A new study of Rhesus Monkeys clearly shows that Borrelia burgdorferi persists following long term antibiotic treatment. There are three reasons this study stands out:

• Macaques were used, not mice. It's more expensize and kinda sad, but it's a better animal host.
• Treatment was longterm and multiple antibiotics were used, ceftriaxone (4 weeks) and doxycycline (8 weeks)
• Persistence was detected using xenodiagnosis using nimphal ticks and PCR/Fluorescence

The paper was published on PLoS One so it can be accessed by everyone at: Link to Paper

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A new spending bill that funds the Centers for Disease Control is calling for a greater focus on Lyme disease, a request by U.S. Congressman Frank Wolf (R-10th).

Within CDC, the National Center for Emerging and Zoonotic Infectious Diseases would receive $253.919 million, up $1.476 million, or 0.6%. Conferees urged CDC to expand efforts to develop improved diagnostic tools and tests for Lyme disease, study the feasibility of developing a national reporting system on Lyme disease, and expand public and physician education efforts to prevent Lyme and tick-borne diseases.

Wolf pushed for the language in the bill and has been a long-time advocate for victims of Lyme. 

See the full article here.

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A fully preserved body of a European man was found on top of an icy mountain in Austria in 1991. The "Iceman" is one of a handful of humans to have their entire genetic code sequenced. During the genetic autopsy there was an incredible finding:

"Perhaps most surprising, researchers found the genetic footprint of bacteria known as Borrelia burgdorferi, in his DNA—making the Iceman the earliest known human infected by the bug that causes Lyme disease."

This incredible piece of news was buried deep in the article from National Geographic:

http://ngm.nationalgeographic.com/2011/11/iceman-autopsy/hall-text

I think you'll enjoy the full article. Early human life is fascinating to me, like how the Iceman had brown hair, brown eyes, and was lactose intolerant. 

Other than mummies, the Iceman is the oldest preserved human. The finding of Borrelia burgdorferi means that Lyme disease is the oldest known human pathogen! Holy cow!! Geneticists believe that the modern form of Borrelia diverged 10,000 years ago from its most common predecessor. In bacterial terms, 10,000 years is an incredibly long time.  Some conspiracy theorists believe that Lyme disease was engineered but I think these new findings are more mysterious and more plausible. Lyme disease is caused by an ancient pathogen that has survived the ages. It will take all of modern human ingenuity to rid the earth of the plague. 

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Abbott’s Ibis Biosciences today introduced a new molecular assay to detect a wide variety of vector-borne microorganisms, including those known to cause Lyme Disease, Rocky Mountain Spotted Fever, Babesiosis, Ehrlichiosis and Anaplasmosis. Vector-borne pathogens are microorganisms that are typically transmitted by arthropods such as ticks, mosquitoes or fleas.

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• Keynote Speaker: J. William Costerton, PhD The Role of Biofilms in Chronic Bacterial Infections
• Eva Sapi, PhD Killing Borrelia: An impossible job?
• Thomas Angel, PhD Lyme disease reflected in the cerebrospinal fluid proteome
• Richard Marconi, PhD Cyclic-di-GMP controls critical processes required for completion of the enzootic cycle of the Lyme disease spirochetes
• Chris Earnhart, MD Lyme disease vaccine: an update on recent progress
• Robert S. Lane, PhD Diversity of Borrelia burgdorferi s.l. genospecies and genotypes in California, and Implications for human infection.
• M. Karen Newell Rogers, PhD A New Model of Intervention for Lyme Disease by Targeting Chronic Inflammation and Selective Aspects of Immune Activation:
• Robert Yolken, MD Infections and Human Neuropsychiatric Diseases
• Josep Dalmau, MD, PhD Clinical spectrum and cellular mechanisms of autoimmunity to NMDA and other synaptic receptors
• John Aucott, MD Early microbiologic and immunologic events in Lyme disease
• Reinhard K. Straubinger, PhD Canine and equine Lyme borreliosis – The animals’ perspective of the disease.
• Benjamin J. Luft, MD Diagnostics: update on protein arrays and new Lyme assays
• Brian Fallon, MD What is Chronic Lyme Disease? Models and evidence
• Andrew W. Walter, MD Update on Ehrlichiosis and Hemophagocytic Lymphohistiocytosis in Children
• Andrea Gaito, MD Clinical Evaluation and treatment of Lyme Arthritis; An autoimmune perspective
• Ingeborg Dziedzic, MD What everyone should know about Eyes & Lyme Disease
• Vijay Thadani, MD Epilepsy update: distinguishing Epileptic from Non-epileptic seizures
• Steve Bock, MD Complementary and Integrative Medical approaches to Chronic Tick-borne Disease
• Elizabeth Maloney, MD The treatment of Lyme disease - a critical review of the literature – lessons, gaps, and future research needs

