Unsung Heroes In Our Battle Against Infectious Disease

Humanity has always been at war with infectious agents, but it wasn’t until 1860 when Louis Pasteur famously theorized that microbes (first observed by Antony van Leeuwenhoek in the 1600s) cause disease. It took another 70 years before Alexander Fleming noticed that Penicillium mold produced a substance that killed bacteria. While most people are familiar with these luminaries in the field, have you heard of Francesco Redi, Ignaz Semmelweis, Theobald Smith, Mary Hunt, and a cow named Blossom? In this presentation, we celebrate some of the “unsung heroes” whose victories are often neglected from the infectious disease saga.

In the talk below, Dr. Bill Sullivan, a professor at the Indiana University School of Medicine, takes us on a fascinating tour through medical history, answering these questions and more:

How did we figure out that microscopic creatures can make us sick?

Why were milkmaids considered to be so beautiful and what does that have to do with vaccination?

How were starfish important to the discovery of the immune system?

What do you mean penicillin wasn't the first antibiotic?

Watch the talk "Unsung Heroes In Our Battle Against Infectious Disease" by Bill Sullivan here.

Why Should You Care How Bacteria Fight Viruses?

Regular readers have been learning a great deal about the human immune system thanks to our ongoing series on allergies by Julia van Rensburg. But did you know that bacteria have an immune system of sorts, too? Yes, even germs get germs!* Bacteria are susceptible to a group of viruses called bacteriophages, or phages for short. Phages resemble early spacecraft and “land” on the surface of bacteria in order to inject their DNA/RNA, much like a syringe ejects its contents.

Houston, we have a problem! A phage has just injected its DNA into our cell!

Bacteria, which have been on Earth for some 3.5 billion years, have had plenty of time to evolve defense mechanisms against predatory phages. Just like human viruses, phages are a most unwelcomed guest. They barge into the cell unannounced, “borrow” cellular components without asking, and then use them to make baby viruses until the cell becomes so engorged with viral progeny that it explodes, releasing the huge viral family so that it can invade more bacteria and repeat the process all over again. Phages that burst the bacterium like this are called “lytic”, but there are other types that don’t blow the house up. These are referred to as “lysogenic” phages and can insert their genetic material into the bacterial genome, becoming a permanent resident of that bacterium. Even more sinister, the incorporated viral genome is copied like all the other bacterial genes when the bacterium divides, so it is inherited by the daughter cell!

Lytic phages will replicate until they blow the infected bacteria apart. In contrast, lysogenic phages can stick around forever, even getting passed on to future generations since the viral genome was inserted into the bacterial genome.

So that sucks – imagine if you had uninvited viral DNA shoved into your DNA – such viruses basically transform you into a GMO. Sorry to inform you, but up to 8% of your genome is already littered with lots of viral DNA. If you oppose GMOs, I hope you can still stand to be in your own skin!

Presently, we don’t know how to remove foreign DNA from our own. But bacteria have figured out a way to get rid of incoming phage DNA, which provides the basis for a type of bacterial immune system.

 

Some combinations work great together, like chocolate and peanut butter. But getting viral DNA stuck into your own DNA, a strategy used by many viruses including HIV, is not a welcome combination.

In 1987, scientists uncovered unusual repeat sequences in the genome of E. coli bacteria, which were later named “clustered regularly interspaced short palindromic repeats”, or CRISPR. In the early 2000s, scientists identified bacterial proteins interacting with CRISPR sequences (now called CRISPR-associated (Cas) proteins) and discovered that they provide resistance to phage infection. Through the efforts of many laboratories, it is now known that bacteria can use a phage invasion as a vaccination by incorporating some of the foreign DNA between CRISPR repeat sequences. This provides the bacteria with a “catalogue” – a memory system, if you will – of foreign DNA that it can pass along to future generations.

But CRISPR is not just a storage system. The bacteria can retrieve these sequences and hook them to Cas9, a nuclease enzyme that can cut DNA. When foreign DNA enters that bacteria, its CRISPR-Cas9 system can specifically target the invasive element and neutralize it.


