyelashes, will surely be featured on some trick-or-treaters. Applying those feather-like eyelashes is harder than one might expect, so leave yourself enough time.

Thinking about this blog for the past year, I recognize that hair, feathers, and birds appear as topics more than would be randomly expected. Why is that? I can see at least two reasons: my early experience in Howard Baden’s laboratory and growing up in Brooklyn, within walking distance to Prospect Park and its zoo, where my eyes and mind could contemplate the wondrous  skin and appendages of many zoo animals. Certainly an ideal upbringing for someone who spends  his personal and scientific life searching out the wonders of the natural world.

A Modest Proposal: Scientist Clinician Jamboree

Two articles in Science Translational Medicine (Sept 25:  Wolk et al, 2013; Clark, 2013) triggered a stream of consciousness response and lead to this proposal. There are not enough productive jamfests between clinicians and scientists to keep advancing research. The articles related to skin TH17 cells in psoriasis producing IL-29 (a gold cytokine on the cytokine hit parade); Il-29 triggers production of several antiviral proteins, whose abbreviations are well known to their friends but not others. This research was stimulated by the clinical observation, known forever (meaning before I trained), that patients with atopic dermatitis often have disseminated herpes simplex infections, while patients with extensive psoriasis do not. This old (no, very old) observation now may have a scientific basis. Why did it take decades to perform this research? The most obvious reason is that methodology in cell and molecular science needed to reach a certain stage just to perform the studies. The other, more subtle, point is that no one thought of, or had funding and a group on which to test, such a hypothesis.  A German group gets the gold ring for these findings.

Just as interesting is the accompanying perspective by Rachael Clark, reviewing several aspects of the skin’s immunological response. In addition to scientific detail are the author’s remarks about whether mouse models will be completely applicable to human disease. This was the topic of a previous post in this space (January 15, 2013) which yielded many comments from our readers. Dr. Clark is in Boston, home of the Red Sox, and she uses an analogy that mouse studies  bring us to third base but may not be sufficient to bring the runner home for understanding human disease. I realize this may not be the most international sports model and would appreciate a soccer analogy to complement the baseball one.

Thus, my idea:  there is a need to bring physicians and laboratory scientists together to brainstorm and be creative. This could be at local (institutional), national, or international levels, to share what each group of individuals knows and what they need and desire to know. This should be an ego-free zone, for most productivity. National clinical and/or scientific societies can convene the meetings and set ground rules. Sure, involve industry. The need for rapid progress is too compelling to let the naysayers overrule the usefulness of this proposed jamboree. I hope our commenters will refine and continue these discussions.

 

REFERENCES:

Wolk K, Witte K, Witte E, et al (2013) IL-29 Is Produced by TH17 Cells and Mediates the Cutaneous Antiviral Competence in Psoriasis. Sci Transl Med 5:204ra129

Clark RA (2013) Human Skin in the Game. Sci Transl Med 5:204ps13

 

Actinic Keratosis — New Chemistry for New Drugs

Lowell A. Goldsmith, MD

Remember those exam questions  in organic chemistry where you were asked to design the synthesis of a compound starting with a simple organic molecule? Some saw  “organic” as a hurdle on the way to biochemistry in medical school; others stayed the course and kept developing new syntheses.  A very long and very detailed article in Science (23 August 2013) describes the short  and inexpensive synthesis of (+) –ingenol — the basis of a new FDA-approved compound for treating actinic keratosis (ingenol mebutate). Before, the only source of the molecule was through relatively inefficient procedures starting with  Euphorbia peplus. The details of the procedure will interest  chemistry aficionados; for me, there were two more general messages:

First: natural compounds — even those that seem, and are, very complex — can be synthesized using today’s techniques. (Jorgensen et al describe a 14-step synthesis with an overall yield of 1.2%, which compares favorably with ingenol’s  isolation from natural materials.)

Second: as  impressive to me was that LEO Pharma supported this research in conjunction with the Department of Chemistry at Scripps, evidence  of very creative interactions between industry and academia  and an important model  for many kinds of research.