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The journal, Clinical Infectious Diseases, has published a supplement packet (Feb 2011) making an argument for the need for a new Lyme Disease vaccine. The supplement contains 5 articles.

• The Lyme Disease Vaccine—A Public Health Perspective
• Vaccines against Lyme Disease: What Happened and What Lessons Can We Learn?
• Relationship between Immunity to Borrelia burgdorferi Outer-surface Protein A (OspA) and Lyme Arthritis
• A New Approach to a Lyme Disease Vaccine
• Correcting a Public Health Fiasco: The Need for a New Vaccine against Lyme Disease

The supplement lays out a convincing argument that we still need a Lyme vaccine despite the "fiasco" of the past. It also highlights the vaccine research at Baxter and Stony Brook. 

The lackluster advancements for new therapies and diagnostics for Lyme Disease is a continuing disappointment. However, the profit motive for a Lyme vaccine is more apparent to business than a therapy or diagnostic. By learning from the past failures, a new vaccine could be marketed and become a real success.

My new requirements for a vaccine based on lessons learned:

• The vaccine should be available to children, better yet, required in endemic areas
• The vaccine should be applicable to European strains
• Strong recommendations from the CDC and FDA are requirements
• Promote to health providers not the public
• Clinical studies need to look for genetic links to adverse reactions, possibly pairing the vaccine with a companion diagnostic to eliminate risky sub-populations

Although Lyme disease has not yet permeated the national milieu, the numbers speak for themselves. Here are the CDC numbers for "Notifiable diseases" that were reported in 2008. Lyme disease is right behind AIDS and within several years will surpass AIDS in the US, if it hasn't already.

Top Ten List

1. Chlamydia trachomatis infections 1,210,523

2. Gonorrhea 336,742

3. Salmonellosis 51,040

4. Syphilis, total, all stages 46,277

5. AIDS 39,202

6. Lyme disease, total 35,198

7. Varicella (chickenpox) morbidity 30,386

8. Lyme confirmed 28,921

9. Shigellosis 22,625

10. Giardiasis 18,908

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The Lyme and Tick-borne Diseases Research Center at Columbia University Medical Center was established in April 30, 2007 in a joint collaboration between Columbia University, Time for Lyme, Inc. (a volunteer not-for-profit activist organization), and the LDA. The center has some very worthwhile goals which include:

• Comparing Laboratory Test Accuracy
• Specimen Bank (blood/CSF from PLDS patients AND cerebral tissue from deceased)
• Second Opinions
• Evaluating SPECT Brain scans as a diagnostic tool
• Establishing a neuro-cognitive profile for Lyme disease
• Neurimaging studies
• Biomarker research as a diagnostic tool
• Training Fellowships(2 Post doc positions and 2 summer MD internships)

Collecting cerebral tissues is a great idea! I would suggest expanding the specimen bank to include other tissue types, urine, skin punch, and fat. The establishment of a dedicated center at a major research university is a huge accomplishment. I encourage you to learn more about the center by reading their website at http://www.columbia-lyme.org

The Interview:

On July 16th, Dr. Brian Fallon, Lyme Center Director and Dr. Carolyn Britton, Associate Professor of Clinical Neurology at Columbia Medical Center appeared on the WNYC Leonard Lopate program entitled "Please Explain - Lyme Disease".  In this informative program, they discussed the basics of Lyme disease and highlighted issues regarding symptoms, treatment, diagnosis and prevention. You can listen to the broadcast on the WNYC website or listen now.

