Science: The Future Of Antivirals In Medicine - Curing The Incurable?

The Future Of Antivirals In Medicine - Curing The Incurable?

(Please Note: Yes, I have touched on D.R.A.C.O. antiviral in a previous article but as D.R.A.C.O. remains my most popular post I decided to expand on this theme. This article covers a far wider array of anti-virals in greater depth)

Antibiotics have called a "magic bullet" in the fight against infectious diseases. This is because a single antibiotic may be capable of destroying a wide variety of bacterial infections, alleviating symptoms of illness complete in many cases. Antivirals have traditionally seen less success in combatting viral infections than their bacterial counterparts. Primarily this is a result of the specificity of typical anti-virals which means that most may only inhibit a single viral infection for as long as the treatment is prescribed. In addition, despite the media hysteria surrounding the potential threat of total antibiotic resistance, viruses mutate at a much faster rate than even bacteria, resulting in anti-virals losing their effectiveness in a very short period of time. In recent years, however, scientists have started to lay the foundations for the emergence of a new generation of broad-spectrum anti-virals capable of inhibiting (or even eradicating!) a variety of viral infections.

One of these broad-spectrum anti-virals currently under development by M.I.T. is D.R.A.C.O. (Double-Stranded RNA Activated Caspase Oligomerizer), a bioengineered microscopic super protein that "can identify cells that have been infected by any type of virus, then kill those cells to terminate the infection" [1]. Under laboratory conditions D.R.A.C.O. has already proven to be "non-toxic in 11 mammalian cell types and effective against 15 different viruses, including dengue flavivirus, Amapari and Tacaribe arena viruses, Guama bunyavirus, and H1N1 influenza" [2] [2] D.R.A.C.O. “selectively induces apoptosis in cells containing viral dsRNA, rapidly killing infected cells” [3], it is important to note that dsRNA is present in almost all virally infected cells but its absent in healthy cells making it a perfect marker. However, some scientists have noted that D.R.A.C.O. is still a long way off from being developed into an actual therapy, detailing how “several sets of trials in larger animals (and eventually humans) will have to meet with success between now and then” [4]. It is important to note that D.R.A.C.O. has only been trialled and successfully eradicated 15 viral infections in vitro and only 2 viral infections in mice and is thus still very much in its early stages towards becoming a viable therapy. Furthermore, D.R.A.C.O. is made up of large super-proteins and as a result oral delivery is unlikely and will likely have to be administered in injection form. This would mean that D.R.A.C.O. would only be used for serious viral infections, as opposed to more common infections such as the rhinovirus, which M.I.T. have mainly trialled D.R.A.C.O. against to date.

    
   Another potential broad-spectrum antiviral, which has demonstrated encouraging results in laboratory testing, is Squalamine. Squalamine is “a compound previously isolated from the tissues of the dogfish shark (Squalus acanthias) and the sea lamprey (Petromyzon marinus), [which] exhibits broad-spectrum antiviral activity against human pathogens, which were studied in vitro as well as in vivo.” [5] The scientist’s began looking for molecules with antiviral properties in sharks, as they are remarkably resistant to viral infections despite having no rapidly responsive adaptive immune system. Squalamine works by displacing proteins associated with electrochemical interactions and the cell membrane without causing “obvious structural damage to the cell membrane as measured by changes in permeability” [6]. The displacement of these proteins associated with such chemical interactions and the cytoplasmic membrane is believed to have the potential to effect the “entry, protein synthesis, virion* assembly, virion budding or other steps in the viral replication cycle” [7]. Squalamine has proven to be 85% effective in combating MCMV, EEEV, HBV and HDV in vitro, it has been shown to completely eradicate Dengue fever in vitro and inhibit Yellow Fever by up to 95% in hamsters during in vivo tests. As a result of Squalamine’s effects in humans already having been studied in numerous pre-clinical trials for cancer it has a known safety profile for therapeutic use in humans. However, Squalamine's effectiveness in in vivo in inhibiting viruses is still under investigation as scientists “have not yet optimized Squalamine dosing in any of the animal models [investigated]” [8].  

