Tag Archives: biology

Transforming Tasmanian Devils: Potential Uses for Synthetic Biology in Conservation

Can we use biotechnology to save Tasmanian devils from extinction? [image source]

Can we use biotechnology to save Tasmanian devils from extinction? [image source]

Last post, I talked about the facial cancer that’s wiping our Tasmanian devils. We understand the problem fairly well – the facial cancer spreads unchecked among the devil population because devils have very similar MHCs, the cellular “flags” that allow your immune system to tell whether a cell is your own or a foreign invader. When the devils fight, cancer cells can get transferred from an infected devil to the face of an uninfected devil. Because of their similar MHCs, the immune system doesn’t recognize the invader and the cancer easily takes root. Since MHC similarity is the root of the problem, introducing MHC diversity might be the solution. What if scientists could create Tasmanian devils with different MHC complexes and introduce them back into the population? These different devils would be immune to the face cancer. In addition, devils born from a match between a Devil 2.0 and an original model would have a mix of their parent’s MHC complexes, creating even more variation. This is all assuming we could make a Tasmanian devil with new MHCs in the first place, something we may be able to do in the near future thanks to advances in genetic engineering and “cloning” technology.


Adding MHC Varaiation to the DNA

The first step is to code new MHC sequences into the devil genome. You could design new devil MHC sequences, or search for DNA samples from devils with different or less common MHC groups. Once you have these sequences, you have to insert them into the right place. Early genetic engineering suffered from the problem of poorly targeted gene insertion. Using viruses, scientists could handily integrate new genes into the genome; however, if the insertion site of these genes isn’t tightly controlled, they can disrupt essential native genes or turn on nearby a cancer-causing genes (aka oncogenes). In a gene therapy trial to treat severe combined immunodeficiency, gene insertion near an oncogene led to leukemia in some of the trial participants.

Viral gene therapy hijacks the ability of viruses to insert their genes into the genomes of their infected host. Scientists replace the viruses genes with the ones they want to insert instead [image source]

Viral gene therapy hijacks the ability of viruses to insert their genes into the genomes of their infected host. Scientists replace the viruses genes with the ones they want to insert instead [image source]

Genetic engineering today is a different story. Scientists have gotten very good at inserting DNA at specific locations in the genome. They use special proteins (or sometimes even RNA) that can target specific sequences in the genome, and then insert the new DNA between those sequences. Recently, these new genetic engineering techniques made headlines when scientists used them to create immune cells (T-cells) that can take out leukemia cancer cells. The therapy is currently in clinical trials. This same technology could be used to add new MHC sequences to a Tasmanian devil genome.

From new devil genome to new devil pups

Okay, so now we have a collection of altered devil cells. How do we turn these cells into an actual Tasmanian devil? The classic technique to turn an isolated cell into a whole organism is somatic cell nuclear transfer (SCNT), the cloning technique that was used to create Dolly the sheep. SCNT combines two cells by replacing the nucleus of a fertilized donor egg with the nucleus of a cell from the animal you want to clone. The word somatic refers to the fact that the non-egg nucleus comes from a non-reproductive body cell (e.g. skin, liver, fat), which are called somatic cells.   

The nucleus contains the genetic blueprints that tell the egg what animal it should become, and the cytoplasm of the egg (everything outside the nucleus) contains the cellular construction workers and machinery who will translate those blueprints into an animal. By taking out the donor egg nucleus and putting in a new one, you are swapping the egg blueprints for the blueprints of whatever your new nucleus came from. After implanting this altered egg in a surrogate mother, (if nothing goes wrong during gestation) you’ll get a new baby based off the inserted nucleus.

A schematic of SCNT, as used to create Dolly the sheep. [image source]

A schematic of SCNT, as used to create Dolly the sheep. [image source]

However, there are significant problems with SCNT. DNA is packaged differently in body cells compared to egg and sperm cells – it’s modified to make sure only the genes that relate to that cell’s function are activated. These modifications are what make a skin cell a skin cell and not a liver cell. In addition, DNA ages as you do. Mutations build up and protective “caps” on the end of the DNA molecule wear down with every cell replication. These modifications can cause improper fetal development or health problems later on.

One way to get around the problems of SCNT may be to create egg and sperm cells from body cells. Cells inside early embryos are blank slates, and can become any of the specialized cells in your body (e.g. bone, skin, and pancreas). Using genetic engineering, scientists can take these specialized cells and turn them back into embryonic-like blank slates called induced pluripotent stem cells (iPSCs). IPSCs can be theoretically reporgrammed into any specialized cell cell in the body – neurons, pancreatic beta cells, and white blood cells have all been produced from iPSCs in the lab.