Foreign DNA, such as that injected by a phage, can be neutralized by CRISPR/Cas9, which serves as a type of bacterial immune system. Bacteria can store foreign DNA sequences in its genome and express them as crRNAs that bind to Cas9. If the bacterium encounters foreign DNA that matches any of the sequences stored in its CRISPR array, the crRNA will deliver Cas9 to that invading sequence to chop it up.

Pretty clever for tiny bacteria, huh? But here is where things get really interesting, or worrisome, depending on your appetite for paranoia. Scientists have adapted CRISPR/Cas9 to work in all sorts of cell types, including human. Cas9 acts as DNA shears that can cut wherever we tell it to by directing it with a “guide RNA” (analogous to how a crRNA operates in bacteria). This provides us with an unprecedented means to easily “edit” the genome of virtually any living thing, including stem cells and embryos. Furthermore, Cas9 has been modified to do more than just cut DNA; versions exist now that can insert new DNA sequences or switch out bad (mutated) DNA with good DNA.

In the hit TV show, Orphan Black, a group of clones discover that their DNA has been “barcoded” to designate them as intellectual property by their maker. Theoretically, CRISPR technology could have been used to tag DNA in this fashion.

The power of genome editing can be used for good. Several diseases, such as cystic fibrosis and sickle-cell anemia, are caused by a single mutation in one gene. CRISPR/Cas9 is a plausible tool that may be able to repair this defect. However, tinkering with one gene can have unforeseen repercussions on other genes, so this exciting technology could have adverse effects. In March, 2015, a group of scientists proposed a ban on editing the human genome, arguing that a greater understanding of how CRISPR/Cas9 works is required before we even consider applying it clinically.

Gene editing using CRISPR/Cas9 can be used to modify the genome of virtually any creature. One recent application is the creation of wheat that is resistant to a fungus that causes mildew.

Here is a video that shows how CRISPR/Cas9 works and some of the applications it may have down the road:

 

 

Contributed by:  Bill Sullivan

Follow Bill on Twitter.

*It should be noted that not all bacteria are “germs”; in fact, many species of bacteria inhabit our bodies to constitute our “microbiome” and provide important services to us. Learn more about your microbiome here.
 

Sander JD, & Joung JK (2014). CRISPR-Cas systems for editing, regulating and targeting genomes. Nature biotechnology, 32 (4), 347-55 PMID: 24584096

Garneau, J., Dupuis, M., Villion, M., Romero, D., Barrangou, R., Boyaval, P., Fremaux, C., Horvath, P., Magadán, A., & Moineau, S. (2010). The CRISPR/Cas bacterial immune system cleaves bacteriophage and plasmid DNA Nature, 468 (7320), 67-71 DOI: 10.1038/nature09523

Horie, M., Honda, T., Suzuki, Y., Kobayashi, Y., Daito, T., Oshida, T., Ikuta, K., Jern, P., Gojobori, T., Coffin, J., & Tomonaga, K. (2010). Endogenous non-retroviral RNA virus elements in mammalian genomes Nature, 463 (7277), 84-87 DOI: 10.1038/nature08695

Horvath, P., & Barrangou, R. (2010). CRISPR/Cas, the Immune System of Bacteria and Archaea Science, 327 (5962), 167-170 DOI: 10.1126/science.1179555

Baltimore, D., Berg, P., Botchan, M., Carroll, D., Charo, R., Church, G., Corn, J., Daley, G., Doudna, J., Fenner, M., Greely, H., Jinek, M., Martin, G., Penhoet, E., Puck, J., Sternberg, S., Weissman, J., & Yamamoto, K. (2015). A prudent path forward for genomic engineering and germline gene modification Science, 348 (6230), 36-38 DOI: 10.1126/science.aab1028

The Friday Five

Highlighting some of the coolest science news we’ve seen lately.

1. Remember the classic 80s B-movie, "Tremors", with Kevin Bacon? It looks like life is imitating “art” in the case of Eunice aphroditois (aka the Bobbit worm). Click here to watch this critter leap from out of the ground to gobble up an unsuspecting fish.

 

 

2. Cinnamon, Boris, and Sylvester. These were the names of the three cats that have helped scientists map the feline genome (no cats were harmed in these experiments!). 