lopate071610dpod.mp3 Listen on Posterous

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"The Current", a radio program broadcast in Canada and Sirius, recently interviewed several Lyme specialists. Canadian Doctor Maureen McShane contracted Lyme Disease and a went through an aggressive treatment regimen and now has devoted her practice to Lyme Disease. She suffered a great deal and has strong opinions about co-infections and Chronic Lyme Disease.  What she experienced is normally called late-stage Lyme disease, the dangers are debilitating symptoms, misdiagnoses, and a potentially fatal outcome.  When patients experience non-resolution of symptoms after treatment the accepted term for the disease state is "Post Treatment Lyme Disease Syndrome" or PLDS. 

Although each Lyme patients story is unique, Doctor McShane's story struck me as quintessential. Listen to how she describes symptoms for late-stage neurological Lyme. 

Link to full interview page

Link to MP3

(The interviews start after the over-population teaser)

The second interview is of Nick Ogden, another Canadian doctor who works for the Public Health Department. The best information from this interview is that Lyme Disease is now a reportable disease in Canada. He wants to somehow warn the public of the rising threat of Lyme Disease but not create an unwarranted scare.  The belief that both are possible is doublethink. In today's desensitized society, it's not possible to penetrate the public's consciousness without the application of fear tactics, large sums of money, or celebrity endorsements.  

New videos made by the cast of the hit show "Vampire Diaries" effectively warn people of the dangers of ticks.

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"Ticks and Tick-borne Diseases" is a new scientific journal published by Elsevier GmbH. The journal comes out quarterly and is already in its second issue. The journal focuses on tick biology, tick ecology, tick-borne pathogens, and tick-borne diseases of animals and humans. The first issue contained 1 Editorial, 2 Mini Reviews, 6 Regular Papers, 1 Short Communication, and 1 Obituary. 

Link

I quickly reviewed the articles and found them very interesting.  A paper titled, "A spatially-explicit model of acarological risk of exposure to Borrelia burgdorferi-infected Ixodes pacificus nymphs in northwestern California based on woodland type, temperature, and water vapor" looked interesting due to the large number of nymphs tested in California. The paper states, "In total, 4.9%(264) of 5431 I. pacificus nymphs tested for the presence of B. burgdorferi were infected." That is a lot of nymphs to capture, extract and test individually. The infection rate is similar to other recent studies where Northern California ticks were tested.  First author on the paper was Rebecca J. Eisen and last author was Robert Lane, the tick ecologist from UC Berkeley.

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Three new grant opportunities totalling $800k are available through the CDC to improve upon the two-tier diagnostic regime for Lyme Disease and to study Post-Treatment Lyme Disease Syndrome (PLDS). Each are small steps in the right direction. Put your applications in by April 14th!

Link to Diagnostic Grants

Link to PLDS Grant

The PLDS grant is an R01 type grant. Typically R01's may be followed up by 4 more years of funding, so the opportunity is larger than it seems. Often this initial work can lead to larger opportunities but to have a shot at the R01 you must already have done some interesting work into PLDS or have an applicable semi-developed technology.

I wish the amounts of the grants were higher but don't look a gift horse in the mouth. 

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Do you know who won the 2009 Nobel Prize for Medicine? Three telomerase researchers. Telomeres are the end caps to linear genetic material. Human telomeres are repeating patterns of genetic code that signal the end of a genetic strand. Like bumper strips that signal to a driver the end of the road is approaching. The shortening of telomere length has been linked to the aging process and increase risk of cancer. Antioxidants are hyped as a way to keep telomeres from shortening with age.  But not all telomeres are built the same, there exist a type of telomere called a "hairpin telomere." Insted of bumper strips of genetic code that signal the end of the linear segment there is a hairpin turn (covalently closed) that caps the end of the double sided helical strand. This forms a very clear end point for the linear segment but imposes a new challenge during genetic replication.

