Why Can't We Be Friends?: A Brief Discussion of the Lost Friends Theory

A long while back, I briefly mentioned something known as "The Lost Friends Theory".  It is also known more scientifically as "The Depleted Biome Theory", but Lost Friends just sounds more fun! The idea behind this theory, no matter what you decide to call it, is that as new medical technologies emerge and rid us of all the bad things that live within us, such as our favorite little hookworms, our bodies actually lose some of their immunological capabilities.


Sounds a little bogus, right? It actually makes perfect sense! Consider for a moment the fact that human parasites, such as parasitic worms, have evolved alongside us throughout most of human history.  Such enduring symbiotic relationships would have to have affected the way each organisms' bodies functions on at least some minor level.  If a population has been carrying a particular intestinal parasite for generations, it would only make sense for that population to eventually develop bodies that either (A) find a way to rid themselves of their parasites or (B) find a way to coexist with their parasites. 

It seems that as far as our hookworm friends are concerned, (B) was the body’s choice for many human populations.  Hookworm infections were once notoriously bad in the southern part of the United States.  Thanks to John D. Rockefeller, hookworms were essentially eradicated in the south, leading to healthier, more productive citizens who could now enjoy a much better quality of life.  While this monumental public health achievement was vital to re-energizing the southern economy, it didn’t go completely without consequence.  Generations later, people whose bodies had adapted to deal with the commonly occurring hookworm infections began to develop health issues that ranged from mild allergies to severe intestinal diseases. 

The causes of such issues were not linked to a loss of hookworms in the body until much, much later.  Research has now shown that having hookworms within your body causes the body to launch an immune response that increases the amount of mucus put out by your intestines. This response is vital to suppressing chronic diseases such as ulcerative colitis, celiac disease, and Crohn’s disease.

For a more technical description of how the immune system works with (or without depending on your perspective) parasites, see one of my older posts titled: Helminthic Therapy. That post does a great job dealing with the creation of regulatory T cells and the interplay of interleukin genes with helminths and autoimmune diseases. Here’s the link if you are interested:

http://parasitophilia.blogspot.com/2012/10/helminthic-therapy.html 

Anyway, back to the discussion at hand.  So by losing friends, like our hookworms, we have caused our immune systems to freak out on our bodies. This immunological temper-tantrum has put us at greater risk of developing autoimmune issues such as the intestinal issues mentioned previous, but also for diseases such as asthma, hayfever, multiple sclerosis, and various food allergies.

Not to fear, however, for as they say, knowledge is power. By knowing that these diseases may be brought on by a lack of something, or someone (which I suppose is more correct), it is easier to treat patients that deal with such issues.  Helminthic therapy is one of the more exciting mechanisms we have developed to restore our lost friends and their benefits. The long description of this can, again, be found on a previous post. (See above link.) The short definition is that the patient is treated for such diseases by purposefully reintroducing a small, easily controlled, number of “parasites” into their bodies to elicit the proper immune response that will inadvertently treat their disease.  Scary as this sounds, it is a virtually harmless, painless treatment that has astoundingly positive results for people who suffer from some of the most brutally painful autoimmune diseases.

There are probably many more examples of how we have put ourselves at risk for various health issues by trying to make ourselves healthier. Paradoxical as it may seem, such is the beauty and mysterious nature of the ever-evolving field of medical science. The Lost Friends Theory is actually a subset of a broader hypothesis called “The Hygiene Hypothesis” which extends this concept to bacteria and viruses.

Moral of the Story
Things are rarely as they seem. It is important that we don’t allow our bodies to be ransacked by preventable diseases, but it is just as important that we don’t wipe out organisms that our body depends on to keep itself healthy. The idea of parasites living inside one’s body is a terrifying thought.  This perception is a result of decades of movies and books that attach a stigma of what Carl Zimmer calls, “A precise horror” to the concept of parasitism. As rational human beings, we sometimes need our perceptions to be challenged.  Such is how we better our chances of unlocking the mysteries of the biological universe. Perhaps it would be good for us to see the often unrealized potential of parasites by looking at these creatures in a less frightening light. Maybe if we start seeing them for what they really are, not agents bent on bodily domination, but rather just as organisms trying to complete their own small circle of life, then we would be able to more easily digest the idea of them being useful, and invited guests. After all, we are ourselves a great conglomerate of a multitude of organisms working together to form what we call our individual selves.  We are positively teeming with bacteria and invisible mites that all add up to the complexity of who we are. So why not make a little room in our bodies for organisms that may alleviate our autoimmune problems if we face them? Why not reconnect with our lost friends when needed? 

