Prions: special proteins

Do you remember mad cow disease? Some years ago it caused media hype because this illness, which affected animals, affected people too. Then, it was discovered that prions were the cause. So, I will discuss what prions are and the diseases that they produce.

WHAT ARE PRIONS?

Prions are proteins, but with different characteristics. Proteins are molecules formed by amino acids, which are bound by peptide bonds. All proteins are composed by carbon, hydrogen, oxygen and nitrogen. They are localized in all cells of the body and they participate in all biological processes that are produced. While DNA carries genetic information of the cell, proteins execute the work led by this information.

Proteins are the most varied macromolecules. In each cell there are miles of different proteins, with an extended range of functions. Between them: to be structural components of cells and tissues, to act in the transport and storage of little molecules, to transmit information between cells and to proportionate a defence in front of an infection. However, the main function is to act as enzymes, which catalyse most of chemical reactions in biological systems.

Prions are proteins with pathogenic and infectious characteristics (Video 1). They are not virus nor alive organisms; they are proteins without nucleic acid, it means, without DNA. They are localized in the surface of the central nervous system, especially in neurons; although they are also located in other body tissues of adult animals. Significant levels have been detected in the heart and skeletal muscle, and to a lesser extent in other organs except the liver and pancreas.

Video 1. What are prions? (Source: YouTube)

THE CELLULAR PRION PROTEIN

There is a change in the configuration of the cellular prion protein PrPc (Figure 1) in the diseases caused by prions. This protein has a protector role for cells and helps them respond in front of lack oxygen. The consequence of prions on this protein is the alteration of its functionality, producing a protein PrPSc with altered configuration. However, both configurations have the same sequence of amino acids. The secret of the different behaviour is the wrong folding, it means, the wrong conformation.

Figure 1. Left: normal protein (PrPc). Right: protein with altered configuration (PrPSc)(Source: Searching for the Mind with Jon Lieff, M. D.)

PRION DISEASES

Prion diseases are neurodegenerative processes produced by abnormal metabolism of a prion protein. These affect humans and animals and have a fatal clinical evolution, with the death as final.

There are various prion diseases, however, symptoms and clinical features are shared (Table 1). Some of these clinical features are dementia, ataxia (discoordination in the movement of body), insomnia, paraplegia and abnormal behaviors. The brain acquires a spongiform aspect, it means, an aspect like a sponge. This is due to accumulation of prion proteins in neurons, where amyloid plaques are formed.

Amyloid plaques are caused by accumulation of amyloid peptide, an essential protein for cellular function of the body. This accumulation in the brain can generate toxicity for nervous cells.

Until today there is any treatment to cure, improve or control symptoms and signs of these diseases.

Tabla 1. Prion diseases and its clinical features (Source: Rubio, T. & Verdecia, M. Enfermedades priónicas. MEDISAN 2009; 13(1))

DISEASE	SYMPTOMS	AGE	DURATION
Creutzfeldt-Jakob	Dementia Ataxia	< 60 years	1 month – 10 years (average 1 year)
Kuru	Ataxia Dementia	40 years (29-60)	3 month – 1 year
Fatal familial insomnia	Insomnia No autonomy Ataxia Dementia	45 years (35-55)	1 year

CREUTZFELDT-JAKOB SYNDROME

During 18^th century, European farmers described a neurodegenerative disease that affected sheep and goats, called scrapie. The affected animals will compulsively scrape off their fleeces against rocks, trees, or fences. Furthermore, its brain looked like a sponge. So, this is the birth of the word spongiform.

However, until 20^th century, in 1920, neurologists Creutzfeldt and Jakob described the first cases of spongiform encephalopathy in humans (Figure 2) and called the disease with their names.

Figure 2. Comparison of two brains: a brain affected by Creutzfeldt-Jakob disease (left) and a healthy brain (right) (Source: Health & Medical Information)

In this disease, there is a loss of memory, lack coordination and damage of mental abilities. The balance problems are common and, sometimes, are manifested in the beginning. Many patients lose autonomy and are unable to take care of themselves in later stages of the disease.