To create iPSCs, scientist expose normal body cells to special factors that turn the body cells into blank-slate embryonic-like cells. These iPSCs can then be differentiated into your specialized cell of choice. [image source]
To create iPSCs, scientist expose normal body cells to special factors that turn the body cells into blank-slate embryonic-like cells. These iPSCs can then be differentiated into your specialized cell of choice. [image source]

More importantly to reproductive biology, viable sperm and egg cells have already been made from mouse iPSCs. Fertilized eggs made with these lab-generated sperm or egg cells successfully became healthy baby mice. Although iPSC techniques are still in their nascent stages, it’s very possible that they could one day be used to turn MHC-altered Tasmanian devil cells into Tasmanian devil pups.

De-extinction and pre-extinction

The focus at TEDx DeExtinction was on how these technologies could be used to bring back extinct species. For example, Dr. Alberto Fernández-Arias semi-successfully used SCNT to create a baby Pyrinian Ibex: the ibex made it through pregnancy fine, but died several minutes after birth due to a lung defect.  Synthetic biology techniques have great potential for conservation (or “pre-extinction”) efforts as well. Before their population was culled by face cancer, Tasmanian devils were in no danger of extinction. If scientists could create a more varied devil population that wasn’t susceptible to the cancer, the devils could likely thrive again. However, careful breeding and monitoring would have to be used to prevent another genetic bottleneck. You don’t want to replace the original devil population with a similarly stunted genetic sampling. Synthetic biologists and conservationists would have to work together to create a varied and resilient devil population.

De-extinction and pre-extinction scientists could cooperate to create an overall healthier Tasmanian ecosystem, one that might prevent future facial cancer outbreaks among the devils. Dr. Michael Archer, who is trying to bring back the thylacine (or “Tasmanian tiger”) recently, discussed this possibility on NPR’s Science Friday. Archer talked about how losing the thylacine disrupted the ecosystem balance and allowed the devils to overpopulate:

“If we could get the Thylacine back, put that king of beasts back in the throne, which is still warm and waiting, it would suppress the number of devils, keep them at a manageable level and the disease would burn itself out wherever it started. So getting these ecosystems back by putting in key species can be critical to maintaining the stability of them.”

Even if the thylacine never returns, de-extinction advances could be used to keep Tasmanain devils from a similar fate. The World Wildlife Federation estimates that over 10,000 species go extinct every year, and many of these extinctions are caused by humans. In the wake of this devastation, we must save every species we can, and de-extinction driven synthetic biology can give us new means to preserve species like the devils.

After all, who would want to lose a face like this one?

Sympathy for the Devils

This work by Mike Lehmann is licensed under a Creative Commons Attribution 3.0 Unported License.

Tasmanian devil, a marsupial native to the Australian island of Tasmania
[This work by Mike Lehmann is licensed under a Creative Commons Attribution-Share Alike 3.0 Unported License.]

Last week, I was lucky enough to attend the TedX DeExtinction event in Washington, DC. The event, hosted by National Geographic and Revive & Restore, was a day long series of short talks about the science and ethics of “de-extinction.” De-extinction is the idea that you can use new reproductive and stem cell biology techniques to revive extinct species, from the recently disappeared (e.g. bucardos and gastric brooding frogs) to the long lost (e.g. wooly mammoths  and giant ground sloths). The event raised quite a few questions on the ramifications of bringing species back from the dead: would de-extinction take funding away from conservation efforts? Would a de-extinct mammoth really be a mammoth? Would there even be a place for these new old species in our changing world? Is de-extinction, like the moon landing, a vehicle to inspire scientific wonder and progress?

We can (and should) argue about the ethics and reasons for reviving lost species, but we should also explore how to use synthetic biology to save dwindling species from imminent extinction. Take for example, the Tasmanian devil. Though these large marsupials were once common across Tasmania, their population has been devastated by a strange form of contagious facial cancer.

In the late 1990’s, facial tumors were spotted on devils in northeastern Tasmania. The cancer was deadly, killing the animals it infected within six months. More importantly, the cancer jumped from devil to devil with ease by taking advantage of the species’ aggressive nature: when Tasmanian devils fight (which they often do), cancer cells can be transferred from the teeth of an infected devil to the face of their uninfected sparring partner. The facial cancer has caused a 90% drop in devil population since it appeared, and total extinction of the species within 30 years is a distinct possibility.

This work by Menna Jones is licensed under a Creative Commons Attribution 2.5 Generic License.

Tasmanian devil face tumors
[This work by Menna Jones is licensed under a Creative Commons Attribution 2.5 Generic License.]