 

3. An excellent video on the development of antibiotic resistance and evolution of scary “super bugs” like MRSA.
 

 

 

4. Also in antibiotic news, new studies indicate that some of these medications may have unintended consequences. In mice, low dose penicillin altered the normal gut bacteria, which had a long lasting effect on metabolism that predisposed them to obesity. But the research here is also in its “infancy”, so no one should withhold antibiotics to treat serious infections.

 

Additionally, another study has suggested that certain antibiotics given early in life may alter immunity in the long-term, again by impacting the normal bacteria inhabiting the gut.

5. While most people try to get rid of parasites, there is at least one man who invites them into his gut. Parasitologist Julius Lukes is using himself as a human guinea pig to convince others that parasites are not always bad and may actually have co-evolved to do good things for us. To prove they can be our friends, he’s infected himself with tapeworms. It will be interesting to see how this turns out “in the end”!      

Science quote of the week:

“The most exciting phrase to hear in science, the one that heralds the most discoveries, is not ‘Eureka!’ (I found it!) but ‘That's funny’..."  --Isaac Asimov

Contributed by:  Bill Sullivan

Follow Bill on Twitter: @wjsullivan

Tamazian, G., Simonov, S., Dobrynin, P., Makunin, A., Logachev, A., Komissarov, A., Shevchenko, A., Brukhin, V., Cherkasov, N., Svitin, A., Koepfli, K., Pontius, J., Driscoll, C., Blackistone, K., Barr, C., Goldman, D., Antunes, A., Quilez, J., Lorente-Galdos, B., Alkan, C., Marques-Bonet, T., Menotti-Raymond, M., David, V., Narfström, K., & O’Brien, S. (2014). Annotated features of domestic cat – Felis catus genome GigaScience, 3 (1) DOI: 10.1186/2047-217X-3-13

Cox, L., Yamanishi, S., Sohn, J., Alekseyenko, A., Leung, J., Cho, I., Kim, S., Li, H., Gao, Z., Mahana, D., Zárate Rodriguez, J., Rogers, A., Robine, N., Loke, P., & Blaser, M. (2014). Altering the Intestinal Microbiota during a Critical Developmental Window Has Lasting Metabolic Consequences Cell, 158 (4), 705-721 DOI: 10.1016/j.cell.2014.05.052’’

Russell, S., Gold, M., Reynolds, L., Willing, B., Dimitriu, P., Thorson, L., Redpath, S., Perona-Wright, G., Blanchet, M., Mohn, W., Brett Finlay, B., & McNagny, K. (2014). Perinatal antibiotic-induced shifts in gut microbiota have differential effects on inflammatory lung diseases Journal of Allergy and Clinical Immunology DOI: 10.1016/j.jaci.2014.06.027

Dying To Make Us Laugh

It is the height of irony that Robin Williams (left) played Dr.

Patch Adams (right) in the 1998 film of the same name.

Adams used humor to heal and promote health, while new

research is showing that humorists are susceptible to more

harm when they improve our health with laughter.

One of the five funniest people to ever live died recently. Robin Williams was at least as funny as Jonathan Winters, Bill Cosby, Steve Martin, and Groucho Marx. He was 63 years old at the time of his death, and the others on my list have lived good long lives as well. Jonathan Winters was 88 when he died in 2013, Groucho Marx was 87, and Steve Martin and Bill Cosby are 68 and 77, respectively.

But a long-lived comedian is more of an exception than a rule. John Belushi, Gilda Radner, John Candy, Lenny Bruce, Patrice O’Neal, Madeline Kahn, Chris Farley, Bernie Mac, and Andy Kaufman all died in their 30’s or 40’s. This is sad to be sure, but it's even sadder when you consider that comedians hasten their own deaths while improving our health.

“Laughter is the best medicine.” The saying has been around for years – and it has merit. Laughter reduces cortisol production, which is a stress hormone that taxes our health and makes us gain weight. Laughter may improve our immune system function as well, and this fights off or prevents infection. A 2009 review showed that several studies indicated that laughter improved immune cell function (natural killer cells) and increased antibody levels (sIGA).