TelomerASEs are the class of proteins that form telomeres during the genetic replication process.  The telomerase responsible for creating hairpin telomeres is called a Telomere Resolvase aka ResT and is the focus of this article.  Before proceeding let's step back, other than the Nobel prize money why should you care about this?  Because ResT is found in some viruses and bacteria, most notably Borrelia Burgdorferi (Bb), the causative agent of Lyme Disease. If the process of telomere resolution could be inhibited using a drug you could discover an effective and very specific treatment for Lyme Disease. It would be specific to Bb because human telomeres are completely different from Bb telomeres.  Since the drug would not be a broad range antibiotic it could safely be taken without spreading bacterial resistance. Lyme Disease patients often take prolonged courses of the most potent antibiotics (sometimes without good results - but that is a different story...). This spreads drug resistance and causes many unintended consequences like fungal infections and organ loss.  Having a targeted drug is better for patients and everyone else. 

Visual diagrams make it easier to understand the action of ResT. The best diagrams and research of ResT comes from the University of Calgary by a researcher, George Chaconas, and his team.

See the full gallery on Posterous

Steps

1. The blue and pink circles can be conceptualized as ResT. During replication ResT recognizes specific sequences (telomere types...) and binds.
2. Prehairpinning is a distortion of the DNA where the proteins and DNA prepare for... 
3. DNA cleavage, look closely in the blue circle for the breakage. The white Y represents the active site. This step is the first of a two step Transterification process.
4. The second step of Transterification seals two hairpin ends (the phalic shaped end pieces) to each long strand of genetic material.
5. From one comes two!

The genetics of Borrelia are fascinating. A complete set of Bb genetic material consists of one large chromosome, eleven circular plasmids, and at least twelve linear plasmids (plasmids are smaller segments of genes than chromosomes). A single Bb organism can contain twenty gene copies. The genetics of Bb tell us a story of an ancient and flexible past. Genes contained on plasmids can be copied between other plasmids and even exchanged between organisms. Faults in the telomere resolution process and a hypothesized reverse resolution process may assist in these mutation events. 

There are 19 unique hairpin telomeres found on the plasmids and chromosome of Bb and they are grouped into 3 types. Each type share conserved code and experiments have distinguished between the three telomere types.  In-vitro studies show a wide variability of activity for ResT (160 fold) against the three types; meaning, ResT is highly performant with Type 1 and Type 2 but ResT has trouble resolving Type 3 telomeres in a petri dish.  However, Type 3 telomeres ARE resolved in-vivo. This implies the presence of an unknown factor that assists or performs Type 3 resolution in-vivo. If the goal is to create an inhibitory drug that stops ResT then this co-factor is of major concern because it may be capable of telomere resolution and/or raises the affinity needed to make a competent inhibitor. But there is a chance that the factor is not involved with Type 1 or Type 2 telomere resolution and that would make a high throughput screen of possible inhibitory targets more likely to succeed.

The Chaconas lab performed a high throughput screen on a small compound library (27,000 compounds). The results did not produce any impressive candidates but a real HTS from a major pharma company would be orders of magnitude larger (2,000,000+) and more refined. That is the hope for the future. What are the chances of any target pulled from research literature making it through the drug discovery process with validated candidates that lead to a drug? So low you don't even want to know. But it does't stop me from having hope for ResT because of its interesting profile and the huge unmet need for Lyme Disease therapies. 

If this topic interests you I recommend following the links and reading these references:

• http://spirochetesunwound.blogspot.com/2009/10/telomeres-without-telomerase-i...
• Kobryn, K., & Chaconas, G. (2002). ResT, a telomere resolvase encoded by the Lyme disease spirochete Molecular Cell, 9 (1), 195-201 DOI:   http://dx.doi.org/10.1016/S1097-2765(01)00433-6
• Tourand, Y., Deneke, J., Moriarty, T.J., & Chaconas, G. (2009). Characterization and in vitro reaction properties of 19 unique hairpin telomeres from the linear plasmids of the Lyme disease spirochete Journal of Biological Chemistry, 284 (11), 7264-7272 DOI:  http://dx.doi.org/10.1074/jbc.M808918200
• Lefas G, Chaconas G (2009). High-throughput screening identifies three inhibitor classes of the telomere resolvase from the lyme disease spirochete.
• Antimicrobial Agents and Chemotherapy, October 2009, p. 4441-4449, Vol. 53, No. 100066-4804/09/$08.00+0     doi: http://dx.doi.org/10.1128/AAC.00529-09