Transmissible cancer isn’t unheard of. Dogs can pass on a form of venereal cancer, and there’s a contagious sarcoma that affects Syrian hamsters. Cancer transmission has also been known to happen in humans after organ transplants or by passing between mother and fetus. However, in most animals, the immune system recognizes and destroys foreign cells (cancerous or otherwise). In fact, this is one of the main hurdles with organ transplants. Recipients have to take immunosuppressive drugs and in some instances immune system reactivity leads to organ rejection. In the case of Tasmanian devils, however, this immune hurdle doesn’t exist.

Immune system recognition of “self” and “other” relies on molecules on the surface of the cell called major histocompatibility complexes (MHCs). MHCs act as signaling flags to the immune system, telling your immune cells whether a cell is normal, infected with a pathogen, cancerous, or an invader. There are two main classes of these molecules, and each one has regions that vary among members of the population. Variation in MHC molecules allow immune cell to differentiate your cells from other cells, kind of like knowing members of your sports team because you all wear the same jersey. Human MHC class I molecules have six sites where they can vary, and hundreds of variations available for most sites.

Tasmanian devils, on the other hand, have very little population diversity in MHCs. At some point in the past, the devils experienced what’s known a genetic bottleneck. A large portion of the population was killed (cause unknown), leaving only a small gene pool, and thus a small sampling of MHC variations.

Tasmanian devil MHC complexes are so similar that their bodies can’t  tell the difference between their own cells and those of other devils. Every team’s jersey is so similar that it’s hard to know who’s on the home team and who’s the visitor. So when cancer cells from an infected devil latch onto an uninfected devil, they go undetected by the immune system and spread unhindered. Genetic studies of the cancer have shown that the DNA of tumor cells is extraordinarily similar across the infected devil population. Furthermore, the tumor DNA is significantly different from the infected devil’s DNA. These facts point to a tumor that arose in one devil and spread as a tissue graft to other devils through bites. Because of their lack of immune diversity, the Tasmanian devil population is being wiped out by one giant tumor run amok.

What can we do to stop the eradication of Tasmanian devils? Synthetic biology may have the answers. Developing technology may allow scientists to create Tasmanian devils with more MHC diversity, devils with immune systems that would spot and destroy the invading cancer cells before they took root. In my next blog post, I’ll talk about the discoveries and technology that could save the Tasmanian devil, and other species that are near (or already) extinct.


How can we save these guys? Tune in next time to see!
[This work by KeresH is licensed under a Creative Commons Attribution-Share Alike 3.0 Unported License.]


O’Neill, Iain. “Tasmanian devil facial tumor disease: Insights into reduced tumor surveillance from an unusual malignancy.” International Journal of Cancer. 127.7 (2010): 1637-1642.

 Siddle, Hannah et al. “Transmission of a fatal clonal tumor by biting occurs due to depleted MHC diversity in a threatened carnivorous marsupial.” PNAS. 104.41 (2007): 16221-16226.

Siddle, Hannah et al. “MHC gene copy number variation in Tasmanian devils: implications for the spread of a contagious cancer.” Proceedings of the Royal Society: Biology. 277.1690 (2010): 2001-2006.

Woods, Gregory et al. “The Immune Response of the Tasmanian Devil & Devil Facial Tumour Disease.” EcoHealth. 4.3 (2007): 338-345.

Sequestration: Much Better in Nature Than in Congress

“You are what you eat” has become a cliché spouted by parents and diet gurus alike. Of course, while most of us might feel a bit sick after eating all the leftover Halloween candy, we’re not going to turn the yellow of Lemon Heads or start oozing chocolate out of our skin glands. For some members the animal world, however, diet is important for more than nutrients and energy. In fact, many species depend on their food to give them the colors, poison, and unearthly glow for which we know them best. Here are four animals for which “you are what you eat” is a fact of life:


The golden poison dart frog. The size of a paper-clip but toxic enough that one frog has enough poison to kill 2 elephants. [image source]

The golden poison dart frog is only as big as a jumbo paper-clip, but so deadly that one frog contains enough poison to kill two elephants. [image source]

1.  The golden poison dart frog goes by the scientific name P. terriblis with good reason. It may be the most poisonous animal in the world – terrible indeed for would-be predators. Despite their diminutive size (up to 55 millimeters long, about two US quarters placed side by side), golden poison dart frogs pack quite a punch. One frog carries enough poison to kill ten to twenty humans. However, unlike many other poisonous animals, golden poison dart frogs outsource their poison production. The frogs isolate and concentrate alkaloid batrachotoxins from the bugs that they eat, a process called sequestration. During digestion, batrachotoxin is shuttled from the frogs’ gut to special skin glands, where it becomes a key ingredient in the deadly slime that coats their skin. Concentrating the poisonous chemicals in their food is a common thread with all poison dart frogs, but P. terriblis’s use of batrachotoxin in particular is what makes it especially deadly. Frogs kept in captivity will lose their toxicity, since their new diet doesn’t usually include the alkaloid-rich bugs crucial to toxin production.