Due to prion nature of the disease, any symptom is possible and it depends on the area of the brain that is being affected.

KURU

It is a rare disease, localized in New Guinea. The main risk factor to suffer the disease is the intake of brain human tissue, which can contain infectious particles.

It is the reason that it is associated with people who practice a form of cannibalism, in which the brains of dead people are eaten as part of a funeral ritual. Although this practice ended in 1960, cases of kuru have been reported years later.

FATAL FAMILIAL INSOMNIA

It is a familial and inherited disease, which people affected suffer progressive insomnia. The human brain needs to sleep and rest, so permanent insomnia (there is not treatment with drugs) causes the death of patients.

Insomnia is due to a permanent and irreversible alteration of the sleep-wake cycle, which is characterized by the inability of the patient to develop REM and non-REM sleep.

REFERENCES

• Alberts, B. et al. (2016). Biología molecular de la célula. Barcelona: Omega.
• Rubio, T. & Verdecia, M. Enfermedades priónicas. MEDISAN 2009; 13(1)
• Wemheuer, W. M. et al. Similarities between Forms of Sheep Scrapie and Creutzfeldt-Jakob Disease Are Encoded by Distinct Prion Types. Am J Pathol. 2009; 175(6): 2566–2573
• Manual MSD
• Early Clinical Trial
• MedlinePlus
• Main picture: Canal44

Cancer for beginners: all you need to know

Cancer is one of the main causes of die in humans. It is estimated that one of two men and one of three women will suffer cancer during their life. We listen to discuss cancer or we know somebody who has cancer, but do we know what cancer is? Then, I explain it.

WHAT IS CANCER?

A malignancy is a tumour. Not all tumours are malignant, there are benign tumours too. A benign tumour does not invade surrounding tissue, while a malignant tumour does it. When a tumour is malignant we call it cancer. If a malignant tumour advances to another tissue it can metastasize, but not all malignant tumours spread.

Cancer can be defined as a group of diseases because it is considered that each one is a different illness. This group of diseases is characterised by an uncontrollably proliferation of cells, caused by genetic mutations. So, cancer is a genetic basis disease. It does not involve that it is also inherited, only 5-10% of cancers is inherited.

Cells have three main pathways where they decide if to live or to die, to divide or not divide and to differentiate or not differentiate. When some of this pathways is broken cancer is produced. There is an abnormal growth where it should not be (Figure 1). It results to interrupt the mechanisms of regulation that govern the normal cellular behaviour.

Figure 1. Evolution of cancer. Firstly, randomly, one cell suffers a genetic mutation. Then, there is a growth of these cancer cells, producing a benign tumor. When this mass advances to another tissue is called malign tumor, and it can metastasize (Source: Cancer Genomics)

TYPES OF CANCER

There are two types of cancer: haematological cancer and solid cancer. Haematological cancers are involved with blood and lymph (leukaemia and lymphoma), while solid cancers are the rest. Inside the group of solid cancer, the most frequents are carcinomas (epithelial tissue) and sarcomas (connective tissue: muscle, bone, fat).

The majority of cancers are carcinomas because epithelial tissue are in constant regeneration and cellular division. This tissue covers or defines the surface of organs, cavities and tubes. Another reason is this tissue is more exposed to carcinogens.

CAUSES OF CANCER

Genetic mutations, which cause cancer, can be produced by external or environmental factors or by internal or intrinsic factors.

In external factors we find physical agents (radiation), chemical agents (diet, tobacco) or biological agents (virus or bacteria). Instead, internal factors can be produced by reparation errors, where random is important. Reparation errors refer to cell’s mechanisms to correct its faults when it replicates. Sometimes, if a mistake occurs, the cell is able to correct it. However, it can always occur that mistake is not repaired that by the likelihood is normal that happens.