This section is for advanced credit.
The official name of Euphorbia peplus is Euphorbia peplus L.  The L. means that the ultimate  authority, Carolus Linneaeus, named the species.  See http://www.plants.usda.gov for some details and pictures of the plant  called the  “petty spurge”. The plant has other names such as ‘cancer weed’ and ‘radium weed’. The origin of those names, especially the latter,deserves some further documentation since the  word “radium” did not exist until  1898. If there are botany namers reading this,  their  responses  are welcomed.

 

REFERENCES:

Jorgensen L, McKerrall SJ, Kuttruff CA (2013) 14-Step Synthesis of (+)-Ingenol from (+)-3-Carene. Science 341:878-882

Lymphatics Keep Flowing Along . . .

by Lowell A. Goldsmith, MD, MPH

Lymphatics were a challenge to me and my fellow  medical students during  our gross anatomy class a half century ago. We could find arteries and veins galore, but where were the elusive lymphatics? Even the two larger connections between the venous and  lymphatic systems were elusive.

Lymphatic biology has progressed  exponentially since then. For two days in May, 2013  the world’s  lymphatic gurus gathered at Yale to fete the rich molecular biology and physiology of the lymphatics, as  summarized recently in Science (Simons and Eichmann, 2013). As of August 17, 2013, lymphedema was  a feature  of almost 70 genetic diseases and syndromes in OMIM, and many common conditions are transmitted  by — or alter — lymphatics.  Vascular endothelial growth factors and their receptors are major players in lymphatic development, and  an RNA binding protein antigen, R(huR), and other molecules are important VEGF modulators.  Lymphatics continue to be the subject of  many narratives, with  implications for cutaneous biology and cutaneous diseases, both inflammatory and neoplastic.  The key role of lymphatic endothelial cells during the transit of dendritic cells from the periphery to lymph nodes is highlighted in the  September issue of JID, underscoring  the importance of lymphatics in cutaneous inflammatory biology.  (Teijeira et al, 2013)

I started with history and end on a historical theme. Dermatology and Yale have a rich history in lymphatic and vascular biology, and Irwin Braverman, currently  a Professor of Dermatology at Yale, published a masterful review in 1983 on the role of blood vessels and lymphatics in skin diseases containing many of his seminal original studies.(Braverman, 1983)   I suspect he is  pleased that skin and lymphatics are still closely intertwined and that Yale was the setting for this vascular biology meeting.

 

REFERENCES:

Braverman IM   (1983) The role of blood vessels and lymphatics in cutaneous inflammatory processes: an overview.  Br J Dermatol.  109 Suppl 25:89-98

Simons M and Eichmann A (2013)  Lymphatics are in my veins  Science 341: 622-4

Teijeira A, Garasa S, Palaez R, et al (2013) Lymphatic Endothelium Forms Integrin-Engaging 3D Structures during DC Transit across Inflamed Lymphatic Vessels. J Invest Dermatol 133:2276-85

 

IMAGE CREDIT:

This image is from Wikipedia, and it is in the public domain.

 

Roots and Routes

By GUEST BLOGGER Ethan Lerner, MD, PhD of Massachusetts General Hospital

 

A 10-year billion-dollar plan is afoot to map all of the connections in the brain. The plan is called the BRAIN initiative, or Connectome. Pretty pictures have already been posted. Really. And really pretty. Perhaps we should concurrently tackle the “Peripherome” – the neural routes from the skin to the dorsal root ganglia and on to the spinal cord. The Peripherome should be sensational to cutaneous biology as it informs us about all sorts of sensations: Itch, touch, pressure, heat, cold, pain, and, with a bit of luck, pleasure. We might even learn a thing or two about hair and sweat, as follicles and glands are highly innervated.

 

Readers may be interested in the recent Science article by Mishra and Hoon (The Cells and Circuitry for Itch Responses in Mice).

 

Image courtesy of the Laboratory of Neuro Imaging at UCLA and Martinos Center for Biomedical Imaging at MGH, Consortium of the Human Connectome Project – www.humanconnectomeproject.org.  (White matter fiber architecture of the brain. Measured from diffusion spectral imaging (DSI). The fibers are color-coded by direction: red = left-right, green = anterior-posterior, blue = through brain stem.)