One of the most anticipated of these new broad-spectrum antivirals is LJ001. LJ001 is an incredibly potent antiviral that works by preventing membrane fusion in viruses, essentially allowing LJ001 to inhibit all enveloped viruses provided it is administered prior or during the viral infection. Despite LJ001 also affecting healthy mammalian cells, researchers detail,  “it is only the viral membrane whose function appears to be impaired” [9]. The scientists studying LJ001 hypothesize “that this is due to the fact that host membranes are continually remodeled and can repair themselves by metabolizing or extracting membrane-active agents” [10]. LJ001 has proven effective against a range of viral infections including “Influenza A, filoviruses, poxviruses, arenaviruses, bunyaviruses, paramyxoviruses, flaviviruses, and HIV-1” [11]. However, unlike other broad-spectrum antivirals pretreatment with LJ001 reduces mortality rates from some of the worlds most serious diseases, including “prevent[ing] virus-induced mortality from Ebola and Rift Valley fever viruses” [12]. However, the lack of specificity in the function of LJ001 it also has its drawbacks, in order to be effective in vivo it would have to be in concentrations too high to be feasible in its current form. 

     Scientists have made significant advances in the treatment of viral illnesses, discovering (or in some cases even engineering) antivirals effective against a whole spectrum of different viral infections. However, it is important to know that despite this, such developments are still in their infancy. Indeed many of the most promising broad-spectrum antivirals have only just begin in vivo testing and will be unlikely to emerge as potential therapeutic treatments which will be widely available for our own use. Indeed, the lack of specificity among such treatments, which makes them such enticing treatments when compared to specific antivirals, may actually be their downfall. As highlighted by researchers studying LJ001, such a lack of specificity may mean that required concentrations of antivirals for them to be effective would be unfeasible in vivo, a potential obstacle as such antivirals progress towards human trials.  

  

*Virion: An entire virus particle consisting of an outer protein shell called a capsid and an inner core of nucleic acid 

[1] Anne Trafton, “New Drug could cure nearly any viral infection”, M.IT. Press Release: http://web.mit.edu/newsoffice/2011/antiviral-0810.html. 

 [2] [3] Todd H. Rider,* Christina E. Zook, Tara L. Boettcher, Scott T. Wick, Jennifer S. Pancoast, and Benjamin D. Zusman, “Broad-Spectrum Antiviral Therapeutics”, PNAS(2011). 

[4] Peter Livermore, “Novel method for apoptosis induction may lead
to development of broad-spectrum antiviral agents”, Future Microbiology. 

[5] [6] [7] [8] Michael Zasloff,a,1 A. Paige Adams,b Bernard Beckerman,c Ann Campbell,d Ziying Han,e Erik Luijten,c,f Isaura Meza,g Justin Julander,h Abhijit Mishra,i Wei Qu,c John M. Taylor,e Scott C. Weaver,b and Gerard C. L. WongI, “Squalamine as a broad-spectrum systemic antiviral agent with therapeutic potential”, PNAS (2011) 

[9][10] Jason A. Wojcechowskyj* and Robert W. Doms, “A Potent, Broad-Spectrum Antiviral Agent that Targets Viral Membranes”, PNAS (2010) 

[11] [12] Mike C. Wolf,a Alexander N. Freiberg,b,1 Tinghu Zhang,c,1 Zeynep Akyol-Ataman,a,1 Andrew Grock,a Patrick W. Hong,a Jianrong Li,d,2 Natalya F. Watson,a Angela Q. Fang,a Hector C. Aguilar,a Matteo Porotto,e Anna N. Honko,f Robert Damoiseaux,g John P. Miller,h Sara E. Woodson,b Steven Chantasirivisal,a Vanessa Fontanes,a Oscar A. Negrete,a Paul Krogstad,h Asim Dasgupta,a Anne Moscona,e Lisa E. Hensley,f Sean P. Whelan,d Kym F. Faull,c Michael R. Holbrook,b Michael E. Jung,c and Benhur Lee, “A broad-spectrum antiviral targeting entry of enveloped viruses”, PNAS (2010) 

Science: Will Climate Change Affect The Evolution of Humans?

Will Climate Change Affect The Evolution of Humans?

A Brief History Of Human Evolution:

 The earliest members of the genus Homo was the Homo habilis which evolved around 2.3 million years ago. The brains of our early ancestors were similar in dimensions to that of a modern day chimpanzee. However, over the course of the next million years encephalisation (an increase in brain mass in proportion to size) was initiated. This meant by the time the species Homo erectus was established cranial capacity had doubled in size. This encephalisation was indicative of a growing intelligence in progressive species of hominins as they developed the ability to use more complex tools which provided them with an evolutionary advantage over earlier ancestors. 

