Where Do “New” Viruses Come From?

Every year there seems to be a new virus that just popped up out of nowhere to cause us a great deal of pain and suffering. Is it the work of a mad scientist vying for global domination? Are these viruses coming back to life after being frozen for millennia? Are they hitching a ride to Earth via meteorites?

The truth is many of these viruses are not so new – but we are creating new opportunities for them to infect us. Many viruses jump from other animals into people – a process known as “zoonotic transmission” – and some of our actions roll out the red carpet for the virus. Let’s take a closer look at where some of these “new” viruses may have originated and how they spiral out of control.

Zika

Microcephaly is a term used to describe babies born with much smaller head size than normal, which is indicative of incomplete brain development. In Brazil, this birth defect occurs about 150 times per year. However, in the past 4 months, nearly 4,000 babies have been born with microcephaly - a dramatic spike that has set off alarm bells.

Photo of a child born with microcephaly, which has been linked to the Zika virus.

While evidence is still circumstantial, the primary culprit is a previously obscure virus called Zika, named after the forest in Uganda where it was first identified in a rhesus monkey back in 1947. Zika is transmitted through mosquitoes, which basically operate like flying dirty syringes. If they fed on an infected person, they can transmit the virus to the next person they bite.

Global warming and increased travel have conspired to create excellent opportunities for viruses like Zika to spread. It only takes one infected person to attend a major spectacle (for example, the 2014 FIFA World Cup in Brazil) to start a chain reaction of viral transmission. Viruses need no passports and can jet set around the world in unprecedented time. Global warming is an issue because it has allowed the species of mosquito that carries these viruses to thrive in areas that used to be too cold. Even El Niño has been catching some of the blame for helping to spread Zika.

Ebola

While Zika jumped to humans from other primates, the African filovirus Ebola is thought to have originated in fruit bats. Bats can transmit a number of other deadly viruses, including rabies. Bats happen to be a source of food in several of the areas where Ebola outbreaks have occurred, consistent with the idea that bats are the culprits. Once Ebola infects a human, it can spread quite easily to other people through bodily fluids.

Bats like this one are now considered to be a major carrier capable of spreading the Ebola virus to people.

Ebola first appeared in humans in 1976 in the Sudan and the Democratic Republic of Congo. The initial outbreak killed an estimated 600 people, but the latest outbreak that began in 2014 in West Africa has been the worst in history, killing over 11,000 people. This wasn’t due to an enormous fruit bat invasion, but rather human-to-human transmission. Genetic studies indicated that the entire epidemic likely stemmed from just a single infected child in Guinea, the so-called “Patient Zero”. A catastrophic mix of poor health facilities and unsanitary practices ignited to spread the virus like wildfire.




The 2014 Ebola outbreak started with a toddler who fell sick in Meliandou village in Guinea. Source.
Credit: Live Science

MERS

MERS, Middle East Respiratory Syndrome, first made headlines in 2012. This life-threatening respiratory virus reared its ugly head in Saudi Arabia first, but has since been reported in 25 other countries, including those not in the Middle East (due to unwitting travelers carrying more than their luggage). MERS is caused by a coronavirus, so the causative agent is typically referred to as MERS-CoV. Like many other respiratory viruses, coughing in close proximity can spread MERS-CoV between people.

But how did MERS-CoV get into people in the first place? According to the World Health Organization:  “It is believed that humans can be infected through direct or indirect contact with infected dromedary camels in the Middle East. Strains of MERS-CoV have been identified in camels in several countries, including Egypt, Oman, Qatar and Saudi Arabia.”

It is easy to understand the respect and admiration one can have for a noble creature like the camel. But getting a little too intimate with a camel may literally leave you breathless.

So stay away from coughing camels! In some areas, camels are butchered for food and their milk and urine (yes, urine) is consumed. These practices provide additional avenues for possible transmission of MERS-CoV to humans.


UPDATE (3/1/16): A new study suggests that we have bats to thank once again for spreading MERS-CoV to camels.

HIV

Human Immunodeficiency Virus (HIV), which causes AIDS, wasn’t on anyone’s radar until an unusually large number of people starting suffering from rare diseases with strange names like Kaposi’s sarcoma, toxoplasmosis, and pneumocystis. These diseases are hardly ever seen in people with normal, healthy immune systems. Turns out they were secondary infections – the primary infection was HIV, which was destroying the very immune cells that are needed to keep those other illnesses at bay.