Genetic predisposition has to be taken into account because to inherit a mutated gene (inherited cancer) or to have a polymorphism can be done susceptibility to cancer. In the last case, environment is very important.

CAN WE PREVENT CANCER?

Every year around 450,000 people are diagnosed with cancer. This figure refers to incidence, which means the number of new cases for a year. Do not confuse with prevalence, which is the total number of cases (Figure 2). The experts estimate that more than 4 of 10 cases can be prevented, if people change their lifestyle.

Figure 2. Representative picture of incidence, prevalence and deaths. Incidence is the new cases in a certain period. However, prevalence is total cases (people with cancer or people being completely healed from cancer) (Source: Epi-demio-logy, modified)

Prevention is the set of actions which have the aim of:

• Reduce incidence: around a 40% of cancers can be avoided with healthy lifestyle habits.
• Reduce mortality: to detect a cancer in its early stage and to apply treatments more specifics.

We have to be taken into account that healthy living is not a guarantee against cancer. For example, we know that it’s possible for a heavy smoker to live a cancer-free life, while someone who never touches cigarettes could develop lung cancer. But lots of large long-term studies clearly show that people who have never smoked are far less likely to develop or die from cancer than smokers.

12 TIPS TO PREVENT CANCER

Prevention is important because it stacks the odds in your favour, by reducing the risk of developing the disease.

If you initiate healthy lifestyle habits and follow these tips (Figure 3), they can help you to prevent cancer:

1. Do not smoke: one of three cancers is related to tobacco.
2. Make your home smoke free: avoid tobacco smoke at workplace too.
3. Take action to be a healthy body weight: you will also reduce your risk in many other diseases.
4. Be physically active in everyday life: minimum 30 minutes of moderate intensity.
5. Have a healthy diet: eat plenty of whole grains, pulses, vegetables and fruits and limit red meat and foods high in salt.
6. If you drink alcohol of any type, limit your intake: not drinking alcohol is better for cancer prevention.
7. Avoid too much sun: use sun protection and do not use sunbeds.
8. Protect yourself against cancer-causing substances by following health and safety instructions, in the workplace.
9. Take action to reduce high radon levels: find out if you are exposed to radiation from naturally high radon levels in your home.
10. For women: breastfeeding reduces the mother’s cancer risk. So, if you can, breastfeed your baby. And hormone replacement therapy (HRT) increases the risk of certain cancers. Limit use of HRT.
11. Vaccination: ensure your children take part in vaccination programmes for hepatitis B (for newborns) and human papillomavirus (HPV) (for girls).
12. Take part in organised cancer screening programmes for bowel cancer (men and women), breast cancer (women) and cervical cancer (women).

Figure 3. Tips of healthy habits to prevent cancer (Source: Codi Europeu Contra el Càncer)

REFERENCES

• Instituto Nacional del Cáncer
• Asociación Española Contra el Cáncer
• OMS
• Globocan 2012
• Cancer Research UK
• European Code Against Cancer
• Main picture: ConceptoDefinición

Danger, poisonous mammals!

We usually associate snakes, spiders, jellyfish, etc. as venomous animals par excellence, but did you know that there are poisonous mammals? In this article we will discover who are they and the nature and use of their poisons.

THE PLATYPUS

The platypus (Ornithorhynchus anatinus) is the most famous among the poisonous mammals, and not just for this feature. With a peak like a duck and oviparous (laying eggs), when it was discovered some scientists thought it was a fraud.

Platypus (Ornithorhynchus anatinus). Photo by Jonathan Munro

They belong to the order monotremes, which means “one hole” in reference to the cloaca, the end of the digestive and reproductive systems. Some evolutionary biologists refer to them as the “missing link” between reptiles and mammals, as they have characteristics of both groups. Monotremes are the only mammals that lay eggs, but his body is covered with hair and the young are fed with breast milk. They are distributed by Australia, Tasmania and New Guinea.