Schistosoma

In light of my last post about Brazil releasing a vaccine for Schistosomiasis, I felt it would be a good idea to do a post on Schistosoma itself. Schitosomiasis has a long history with humans. In fact, some sources assert that it was a common cause of death amongst the ancient Egyptians during the Greco-Roman period. It continues to be a problem today that about 1/6 of our world’s population has to deal with. It is to blame for lowered productivity and social stigmas that drag down the economies of developing countries. Its population even exploded as man feebly attempted to divert the great waters of the Nile. (*Side note*: As cases mounted due to Nile irrigation projects from the 1950s-1980s, people were being treated with shots of tartar emetic, which later increased the spread of hepatitis C via unclean needles….good job, Egypt!)

Taxonomy

Like all helminths, this worm belongs to kingdom Animalia.  It is a type of flatworm known as a “fluke” putting it in phylum Platyhelminthes and class Trematoda.  Other platyhelminths include tapeworms and some nifty non-parasites called turbellarians (google it…they are really neat!) The term “fluke” is synonymous with the term “trematode” and I might use them interchangeably, so beware! This particular parasite is in order Strigeidida under the suborder Strigeata.  It further belongs to the family Schistosomatidae.  Members of this family spend their larval stages within molluscs and their adult stages within vertebrates.  All members are dioecious (meaning they have separate male and female sexes) unlike many other flatworms that are hermaphroditic (having male and female organs within a single individual).  The family has14 genera, 9 of which infect birds. 

Unamused Hippo is Unamused

The only genus that infects humans is the genus Schistosoma. Seven species within Schistosoma infect humans, but there are other mammals that carry Schistosoma.  Most of these other animal are ruminants, but there are two species that infect hippos. (I’ll list one of them here because the name is intuitive, so you will never forget it: Schistosoma hippopotami.)

Life Cycle

These parasites are known as “blood flukes”…and I bet you can guess why! (Because you are a smart cookie!) The first person to ever describe the full life cycle was Dr. Pirajá da Silva in 1908. 

S. haematobium egg

S. mansoni egg

Let’s start with the eggs.  The eggs of these little guys are pretty scary-looking. They have tiny spines that may be found in various places on the egg depending on the species of Schistosoma from which they came. Eggs are passed via urine or feces from an infected host into a fresh water system.  The eggs then hatch, releasing a miracidium that then proceeds to penetrate a snail host (which is often species specific). Inside the snail, the parasite undergoes a few different morphological changes before popping out as a tailed cercaria. These cercariae swim about in the water until they find a suitable host and then they burrow their way into that host through the host’s skin.  They then wiggle their way into the circulatory system and eventually make their way to a specific destination in the body where they mate and spend the rest of their lives eating and pumping out babies.  The destination depends on the species of Schistosoma that is infecting its host. Some like the liver, some like veins associated with the intestines, and some like the bladder.

Living Encopula
(Female's head is in orange
poking out of the canal .)

One of the more interesting aspects of the life cycle for S. mansoni is that these parasites are monogamous.  The males have a special canal that runs the length of their bodies which is referred to as the “gynecophoric canal”.  The smaller, more slender female finds a mate and slips into this canal to live out her life, literally, inside of the male. This life style is called living “encopula”. They only take one mate, and if the female dies, the male retains her dead body within his canal until he too dies. He eats a ton of glucose that he passes on to her as she pumps out eggs that invade the liver or are passed out of the host to start the life cycle over again. Homosexuality has also been observed in these animals even though the anatomical fit isn’t quite as perfect. When curious scientists tried to separate the homosexual couples mechanically, they always went right back to one another. How cool is that?!?

Schistosomiasis

As previously stated, there are seven species that infect humans.  These infections are aptly named “schistosomiasis” despite which species causes the infection.  Most of the species are found in or near South East Asia or Africa, but there is a species that spans from Africa and the Middle East all the way to the Caribbean and into South America.  This disease infects a large portion of the human population.  In fact, it runs right behind malaria in terms of the devastating socioeconomic impacts. The CDC and the WHO both classify schistosomiasis as a NTD (Neglected Tropical Disease).  This is WHY it was such a BIG DEAL when Brazil announced that they had finally found a vaccine for this detrimental and disfiguring disease. That and the whole first-vaccine-against-a-worm thing…that was important too. :p Anyway, back to the disease.

