Human genome changes with age - AFP

Summary:
Researchers at Johns Hopkins University found that the epigenetic marks on the sequence of a person's DNA modify over the course of their life and the extent of such changes is similar among family members. Epigenetic changes, unlike DNA sequence which is the same in every cell, can occur as a result of dietary and other environmental exposure. Epigenetics may play a role in diseases like diabetes, autism and cancer. Inappropriate methylation levels can contribute to disease: too much might turn necessary genes off, too little might turn genes on at the wrong time or in the wrong cell. (Published: 24/06/08)

Notes:

• Andrew Feinberg:
• "We're beginning to see that epigenetics stands at the center of modern medicine because epigenetic changes, unlike DNA sequence which is the same in every cell, can occur as a result of dietary and other environmental exposure. Epigenetics might very well play a role in diseases like diabetes, autism and cancer."
• team analyzed the DNA sequences from 600 people taking part in the AGES Reykjavik Study
• formerly called the Reykjavik Heart Study in Iceland
• participants supplied DNA samples in 1991, and then again between 2002 and 2005
• measured the variations in the levels of methylation in 111 samples.
• main epigenetic modification
• in about a third of cases, the methylation levels had changed over the years
• Vilmundur Gudnason, professor of cardiovascular genetics, University of Iceland
• "Inappropriate methylation levels can contribute to disease -- too much might turn necessary genes off, too little might turn genes on at the wrong time or in the wrong cell"
• Daniele Fallin, John Hopkins:
• "What we saw was a detectable change over time, which showed us proof of the principle that an individual's epigenetics does change with age."
  

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Clone cell cancer 'cure' hailed - BBC News

Summary:
Scientists claim they have cured advanced skin cancer for the first time using the patient's own cells cloned outside the body. A 52-year-old man involved was free of melanoma two years after treatment which consisted of selecting a number of cancer-fighting immune cells, making five billion copies, and putting them back in the body. Two months later, scans showed the tumours had disappeared. The researchers focused on melanoma because the disease was well understood compared with other cancers, but other cancers could potentially be targeted. (Published: 19/06/08)

Notes:

• Scientists at the Fred Hutchinson Cancer Research Center in Seattle, led by Dr Cassian Yee
• selected CD4+ T immune cells from a sample of the man's white blood cells which had been specifically primed to attack a chemical found on the surface of melanoma cells
• were multiplied in the laboratory, and put back in their billions to see if they could mount an effective attack on the tumours
• two months later, scans showed the tumours had disappeared
• after two years, the man remained disease-free
• The new cells persisted in the body for months after the treatment.
• Authors point out that their technique applied only to a patient with a particular type of immune system and tumour type, and could work for only a small percentage of people with advanced skin cancer.
• Karol Sikora, a cancer expert at Imperial College in London:
• described the research as "pretty exciting" with potentially wide application
• said the researchers had focused on melanoma because the disease was well understood compared with other cancers, but other cancers could potentially be targeted
• "I think we will be able to harness the power of the immune system. Eventually we will learn how to control cancer, in other words we will suppress it. Patients will live with their cancer, and die with their cancer, but not of their cancer - it will be like diabetes today."
• spokesman for Cancer Research UK:
• said more research would be needed, adding: "This is another interesting demonstration of the huge power of the immune system to fight some types of cancer. Although the technique is complex and difficult to use for all but a few patients, the principle that someone's own immune cells can be expanded and made to work in this way is very encouraging for the work that ourselves and others are carrying out in this field."

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Battling Bad Bugs - Drug Discovery & Development

Summary:
Microbes are evolving resistance faster than the pharmaceutical industry can bring new products to market. Microbes have been persistently clever in evolving resistance to antibiotics soon after introduction. Emergence of "Bad Bugs, No Drugs" situation; high economic burden and will gradually worsen. Call to action from the infectious disease community (IDSA). A new type of product specialization is required (relying on rapid molecular diagnostic tests), but this runs counter to the blockbuster model of large pharmaceutical companies. Opportunity for smaller companies. US government under pressure to create incentives for the large pharmaceutical companies to remain in antibiotic discovery. Some incentives in the FDAAA act, but disincentives remain. (Published: 08/05/08)

Notes:

• early 1940s: streptomycin and penicillin
• treatment of staphylococcus, streptococcus and Mybacterium tuberculosis infections
• today: more thatn 130 antibiotic products available
• problem: despite/because of number of antibiotic products, microbes are getting upper hand
• evolving resistance faster than the pharmaceutical industry can bring new products to market
• number of patients infected with resistant microbes small
  