Platypuses have a spur on the hind legs, which only in the case of males, release poison produced by femoral glands (located in the leg). The male uses it mainly to defend their territory and establish their dominance during the mating season, although if it is bothered also uses it as a defense. This poison can kill small animals, including dogs, and cause severe pain and swelling in humans. This pain can last days or months.

Spur on the hind leg of a platypus. Photo by E. Lonnon

Toxins are four proteins, three of which are unique to the platypus. They are like the defensins (DLP, defensin-like proteins). These are globular proteins, small and compacted, involved in the activation of pain receptors. Understanding how these toxins act it has special interest because they cause a lasting and severe pain; it may open new chances in the synthesis of analgesic drugs.

Short-beake echidna (Tachyglossus aculeatus). Photo de Tony Britt-Lewis

Echidnas (family Tachyglossidae) complete the order of monotremes with the platypus; consequently they are also oviparous. The family consists of four species, with the common characteristic of having the body covered with dense hair and spines. They are mainly insectivores specializing in ants and termites.

Like the platypus, they also have spurs behind the knees, but their secretions are not poisonous. The substances are used to mark their territory, according to the recent studies.

SLOW LORIS

As we saw in a previous post, lorises are primates in the prosimians suborder. They are nocturnal, arboreal and feed primarily on insects, vegetables and fruits. The slow lorises (Nycticebus) living in Southeast Asia, are the only poisonous primate. They possess poison glands on the elbows (brachial gland), and poison their body with arms and tongue, which can also join saliva and be transmitted by bitting.

Pygmy slow loris (Nycticebus pigmaeus). Photo by Ch’ien C. Lee

In this case the poison is used as a defense against predators, causing them pain, inflammation, necrosis (cell death) in the area of the bite, hematuria (blood in urine) or in some cases anaphylactic shock (allergic reaction) which can lead to death, even in humans (some are threatened by the illegal pet trade and traditional Chinese medicine). The poison also serves as protection for the young, they are licked by their parents and the poisonous secretion is distributed throughout the coat. Being poisonous, unusual among primates, can help counteract the disadvantages of its slow movements. Exudate from glands, as in echidnas, can also give olfactory information of range and territory between individuals of loris (Hagey et al., 2007).

Kayan loris (Nycticebus kayan). Photo by Ch’ien C. Lee

Toxins are polypeptides (generated when glandular secretion is mixed with saliva) and an unidentified steroid. Secretion is similar to the allergen Fel d 1 which is in the domestic cat and cause allergies in humans (Hagey et al., 2006; Krane et al., 2003).

It is believed that slow lorises even have converged evolutionarily with cobras, for his defensive behavior when threatened, whistling and raising his arms around his head. (Nekaris et. al, 2003).

Mimicry between loris and cobras. 1. Javan slow loris, 2 y 3. Spectacled cobra, 4. Bengal slow loris. Photo by Nekaris et. al.

In the following video a lazy lori is disturbed and hisses like a snake while trying to bite:

SOLENODON OR ALMIQUI

They are small and nocturnal mammals, basically insectivores, that live in the West Indies. The Hispaniolan solenodon (Solenodon paradoxus), also known as the Dominican solenodon, Haitian solenodon or agouta, lives on the island de La Española (Dominican Republic and Haiti) while The Cuban solenodon or almiqui (Solenodon cubanus) is distributed throughout Cuba. They are considered living fossils because they have similar characteristics to primitive mammals of the end of the Mesozoic Era (kingdom of the dinosaurs).

Hispaniolan solenodon (Solenodon paradoxus). Photo by Eladio M. Fernández.

Unlike other poisonous mammals, toxic saliva is produced under the jaw (submandibular glands), which is transported by pipes to the front of the mouth. The second incisor teeth have a groove where toxic saliva accumulates to promote their entry into the wounds. They are the only mammals that inject venom through its teeth, similar to the way snakes do.

Paradoxus Solenodon lower jaw incisor showing the groove. Photo by Phil Myers

The main function of this venom is to immobilize prey, as well as insects they can hunt small vertebrates such as reptiles, amphibians and birds.

Cuban solenodon (Solenodon cubanus). Photo by Julio Genaro.

This poison may have been developed to keep alive but immobilized prey during times of shortage, to aid in digestion, minimize energy expenditure in the struggle for hunting and face prey even twice as big as them. This venom is not deadly to humans.

SHREWS

The northern short-tailed shrew (Blarina brevicauda), the Eurasian water shrew (Neomys fodiens) and the Mediterranean water shrew (Neomys anomalus) also have submandibular glands similar to solenodons. They are distributed by North America (northern short-tailed shrew) and Europe and Asia (water shrews), including the Iberian Peninsula.

The northern short-tailed shrew (Blarina brevicauda). Photo by Gilles Gonthier.

The short-tailed shrew can consume up to three times its weight in food per day. Their saliva is the most poisonous and uses it to paralyze their prey, to eat them or keep them alive in times of shortage. The water shrews also store its immobilized prey under rocks.

Mediterranean water shrew (Neomys anomalus). Photo by Rollin Verlinde.

These animals attack from behind and bite the neck of its prey so that the poison acts more quickly, affecting the central nervous system (neurotoxins). The respiratory and vascular system is also affected and causes seizures, incoordination, paralysis and even death of small vertebrates.

Eurasian water shrew (Neomys fodiens). Photo by R. Altenkamp.

Its teeth don’t have grooves as the solenodons do, but a concave surface to store the toxic saliva.

Lower jaw of Neomys anomalus. Photo by António Pena.

It is suspected that other mammals also produce toxic saliva similarly, as the European mole (Talpa europaea) and other species of shrew, but there are no conclusive studies.

MANED RAT

The maned rat or crested rat (Lophiomys imhausi), lives in Africa and  uses his poisoned hair to protect themself from predators.

Maned rat (Lophiomys imhausi). Photo by Kevin Deacon

Unlike other mammals that produce their own poison, the crested rat gets toxin (called ouabain) from the bark and roots of a tree (Acokanthera schimperi). Chews the bark and the mixture of saliva and toxins are distributed on the body. Their hairs are cylindrical whith a perforated microscopic structure, which favors the absorption of venom. In case of danger, it bristles and shows his brown coat with white stripes, warning of its potential danger. This strategy of persuasion based on brightly colored warning is known as aposematism present in many animals, such as bees.

In this BBC video you can see a crested rat and a hair under the microscope absorbing ink, showing its porous structure:

It is unknown how it is immune to the toxin, since it is the same substance used by some African tribes for hunting such large animals like elephants.

Ouabain is a glycoside which controls the heartbeat, causing infarcts if absorbed in large quantities. The study of the mechanisms that protect the crested rat of a substance that regulates the heartbeat, can help develop treatments for heart problems.

European hedgehogs (Erinaceus europaeus) have similar behavior (smearing the body with foreign poison), but it is not established whether the objective is defensive because it does not scare away predators.

In conclusion, strategies, practices and nature of the poison in mammals are varied and their study may have important medical implications for drug development and increase awareness of the evolutionary relationships between different groups of living animals (reptiles-mammals) and their ancestors.

REFERENCIAS

• Platypus poison
• Scientists discover the function of the echidna’s spur
• Los primates venenosos existen
• El único primate venenoso del mundo ya no está solo
• “Venom” of the slow loris: sequence similarity
  of prosimian skin gland protein and Fel d 1 cat allergen
• Venomous Slow Loris May Have Evolved To Mimic Cobras
• La rata que se unta con veneno para defenderse
• ¿Es cierto que los erizos se embadurnan de veneno?
• Pequeños pero feroces: mamíferos venenosos
• Are slow lorises really venomous?
• Encuentro con un “fósil viviente” en R. Dominicana
• Imagen de portada de Dave Watts

Grief in animals: the case of elephants

Have you ever wondered if humans are the only ones who give importance to the death of our fellow? Some years ago it was believed that this distinguished us from other animals, but is now known that elephants show special behaviors with corpses and death of their congeners.

BRIEF DESCRIPTION OF THE AFRICAN ELEPHANT

The African elephant (Loxodonta africana) is the largest land animal that exists today, with a height of almost 4 meters, weighing up to 6 tons and having one of the highest life expectancies among mammals (it is estimated to be living up to 70 years).
Elephants are organized socially in groups composed of a older female, more experienced, called matriarch, and other related females of various ages with their offspring (males and young females). Sometimes to protect or feed on leafy areas, small herds can be combined to form groups of several hundred individuals. The males join the herd when they find a sexually receptive female, since otherwise are solitary (old males) or form bachelor groups (young males). However, they never go too far from their family and recognize it when they meet again.

African elephants (Vaughan Leiberum)

BEHAVIOR

Although they have not been so studied as primates, elephants are considered intelligent animals and show complex behavior such as altruism, empathy, cooperation and problem solving. The matriarch passes on his knowledge to the rest of the family, as migratory routes, where to find water, food, salt, etc. In this article, however, we will focus on behaviors that have elephants in relation to death, which some studies may qualify for funeral rites. We have the idea that only humans keep vigil our dead and we are aware of death, but it might not be true. Although sometimes we apply our criteria to what we see in other animals and we must discuss these issues with caution, especially elephants, dolphins and apes have been recorded special behaviors related to the death of relatives.

Elephant skeleton (Mike Richardson)

FUNERAL RITES

When we talk about elephants and death, we are not referring to their popularly famous graveyards, which has been proven its inexistence, but other events surrounding the death.
Cyntia Moss is a ethologist who has studied the behavior of a herd of African elephants for over 30 years. His observations allowed to know that elephants show special interest in the bones and remains of other individuals of their species, unlike most animals, that do not specially mark the death of other individuals. According to a study of Sussex University, directed by the Dr. Karen McComb, elephants are the only animals along with humans that can recognize the bones of another individual of the same species althougt it had been dead for years.

Over the body of an elephant, the whole family stops and becomes tense. First approach their trunks to smell it, then move carefully and palpate the bones, especially the skull. Other times, they throw sand and leaves on its remains.

Elephants in front of an elephant, rhino and buffalo skull: they only became interested in the elephant one. (Photo: Karen McComb/Royal Society)

When an elephant dies, the whole herd is concerned. If it’s a baby, his mother stays with the body several days and even tries to transport him using the trunk or tusks. The rest of the herd stays at her side or slow down. When an adult dies, the other elephants try to raise it and not separate from it until his remains fall into putrefaction. Sometimes they hold a wake over, driving away the scavengers, and even half burying the body in litter. They are also able to systematically recheck the bones and tusks that are on the road and even –the researchers suggest-, they visit the bones of their relatives. The premature death of the matriarch of the family cause general consternation and can lead to the disintegration of the group. Some females may take up to 20 years to return to rebuild the family unit, others will never achieve it.

These behaviors and social structure are used by hunters and ivory traffickers because killing one adult specimen, especially the matriarch, leads to an almost certain death to the group. But that is another issue to be discussed in future posts.

REFERENCES

• Amboseli trust for elephants
• Animal intelligence: dolphin, dogs, elephants smarter than some realize
• Elefantes, delfines, simios y hombres
• Elephantvoices.org
• El duelo de los elefantes (BBC)
• Los elefandes lloran a sus muertos
• Mosterín, Jesús. 1998. DeBols!llo.

Cover photo by John Chaney (National Geographic 2012 Traveler Photo contest 2012)

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