Historical records have placed the earliest cases of HIV infection to the 1950s, which suggests it has been moving through humans slowly through the decades prior to its explosion in the early 1980s. An increase in international travel, unsafe sexual practices, and intravenous drug use are all factors that have contributed to accelerating the epidemic.

HIV (yellow particles) is a cunning foe that destroys the immune cells (blue) designed to protect us from foreign invaders.

We still don’t know how HIV leapt into the fabric of human DNA, but the evidence is very strong that it came from other primates. SIV, or simian immunodeficiency virus, has been found in African primates and is highly similar to HIV; it is easy to imagine that blood from infected primates, some of which are butchered for food or kept as pets, found its way into a person's open wound. Once in humans SIV evolved into HIV, transmissible to others through bodily fluids. HIV likely spread around Africa in its early days through the use of shared needles in impoverished hospitals.

It’s a virus world after all

As you can see from these examples, many “new” viruses were actually pre-existing in other animals and just made a “species jump” into humans. But how did these viruses get into the other animals in the first place? That question is a lot harder to answer.

Viruses are little more than a fragment of DNA or RNA, perhaps rogue genes that escaped a cell and became independent, infecting other cells in order to replicate and spread. Richard Dawkins coined the term, “the selfish gene”, and that is a very accurate description of viral DNA/RNA. What we do know is that viruses have been around a long, long time, perhaps before the dawn of life itself. There are even viruses that infect bacteria.

Once inside host cells, viruses replicate quickly, which means they are very adaptable. Their ability to evolve quickly is likely to be a key factor explaining why these selfish genes can make a reproductive factory out of a wide variety of different hosts…and why “new” viruses can appear to spring out of nowhere.

While viruses are a nuisance to us now, they may have been important drivers of evolutionary change in the past. It has been proposed that RNA viruses may have led to the formation of DNA and DNA replication mechanisms, without which we would not even be here to complain about them!

Contributed by:  Bill Sullivan, Ph.D.

Follow Bill on Twitter.

Simpson, D. (1964). Zika virus infection in man Transactions of the Royal Society of Tropical Medicine and Hygiene, 58 (4), 339-348 DOI: 10.1016/0035-9203(64)90201-9


Forterre P (2006). The origin of viruses and their possible roles in major evolutionary transitions. Virus research, 117 (1), 5-16 PMID: 16476498


Koonin EV, Senkevich TG, & Dolja VV (2006). The ancient Virus World and evolution of cells. Biology direct, 1 PMID: 16984643


Baize, S., Pannetier, D., Oestereich, L., Rieger, T., Koivogui, L., Magassouba, N., Soropogui, B., Sow, M., Keïta, S., De Clerck, H., Tiffany, A., Dominguez, G., Loua, M., Traoré, A., Kolié, M., Malano, E., Heleze, E., Bocquin, A., Mély, S., Raoul, H., Caro, V., Cadar, D., Gabriel, M., Pahlmann, M., Tappe, D., Schmidt-Chanasit, J., Impouma, B., Diallo, A., Formenty, P., Van Herp, M., & Günther, S. (2014). Emergence of Zaire Ebola Virus Disease in Guinea New England Journal of Medicine, 371 (15), 1418-1425 DOI: 10.1056/NEJMoa1404505

Everybody’s Free To Wear Sunscreen…And Prevent Skin Cancer

Our last article discussed using sunscreen to help protect skin against damaging UV radiation. When used properly, sunscreen prevents sunburn and sun-induced skin aging, and protects from skin cancer. Studies have shown that sunscreen use reduces the incidence rate of squamous cell carcinoma (SCC) and melanoma, but currently no evidence supports a protective role against basal cell carcinoma (BCC).

While some people, including supermodel Gisele Bundchen, believe sunscreen is dangerous (she declared “I cannot put that poison on my body”) experts such as The Skin Cancer Foundation and the American Academy of Dermatology—and even Cosmopolitan magazine—disagree with her and other skeptics.

A large, randomized controlled trial examined the effect of daily sunscreen use on the development of skin cancers. Researchers followed 1621 Australians from 1992-2006. From 1992-1996, participants were randomly placed in a group and instructed to either use the study-provided broad spectrum SPF 16 sunscreen daily on face, arms, neck and hands, or to continue personal discretionary use of sunscreen. At the 2004 follow up, researchers noted that the daily sunscreen use group had a 35% rate reduction in the incidence of SCC (considering all SCCs that appeared throughout the entire study). However, the incidence of BCC was not statistically different between the two groups. More recent studies corroborate these results.

US Senator and 2008 Republican Presidential Candidate John McCain has had multiple melanomas removed. Other political figures have battled skin cancer, including former Presidents Jimmy Carter (metastatic melanoma) and Bill Clinton (BCC), and former First Lady Laura Bush (SCC).

In 2006, researchers followed up again, this time looking for melanoma. The overall incidence rate of melanoma was 50% less in the sunscreen intervention group than the discretionary use group (out of approximately 800 people in each group, 11 people in sunscreen group and 22 in the control group developed melanoma). It should be noted that these results had borderline statistical significance, with a P value of 0.051 (P = 0.05 is the accepted cutoff for significance). This essentially translates to a 5.1% probability of these findings being due to chance, rather than to the actual sunscreen intervention. Also, there was a 73% lower rate of invasive melanoma in the sunscreen group. Although there was no significant difference in number of melanomas diagnosed at the prescribed intervention sites, it is possible that sunscreen use reduced the risk, as participants in the sunscreen intervention group reported more frequent use of sunscreen over the whole body after the intervention terminated.

Although these results are not the most compelling, they nonetheless point to a protective role of sunscreen. Many factors may contribute to a less than straightforward outcome. First, the sunscreen intervention was in adults and lasted 4.5 years. Melanoma and BCC are thought to result from both long term sun exposure and intense, intermittent episodes (sunburns), whereas SCC is mainly caused by cumulative UV exposure (both natural and indoor tanning bed). Furthermore, blistering childhood sunburns are a risk factor for melanoma. One study that examined sunscreen use in children found a significant protective benefit. Regular use (applied any time sun exposure would exceed 30 min) of a broad-spectrum SPF 30 sunscreen over a 3-year period resulted in significantly fewer newly developed moles, the number of which is a risk factor for melanoma.

Second, participants in the non-sunscreen intervention group continued their discretionary use of sunscreen. No trial in humans could ever prohibit sunscreen use or provide a placebo for ethical reasons. Therefore, perfectly delineating the protective effect of sunscreen is difficult.

Many questionnaire-based studies that rely on participants’ memory of sunscreen use suffer from recall bias. Some of these studies showed no benefit of sunscreen for melanoma prevention but memory limits the reliability of these results. The bottom line is that sunscreen protects from UV radiation, a known human carcinogen.

The skin consists of two layers, the dermis and epidermis. The epidermis contains a variety of cell types, including squamous cells, basal cells and melanocytes. These are the sources for squamous cell carcinoma, basal cell carcinoma and melanoma, respectively.

UV radiation is implicated in up to 90% of nonmelanoma skin cancers, squamous cell carcinoma (SCC) and basal cell carcinoma (BCC). Mutations consistent with UV radiation were also found in the genomes of melanoma tumors; UV radiation is thought to be responsible for the majority of melanoma. Whereas SCC and BCC are more frequent, melanoma is more often fatal. While UV radiation is the single most important risk factor for skin cancer, it’s worth noting that it is not responsible for all skin cancers. Aside from environmental carcinogens, cancer can arise due to a person’s genetics (familial effect) or random mutations.

Acral melanoma is a type of skin cancer not caused by UV radiation and is genetically distinct from UV-induced cutaneous malignant melanoma. Bob Marley’s acral melanoma metastasized and ultimately claimed his life.

UVA radiation primarily damages the components of skin cells by generating reactive oxygen species, or ROS. These highly active molecules can cause single-strand breaks in the DNA or crosslink DNA to protein, resulting in mutations or improper functioning. Both UVA and UVB can cause a more significant type of DNA damage called pyrimidine dimers, where two adjacent pyrimidine nucleotides (the “C” and “T” of DNA; the “A” and “G” are purines) fuse together. Because the higher energy UVB is absorbed directly by DNA, UVB can cause other modifications that compromise the integrity of DNA, leading to instability of the genetic code.

Indeed, the cell has repair mechanisms to fix pyrimidine dimers and other errors, but sometimes the very genes encoding the repair mechanisms are mutated. UV-induced DNA damage can result in highly characteristic mutations in critical genes, for example in the tumor suppressor gene p53. As the “guardian of the genome”, the p53 protein is involved in directing the repair of mutations and guiding the cell through its controlled death pathway, called apoptosis. Mutations in p53 are thought to be among the first steps in development of non-melanoma skin cancer. Formation of malignant melanoma is more complicated and not fully understood.

Yes, p53 has its own superhero persona. That’s how cool (and significant) it is. Image by Susanne Harris.

Cells that carry mutations in p53 proliferate uncontrollably, a hallmark of cancer. In some cases, the immune system will recognize malignant cells as a threat and effectively eliminate them. However, UV radiation is also known to suppress the immune system by at least two mechanisms. One is by diminishing the production of antigen-presenting cells, which engulf foreign-looking cells and display an alert to activate the immune system). The other is by inducing the production of an immune suppressive cytokine, interleukin-10. Additionally, some skin cancer cells display proteins on their surface that prevent the immune cells from killing them. Thus, in addition to mutations in key genes, immune suppression and immune evasion contribute to the development of skin cancer.

Even the mutant Wolverine wears sunscreen! In this Instagram post, Hugh Jackman urged his fans to use sunscreen. He became a fervent sunscreen proponent after having a BCC removed from his nose.

Contributed by: Julia van Rensburg, Ph.D.
Follow Julia on Twitter.

van der Pols JC, Williams GM, Pandeya N, Logan V, & Green AC (2006). Prolonged prevention of squamous cell carcinoma of the skin by regular sunscreen use. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 15 (12), 2546-8 PMID: 17132769

Lee TK, Rivers JK, & Gallagher RP (2005). Site-specific protective effect of broad-spectrum sunscreen on nevus development among white schoolchildren in a randomized trial. Journal of the American Academy of Dermatology, 52 (5), 786-92 PMID: 15858467

Koh HK, Geller AC, Miller DR, Grossbart TA, & Lew RA (1996). Prevention and early detection strategies for melanoma and skin cancer. Current status. Archives of dermatology, 132 (4), 436-43 PMID: 8629848

Leiter U, & Garbe C (2008). Epidemiology of melanoma and nonmelanoma skin cancer--the role of sunlight. Advances in experimental medicine and biology, 624, 89-103 PMID: 18348450

Brenner M, & Hearing VJ (2008). The protective role of melanin against UV damage in human skin. Photochemistry and photobiology, 84 (3), 539-49 PMID: 18435612

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 Avengers: Is It Possible Someone Could Turn Into A Hulk?

"The Avengers: Age of Ultron" has finally arrived, reuniting fans with their favorite superheroes and introducing them to new ones to cheer on, like Quicksilver.  

 

 

Judging from the never-ending string of successful superhero films, it seems safe to say that we're obsessed with champions of justice who harbor extraordinary abilities. No doubt we've shared this fascination with superpowers since the beginning. Some of us are born faster, stronger, smarter - causing the rest of us to wonder whether we can tap into some hidden superpower within ourselves. We love hearing stories of genius and watching talent shows, just to catch a glimpse of someone crossing the threshold of what we thought was the boundary of human capability.

Stanford biologist Sebastian Alvarado is no exception, but he is endeavoring to put some scientific plausibility behind some of our favorite superheroes. Take the Hulk, for instance. The Hulk is the muscular green beast that scrawny scientist Bruce Banner transforms into whenever he gets enraged.

A lot of scientists can identify with Dr. Banner’s plight, and I have seen many undergo an analogous transformation while reading their grant reviews.

 

How did Dr. Banner gain this blessing and curse? As a scientist, he was researching how people summoned these unusual bursts of strength. Using himself as a guinea pig, he exposed himself to gamma radiation in an attempt to become stronger. There was no noticeable effect at first, but when Dr. Banner got angry, his skin turned green and his muscles burst out of his shirt. Since Dr. Banner is a good guy, the Hulk is generally a good beast, although somewhat messy. When the anger subsides, Dr. Banner returns to his modest, wimpy self and heads to the store to buy new clothes.

The comic book tale prompted Dr. Alvarado to wonder:  is this even remotely possible? He addresses the question in the video below.

 

Let’s clarify a few of these points for those who might be less familiar with the concepts. First, gamma radiation blasts your DNA (chromosomes) apart. As Dr. Alvarado mentioned, there are enzymes that will “heal” the DNA, but it doesn’t always heal correctly, which might result in new genes (and the loss of other genes). Second, we are learning more and more that genes are regulated in a surprising number of ways. They are not merely binary switches that turn on and off, but rather they are controlled more like volume knobs. Epigenetics refers to the factors in your cells that have their fingers on those volume knobs.

We discussed epigenetics in a previous article covering Ozzy Osbourne’s genome; in the case of the Hulk, epigenetics provides an attractive means to account for how Dr. Banner can switch between Hulk and normal guy. Between transformations, Dr. Banner’s genes are not changing, but which ones are active – and the degree they are active – is changing. For example, epigenetic factors can crank up genes controlling muscle development when they receive a signal in the form of a stress hormone that increases during temper tantrums. As this hormone subsides, other epigenetic factors return the volume of those genes to their normal level. You can think of genes as the selection of music, but epigenetic factors are the DJs.

 

So what kinds of epigenetic factors are there? We are discovering a dizzying array of cellular components that can alter gene expression, which can result in changes in physical appearance, behavior, mental abilities, and more. It has long been known that chemical modification (i.e. methylation, delivered by enzymes called DNMTs – DNA methyltransferases) of DNA itself can shut down genes. DNA methylation marks are like orange construction cones blocking the highway. Scientists then discovered that histone proteins, which congregate in bundles of 8 to form nucleosomes, could also be chemically modified in several different ways. The nucleosomes give DNA the “beads on a string" appearance shown below.

This is your DNA, not a pearl necklace! The DNA "string" wraps around the "beads", which are nucleosomes composed of 8 histone proteins. Once thought to merely help package DNA, we now know these nucleosomes are major contributors to the regulation of genes on the DNA.

These proteins were long thought to be just scaffolding components for the DNA, but now we know they play a major role in directing the activity level of nearby genes. Numerous chemical modifications, such as acetylation, methylation, phosphorylation (and more), can take place on multiple places of each histone protein. These may alter the binding between nucleosomes and DNA, making certain genes more accessible, or these modifications may form a cellular “code” that can affect gene expression levels.

Histones can also be moved, replaced, or evicted by epigenetic factors called SWI/SNF ATPases. As the name implies, these enzymes require energy from ATP to affect gene expression. More recently, it has also been found that small non-coding RNA molecules can regulate genes.

A summary of the major epigenetic factors that can regulate the "volume" of gene expression.

While these complex methods a cell employs to influence gene expression offer a potential explanation for how someone could temporarily become a Hulk, it is by no means probable. Most massive gamma radiation doses would destroy genes that are essential to survival. But it is fun to use cutting-edge science to put just a tiny hint of credence behind the superpowers. And even more fun to think that with enough knowledge we may be able to modulate epigenetic factors to treat disease or maximize human potential.

Contributed by:  Bill Sullivan

Follow Bill on Twitter.

Falkenberg KJ, & Johnstone RW (2014). Histone deacetylases and their inhibitors in cancer, neurological diseases and immune disorders. Nature reviews. Drug discovery PMID: 25131830

Haggarty P, Hoad G, Harris SE, Starr JM, Fox HC, Deary IJ, & Whalley LJ (2010). Human intelligence and polymorphisms in the DNA methyltransferase genes involved in epigenetic marking. PloS one, 5 (6) PMID: 20593030

2-7 Offsuit: Is Cancer Just "Bad Luck"?

There are many forms of cancer that ravage the body, but the key feature they share is uncontrolled cell growth. Virtually any cell type can suddenly go rogue and start reproducing itself again and again – this is what we call a tumor. Some of these rogue cells venture to other parts of the body where they don’t belong and establish a new colony there – this is called metastasis. As cancerous tumors grow and spread around, they can do a number of things that endanger the life of the patient, such as interfere with organ function and steal nutrients from other cells or tissues.



This cartoon illustrates a general model for the development of cancer. A "benign" tumor is not considered cancerous because they do not invade other parts of the body. In contrast, "malignant" tumors, like that ugly looking thing above, are cancerous because they invade nearby tissues. If cells from a malignant tumor get into the bloodstream, they can establish life-threatening satellite tumors elsewhere in the body, making them all the more challenging to eliminate.

Cancer is caused by a change, or mutation, in one of our cell’s DNA. Our DNA contains tens of thousands of genes that encode proteins that make our cells tick. Some of these proteins regulate cell division, but they are normally shut off after the job is done. A mutation that turns one (or more) of these regulatory proteins back on can turn that cell into a Xerox machine stuck on "copy". Since there are so many different types of genes that can mutate in a wide variety of cell types, a “one size fits all” cure is very difficult to conceive.

Scientists (and many pseudoscientists) have long been trying to identify things in our environment that cause mutations that lead to cancer. Others have argued that cancer is just “bad luck” and that our genes play a larger role. This is important to sort out:  should we invest more money to identify potential carcinogens in the environment or to find ways to repair “bad” genes?

