The ability of a cell to degrade misfolded proteins, or discard proteins which are no longer useful is essential to the integrity of the cell. These unwanted proteins can occur or develop naturally, as they may be the product of errors in transcription, mutation, failure to fold correctly, or spontaneous degeneration. The normal pathway responsible for the effective removal of abnormal proteins is the ubiquitin-proteasome pathway, which utilizes a protein specific tagging system facilitated by ubiquitin, having proteasome degrade the enzyme. Upon onset, many diseases are identified to posses attributes which increase the amounts of ubiquitin tagged proteins that have not been degraded, or an increase in untagged, and abnormal proteins indicating a failure in the ubiquitin proteasome system entirely. The diseases associated are cystic fibrosis, amyotrophic lateral sclerosis, Parkinson’s, Lewy-body dementia, Huntington’s disease, and Alzheimer’s.
The mechanism by which these proteins inhibit adequate function in cells remains unclear, yet it is assumed that the proteolytic system is somehow inhibited to allow the buildup of these amyloid proteins. Kristiansen et al has reported evidence that a form of prion disease may be caused by an inhibition of the 26S proteasome. The diseases typically associated are spongiform encephalopathy, creutzfeldt-jacob syndrome, and kuru. These diseases are caused by a toxic prion protein which changes the conformation of the proteasome responsible for degrading abnormal proteins. When this occurs the function of three of the processes associated with the proteasome are inhibited. It is shown that cells have the ability to regenerate normal proteasome activity if the toxic prion is removed.
The ubiquitin-proteasome pathway has shown to be an integral component of cell signaling networks, and metabolic pathways. For that reason it has been the selected target of the anticancer drug bortezomib, which is widely used for treatment of Melanoma. This is the target of this drug as the cancer seems to be widely dependent upon proteasomes for survival. It does not inhibit neural function however since it does not cross the blood brain barrier.
N Engl J Med 2007; 357:1150-1152September 13, 2007
Kuru is a type of spongiform encephalopathy, indicating that it is a prion disease. Kuru almost exclusively affected the population within the eastern highlands and province of Papua New Guinea. Within the population the disease became epidemic for a period of time as the disease was transmitted between individuals in the community. After anthropologic inspection, the disease was only found to be transmitted to females and young children under the ages of six, excluding males after the age of six. IT was identified that the disease was passed through ritualistic cannibalism of diseased relatives, thereby being the mechanism of transmission. The disease was eradicated in the 1950’s when government officials in the area ensured prohibition of cannibalism. The disease however serves as a model for other forms of spongiform encephalopathy as other forms are still existant today, as Creutzfeldt-Jacob, and bovine spongiform encephalopathy in animals.
Genetic and clinical genealogic assessments of 3000 persons from the regions including those that participated in mortuary feasts were studied for variant alleles critical in resistance for developing Kuru. It was found that most individuals are heterozygous for the understood resistance factor at codon 129 of the prion protein gene PRNP. More interesting however is a new identified prion resistance factor being the 127V polymorphism. This variant has only been found in individuals within the communities that have been exposed to Kuru indicating that this is a developed resistance to the disease. This variant has developed during the epidemic and represents a significant progression of recent selection in humans.
N Engl J Med 2009; 361:2056-2065November 19, 2009http://www.nejm.org/doi/full/10.1056/NEJMoa0809716
There are a number of biological processes which can influence the progression and pathogenesis of diseases experienced by humans. Upon identifying the number of processes which can contribute to a disease state, being inflammation, apoptosis, and metabolism, it can be concluded that these pathways are critical in treating a particular disease state. Recently, these pathways have been the targets of various drug pathways. The most notable of which is the process of autophagy. The process of autophagy occurs in response to regulatory cues stimulated by environmental factors. Simply, autophagy is the ability of a cell to consume debris and particles outside of a cell. Primarily, this process serves as a protective mechanism to prevent cell death. Many processes that involve disease states are identified. The development of cancer can be both inhibited and facilitated through autophagy. In existing tumors, autophagy can be used by the tumor cells to prolong survival, where autophagy regulates or inhibits the initiation of cancer in healthy cells. In neurodegenerative diseases, it is found that the processes involving autophagy are altered. Autophagic enzymes are often over expressed in a compensatory type fashion to existing neurodegenerative diseases, or under expressed as the neurodegenerative disease inhibits their function or formation. Pathways for autophagy also exist within infectious disease responses. Autophagy helps in the elimination of diseases such as herpes encephalitis, bacterial infections such as salmonella, and parasites while aiding in the cleaning of debris from immunologic responses.
As the role of autophagy in the development and pathogenesis of diseases, the applications in targeting these pathways are of value. Currently, anticancer drug Sirolimus activates autophagy as an immunosuppressive drug and anticancer drug. A progression in our understanding of autophagy will elicit further drug targets and ways in which the pathogenesis of diseases can be inhibited.
N Engl J Med 2013; 368:651-662February 14, 2013http://www.nejm.org/doi/full/10.1056/NEJMra1205406
Since their discovery, antibiotics have served as a vehicle for medical and human advancement. There are medical procedures now performed that would be entirely ineffective or even outrageous without the effects of antibiotics. The effects of antibiotics have largely infiltrated many parts of our lives, as we are practically ensured protection from infection. Despite the miracles performed by antibiotics in the past, antibiotic resistant infections are now killing more lives than the current epidemics of the globe. These epidemics include HIV in America and Ebola. By the year 2050 the cumulative healthcare costs of these resistant infections will total over 100 trillion dollars to the global economy. That will occur only if we continue down the current path of resistance we are experiencing. There have been decreased incentives for pharmaceutical companies to produce new antibiotics as lead discovery costs are now around a million dollars, with a very low compound advancement. Investment efforts are allocated elsewhere.