Isolation of M. leprae and M. lepromatosis protein antigens and the impact on global leprosy

By guest bloggers William Levis and Frank Martiniuk of NYU School of Medicine, Departments of Medicine and Dermatology

 

In the 1980’s, we made significant advances in the serodiagnosis of leprosy using carbohydrate antigens (Levis et al, 1986).  Since then, with the rapid advances on isolation and advances in protein technology, an international consortium of Dutch (Geluk et al, 2011), Brazilian and US scientists led by Duthie (Rada et al, 2011) and Spencer (Spencer et al, 2012) have added to this early work, making leprosy the most exciting immunologic disease for the study of antibodies and T-cell subsets including the old TH1-TH2 paradigm (Modlin, 1994) and the newer subsets of TH17, TH9 and TH22 now under intense study in human inflammatory and neoplastic skin diseases (Martiniuk et al, 2012; Lowes et al, 2013).

The recent Duthie and Spencer serologic test for leprosyis a major advance in leprosy diagnosis and management, as it can monitor therapy and detect subclinical cases that allow for early detection and treatment,  resulting in reduction of residual deformity.  The current difficult and technically challenging Fite histochemical method cannot detect subclinical cases.  Unpublished data also indicate the Duthie/Spencer test can detect but not distinguish what appears to be an emerging microbe, M. lepromatosis (Lowes et al, 2013; personal communication (John Spencer)).  The newly discovered mycobacterial species, M. lepromatosis, originally identified in Mexico, has also been reported in two Chinese immigrants from Asia (where two-thirds of all global leprosy exists ) with Lucio’s (Levis et al, 2012).

Lucio’s has been described as far back as 1948, and until recently, most, but not all, cases have traditionally been from Mexico.  With a phenomenon as uncommon as Lucio’s it is difficult to perform accurate global surveillance.  However,  it may be an emerging virulent mutant of the original M. leprae — or is this only a recently discovered species (or strain) that escaped detection until Han and associates identified the first cases at M. D. Anderson Cancer Center in Houston, Texas? (Han et al, 2009).

Further investigation of these peculiar cases is required before it can be concluded that M. lepromatosis is a more virulent emerging species of M. leprae; this should include sequencing the whole genome.   Duthie, Spencer and the Dutch/Brazilian investigators including Orangelife, Inc. are continuing to work on combination of carbohydrate and protein antigens for diagnosis, contact survelliance, vaccine development, and distinguishing M. leprae and M. lepromatosis.

 

REFERENCES

 

Geluk A, Duthie MS, Spencer JS. (2011) Postgenomic Mycobacterium leprae antigens for cellular and serological diagnosis of M. leprae exposure, infection and leprosy disease. Lepr Rev 82:402-21

 

Han XY Sizer KC, Tan H-H. (2012) Identification of the leprosy agent Mycobacterium lepromatosis in Singapore. J Drugs Dermatol 11:168-172.

 

Han XY, Sizer KC, Thompson EJ, Kabanja J, Li J, Hu P, Gómez-Valero L, Silva FJ. (2009) Comparative sequence analysis of Mycobacterium leprae and the new leprosy-causing Mycobacterium lepromatosis. J Bacteriol 191:6067-74

 

Levis WR, Meeker HC, Schuller-Levis G, Sersen E, Schwerer B. (1986) IgM and IgG antibodies to phenolic glycolipid I from Mycobacterium leprae in leprosy: insight into patient monitoring, erythema nodosum leprosum, and bacillary persistence. J Invest Dermatol 86:529-34

 

Levis WR, Zhang S, Martiniuk F. (2012) Mycobacterium lepromatosis: emerging strain or species? J Drugs Dermatol 11:158

 

Lowes MA, Russell CB, Martin DA, Towne JE, Krueger JG. (2013)  The IL-23/T17 pathogenic axis in psoriasis is amplified by keratinocyte responses. Trends Immunol  Jan 3 S1471-4906 [Epub ahead of print]

Martiniuk F, Giovinazzo J, Tan AU, Shahidullah R, Haslett P, Kaplan G and Levis WR. (2012) Lessons of leprosy: The emergence of TH17 cytokines during type II reactions (ENL) is teaching us about T-cell plasticity. J Drugs Derm 11:507-511

 