Archaic Homo sapiens, the precusor to of 'modern ' humans, evolved between 250,000-400,000 years ago. Neanderthals and other species of the genus homo may have contributed up to 6% of their genome to present-day humans. This suggests some interbreeding between these species. The transition to modern behaviours with the development of culture and language happened around 50,000 years ago.

 Are Humans Evolving Now?

Humans are perhaps unique in the fact that we have adapted to survive in almost all the worlds ecosystems. Humans live in tropical, temperate, desert and arctic conditions exploiting the resources of our natural surroundings and our proficiency with technology. Today over 40% of the earths land mass is adapted for agricultural or urban purposes and this figure is likely to increase as the human population grows. Since the advent of farming genetic evolution in humans has largely been confined to the development of resistance to various infectious diseases. 

One of the most notable of these genetic adaptations is the development of “Sickle Cell Anaemia” in areas in which malaria is widespread. Sickle Cell Anaemia provides an advantage to these populations in the event they become infected with malaria as it results in less severe symptoms. This is because the presence of malaria in haemoglobin of sickle cells causes the cell to rupture prematurely, meaning that the plasmodium is unable to reproduce. 

Although humans have alleles which code for genetic resistance to various diseases we are still susceptible to a vast array of other diseases, some of which we have no known cure for. However, through the use of medicines such as antibiotics, phage therapy and surgical procedures we can extend our lives or even cure us of many diseases. Through medical and technological advances the human population has been able to adapt to a spectrum of environments. As a result of our adaptability as a species and the fact that such technological developments will continue to increase rapidly in coming years.

How Will Climate Change Affect Humans?

In comparison to most other species humans are likely to fare favourably even if global warming does occur. This is a result of technologies conferring to our species the ability to survive in a number of different environments. It is also important to note that of the new species of hominid that evolved previously 13 out of 15, appeared during pulsed climate periods.Furthermore, despite the progressive encephalisation tin the Homo genus over 2 million years the majority of brain growth is believed to have taken place in the last 800,000 years. This time frame coincides a period noted for the strong fluctuation of global climate. Larger brains were necessary to process new information, to plan ahead and solve more abstract problems and there is still the potential for an increase in our cognitive abilities. Global Climate Change is cyclic and Homo sapiens and closely related but less evolved hominins have survived abrupt changes in climate before. A study by Stanford University on an African Yoruba tribe investigated the differences between the tribal genes for water retention and European gene pools. The team found that 85 per cent of the Yoruba had an identical sequence of genetic information that was longer than it would have been if it was a result of random recombination and genetic shuffling. This provides evidence that this gene had been naturally selected amongst the Yoruba. The length of the genetic signature suggests that the change occurred in the last 10,000 to 20,000 years, which coincided with the initial stages of the desertification of the Sahara. 

However, despite these previous trends of how climate change has impacted evolution there are reservations as to whether such trends will continue. Many palaeontologists support the idea of the “refugium” theory. A 'refugium' is a small area of relatively livable conditions that a population can use to survive the lethally harsh environmental conditions i.e. an ice age. In these isolated areas (such as caves) the founder effect can take place in these small groups of isolated individuals that contain only a small number of alleles of the whole population. The isolation of these individuals and interbreeding will cause them to become more genetically dissimilar from the main population due to the lack of gene flow until they can eventually be deemed a new species. This meant these groups, adapted to live in the more temperate conditions of their refugium had an evolutionary advantage over Neanderthaals when the environment became more hospitable. This is an aspect many tabloid scientists have over looked when detailing how humans are likely to evolve in future. The availability of flights and other technological advances in infrastructure the world is truly a “global community”. This has led mixing of different ethnicities (and thereby a variety of alleles) but also architectural improvements make the prospect of humans withstanding more extreme weather in caves unlikely. In a physiological sense humans are likely to evolve much slower for the foreseeable future due to the lack of isolation of groups of humans. Instead a more likely cause of evolution in humans in the future maybe as a result of the growing influence of technologies and the global community. Such a reliance on technology may result in such traits as humans developing weaker immune systems as a result of patients whose conditions may have previously rendered them unable to reproduce to be pass on genetically hereditary disease and other alleles which might not otherwise be selected by natural selection to their children. Improvements in modern medicine will reduce the selection pressure for humans to have strong immune systems to survive illness and are another area in which technologies have allowed us to supersede our biological weaknesses.

-Adam