Despite this decreased incentive for development, new technologies and approaches are aiding in the arms race against resistance. Researcher Ling et al. has been using novel culturing techniques through an isolation chip process to identify new antimicrobial compounds. Through this process he has discovered a compound called teixobactin. This compound is produced by the bacterium Eleftheria terrae, which inhibits the growth of Staphylococcus aureus. The compound is shown to be highly effective against gram negative pathogens, particularly tuberculosis. However despite advancements in clinical trials, it may take years before a commercial product.
It appears as though another promising antibiotic has been found. But what is more important is understanding the challenges we face in this arms race with evolution. Our current understanding of the cell tells us that this antibiotic targets an irreplaceable component of the cell, and this drug should be effective for years to come. However, we have already learned this lesson through vancomycin, as we previously thought that cells would not be able to adapt to overcome its inhibitory effect through its critical target area. After the large use however, as one could predict, cells became resistant. For now, we must utilize our advances as they come to combat infection and save lives.
N Engl J Med 2015; 372:1168-1170March 19, 2015
Thanks to advances in medicine, the once present fear of rabies as a disease shielded by the immunity acquired through immunizations. If acquired without antibody resistance, a rabies infection followed by medical treatment can prolong death to 133 days after symptom onset, and seven to nine days without medical treatment. There have been 5 instances of survival of rabies when administered immunoprophylaxis, yet the induction of a coma to allow the native immune response to wrid the body of the virus has shown effectiveness in one particular incidence.
A 15 year old patient contracted rabies through a laceration to the hand from a bat. The subject continued normal life activities without seeking medical treatment or prophylaxis. Symptoms began one month after contact with the bat beginning with general fatigue, and abnormal sensations from the left hand. By the fourth day, blurred vision, weakness of the left leg, and gait abnormalities were present. On the fifth day symptoms progressed to fever, slurred speech, tremors, involuntary eye movements. Patient began salivating, with uncoordinated swallowing and worsened symptoms. Upon positive identification of rabies, the patient was offered an untested treatment of antiviral drugs, and antiexcitatory drugs, with supportive care. Ketamine, and Midazolam were administered to slow neural functioning and avoid the catecholamine storm which would otherwise harm the brain, Oxygen was administered to maintain hemoglobin levels. Heparin was administered to avoid the onset of blood clotting. Ribavirin was administered as an antiviral therapy. Burst suppression was induced through high levels of benzodiazepines, and barbituates. On the tenth day of hospital treatment, a lumbar puncture indicated heightened levels of rabies antibodies. The withdrawal of the induced coma, along with a clinically adapted reduction in sedative drugs occurred for 31 days, with effects of fever and decreased responsiveness and alertness present yet diminishing over time. Rehabilitation occurred following when patient was considered cleared of transmissible rabies on the 31st day until the 76th day. In a clinical visit on the 131st day patient interacted with examiner, was able to attend school part time, and had constant buccolingual choreoathetosis, a lurching gait, and fine motor difficulties.
While the patient still encounters difficulties, the treatment was a success, which allowed the immune response to develop antibodies to the viral infection while sparing the brain from a “neurotransmitter imbalance” also described as a catecholamine storm, and autonomic failure which typically results in death.
N Engl J Med 2005; 352:2508-2514
The discovery of recombinant DNA, a defensive mechanism within bacteria, breathed life into the developing field of Biotechnology. Occurring 50 years later, the discovery of another regulatory immune system within bacteria may not only prove hugely disruptive the field of biotechnology, but to our future genomes. The discovery is that of the CRISPR-Cas9 system. This innate prokaryotic system uses a programmable nuclease directing mechanism labelled Cas9, which operates on targeted DNA’s as identified by clustered regularly interspaced short palindromic repeats (CRISPR). When adapted, this mechanism allows deliberate removal of unwanted genetic sequences, and insertion of more favored ones. The next significant adaptation or discovery in terms of this mechanism was allowing it to become effective in mammalian cells. Allowing this system to be efficacious in human cells allows scientists and the medical community to explore the practical applications ethical considerations of such a development. The foremost of the possible implications of such a technology may be the elimination of genetic disorders such as huntingtons disease, and other recessive diseases. Upon further consideration, the benefitting populations must be relatively large for the procedure to be effective. As it turns out the populations affected by such disorders are 1 per 10,000 or 1 million. Unless all individuals in the larger populations are screened, pre conception and then conception occurs in vitro, then the process will be ineffective. This barrier may provide excessive cost relative to the reward of eliminating these disorders and may therefore become exceedingly ineffective due to inefficiency.
More generally acquired diseases are the next alternative, such as heart disease, diabetes and Multiple Sclerosis. When determining efficacy of CRISPR-Cas9 for being a viable medical intervention, one cannot overlook the polygenic influences encompassed by these conditions, where altering one gene may influence a very small percentage of the condition, or worse, exhibit unwanted effects such as cancer promoting alterations. The most realistic genetic altering candidate for such technology, would alter a gene that promotes Alzheimer’s and cardiovascular disease. Even this candidate is riddled with problems as the gene is linked to increased episodic memory and working memory in young adults.
Currently, there are coordinated efforts on an international level that recognize the implications of such a gene editing technology and pay fair warning to all considering its utility. As its effects are largely unknown, and the alterations of the genes would be permanent to all future offspring, it is urged that the science community progress with great caution and sensitivity to the issue.
N Engl J Med 2015; 373:5-8