Schistosomiasis is sometimes called “Bilharzia” (after the first physician to describe the cause of urinary schistosomiasis in 1851: Theodor Bilharz) or “Snail Fever”. S. mansoni and S. intercalatum cause intestinal schistosomiasis. S. haematobium causes urinary schistosomiasis. S. guineensis can cause liver disease. S. malayensis is rarely known to infect humans at its preferred host is von Muller’s rat. And finally, S. japonicum and S. mekongi cause Asian intestinal schistosomiasis.

The disease itself is often chronic and debilitating, but not necessarily fatal. 

Skin lesions left from Schistosoma penetration.

Symptoms include abdominal pain and diarrhea, coughing, anemia and malnutrition, elevated white blood cell counts, fevers, fatigue, enlargement of the liver or spleen, genital sores, and dermatitis caused by host skin penetration. The longer the infection, the more detrimental the parasites are to their hosts, often leading to calcifications and cancers if left unchecked for too long. (*Side Note*: Because young boys often pick up S. haematobium when they reach puberty and start working in rice fields, they will often experience bloody urine. Infection in these cultures is so pervasive, that this is not seen as abnormal, but as a form of “male menstration”. There are even instances of boys who didn’t go into working in rice fields, thus they didn’t get infected, and parents taking them to doctors to find out why their sons weren’t menstruating! Wild huh??)

Diagnosis, Treatment, and Prevention

To diagnose schistosomiasis, most hospitals test for antigens using ELISA and a patient’s blood sample.  This is the best method for diagnosis, but it can also be diagnosed via demonstration in a stool sample, or (rarely) a urine sample. Sometimes a tissue biopsy is performed, but is less commonly used because it is more invasive.

To treat patients diagnosed with schistosomiasis, most places recommend a single, yearly dose of a de-wormer known as praziquantel. Outside of the US, some places have developed species specific treatment such as oxaminiquine for S. mansoni and metrifonate for S. haematobium. 

To prevent the transmission of this disease, some areas treat fresh water sources with chemicals to kill off the snail intermediate hosts. However, these chemicals often kill more than just the snails. Even if they didn’t, the snails are still a vital part of the ecosystem, so every time this prevention method is used there are ecological effects that forever change the flora and fauna of the freshwater sources.

Now, because Brazil is awesome, we have…for the first time ever…an effective vaccine against schistosomiasis. Check out my last blog post for more details.

Moral of the Story

If your son didn’t get his period, it’s totally normal! :p If he did, see a doctor and get rid of it! (Reference from The Jerk, anyone?) Anyway, the vaccine for this is super awesome, and super important. It will be interesting to see the socioeconomic impacts that this vaccine has over the next few years! :D

Another thing we can take away from this is that there are great examples of monogamy among animals...there's even homosexual monogamy! Ahh true parasitophilia in the strictest  sense of the made-up word! It's enough to make you want to weep with joy!

Protection From Infection: Brazil Develops SM-14

Human Blood Flukes (Schistosoma sp.)

     As I finally closed in on the end of my first semester as a PhD student, I found myself being rather lazy. I missed posting last Sunday because I was preparing for finals, and then it just slipped my mind later in the week. That being said, I thought I would inform all of you that I will be taking a seminar class next semester titled: Tropical Medicine, Infectious Disease, and Global Health. Pretty cool huh? :) Anyway, for this year, the professor has decided that everyone will be given a country about which all of their weekly topic papers will be. I have a copy of the syllabus already and the topic papers due each week are pretty exciting! I was thinking to myself, "Man, I wish I knew which country I was going to have so I could get started early!". Sometimes I'm pretty sure professors can read minds...a few days later I got an email asking me to pick between India and Brazil. As my major advisor has done lots of work in Brazil and will be there three months out of the year for the next few years, I obviously picked this country!  
     As I began doing a little light research, I ran across some articles that I am surprised I haven't heard more about. Apparently back in June, scientists in Brazil successfully created a vaccine for Schistosomiasis in mice! This is the first time (to my knowledge) that a vaccine has ever successfully been created to battle helminths! Before I get too carried away, Let's talk a little about Schistosomiasis.