Every now and then, someone gets lung cancer who never took a single puff on a cigarette. Why? To understand the answer, consider poker. You can study dozens of books on how to play to win, practice for 10,000 hours, pay hundreds of dollars to learn all the secrets from the professional players. But none of this will help you if the dealer gives you junk cards. To look at this another way, there are some people who start chain smoking at twelve and live to be 90 with no trace of cancer (perhaps breathing through a tube in their throat, but no cancer). That’s like a rookie at the poker table being dealt a straight flush. Long story short:  cancer is not always the patient’s fault, and a lack of cancer is not always indicative of a healthy lifestyle.

In Texas Hold’em poker, you begin with just two cards. Being dealt a 2 and 7, offsuit, is considered the worst possible hand you can get. In contrast, being dealt two aces is one of the best starting hands. The genes that combined to form your DNA are analogous to the cards you would be dealt at a poker table. Unlike the poker game, though, you can’t win by bluffing.

Researchers have found plenty of environmental agents that can mutate DNA. For example, exposure to UV radiation is one of the more notorious risk factors for skin cancer. But there are a few people who worship the sun and never get skin cancer. In addition, most children have not had extensive exposure to environmental carcinogens, yet, tragically, they can still get cancer. In 2014, it was estimated that 15,780 children and adolescents ages 0 to 19 years would be diagnosed with cancer and nearly 2,000 would not survive. Facts such as these support the notion that cancer is largely due to bad genes, not necessarily the environment.

Scientists at Johns Hopkins recently set out to tackle the question by constructing mathematical models of the disease. Their findings might take you by surprise:  in the majority of cases, the reason why a cell starts running all the red lights is due to a random mutation that occurs during cell division. In other words, lifestyle choices and even your genetic makeup play a lesser role in your chances in getting cancer. Let that sink in for a moment: RANDOM mutation - not mutation caused by UV light, engine exhaust, or some other carcinogen. Since the mutation appears to be a random mistake made by cell division enzymes, the authors dubbed this "bad luck".

DNA replication is a complex process in which the two strands are separated and used as a template to make a complementary second strand. But replication enzymes are not perfect (if they were, there'd be no evolution) and sometimes insert the wrong DNA base, causing a mutation.

 

This new study reminds us that every cell division contains an inherent risk that the daughter cell acquires a mutation that makes it divide like gangbusters. This doesn’t mean you should grab a carton of Marlboros to smoke as you suntan on the beach while devouring a couple extra-charred burgers for lunch.

Highlighted in this study was the finding that not all cell types give rise to cancer equally. Not surprisingly, tissues with a higher number of stem cell divisions are more prone to cancer, which explains why we don’t hear a lot about duodenum cancer. Importantly, the researchers identified several types of cancer that are influenced more by our lifestyle choices or inherited mutations: colon cancer, basal cell carcinoma, and lung cancer.

The findings essentially assert that since cells divide they are veritable time bombs. Somewhere down the line a mistake is going to happen regardless of environmental insults, and if that mistake occurs in the wrong gene, cancer can ensue. These are noncontroversial statements and not news to most people. However, the idea that "most" cancers are due to "bad luck" is a more controversial conclusion. A major limitation is that the model did not incorporate some of the most common cancers, such as breast and prostate cancer, because the frequency of stem cell divisions is unclear. Readers would be wise to check out this article by David Gorski at Science-Based Medicine, which provides detailed insight into the strengths and weaknesses of the experimental design. The World Health Organization was so opposed to the message this study sends that they issued a press release critical of the study.



Obi-Wan (Ben) Kenobi famously said, “In my experience, there’s no such thing as luck.” Some scientists who take issue with the Hopkins study would agree with Ben. 

 

At the end of the day, since we don’t yet know how all genes operate, much less which ones you might have in your DNA, it is wise to take common sense steps to minimize your exposure to known carcinogens and take advantage of tests designed to detect cancer at its earliest stage. Bad luck may be a major factor in cancer, but there are plenty of simple lifestyle changes you can make to try and beat the odds.

Contributed by: Bill Sullivan

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Tomasetti, C., & Vogelstein, B. (2015). Variation in cancer risk among tissues can be explained by the number of stem cell divisions Science, 347 (6217), 78-81 DOI: 10.1126/science.1260825

Ward E, DeSantis C, Robbins A, Kohler B, & Jemal A (2014). Childhood and adolescent cancer statistics, 2014. CA: a cancer journal for clinicians, 64 (2), 83-103 PMID: 24488779