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Tigecycline, sold under the brand name Tygacil by Wyeth (now a part of Pfizer) has been proven to be more effective at killing Borrelia Burgdorferi in-vitro than the most commonly prescribed antibiotic for early stage Lyme, Doxycycline.

I know of two literature papers that have recently been published about Tigecylcine and Borrelia Burgdorferi. 

Paper 1: In vitro activity of tigecycline against multiple strains of Borrelia burgdorferi

Paper 2: Destruction of spirochete Borrelia burgdorferi round-body propagules (RBs) by the antibiotic Tigecycline

A word of caution, the first paper was sponsored by the pharmaceutical company Wyeth.  But it was performed by a respectable Lyme researcher Ben Luft. If you have ever heard Ben Luft talk about Lyme Disease you will be impressed (view the archives of the IDSA Lyme Hearings to see what I mean)

Tigecycline targets the 30S Ribosomal subunit and blocks the translation of proteins. Its a different mode of action than Penicillin-like antibiotics that target the cell wall. Some have associated Penicillin like antibiotics with including phase changes in Borrelia to cell wall deficient forms because of the environmental pressure of that class of antibiotics. 

Tigecycline is believed to be very effective because of a chain that hangs off the side of the structure that blocks the efflux pump of the bacteria from expelling the antibiotic. 

The second paper describes the killing effect of tigecycline on round body Borrelia.  Round Bodies are synonymous with L-Forms, CWDFs, coccoid bodies, granules, cysts, sphaeroplasts, vesicles, etc.. The round bodies have been shown to be viable (infective when directly administered to a host). 

Given the success of the in-vitro study I'm sure Wyeth will pursue animal models. Labeled uses of Tigecycline do not include Borrelia but it looks promising and I hope more studies come out soon. I additionally hope that Wyeth considers making different formulations of Tigecycline since IV is the only formulation now offered.

UPDATES

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Many studies have sought to determine the length of time a tick must be attached to a host before transmission of Borrelia becomes likely. Doctors are told to avoid prophylactic antibiotics if the tick was not attached for more than 36 hours ("faculty peer reviewed" guidelines).  Even though there may be some truth to the timelength argument - I disagree with these guidelines because I feel the danger of letting early Lyme Disease go untreated is far worse then the over prescription of prophylactic antibiotics. 

But what is known about the other side of transmission - when Borrelia moves from host back to the tick? I call it "hopping on the bus".  There is a paper from 1995 published in the Journal of Clinical Microbiology that compared the host-to-tick infection rate of 2-month spirochete-infected mice (early) versus 8-month spirochete-infected mice (late) with varying lengths of tick attachment. 

Link to Paper

The 8 month infected mice required longer tick attachment  before reaching the same infectivity rate. Borrelia could be at lower levels in later infection, in less motile forms, or  sequestered deeper and take longer to migrate to the site of vector attachment.  

This study also showed that culturing Borrelia from blood was unsuccessful in both 2 month and 8 month mice. But culturing Borrelia from the biopsy of the ear tips was successful.  This supports the collagen theory that some Lyme researchers have postulated, that Borrelia prefer the fatty tissue of nerves and skin than the oxygenated and immune protected environment of blood.  (This is counter intuitive because the tick feeds on blood and that is the first logical tissue type to investigate for presence of Borrelia).

This study shows that the Borrelia remain virulent after a long 8 month infection. So this begs the questions: If not blood - in which tissue type do they reside? And if a tick bite attracts the Borrelia in late stage infection - can mimicking nature be successful in increasing diagnostic sensitivity?