Modlin RL. (1994) Th1-Th2 paradigm: insights from leprosy. J Invest Dermatol 102:828-32

 

Rada E, Duthie MS, Reed SG, Aranzazu N, Convit J. (2011) Serologic follow-up of IgG responses against recombinant mycobacterial proteins ML0405, ML2331 and LID-1 in a leprosy hyperendemic area in Venezuela. Mem Inst Oswaldo Cruz 107 Suppl 1:90-4

 

Spencer JS, Duthie MS, Geluk A, Balagon MF, Kim HJ, Wheat WH, Chatterjee D, Jackson M, Li W, Kurihara JN, Maghanoy A, Mallari I, Saunderson P, Brennan PJ, Dockrell HM. (2012) Identification of serological biomarkers of infection, disease progression and treatment efficacy for leprosy. Mem Inst Oswaldo Cruz 107 Suppl 1:79-89.

Coal Tar Rational Drug Design

In dermatology, as in many specialties, there are a number of “tried and true” treatments that have been utilized, in some cases for millenia, to treat cutaneous diseases.  These therapies continue to comprise an important part of our therapeutic armamentarium, despite the fact that the mechanisms by which these compounds improve clinical disease courses are often poorly understood.    Modern efforts to understand pathologic disease mechanisms, particularly when undertaken or funded by pharmaceutical companies, tend to focus attention toward the development of novel classes of compounds whose marketing and prescription are likely to be financially lucrative.   Rational drug design describes the concept of designing novel compounds that could structurally or functionally be predicted to modify a pathologic process or target through modification of gene or protein expression (Mandel et al., 2009).  High-throughput computer-based algorithms can be constructed to screen a database of small molecules with unknown targets, or to screen a host of known targets for their potential response to a particular synthesized molecule, to rapidly and efficiently identify potential novel molecule-target combinations.  Similarly, modeling programs can also be used to predict potential toxicities or untoward effects of these novel compounds (Mandel et al., 2009); these potential effects should, of course, then be investigated in experimental settings.

Given the potential for rational drug design methods to identify lucrative novel therapies, much less attention is often paid to gaining a better understanding of the mechanisms of compounds that have been used successfully for hundreds or thousands of years.  Studies undertaken to elucidate the mechanisms by which these therapies exert their actions, however, represent valuable opportunities both to better understand their biological effects and to provide insight into physiologic processes that underlie the diseases these compounds affect.  A recent study published in the Journal of Clinical Investigation provides a fine example of such work (van den Bogaard et al., 2013).  The authors describe a mechanism by which coal tar, via activation of the aryl hydrocarbon receptor (AHR), restores epidermal barrier protein expression and attenuates Th2-cytokine-mediated effects in both in vitro models and in vivo in atopic dermatitis (van den Bogaard et al., 2013).  A commentary in the same issue discusses that although coal tar is comprised of a wide variety of compounds that are likely to have effects on multiple targets in diseases like atopic dermatitis, a better understanding of known biological targets could allow for the extraction of specific active ingredients from coal tar which would hopefully allow for the creation of “cleaner” preparations that would allow patients to refrain from applying sticky, smelly, and stain-inducing coal tar to the skin (McLean and Irvine, 2013).  Identification of new targets (like the AHR) in atopic dermatitis could also guide rational drug design methods to identify or construct novel compounds that could be added to the therapeutic armamentarium.  These articles remind us that despite the current exciting climate of “smart” drug design, which has enabled the rapid introduction of new classes of therapeutic agents that revolutionize the way we treat various cutaneous diseases, we should not entirely neglect the study of “tried and true” therapies – there is likely a very good reason we use them, even if we don’t yet know what that reason is.

 

 

References

Mandel S, Moudgil M, Mandal S (2009) Rational drug design. Eur J Pharmacol 625:90-100.

McLean WHI, Irvine AD (2013) Old King Coal – molecular mechanisms underlying an ancient treatment for atopic eczema. J Clin Invest 123:551-3.

van den Bogaard EH, Bergboer JGM, Vonk-Bergers M, van Vlijmen-Willems IMJJ, van der Valk PGM, Schröder JM, et al. (2013) Coal tar induces AHR-dependent skin barrier repair in atopic dermatitis. J Clin Invest 123:917-27.