Schistosomiasis-a.k.a. "Bilharzia"-a.k.a. "Snail Fever" as an NTD
     This is a disease caused by a trematode (flatworm) belonging to the genus Schistosoma. There are a few that cause disease in humans and many that cause disease in other animals. Most human cases are caused by S. mansoni (Throughout Africa, Brazil, Suriname, Venezuela, and a few islands in the Caribbean), S. haematobium (Throughout Africa and in parts of the Middle East), or S. japonicum (Indonesia, parts of China, and Southeast Asia). There are a few others that infect humans, but they aren't nearly as widespread. (S. mekongi in Cambodia and Laos and S. intercalatum in Central and West Africa) None of these worms are not found in the US, but pose major threats to public health in Asia and South America. Schistosomiasis is a devastating disease that infects more than 200 million people globally. According to the CDC, it's second only to malaria in terms of impact on global health, and is considered one of the five NTDs (Neglected Tropical Diseases). The other four are Trachoma, Onchocerciasis, Lymphatic Filariasis, and Guinea Worm Disease. NTDs kill about 534,000 people worldwide every year. Sadly, the treatment cost for most NTD mass drug administration programs work out to less than $0.50/person/year, and these programs are still underfunded. The CDC also reports that 149 countries and territories are affected by at least one NTD. In fact, I'll let the CDC have the last word about NTDs:

"More than 1 billion people—one-sixth of the world's population—suffer from one or more Neglected Tropical Diseases (NTDs). NTDs are a group of infectious diseases that are the source of tremendous suffering because of their disfiguring, debilitating, and sometimes deadly impact. They are called neglected because they have been largely wiped out in the more developed parts of the world and persist only in the poorest, most marginalized communities and conflict areas. Social stigma is a major consequence of NTDs. In addition to causing physical and emotional suffering, these devastating diseases hamper a person's ability to work, keep children out of school, and prevent families and communities from thriving."

Distribution of Schistosomiasis

Biology of Schistosomes

Egg of S. mansoni
(Note the lateral spine.)

     We already talked about the worms that cause this disease a little bit. The life of a schistosome is quite a watery journey. They start off as eggs in feces or urine of an infected host. The eggs must be passed in a fresh water environment. Once in water of the right temperature, the eggs hatch and a little miracidium pops out to look for an unsuspecting intermediate host. 

Biomphalaria sp.
Intermediate Host for Schistosoma

     That host is a freshwater snail, which species of snail depends on which species of schistostome we are talking about specifically. From there, the parasite undergoes a series of changes before morphing into little cercariae that eventually leave the snail. This is the infective stage of the parasite's life cycle. The cercariae find and penetrate a human's skin before shedding their tails and swimming through tissues in search of the perfect place to settle down with a nice member of the opposite sex. Some settle near the bladder, some in the veins around the liver, some move towards the intestinal lumen. Many animals serve as reservoirs for this disease. It seems to be carried by dogs and cats, rodents, and several types of livestock, such as pigs, horses, and goats.

Generalized Life Cycle of Schistosomes

Pathology and Detection of Schistosomiasis

Brazilian children suffering from Schistosomiasis.

     Most people don't have any symptoms when first infected, but after a few days there is often a rash or itchy skin sensation. If gone unchecked for a few months, people experience chills, caughing fever, and muscle aches. If not treated, the disease can last for years and cause enlarged liver, bloody urine or stools, abdominal pain, and even bladder cancer. These symptoms are not caused by the worm itself for the most part, they are caused by the body's reaction to these little invaders. They symptoms lead to other problems, especially if the disease progresses to a chronic stage. Distended abdomens and dis-figuration are often observed.

Tortuous varicosities in a 24-year-old man
suffering from chronic schistosomiasis.

     To diagnose schistosomiasis, one must demonstrate the presence of the eggs from sample's of a patient's urine or feces. A blood serologic test is often useful in detecting presence when eggs were not found in urine/stool samples, as the eggs are shed intermittently rather than continuously.

The Whole Point of this Post
     An antihelminthic drug, Praziquantel, is an effective treatment for this disease. However, after treatment, many people become reinfected because they return to conditions that are conducive  to parasite proliferation. Efforts to prevent the disease have focused on killing off the intermediate host snails and telling people to stay out of the water. Neither of these "preventative" measures has been entirely successful. Snail-killing chemicals often harm other important species in freshwater ecosystems and must be administered fairly often to keep snails from returning. And let's face it, people need water. People in third world countries don't always have sources of clean water, and often people defecate in or near water sources from which they drink, or use for bathing or for livestock. Domesticated animals need water too. Just like humans, these animals can carry the parasites and pass eggs in their waste products. These products often find their way into freshwater sources.

Researcher holds a vial of SM-14.

     Since preventative measures are ineffective and impractical, researchers began work in the 70s to develop a vaccine. Vaccines are wonderful because they aren't temporary solutions to long-term problems. Vaccines are less costly in the long run because prevention can be delivered in a short series or even a single dose, rather than treating something that may reoccur later in a patient's life only to have to be treated again. Vaccines teach our immune systems how to fight off infections rather than requiring medication aimed at suppressing isolated infections. I love vaccines, and you should too. However, creating a vaccine for parasites is more difficult than creating vaccines against viruses or bacteria. Parasites are more complicated organisms...especially when we start talking about worms such as Schistosoma.
     After years of progress, Brazilian researchers have developed a vaccine for this disease! The vaccine is called Sm-14, and may be the first antihelminthic vaccine ever created.  It's also extremely safe. From what I understand, they found proteins on the worms that could be manipulated with enzymes to induce immunological protection. The proteins were located on the tegument (skin) of the worms. Research has shown that using these proteins in a vaccine tested on mice either eliminated or at the very least greatly reduced the infective capability of the parasites. Immunization combined with drug treatment and sanitation efforts offer the best solution to protecting those affected by the devastation of this disease. Brazilian researchers believe that immunization of populations in areas of endemic schistosomiasis can be completed in five years, eradicating the disease from such places.

An awesome poster showing the lead SM-14 researchers: (from left to right) Peter Hotez, David Dunne, and Alan Fenwick.

Moral of the Story
     This. Is. HUGE. Seriously, this is history in the making. The development of Sm-14 was publicly announced on December 6th, 2012. For those of you counting, yes, that was a mere 10 DAYS AGO! Just over a week ago, the results of clinical trials were released giving hope to the 200 million+ people who suffer from the second most-devastating tropical disease (just behind malaria). Be excited that you are living at a time when this medical breakthrough occurred. Then be sad that many people have never heard of schistosomiasis despite how many lives it's claimed. Then be excited again that the people who HAVE heard of it...the people who SUFFER from it or have friends or family members suffering from it at this very moment...have something to look forward to when vaccine administration programs begin distributing these little bottles of hope. This could very well be the beginning of the end for schistosomes. Maybe the Mayans were talking about them rather than about us....we will see what happens on Dec. 21st! :p

P.S. In looking for photos, I stumbled onto a website for an organization called United Against Infectious Diseases (UAID). Below is their mission statement and one of the posters they've created relating to this post.

"To empower students in making our world a better,
healthier place through awareness, prevention,
and treatment of infectious diseases."

Küchenmeister's Tasty Tapeworm Soup and Sausage

It is important for us to learn not just about the organisms we like to study as parasitologists, but also about the history of our chosen profession. The field of parasitology has a rich and colorful history full of people who make it such. Today, I’ve decided to post not about a parasite, but about one of the many parasitophiliacs who contributed to what we know about parasites today.

Gottlieb Heinrich Friedrich Küchenmeister

 Today’s parasitophiliac of interest: Gottlieb Heinrich Friedrich Küchenmeister (No, not the alcoholic cake, silly pants! The person!)

 

Can you guess where Dr. Küchenmeister hailed from? That’s right! He was born in Germany in 1821. After studying medicine in Leipzig and Prague he became a general practitioner in Zittau. In 1856, he and his wife moved to Dresden where he began his research on parasites such as Trichinella spiralis and various tapeworms. In 1852, he came up with a theory that would lead him down a controversial path as a parasitologist.

Parasitology After Steenstrup

To tell his story, let’s back up just a tad. A Danish zoologist named Johann Steenstrup made some great contributions to the field of parasitology in the 1830s by discovering that flukes had various life cycle stages that were morphologically different. This researcher proved that the eggs, rediae, cercariae, and adults were all different parts of the life cycle for a single species rather than being four distinct species as had been believed previously by science. These were the days when people believed that parasites were spontaneously generated by the body because they didn’t understand how parasites worked. 

After his ground-breaking work, Steenstrup decided to do some work with “bladder worms”, which lived in mammalian muscles. He thought these worms might actually be juvenile stages of some other unknown worm. Other scientists began postulating that these little worms that ended up in the tongues of sheep and pigs were baby tapeworms that somehow screwed up their life cycle and were malformed pockets of babies that would eventually die because they were in the wrong host.

Enter Küchenmeister

When Küchenmeister heard about this in the 1840s, he was more than a little upset. Küchenmeister was a very religious man, and he refused to accept the idea that God could screw up so badly and sentence his own creations to such an awful, and frequently occurring, dead end. So, in the interest of biological science as well as proving that ALL of God’s creatures had a purpose, this man set out to unlock the mystery of the “bladder worms”. Küchenmeister believed that the “bladder worm” stage was a very much natural and integral part of the tapeworm life cycle.

By 1851, Küchenmeister was busy conducting experiments to prove his theory. He harvested bladder worms from rabbits and fed them to foxes. A few weeks later he would cut open the foxes to find adult tapeworms. He did the same thing with mice and cats using a different species of tapeworm. He eventually moved on to harvesting from a sheep and infecting a dog. This time, when the dog began to pass proglottids in its feces, Küchenmeister fed the proglottids back to a healthy sheep. After 16 days the sheep became ill, and after it died Küchenmeister gazed inside its skull. He found little bladder worms resting atop the brain of the recently deceased sheep.

 

When he reported his findings, an uproar ensued amongst the biological community. This guy was a general physician who played with parasites for fun and was uber-pro-cremation. He wasn’t a serious researcher like so many others who had not been able to unlock such mysteries on their own. He couldn’t possibly be taken seriously. Established scientists worked hard to poke holes in the good doctor’s theories, but none of them managed to do so. Why? Because he was RIGHT!

Dr. Küchenmeister did manage a few little slip ups with his research. Apparently he sometimes lost parasites because he fed them to the wrong hosts and failed to get the next life-cycle stage. But this negative data wasn’t really wrong…it just proved that tapeworms were species-specific. So his theory still stood.

Bladder Worm Soup with a Side of Blood Sausage

So what’s the big deal? They guy fed some tapeworms to some animals and figured some stuff out? What should we care? Küchenmeister wasn’t done with his research yet. Hang in there people, this is where it gets interesting!

To further prove his theory, the good doctor began experimentally infecting humans with tapeworms. That’s right, HUMANS! He started feeding bladder worms to prisoners with the permission of the prisons, but not with the knowledge of the prisoners themselves. He found prisoners nearing their execution dates and fed them delicious meals full of little parasites. After the prisoners were executed, he would cut them open like one of his foxes to find fully-grown adult tapeworms in their intestines.

Interesting sidenote: He cooled a noodle soup to body temperature and added some bladder worms for his first prisoner, who liked the soup so much that he asked for seconds. Küchenmeister, being the nice guy he was, gave the prisoner seconds AND gave him a nice bladder worm-spiked blood sausage to go with it.

The first prisoner was executed three days after eating Küchenmeister’s special meal and upon dissection, Küchenmeister found tapeworms belonging to the genus Taenia. His second prisoner was fed four months before his execution and his corpse revealed a nice five-foot tapeworm.

Küchenmeister’s experiments were looked on as barbaric by most of his colleagues. However barbaric it was, his work helped to establish the life cycle of these tapeworms. His work was also very important because he was the first person to demonstrate that not all parasites had to spend part of their lives out in the environment. Küchenmeister proved that some parasites could be transmitted from host to host simply by being eaten.

Life Cycle of Taenia from the CDC

Moral of the Story

Taenia solium scolex

Sometimes it takes someone who isn’t an “expert” to make remarkable discoveries. Sometimes we need to look at a problem with fresh eyes and open minds if we want to figure out how things work. The beauty of biology is that what we KNOW today may or may not be the great truth of tomorrow. There is constant change and adaptation in the field just as there is constant change and adaptation in nature. It’s amazing how even the history of our field reflects the very essence of life as we understand it! So remember to always question even the most well-established principles for yourself. And if you can develop an experiment to test your hypothesis, it’s always nice to be able to test it out on prisoners lab rats.