• but economic burden high
• number of resistant bugs expected to increase
  
• Infectious Disease Society of America (IDSA)
• documented the microbial infections that are especially troublesome in a "Bad Bugs, No Drugs" policy statement
• provided a call to action from the infectious disease community
• MRSA among the "Bad Bugs" that has received appropriate notoriety
• S. aureus
• normal skin flora
• becomes a problem when the skin is broken
• from abrasions, traumas, surgeries and placements of in-dwelling devices
• staphylococcal infections can quickly become deadly
• those infected rely on antibiotics to eliminate the infection
  
• MRSA infection has been health problem in hospitals for more than a decade
• more than 60% of US hospital-acquired S. aureus infections are now MRSA
• new MRSA strain has become prevalent in community-acquired infections
• total number of infections due to MRSA increased 119% between '99 and '05
• large economic cost
• estimated in the billions in the US
• due to longer hospital stays and increased expenses of treatment
• until very recently, antibiotic treatment for hospital-acquired MRSA limited to vancomycin
• first developed in US in 1958
• new antibiotic therapies approved for treatment of hospital-acquired MRSA include Zyvox (Pfizer), Cubicin (Cubist) and Synercid (King Pharamceuticals)
• resistance to these products already posing challenges
• microbes have been persistently clever in evolving resistance to antibiotics soon after introduction
• even vancomycin proved vulnerable
• initially purported to be "resistance-proof" because its target is a necessary component of th ebacterial cell wall, not an evolvable protein
• wide range of molecular mechanisms of resistance have emerged
  
• e.g. broad spectrum efflux pumps
• eliminate most antibiotics from the bacterial cell possessing these pumps
• e.g. expanded spectrum beta-lactamases (EBSLs)
• inactivate the newest generation of beta-lactam products
• these resistance mechanisms make the discovery of effective new antibiotics even more difficult
• create market opportunities for new products
• emergence of "specific spectrum" agents
• aimed at specific species and resistance targets
  
• e.g. Affinium Pharmaceuticals antibiotic in Phase 1: targets Stahpylococcus, including MRSA, but is relatively inactive against other bacterial species
  
• utiliy will rely on the recent emergence of new FDA approved molecular diagnostics for MRSA
  
• can assess the infectious agents in hours, rather than days
• e.g. BD GeneOhm StaphSR Assay
• this type of product specialization runs counter to the blockbuster model of large pharmaceutical companies
• maturation of the antibiotics market over the past decade has resulted in a large number of marketed antibiotics products
• each with relatively low annual sales revenues
• 2001: six antibiotics products had blockbuster status
• today: only Augmentin and the Levaquin/Floxin franchise have billion-dollar annual revenues
• recent introductions have failed to reach blockbuster status
  
• patents expirations, generic competition, and the withdrawal due to safety challenges or limited use have fragmented the market
• loss of profitability of antibiotics has caused the departure of many pharmaceutical companies from investing in the discovery of new antibiotic products
  
• smaller companies have seen opportunity and some generic companies have expanded into proprietary products
  
• Forest Laboratories invested significantly in new antibiotic products
• several large pharmaceutical companies spun out their antibiotic and development efforts into new companies, or licensed their later-stage products to biotechnology companies
• new entrants into antibiotic development face cash constraints that often limit the size and complexity of clinical trials
• US government
• has been under pressure to create incentives for the large pharmaceutical companies to remain in antibiotic discovery
• has largely been resisted
• however: Food and Drug Administration Amendment Act (FDAAA) of 2007
• includes creative incentives for the development of new treatments for tropical diseases, including tuberculosis, malaria and other specifically named diseases
  
• as well as "any other infectious disease for which there is no significant market in developed nations, and that disproportionally affects poor and marginalized populations, designated by the Secretary."
• priority review vouchers are awarded for the succesful approval of new products to treat these "tropical diseases"
• can be transferred or sold to the sponsor of any new drug application
• falls short of pharmaceutical industry's desire for patent extension
• but may have sufficient value to influence the discovery and development of new agents for treatment of these diseases
• additionally, FDAAA provides a mechanism in which new drugs for the treatment of antibiotic-resistant infections may qualify for Orphan Drug status
• incentives associated with Orphan Drugs, e.g. access to government funding of clinical trials
• disincentives remain
• IDSA: documented the uncertainty of antibiotic clinical trial designs and the lack of guidance documents for antibiotic development

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Super Drugs for Super Bugs - Drug Discovery & Development

Summary:
Antimicrobial resistance is a monumental health problem, affecting everyone from infected patients and physicians to researchers and drug developers. E.g. evolution from S. aureus to MRSA, hospital acquired versus community acquired. Dangers of SCCmec. Many antimicrobials coming out for resistant Gram-positive bacteria like MRSA, but there is nothing for Gram-negative bacteria. Increased research effort toward understanding mechanisms of resistance, as well as identifying new antimicrobial targets, is greatly needed. Large drug companies are well aware of the problem, but have been fighting an uphill battle to develop antibiotics that exist long enough on the market to profit. Smaller drug companies and academic institutions have taken it upon themselves to develop new antimicrobials. These drug developers require large drug companies to put their discoveries on the market. (Published: 01/05/08)