Frogs aren’t the only animal that uses the capture-and-concentrate tactic for making poisons. For example, the monarch caterpillar is also poisonous because of an alkaloid-rich diet (in this case, the leaves of the milkweed plant). Some of this toxin carries over to the adult butterfly, making it an unpleasant meal for predators.  There are even several species of birds in Papua New Guinea that use the same strategy, appropriating insect alkaloid toxin and storing it in their skin and feathers.



Flamingos and many other birds get bright colors by sequestering pigments from their food [image source]

Flamingos and many other birds get bright colors by sequestering pigments from their food [image source]

2. Sometimes an animal’s signature color comes from what it eats – flamingos owe their lovely pink-red hue to a class of pigments called carotenoids. Carotenoids are first produced by plants (beta-carotene is what gives carrots their orange color). Flamingos get their carotenoids from the plankton, algae, and brine shrimp they eat. In fact, a lot of the color variation across flamingo species comes from their food source. Flamingos that feed on carotenoid-producing algae directly are a darker hue than those that get their carotenoids through a second-hand source (like eating shrimp that eat algae). Without this dietary infusion of color, flamingos would be a dull gray or white. Flamingo coloring is a big concern in zoos and aquaria, where the birds don’t get all the carotenoids they would in the wild. To keep their animals more naturally colored (and attractive to visitors), zookeepers may feed them extra prawns or sprinkle their food with a concentrated carotenoid additive.

Scarlet tanager males and females are both colored by carotenoids [image source: male female]

Scarlet tanager males and females are both colored by carotenoids [image source: male female]

Carotenoid-derived coloring is not uncommon, especially among birds. The red plumage of scarlet ibises and cardinals and the pink bellies of salmon all owe their distinctive color to a diet high in the pigment. Scarlet tanager males are turned (you guessed it) scarlet by a high-carotenoid diet, while the females are an olive-green from the interaction of carotene and another pigment, melanin.



Nudibranch sea slugs steal both color and poison from their food [image source]

Nudibranch sea slugs steal both color and poison from their food [image source]

3. Members of the nudibranch sea slug family scavenge both color and toxins from their prey. Among the family are some of the most brightly colored denizens of the ocean – and that’s saying a lot for since nudibranchs make their home in the kaleidoscopic world of coral reefs. These slugs dine on other invertebrates like baby jellyfish, coral polyps, anenomes, and even other sea slugs. Nudibranchs can sequester pigments from their prey and then display them on their own skin, creating a colorful pattern well matched to their environment. Among the brilliant background of a coral reef, the nudibranchs’ rainbow hues are the perfect camouflage.

Considering the fact that many nudibranchs can also recycle more active defense mechanisms, their bright skin is also warning to predators. Nudibranchs that feed on jellyfish can steal their prey’s special stinging cells (nematocysts). The nematocysts travel harmlessly through the slug’s digestive tract and are transported to their back, where the nematocysts begin their new life as a slug defense mechanism. And like poisonous dart frogs, certain nudibranchs concentrate toxins from the sponges they eat to make their own poisonous brew. 



Aequorea Victoria jellies need to eat fluorescent food to flow [image source]

Aequorea Victoria jellies need to eat fluorescent food to flow [image source]

4. Aequorea victoria jellyfish, like many other bioluminescent animals, glow a soft fluorescent blue and green thanks to a chemical cascade taking place inside their clear flesh. This species of jellyfish holds a special place in the hearts of many biologists, who use the jelly’s green fluorescent protein (GFP) in everything from imaging to genetic engineering. In fact, the discovery and development of GFP as a tool won several scientists a Nobel Prize in 2008.

For all the glory given to GFP, it’s not actually the piece of the cascade that supplies the jellyfish their glow. GFP simply takes the light from another molecule, coelenterazine, and shifts it from blue to green. Coelenterazine is a type of luciferin, a light-emitting molecule. During the light-producing chemical cascade, coelenterazine is energized to an excited state by the enzyme luciferase. Coelenterazine then returns to an unexcited state by releasing energy in the form of light.


A simplified version of the light-producing cascade in A. victoria jellies

Scientists in the lab have to externally supply coelenterazine to their specimens for them to glow; as it turns out, the A. victoria jellies have to import coelenterazine as well. A. victoria at the Monterey Bay aquarium slowly lost their ability to glow, but when the jellies were fed a diet of bioluminescent plankton, they lit right back up. The luciferase enzyme part of the bioluminescence cascade is coded into the jellyfishes’ DNA. However, they need to scavenge the actual light source from already glowing prey – like having to steal a bulb from a neighbor every time you wanted to turn on your lamp.

What goes munch in the night?

A historical reenactment of a night eating rampage. