Science. How hard can it be?

Primary Immune Deficiencies (PIDs) can be defined as defects in the immune system. 

No, that can’t be enough.

PIDs are defined as inherent defects in the immune system?

Nope. Still not good enough.

PIDs are defined as the susceptibility to rare pathogens?

Not quite.

Recurrent infections?

Nope.

We’ve known about PIDs atleast since the 1950s. We shed a tear at the John Travolta movie “The boy in the plastic bubble” (partly because of the movie but mostly because it had John Travolta). Indeed, Severe Combined Immunodeficiency (SCID) as described in the movie is the most well known of the PIDs. But is that all? Are PIDs simply the abcence of a functioning immune system?

The first PID described was Bruton’s agammaglobulinemia in the 50s. 

No wait! The first PID to be described was Epidermodysplasia Verruciformis (insert length of name joke here) in 1922, although it was only officially classified and allowed to sit along with the cool kids at the PID table upon discovery of causal mutations in the immune response in the 2000s. Trust me, you’ve heard of this PID.

The Indonesian tree man. Source- www.whatsonxiamen.com

EV is caused by a severe susceptibility to common forms of human papillomavirus. The same stuff that causes tiny warts is us can grow unchecked in people with mutations in two genes present in the skin (skin!), resulting in uncontrolled growth of warts. 

There are many misconceptions on what PIDs are, and whom they affect. For instance, once misconception is that defects in the immune system as we know it (T cells, B cells and macrophages) are responsible for PIDs. However, the above example showed that PIDs can occur when the immune system is normal, but defects in skin can result in susceptibility to certain infections. 

Other misconceptions include PIDs being present only in infants and children. This is true for PIDs such as SCID, where severe deficiency in the immune system results in infections from the most common of pathogens, and hence death. However, people now realise that a previously under-appreciated number of PIDs do occur in adults; and sometimes can initiate suddenly during adulthood. Common Variable Immunodeficiency (CVID), which is characterised by decreased immunoglobulins and no memory B cells is the clinically most common PID known, with a frequency between 1:6000-1:10,000. Incomparison, breast cancer incidence rates in the US are around 13:10,000 (or about 1:1000). 

Think PIDs are rare? Think again. The most common PID is Selective IgA Deficiency. How common is it? 1:600. However, the rest of the immune response is capable of handling the defects in IgA deficiency, and thus this PID is not as clinically prevalent. For all you know, you might be IgA deficient and not know about it!

PIDs are not defined by susceptibility to a host of pathogens that wouldn’t bother infecting our more immune competent brethren. Rather, certain PIDs have been identified that confer susceptibility to single pathogens. The above example of EV is one. Deficiency in our immune response to single pathogens such as Herpes have been identified, where these individuals lack functioning toll like receptors, and thus increased virus replication occurs in the central nervous system resulting in death. If these kids survive, then they are completely protected against reinfection by Herpes, as well as other infectious insults. There are those individuals who are increasingly susceptible to mycobacteria, including those in the vaccine strain BCG. Given the inherent variability of clinical phenotypes of PIDs, it has been impossible to define what a PID really is. The recent increase in classification of PIDs has been primarily due to a willingness of physicians to diagnose for these diseases, as well as improved detection techniques. 

Casanova and Abel call PIDs “Experiments in Nature”. They argue that PIDs might not only be more common than previously thought, but might infact be the rule rather than the exception. A few hundred years ago, the life expectancy was about 40 years of age, with most people dying due to infectious diseases. Now the life expectancy in most parts of the world is around the 70s. Has our immune system developed in the past 100 years? Not really, but we have become cleaner. We only drink sterile water. We are more judicious of our waste disposal (rather than pooping in the city drinking water). We’ve developed antibiotics. We’ve developed better quarantine techniques. We have vaccines (although those who don’t use them should be prime candidates for the Darwin awards).  What indeed could be happening is that we all might be immunodeficient. Perhaps to a common pathogen that is currently prevalent in countries we would never visit. Perhaps to an extinct  pathogen. Or perhaps even to a pathogen that lies around us, but we were protected initially by a vaccine. 

PIDs have had their uses to. PIDs are often due to genetic alterations in the immune system. Studying these individuals can teach us a lot about how the body has evolved to respond to pathogens. Just as researchers try to recreate nature and generate mutations in a mice to study a phenotype, so has nature played… nature (?) and created mutations in us. 

That mouse is you. And nature’s watching. Source- http://blog.cd-writer.com

So the next time your friend says he doesn’t get sick because he has a strong immune system, introduce him to the ebola. Lets see how strong his immune response to that pathogen is :). 

References:

1) Laurent and Abel, 2004. Nature Reviews Immunology (4): 55-66.

Sometimes, I think that as scientists, we enjoy portraying an aura of complexity. Be it in describing what we do, what we say, or how we think. We like to present science as this complex phenomenon that could only be appreciated by the few who are worthy enough. Or have jumped through all the educational hoops. Try asking a graduate student to explain their research in layman’s terms and they struggle.

Inherently, Science; although I should probably narrow down my rant into what I study-Immunology; is quite simple. It is the host’s reaction to a something foreign. How is that mediated? A pre-existing response that we inherited from our ancestors, namely invertebrae, to a specific immune response that we inherited from our vertebrate ancestors, but was fine tuned to the insults we are more likely to face.

In our quest to understand the intricate details of what we study, sometimes we lose track of the bigger picture. For instance, a professor that I met was a leading expert (or only expert- nearly all articles in pubmed on the topic are from him) was interested in studying how HIV-1 RNA is packaged into the viral particle, and how reverse transcription occurs from said RNA in a newly infected cell. A worthy quest, I’ll admit. But so involved had he gotten with this subject of his, that he refused to acknowledge the work of other researchers in the field, nor the potential therapeutic implications of his work. He still sits now in his office, talking about GAG-POL interactions with tRNAlys3 that result in incorporation of this reverse transcriptase primer into virions. History of medicine suggests that people first started studying science to understand the wonders of the world. And while I definitely agree with this, I think that as People of the Lab Coat, we have reached a point in research where the needs of the many outweigh the curiosity of the few.

Changing track, I don’t see the point of unnecessarily complicated papers. By making a paper immensely hard to read, does it make the level of research that much more higher? Not really. Some of the easiest papers I’ve read have some great science in them. And then we wonder why, as scientists, we get a hard rap.

Science is inherently simple. All you need is a phenomenon (be it a pathway, a question, anything), some simple conditions to study it (in the presence of and the absence of) and the appropriate techniques that would help answer the question. Advances in science have shown us interactions that would take lifetimes to study. Conditions are not as simple as “have” and “remove” and see what happens. Studying, for instance, proteins involves western blots, immunofluorescence, immunohistochemistry, columns, animals models…a potentially infinite list. Theoretically, the conclusion from each of these should be comparable. Is it? Not really. I found, reading papers on respiratory syncytial virus surface proteins that for every paper that showed one conclusion, there was another paper that arrived at a different conclusion. The difference? Different mouse strains, different techniques for analysis…And what is the right answer? Well, depends on who you ask. Going back to the professor I mentioned earlier, a review for a class assignment that I submitted to him came back with a poor score; simply because I have equal importance to a model that contradicts his research. Another non-biased reviewer gave that assignment an excellent grade.

No, I m not bitter about the grade. I m here to learn. In any form or manner. What I’d like is consensus. An appreciation of the bigger picture. A reduction in egos involved. An appreciation of the natural world. In my opinion, biology is simply a study of interaction between two phenomenons. Host vs prey. Protein vs protein. Virus vs cell. The list is endless. Rather than bickering about the right way to study a pathway, creating new machines to do cooler things (i’d love to have a 64 colour flow cytometer. Do I need one? Err…) perhaps we should use the knowledge that we have, the knowledge that is yet to come to identify solutions to problems that still face the world. 

Am I being naive? Most definitely. The business of science is far too removed from its initial goals of studying the world around you. Caught in this stream of madness, graduate students are simply pawns. Got an idea for the role of a protein in a pathway? Good. Now do a buttload of in vitro tests to show potential, then knock out the pathway in a mouse, then add it in, then if possible study it in human PBMCs…

And for heavens sake, what is the point of having 16 sub figures in one figure, and having 6 figures like that in a paper? Seriously, Nature? Seriously?

Generation 1.

He could see it happening before his eyes. The story of his birth. And that of his siblings. They surrounded him, his brethren. He could see them. Being assembled. Just like in a factory. He saw as bits were formed from The Eight, and were added onto himself and his siblings. He knew that he was born to serve a purpose. One purpose. He served The Eight. It was his job, nay, his duty to safeguard The Eight from the perils of the world. For The Eight were the reason for his existence, and those of his kin next to him. He would carry The Eight out of the room of his birth, and to another room, where he would release The Eight. Who would give rise to more just like him, who would then serve The Eight. The Eight were immortal. He was, but a carrier, a momentary flicker in the immortal existence of The Eight.

He looked around. It was chaotic. His siblings had had the final touch. They all now carried with them, The Eight. They were ready. He was ready. Suddenly, there was movement. He felt himself being carried. Closer and closer to the wall. The wall surrounding the room of his birth. He was at the wall. He was inside the wall. Suddenly, he was outside the wall. He was at the abyss. He looked around. He saw his siblings holding on the wall. He saw his cousins holding on to the walls of adjacent dungeons. All of them. Waiting. Waiting.

And suddenly, he was free.

Floating.  Along with his kind in the vast openness. In the distance, he saw more dungeons. Their walls still clean. Undisturbed. He saw some of his kin grab on to the walls. And in the blink of an eye, they were gone. Swallowed whole by the wall. He knew not what happened inside. What horrors awaited them. Or perhaps redemption. All he knew was that he could not stay on the outside. The Eight were precious. They needed the wall. They needed to be inside the wall. Safe. Protected. He floated. Waiting to get near a wall. And then it happened. He got close to a wall. He grabbed on. He was happy. For a fraction of a second, he was on the outside. He felt himself being swallowed. Swallowed by the wall. But this was different. He did not feel safe. In fact, he felt pain. A numbing pain, as he saw parts of himself fall off. Exposing the core. Was this meant to be? Was this what The Eight wanted? And as he pondered, he saw The Eight escaping. Escaping out of the gapes on his body. He saw the robots in the dungeon grabbed onto the Eight. He saw as bits of his own body aided the robots in grabbing onto The Eight. Perhaps to keep them safe. He kept observing. First, there were The Eight. And then The Sixteen. And then The Thirty Two. Soon, there were too many to count. The room was filled with many of The Eight. And from some of these, he saw bits being formed. Bits of himself. Bits that would be used to form his children. He started to see his children take shape. He saw The Eight entering his children. His job was done. To transport The Eight to their destination. And to give rise to his children, who in turn would to transport The Eight. The Eight were important. The Eight was the reason for his existence. And then he was gone. His progeny stirred. The cycle was complete.

Generation 2.

He could see the last of his father disappear. Eaten up by the faceless robots in the room. He looked around. He could see his siblings. He saw them form. A bit at a time. Like a factory. The same thing was happening to him. He felt nothing as bits were added to him. He knew what to do. He was born with the knowledge. He saw where all the chaos originated. Therein, lay The Eight. He knew not what they were. Or whence they came from. He simply knew that it was his job to protect them. Him and his siblings. To carry The Eight onto another dungeon. From where the cycle would continue. He saw as The Eight were carried into his core. He then felt the finishing touches being made to his body. He was ready. Him and his siblings were ready. He felt movement. He felt himself being carried, along with his siblings to the wall. Suddenly he was outside. He was staring into the abyss. Holding on with all the strength that he could.

And then he was floating. Free.

He saw as his siblings grabbed onto the wall. When his turn came, he held on tight to the wall. Momentarily, he was outside. He could see his siblings get sucked in one by one. And then he couldn’t see them. He was inside the wall. He felt himself being dismantled. He saw The Eight quietly leave from inside of him and enter the chaos of the wall. But something was different. The Eight were already in the wall. He saw as The Eight he had carried, at the cost of his life mix with The Eight that was there before. As he saw horrified, he saw bits similar to him being formed. He saw his children being formed, from two different sources. Bits from the eight that he had brought in, and bits from The eight that were already present. Horrified, his last thought was that he had failed. That his children would be different. That he might be the last of his lineage.

Generation 3.

 He felt himself being formed. He saw where he came from. He observed as he was assembled. A mix of parts from two sources. Is this what The Eight wanted? But which Eight was he carrying? He looked around. He felt different. He saw that each of his siblings were slightly different. He saw bits of The Eight enter into his body. He was complete. He looked around. Him and his siblings were ready. He felt different. He felt stronger. The time had come. He felt himself exiting the room of his birth. Momentarily he was holding onto the outside of the wall. His siblings surrounding him. And then he was free.

He felt a force beneath him. He looked around as his siblings were carried by the wave, towards the light. He and his siblings felt stronger. He looked around and smiled. He was born of two parents. He carried within him, the strengths of both. He was Influenza. and he was ready to take over the world.

“It takes all the running you can do, to keep in the same place.” 

The Red Queen, Through the Looking-Glass, Lewis Carroll.

How did sexual reproduction evolve? How do parasites and their hosts survive together? Why do predators manage to catch their prey only some of the time? To answer  these questions, we journey into the Kingdom of the Red Queen. A realm in the universe of biology that has an answer for all these questions and many more. In its entirety,  the Red Queen Hypothesis states that in any co-evolving environment, each species needs to continually change itself to adapt to environmental changes in order to compete and co-exist with another co-evolving species in the same environment. Confused? 

    Here’s a simpler example. Imagine the savannahs of Africa. Sunny. Warm. Beautiful. Dangerous. The lionesses stalk the gazelle. Silently creeping up to the ungulate until the last moment when all hell breaks lose and it ends being a race to the finish. The gazelle is fast and nimble, the lioness more plodding but equally fast. In a scene right out of the Discovery Channel, the lioness finally fells the hapless gazelle and there’s food for the pride. The hunt has been going on identically for hundreds of thousands of years, except for one variable. Speed. The gazelle gets a little bit faster to avoid being eaten. The lioness becomes that little bit faster to catch the gazelle. And then the gazelle gets a little faster again. And so on. The arms race of biology.

    Examples of such attempts at biological one-up-manship abound. The African cuckoo finch lays its egg in another bird’s nest, and once the cuckoo’s egg hatches, the fledgling eliminates competition for food by pushing the other eggs out of the nest. Over time, the victimised birds have evolved a strategy of laying coloured eggs that are easily distinguishable from the cuckoo finch. Right now, the victims have the advantage. For the cuckoo finch to survive, it has to be capable of evolving the ability to compete; potentially by laying similarly coloured eggs that are indistinguishable from that of the victim. 

    The Red Queen has her reach in the many other fields of biology too. One of the biggest questions in evolutionary biology is on the origin of sexual reproduction. Essentially,  males are expensive and worthless. They are simply, a bag of genes. While required for sexual reproduction, males are incapable of producing offspring themselves, which results in something called the “twofold cost of sex” or “the cost of males”. Simply put, in a stable environment, without any external pressures (such as a parasite), selfing (or self-fertilisation, the act of reproduction without the requirement of another individual of a different sex) results in higher numbers of progeny than a species that are out-crossers (require another individual of a different sex, ie male or female). This is because while the out-crossing species requires two parents to produce offspring, the selfing species requires just one parent to produce offspring. 

Thus, over time, the selfing species will produce two times the number of offspring than the out crossing species, and will eventually be the dominant species in the given environment. Given this, why do a number of vertebrates and plant species still exhibit sexual reproduction? It was widely assumed that sexual reproduction; ie the mixing of two different genetic backgrounds would produce a variant of an offspring that could respond better to drastic changes in environmental conditions. This is in contrast to selfing, where offspring would be essentially identical to their “mother” (or hermaphroditic parent). For instance, when a species is challenged by a pathogen, then the out-crossing species, with the inter-mixing of genes would be better capable of producing a variant that was immune to the onslaught of the pathogen. Over time, this variant would survive and reproduce more succesfully than the other variants, and eventually become widespread in this environment. The selfing species however, would produce a variant progeny much slower (because a change has to occur in the parent by mutation, which is rarer) and establishment of this variant would require the replacement of all other non-variant individuals.

     While this makes sense as a thought experiment, it was only recently proved in a truly biological setting. The laboratory.  Researchers at Indiana University used  Caenorhabditis elegans (C elegans), a commonly used laboratory microscopic worm to test for the ability of the worm to shift from  the more common hermaphroditic form of reproduction to sexual reproduction in the presence of the pathogenic bacteria, Serratia marcescens. A normal (wild type) population of C elegans primarily exists in hermaphroditic state, with only 15-20% of all the worms being males (implying about 15% of sexual reproduction in a population). However, once the pathogenic bacteria was added, the proportion of males sky rocketed from 20% to 70% suggesting that presence of the pathogen resulted in “selection” for the out-crossing individuals.

They also showed that increase in prevalence of males was dependent on the ability of the bacteria to evolve. When exposed to bacteria that did not evolve, the proportion of males rose, but dropped back to normal levels of 20%. This is suggestive of the fact that an increase in out crossing would result in potential genetic variants that could be resistant to continual bacterial infection. This interaction is suggestive of the Red Queen effect, wherein the worm had to evolve faster in order to keep pace with the co-evolving bacteria. Once the evolution of the bacteria was stopped, then there was no advantage to the out-crossing worms, and there was a return to hermaphroditic ways. 

The researchers further concluded the benefits of sexual reproduction by allowing bacteria to infect worms that were obligate selfers (ie mutated to be capable only of selfing) or obligate crossers (only capable of out crossing). Upon infection with a co-evolving bacteria, the obligate selfers were extinct within 20 generations, but the obligate crossers never went extinct. Thus, the authors concluded that this co-evolution experiment with the worm and its pathogen was direct proof of the Red Queen hypothesis. Out crossing was selected for in the presence of continual environmental change, but the cost of sex was not worth it in a stable environment (non- evolving bacteria or lack of bacteria). 

    This further raises the question of why many vertebrates, such as mammals exhibit out crossing, when many invertebrates, some fish and a few reptiles are either hermaphrodites, can change sex depending on the environmental condition or exhibit parthenogenesis (female birth/virgin birth). This again is related to changing environments. Many obligate selfing or asexually reproducing species are highly restricted to one environment, since they cannot survive if the environment condition changes or a pathogen arrives and changes faster than they can. Out crossing individuals however are capable of evolving to meet the challenge, and therefore more widespread in their distribution and ability to survive. Over evolutionary time, the benefits of survival  and expansion into new pastures far outweigh the numerical benefit that selfing offers, resulting in a fixation of sexual reproduction as the predominant means of producing offspring. 

    The Red Queen hypothesis can be used to answer some other questions as well. The presence of certain inherent proteins in monkeys and humans that can restrict HIV or its relatives (Simian Immunodeficiency Virus; SIV) can also be traced back to the co-evolution of the host (either human or monkey) to that of the virus (SIV). The Red Queen can also be used to explain the development of the immune system. Despite the wide ranging implications of the Red Queen hypothesis, she is not the only contender in the evolutionary battle. 

The Red Queen hypothesis was originally used to describe competition between species being the driving factor behind the large number of species we see today. Another hypothesis, known as the Court Jester hypothesis suggests that changes in species may result not due to competition between species, but due to random geological or climate events that act as the driving force behind evolution, and the formation of new species. 

    Finally, the Red Queen can also be used to explain certain observations in the real world. Would the Americans and Soviet spent so much on weapon development if the other was absent in the global battlefield? Would so many tech companies care to develop their tech toys if it were not for Apple’s forays into the iPhone and iPad? 

The world of evolution need not be restricted to studying fossils or our present biodiveristy. A change in our thinking, the decisions we make, can all be linked in some aspect, to the basic framework of evolution. And many of these choices fall into the hands of the Red Queen, who suggests that the constant battle of survival, between animals, technology or arms is responsible for the world we live in today. 

    The Red Queen is not dead. Long live the Red Queen. 

References:

 1. Spottiswoode and Stevens. How to evade a coevolving brood parasite: egg discrimination versus egg variability as host defenses. 2011. Proceedings of the Royal Society B: 1-7. 

2. Feigel et al. Sex is always well worth its two-fold cost. 2009. PloS One. 

3. Brockhurst, MA. Sex, death and the Red Queen. 2011. Science :166-167.

 4. Morran T et al. Running with the Red Queen. Host-Parasite Coevolution selects for Biparental Sex. 2011. Science: 216-218. 

5. Barnosky, A.  Distinguishing The Effects Of The Red Queen And Court Jester On Miocene Mammal Evolution In The Northern Rocky Mountains. 2001.  Journal of Vertebrate _Paleontology: 172–185.

Note: this article was previously published on science20.com. Here it lies while I try to come up with something else to write about.

So. I’ve wanted to try my hand at this science writing business. Lets see how this goes.

Nerdy stuff. I m trying to submit my blog to scienceseeker.org. sciseekclaimtoken-4f67d1d27d510