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A story of a San Diego company, Cypress Bio, that is doing very well financially developing therapies for Fibromyalgia. A good business strategy is to find a therapy that is half developed, buy it, and move fast.

link

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THEATRICAL PREMIERE SET FOR JUNE 19TH IN NY

It's official: UNDER OUR SKIN finally has a release date in theaters. The film will premiere at the IFC Center in New York City on June 19th for a one week run. It will open on June 26th in Los Angeles at the Music Box Theater. After this, the film will will play in select markets across the country. These venues and dates have not yet been determined, but our distributor--Shadow Distribution--is working on the line-up. If you'd like to see your local independent theater show UNDER OUR SKIN and you believe you can rally your community to show up, then please ask the theater's management to contact Shadow Distribution. Also, if you or your group would like to "sponsor" a screening and organize a community awareness event, contact us with your thoughts. We'll need to fill the theaters so that the film will be seen by wider and wider audiences and help create a tipping point in Lyme awareness. 

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WBT Radio in Charlottesville held a lengthy discussion on Lyme Disease. Dr. Joseph Jemsek, a controversial LLMD, Kathy Fowler, a TV medical reporter who contracted Lyme, and Jordan Smith, a former ranger from California who was featured in "Under Our Skin" all joined the radio talk show.

The discussion is slanted towards the ILADS side and exposing the controversy. The callers into the show have sad stories, especially a girl who's father forced her off treatment because a Duke doctor told him that North Carolina has no Lyme Disease. Really crushing. 

A lot of the discussion about the medical system I agree with but some of the claims of Jemsek are unfounded in the literature. 

Take a listen if you have some spare time:

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On July 17, 2009 the HHS Appropriations Committee reported an increase of $3.66 million for Lyme disease, from $5.27 million to $8.93 million, for the Centers for Disease Control & Prevention (CDC), the only increase for diseases in the National Center for Zoonotic and Vector-Borne, and Enteric Diseases.

Read the full Article

The total amount of research for tick borne diseases is pretty low but trending in the right direction. Excellent!

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The saga continues! The IDSA is not following the guidelines agreed upon during the settlement with the Connecticut AG, Dick Blumenthal. 

The ethical makeup of the IDSA is in question. They agreed to a settlement to avoid going to court and they must follow the letter and spirit of the settlement terms.  The actions of the IDSA remind me of Wall Street executives - ignoring the gravity their decisions have in the real world and flippantly neglecting their responsibility to correct missteps from the past.

Okay, rant over.

The violations surround voting procedures of the newly formed Lyme Disease panel. Here is a link to a more detailed analysis:

PDF Link

Technically, the IDSA is not the party that is violating the agreement - the external Review Board is not following voting procedures correctly. The actions are stunning because the head of the review board is a recognized expert in medical ethics. Why is he stirring a boiling pot by skipping procedures? What an idiot!

Blumenthal is defending the citizens of Connecticut. Although the IDSA "guidelines" are not supposed to limit doctors treatment options, the guidelines are used by insurance companies to deny payment. Because of this fact, the guidelines are more than casual recommendations - they carry grave consequences for Lyme disease patients.

Although I like Peter Schiff (another candidate for Connecticutt Senate seat) for his views on hard money and limited government - Blumenthal is showing courage to fight and maintain vigilance while running a full campaign. Kudos sir! 

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Lyme and Tick-Borne Diseases Prevention, Education & Research Act of 2009

A new version of federal legislation about Lyme disease has been introduced this week by New Jersey Congressman Chris Smith. It calls for $100 million over five years for Lyme disease research, prevention, physician education and the formation of a federal Advisory Committee. A Senate bill is expected to be introduced shortly.

 The final bill text will be available for viewing on the official government web site once it has been entered by Congressional staff members.  

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The National Capital Lyme Disease and Tick Borne Disease Assocation is holding a 2009 "Lyme Legislative Forum". It will try to bring Lyme leaders to a consensus on how to promote Lyme disease in Washington. 

Link

Very worthwhile effort, I'm just cautious and a bit weary about what will be promoted. I've found that a small number of people with very little money can make huge impacts if the direction of research is on target. I believe that diagnostic research is the most important research area for tick borne disease and I hope this forum will make the same conclusion. 

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