Ebola virus - 2014 epidemic

Epidemiology

Ebola haemorrhagic fever is a severe and fatal illness caused by Ebola virus. The recent outbreak which claimed 4,500 lives and left 9,000 sufferers, originated in Gueckedou, Guinea; before spreading to Liberia and Sierra Leone, and concentrating around remote villages in Central and West Africa and near tropical rainforests (WHO). Tulane University virus expert Dr. Daniel Bausch told the Voice of America that years of war and poverty make these countries vulnerable to an outbreak. First discovered in 1976 by Professor Peter Piot near the Ebola River what is now the Democratic Republic of the Congo, the virus in the recent outbreak could have come from the deadliest and most aggressive strain according to medical charity Medicins Sans Frontieres. Prof Peter is worried that the outbreak could last well into next year. WHO has warned there could soon be 10,000 new cases a week.

Fruit bats as local delicacy especially three different species of Hypsignathus monstrosus, Epomops franqueti, Myonycteris torquata are to blame, because of detected immunoglobulin G specific for Ebola virus in these species. They are not the only reservoirs for Ebola but also Marburg viruses.  During the dry seasons when fruit is scarce – conditions that foster contact between animals as they compete for food, an increase in infection amongst great apes such as gorillas and chimpanzees is triggered. Immune function in bats also changes during these periods, for examples as a result of food scarcity or pregnancy which would favour viral replication aided by aggressive primate interactions (1). 

Ebola virus

During the incubation period of 2 to 21 days, manifested symptoms are sudden onset of fever fatigue, muscle pain, headache and sore throat, followed by vomiting, diarrhoea, rash, symptoms of impaired kidney and liver function; and in some cases, both internal and external bleeding such as oozing from the gums or blood in the stools.

                         

                                 

         

Figure 1. Ebola fever symptoms (WHO) include those found in common cold such as headache and sore throat at early stages; and severe symptoms of vomiting, rash, diarrhoea, bleeding from eyes, nose and mouth, impaired liver and kidney only seen at advanced stages.

28-year-old Dr. Oliver Johnson and the brave British medic team who are working in Freetown as part of the King’s Health Partners scheme (partnership between Guy’s and St Thomas’, King’s College Hospital and South London and Maudsley Trusts as well as King’s College London), said that the locals believe the disease maybe a government conspiracy. They also describe the Ebola patients as looking healthy until their conditions deteriorate shortly before their deaths. It's not only dangerous in its own right, but also still present in the body after death; therefore, prompt and safe burials are now being urged.

                                   

Ebola shares the same encoded peptide motifs for viral particle assembly after host cell replication as deadly HIV-1 virus (2). Natural selection of secondary immune response is shuffled for survival of those with best fit antibodies. Supportive care such as rehydrating patients who have diarrhoea and vomiting can also help recovery. Even though it is widely assumed that a person cannot contract Ebola twice, it is not scientifically proven. However, it is known for certain that viral replication is error-prone hence the ease of its genetic mutation; so there is still risks of relapse to certain degree. Despite relapse warning, British nurse Will Pooley who recently recovered from Ebola has returned to work in Sierra Leone. 

Another question is that why being benign for years, fruit bats could suddenly cause an Ebola outbreak? Viral mutation could take years to perfect transmission despite being error-prone in replication between bats and humans. Perhaps primate Simian virus or HIV-1 allows cross-mutation between viruses, or it could simply be a government conspiracy. There is no definite answer. The urge now lies in vaccine. 

Vaccine

Treating patients with serum injected from survivors during the 1995 outbreak offer one solution. Further trials of prototypes will start soon and potential vaccines maybe available in 2016. The challenge rises when pharmaceutical companies are un-interested to invest on the vaccine which will only be used occasionally in small number of people. Indeed, UK pharmaceuticals firm GlaxoSmithKline and WHO had mutual decision on not to accelerate the development of the Ebola vaccine and decided to “watch very closely”, so Dr Ripley Ballou, head of GSK’s Ebola vaccine research, said full data on its safety and efficacy would not be ready until late 2015, which will be too late for the epidemic. Clinical trial of 10 years will have to be compressed into 12 months, there have already been volunteer, Nick Own, who was injected at the centre for Vaccinology and Tropical Medicine in Oxford and will have regular check-ups for the next six months. Well, by the time vaccines are available, the virus might have been mutated, and just how effective the vaccine is just depends on the speed of mutation and what kind of mutation(s) it is.

Other effort to eradicate the disease is worth praising. Some US laboratories such as Arizona State University (3) are already established in Ebola research and vaccine. Huge gifts also seen from American billionaires, listing: $50 mil from Bill & Melinda Gates Foundation, $11.9 million from Microsoft Paul Allen’s foundation, $25 million from Facebook Mark Zuckerberg and his wife Priscilla Chan to Centers for Disease Control and Prevention, WHO, and the US Fund for UNICEF. World Health Organization in Birmingham UK current research is on convalescent plasma therapy.

Canada is fast-tracked as the country has already shipped 800 vials of vaccines to WHO which is the result of decade of research at the Public Health Agency of Canada’s main laboratory in Winnipeg. The vaccine had shown ‘very promising results in animal research’. Despite no any Ebola cases in Canada, the Canadian government pledged a total of 65 million Canadian dollars through the Red Cross and other humanitarian agencies in the global fight against the spread of Ebola. And the Russian project is planning to do the same. The Canadian pharmaceutical company that also make experimental vaccines is Tekmira. Its Sarepta therapeutics an RNA-based therapeutics is combination of two phosphorodiamidate morpholino oligomers which target the viral matrix proteins VP24 and VP35.

How effective are current prevention?

In the UK, the only Ebola infection isolation unit is Royal Free Hospital, London. In addition, airport screening is not effective, especially Heathrow Airport in which screening is optional, so passengers from Africa could easily go through. The US treats air passengers returned from Africa with more precaution as they quarantine them all before firm diagnostics confirm negative result.

What shall we do? Preventions are better than treatments

For Africa, avoid eating raw bush meat or contact with hosts (infected bats, monkeys, apes).

For everyone, avoid contact with Ebola patients and their bodily fluids (WHO), do not attempt to touch anything such as shared towels, handshakes or kisses or sexual intercourses. Bleach and chlorine can kill Ebola. Men can still transmit the virus through semen for up to seven weeks after recovering from Ebola.

Source

BBC, WHO, Reuters, Centers for Disease Control and Prevention

1.Eric M. Leroy, Brice Kumulungui, Xavier Pourrut et al. Fruit bats as reservoirs of Ebola virus. Nature Brief Communications (2005), vol 438

2. Juan Martin-Serrano et al. HIV-1 and Ebola virus encode small peptide motifs that recruit Tsg101 to sites of particle assembly to facilitate egress. Nature Medicine (2001) vol 7 (12).

3. Waranyoo Phoolcharoen et al. A non-replicating subunit vaccine protects mice against lethal Ebola virus challenge. PNAS (2011), vol 108 (51): 20695-20700

Nano-effects in nature

At the nanoscale, all properties change including optical properties. The phenomenon was first observed by Isaac Newton (the discoverer of the gravity theory) and Robert Hooke (the inventor of the microscope and telescope) and was described by Thomas Young in details a century later as wave interference - at certain angle light waves can interfere constructively (light reflected from both surfaces) or substracted (light cancelled out from both surfaces).

When visible light strucks the fine nano-structure or topography of pigmented parts on butterfly wings, peacock tail feathers and duck neck feathers and even soap bubbles; the wings, feathers or soap bubbles will turn iridescent - green, blue and turquoise beautifully blended according to the electromagnetic spectrum. Apart from interference ability, duck feather is also hydrophobic (water-repellent) which keeps air trap within its feather and increases its buoyancy.

Other nano-scale effects are wave-particle duality, higher surface to volume ratio, higher reactivity, Brownian motion, electromagnetic forces (at atomic scale) and weak and strong nuclear forces (anything greater than 10^-4 nm) while gravitation force is negligible. Nano-scale effects are pretty much everything that is related to Quantum Physics.

From nature, many bio-mimetic materials could be used for industry and commercial purposes such as anti-reflective window glass (by using array of pillars that are smaller than wavelength of light), optical-switches and military camouflage. 

Ducks at Kew Royal Botanic Gardens, London 

Ducks at Hyde Park, a Royal Park, London 

                    
                    Note: Any above photographs belong to the blog author. Please ask if you want to use it elsewhere. 

  

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Cellular processes hijacked by cancer cells

Cell growth is driven by mitogen and growth factors binding to receptors such as Tyrosine Kinase receptors to trigger intracellular downstream signalling cascade. Tumour has reduced growth factors requirement due to their overexpression of growth factors, aberrant growth factor receptors such as truncated growth factors.

Once the transformed cells have proliferated to certain extent, they secrete more proteases such as metalloproteases (MMP) to break down the basement membrane. Fibroblasts (a type of long thin cells) underneath the basement membrane also contribute to this process. In addition, cancer cells hijack cellular cytoskeleton, cell-cell adhesion molecules and receptors to become mobile. This leads to the loss of cellular polarity from epithelial (oblong shape) to mesenchymal (elongated, fibroblast-like shape) transition. Recently discovered cancer cell movement is three-dimensional (3D) migration from amoeba (rounded shape) to mesenchymal transition. This is due to the cytoskeleton (the cell internal skeleton) and GTPases being hijacked to make collective cancer cell migration in 3D possible.

Metastasis - Alberts, B. (Bruce Alberts) et al. Molecular Biology of the Cell, 4th ed., New York - Garland, 2002, p. 1325:

Cancer cells proliferate, then break through the basal lamina or basement membrane to migrate into the capillary to find other suitable tissue sites for invasion and proliferation

Apart from that, cancer cells also hijack autophagy process (auto-: self + phagy: eating: so cell eating their own internal organelles or debris) to help cancer cells to stay dormant. Autophagy is the double-edge sword because it is either cancer protective or cancer promoting which depends on tumour types and stages. Autophagy promotes normal homeostasis so suppressed autophagy will promote tumour by disrupting cell normal health maintenance and leads to early tumorigenesis. In contrast, if autophagy is supressed at the early cancer stage, there will be no further progression, otherwise, later stage progression can occur.

Tumour mass cannot proliferate beyond 2mm in diameter without oxygen and nutrients, so by secreting Vascular Endothelial Growth Factor (VEGF) and other pro-angiogenic factors as false signal towards existing blood vessels, tumour encourages aberrant angiogenesis for rapid growth and metastasis. VEGF is one of the most potent angiogenic factors.

Note:

Angiogenesis: formation of new blood vessels from pre-existing vasculature.

Receptors: the protein on the cell membrane that recognize and bind to specific molecules such as growth factors or hormones to elicit a cascade of biological responses inside the cells.

What is cancer?

According to National Cancer Institute at National Institute of Health, Cancer is a disease in which abnormal cells divide without control and are able to invade other tissues.

The environment we live in contains cancer promoting agents such as the UV light from the sun (often long exposure to the sun from sunbathing activity), smoking, asbestos and viruses. About 10-20% of human cancers have viral involvement. Different viral transmissions are via blood products, sexually-transmitted diseases and recreational drugs.

Cancer is disorganized mass composed of malignant cells, disease bioactive molecules, disorganized extracellular matrix, leaky blood vessels and lymph. By hijacking all possible cellular processes especially the cell cycle, developmental genes and proteins to ensure its survival, cancer cells are incredibly adaptable under any conditions. The keys to cancer are the decrease in cell death and increase in cell growth. The causes of cancer are inheritance, environmental factors or both or spontaneous mutations. In the inherited case, the genes are mutated since birth or early life so some people have higher cancer susceptibility. In all cases, healthy cells (germ and somatic cells) are transformed to cancer cells due to in situ accumulated mutations. Common mutated genes are oncogenes such as Ras and ß-catenin and tumour suppressor genes (protect us from cancer) such as Apc and p53.

Sunbathing - use sun cream to protect your cells

Different stages of cancer at the tissue level is the transformation from normal to benign, then carcinoma in situ then malignant stage. At the molecular level, the hallmarks of cancer is acquiring new behaviour which are evading apoptosis (decrease cell death), self-sufficiency in growth signal (can grow by itself), insensitivity to anti-growth signals (resist to anti-cancer signals), tissue invasion and metastasis, limitless replicative potential and sustained angiogenesis (formation of new blood vessels from existing vasculature). Once cancer can be able to metastasize via vasculature and lymph systems, it can evade any tissue or organs and this stage is critical in terms of survival for patients. 

Regeneration a possibility?

The advancement in medical treatments and standards of livings has increased human lifespan by more than double compared to 1.5 million years ago. But is immortality achievable? If you can live to eternity, what would you trade for? Perhaps becoming better human with as many good manners defined by society as possible as opposed to unhealthy lifestyles to forgo the birth of next generations which includes potential innovations and deal with the problems of aging population growth but will the immortal people commit to this?

So can we achieve this infinite lifespan? In human, we have very limited capacity for regeneration because of perhaps limited number of stem cells. What about other creatures? Jellyfish was one of our ancestors which first appeared approximately 540 million years ago during the Cambrian period. A type of jellyfish named Turritopsis nutricula is immortal through a process called transdifferentiation adopted in its cell cycle. American Lobsters or Homarus americanus as a crustacean has very long lifespan if it does not suffer diseases or injuries or caught by humans for food. Apart from that, the lobsters become brawnier and increase in its reproduction after every time they rejuvenate themselves. Being formed just after Jellyfish according to the Tree of Life, Starfish possess excellent limb regenerative ability. First existed 400-300 million years ago, salamanders (amphibian) and geckos (reptile) also have great limb regeneration. Since they are our ancestors, they are related to us but due to divergent evolution to adapt to different habitats, we evolve into different appearances, structures and functions like we are today. Majority of these species live in wet or ocean environment, while we live on land, breath in O₂ as part of our respiration. There also seems to be a trade-off between reproduction and survival. Maybe somehow during revolution, we have lost the regenerative capacity to trade for sexual reproduction which enhances the gene pool hence diversity in the population.

American Lobsters – sharp and strong claws can cut the metal Coke can in half

Starfish - limb regeneration 

So is there similarity between us and these creatures? In 1962, a scientist named Sir John B. Gurdon transferred the nucleus of frog differentiated epithelial cells into an enucleated egg which then generated a fully mature tadpole. He then proved that every cell in the same body has the same genetics. Taking inspiration from this genius experiment on frog which is an amphibian, a doctor named Shinya Tamanaka dedifferentiated human fibroblasts into its pluripotent state.  Despite the current debate on whether this induced pluripotent stem cells are similar to embryonic stem cells, we have learnt that nature has taught us many things from disease treatments such as penicillin (from the mold formed by Penicillium fungi) to today ground-breaking discovery about cellular differentiation which is a reversible process. This might mean wherever there is life, there is scope for regeneration but to different extent, and human beings are trying to figure out how to obtain the complete regeneration process to permanently repair tissues, organs and body parts. 

Maybe our immunity holds the key. According to Australian Regenerative Medicine Institute at Monash University, macrophages a special type of cells which can phagocytose cellular debris, pathogens or dead cells plays a part in initiating a scar-free regeneration outcome in salamander. 

Many doubts still remain, but we turn our attention towards the 3D printers for now. By using biomaterials in the printers, so far 3D structural scaffold of five organs which are the ears, kidneys, blood vessels, skin grafts and bones have been designed and printed. What would you envisage in the far future? Possibly limb regeneration like Dr. Curt Connors who turned himself into the Lizard in Spiderman with the genetic cocktail or Khan according to Star Trek sci-fi world, he was genetically modified to be superior in regeneration.

STDs at molecular level

Pathogen population outweighs human by thousands of times as they easily colonize under any environment. Being invisible to the naked eyes makes us unaware of their stealthy invasion into our bodies. Viruses are particularly mischievous because once infected, you could carry them for life if you have weak immune system or are immuno-compromised, in the worst case HIV currently has no effective cure. Contacts such as sexual one are one of the ugly forms of transmission, of which young adults are most vulnerable because they tend to be highly sexual active. 

As one of the most common Sexually-Transmitted Infections (STIs) in Western countries, genital warts or abnormal tissue growth in the cervix or throat are caused by a highly contagious virus called Human Papilloma Virus (HPVs). HPV is divided into two groups which are low-risk and high-risk types. The low-risk HPVs infect mainly keratinocytes causing benign lesions or genital warts while the high-risk HPVs infect the mucosa of the mouth, throat and anogenital tracts which can cause malignant carcinoma particularly cervical cancer. As condoms or contraceptives are not sufficient for viral protection, women have to be vaccinated with Gardasil or Cervarix but only to get protected against the high-risk types of 16 and 18 which cause about 70% of cervical cancer in women.

The HPV viral life cycle consists of an entry phase, genome replication or amplification phase and then viral assembly and release phase. The icosahedral capsid viruses enter the body via receptors on epithelial basal cells and the identified receptor protein so far is heparan-sulphate proteoglycans. At first, the viral genome is entered as stable episomes (close-circular DNA molecules) of which replication is maintained via the viral proteins E1 and E2, then the viral expression or production of E6 and E7 proteins allows infected cells to expand and produce more virions. To amplify the viral genome, the viruses hijack the cell cycles by disrupting the association between the protein pRb (Retinoblastoma) and a transcription factor E2F and other proteins that involve in cell proliferation. Current treatment is dedicated to the warts only and not the actual viruses, but this helps to reduce their number to ease the immune systems from dealing with too many.

 Human Papilloma Virus under microscope (source: dailymail online): pretty appearance but the symptoms can be nasty

According to medicalnewstoday, 10% of women up to the age of 16 in the UK have carried one or more strains of HPV, 26% of US girls age 14 to 19 have at least one STI. Fortunately, certain genetic variations protect women against cervical cancer and there are no visible symptoms in some cases.

Unlike HPV which causes by virus, Chlamydia is one of the most common bacterial STDs responsible by an agent called Chlamydia trachomatis. The bacteria attach to host cells with its Type III Secretion system (outer membrane protein) to remodel host cell membrane for invasion. Chlamydia is treated with antibiotics but recurrence can occur.

The mouth transmission route is certainly "romance" for pathogens one of which is a Herpes virus family called Epstein-Barr virus (EBV) which causes glandular fever/ infectious mononucleosis or "kissing disease". Immuno-compromised people could progress to cancers such as Hodgkin’s lymphoma, Burkitt’s lymphoma and nasopharyngeal lymphoma, the latter two are prevalent in Africa and East Asia. However, the west is not immune from this disease either, in fact, it is very common in early adulthood, as common as 95% of US citizens and similar figure for the UK. The virus infects specific epithelial cells that lines the mucosa surfaces of the mouth and throat and a type of immune cells called B-cells and once infected, you carry the virus for life. It has its own unique set of latency genes that allow its recurrence through latent infection with manifested symptoms in people with dysfunction immune systems.

On the positive side, STDs can sometimes be misdiagnosed as harmless conditions such as non-contagious Fordyce spots. Despite STD nasty symptoms, it is rare for infection to progress to cancer stage, which depends on environmental influences and individual genetics.