Laughter improves respiratory function and cardiac function because it increases respiratory rate and requires increased blood flow. These were reviewed in a very funny Christmas article in the British Medical Journal in 2013.

Laughter works on our brain too. Besides relieving stress, laughter triggers the release of endorphins that help our mood – and a good mood is a definite benefit to our health. Laughter also works on the neural pathways of resilience, so that we bounce back from disappointment better.

Gelototherapy is a pseudoscientific term for laughter therapy.

I say pseudo- because I can’t really find anyone who uses the

 term. But other health ideas have sprung up around laughter

as well. Laughter yoga (hasyayoga) is done in groups with eye

contact. It may start out as forced laughter, which is said to

have much less effect on health, but forced laughter turns

readily to spontaneous or mirthful, laughter, which lengthens

our life so we can go out to more yoga classes.

As far back as the 1970’s, journalist Norman Cousins advocated laughter therapy (gelototherapy) after he was said to have healed himself of heart disease and ankylosing spondylitis using Marx Brothers movies. He was an adjunct professor of Medical Humanities at UCLA where he did more research on the healing aspects of spontaneous laughter. But most of his results were on a case description basis – anecdotal at best.

There have been few if any studies that link laughter to extended longevity; however, a 2013 study of centenarians showed that they do tend to laugh more, as part of the PATL (positive attitude toward life). Linking laughter directly to longevity would be very difficult in the scientific sense, but the above stated health benefits can’t be hurting us, can they?

Apparently all this benefit comes at a cost to those giving us their gift. Comedians don’t just seem to die young, they are dying younger. Several studies have looked longitudinally at the health problems and obituaries of people in different professions, and that funny kids have more health problems later in life.

As part of a study of high intelligence individuals called the Terman Life Cycle Study (1922-1991), those kids rated by their parents as having a good sense of humor tended to have more health problems as adults, including alcoholism and lung disease from smoking.

People say that fat guys are funny. I’m fat and my kids say I’m

not that funny. But the question remains, do fat boys become

funny to survive, or does being funny make guys fat? Curly

Howard of the Three Stooges got fat after a bout of depression

at the end of his first marriage. He had a series of strokes late in

his movie career and died at the age of 49.

In a three-year study of police officers in Finland, those that were rated funnier or more humorous tended to be overweight, smoked more, and have more cardiovascular disease. For funny people who choose to become comedians then numbers just get worse. A 1992 study showed that comedians and humor writers died at younger ages. They tended to have more physical and mental health problems. This might relate to the environments in which they work – smoke and alcohol filled clubs, or it might reflect their tendency to see the humor and positive in things and not pay attention to risks of the unhealthy habits in which they engage.

A recent review of deaths by profession shows that performers of all sorts, including comedians, tend to die younger – health problems most certainly playing a role in their earlier demise. Robin Williams had suffered for years with substance abuse problems, bouts of severe depression, and heart disease. Comedians tend to have more depression than the general population and the suicide rate of performers, including comedians, is twice that of the general population.

But which comes first, do depressives become comedians because their altered thinking lends itself to looking at the world differently, or perhaps it is a way of self-medicating (as is drug abuse they tend to fall into) and fitting in with the world. Or, does comedy and the rejection that often comes with it, lead to more bouts of depression? Whichever it is, the physical and mental health problems of humorists seem all the more tragic when it is considered how much good these people do for us.

Contributed by Mark E. Lasbury, MS, MSEd, PhD

As Many Exceptions As Rules

C.R. Epstein, R.J. Epstein (2013). Death in The New York Times: the price of fame is a faster flame QJM: monthly journal of the Association of Physicians, 106 (6), 517-521

Greengross G (2013). Humor and aging - a mini-review. Gerontology, 59 (5), 448-53 PMID: 23689078

Ferner RE, & Aronson JK (2013). Laughter and MIRTH (Methodical Investigation of Risibility, Therapeutic and Harmful): narrative synthesis. BMJ (Clinical research ed.), 347 PMID: 24336308

Bennett MP, & Lengacher C (2009). Humor and Laughter May Influence Health IV. Humor and Immune Function. Evidence-based complementary and alternative medicine : eCAM, 6 (2), 159-64 PMID: 18955287