Notes:

• Alexander Fleming: discovery of penicillin
  
• mold grown on bacterial culture plate
• closer inspection showed that mold has inhibited the growth of bacteria in area around it
• penicillin, produced by Penicillium species of mold
• penicillin was viewed as panacea by microbiologists and clinicians alike
  
• though no more microbiological research needed to be done
• but: due to its widespread use in WWII, bacteria quickly became resistant to penicillin
• rendered the antibiotic useless
• bacteria were producing enzymes that could destroy the structure of penicillin
• drug developers produced semi-synthetic versions of penicillin in 1960
• bacteria became resistant year later
• Staphylococcus aureus
• became penicillin resistant
• due to beta-lactamase (penicillinase) production
• methicillin (derivative of penicillin) introduced in 1959 to overcome problem
  
• S. aureus became resistant in 1961
• methicillin-resistant Staphylococcus aureus (MRSA)
• source of resistance: methicillin-resistant gene (mecA)
  
• carried on a mobile genetic element, staphylococcal cassette chromosome (SCCmec)
• danger of SCCmec
• not only does it carry the methicillin-resistant gene
• also, carries resistance genes for other microbials
• cassette can be transferred to susceptible bacteria found in the same environment as resistant bacteria
• community-acquired MRSA
  
• Kunyan Zhang (prof., MD, Calgary):
  
• "It used to be that MRSA was limited only to the hospital and confined to vulnerable hospital patients. But starting early 1990, MRSA started to be found in the community. This newly emerging, community-associated MRSA is now causing serious community-acquired infections/outbreaks in otherwise healthy children, athletes, and other individuals lacking typical risk factors for nosocomial MRSA acquisition."
• community-associated MRSA appears to be more virulent
• has now gone back to the hospital in a multi-drug resistant form
• Bala Bota (prof., MD, Chicago):
  
• looked at hospital-acquired MRSA
• found that hospital strain was being replaced by a community-acquired strain, called USA300
• has occurred in half of all US hospitals
• another study showed a seven-fold increase in the incidence of community-acquired MRSA over a seven year period
• those who had served jail time or had lived in public housing were the greates sources of community-acquired MRSA
• efforts to reduce the incidence of MRSA are occurring nationwide
• e.g. hospitals in state of Illinois require that, prior to admission, all patients be screened for MRSA colonization
• Hota: "The common site that S. aureus colonizes individuals is in the nose. What hospitals are doing is taking a cotton swab, rubbing it in the nose and then setting that up for culture. That will either show MRSA or not."
  
• Hota interested in better characterizing community-acquired strains of MRSA
• for all of the clinical isolates, first the strain type is identified using pulsed-field electrophoresis; determine by PCR whether or not the strain contains the SCCmec4; and, determine by PCR whether or not the strain carries specific toxins such as Panton-Valentine leukocidin (PVL), which is associated with boils produced by MRSA
• "We are finding that SCCmec4 and PVL are very strongly associated with community-associated MRSA strains"
• the results of these tests are then compared to strains from national outbreaks
• Hota's strains are identical to those found in the national outbreaks
  
• issue of antimicrobial resistance has caused a significant decrease in the number of available antibiotics for treatment
• Margaret Hammerschlag (prof., MD, New York):
  
• "I think, especially in children, we are running out of therapeutic options."
• "There are many antimicrobials coming out for resistant Gram-positive bacteria like MRSA, but there is nothing for Gram-negative bacteria like Klebsiella sp. and Acinetobacter sp."
• facing bugs that are resistant to every antibiotic and for which there is no forseeable antibiotic development
• "We have got a real crisis. We'll be looking down a hole to the pre-antibiotic era and antibiotics might end up as orphan drugs."
• designing novel antimicrobials to combat resistance requires a higher degree of understanding of the biology of superbugs
• Vanessa Sperandio (Texas), Vincent Tam (PharmD): designing antibiotics to combat the resistance problems in Gram-negative bacteria
• Sperandio: studying signalling system between that allows for communication between bacterial cells and between the bacterial cell and the host (human)
• bacteria can sense that it's inside the colon, the right site for infection
• developed a antimicrobial agent that does not inhibit bacterial growth and does not kill the bacteria
• would cause bacteria to release potent toxin that can cause immediate kidney failure, in some cases leading to death
• "The line of thought is that if you're going to try to develop something that is going to prevent pathenogenesis, but is not at the same time going to kill the bacteria, you're engendering less evolutionary pressure for development of resistance."
• "Basically what the inhibitor does is compete with the signals to bind the kinase. So the signal cannot activate in the animal. And if the kinase does not activate, the virulence genes do not activate. And in this way the bacteria just passes through."
• 
  

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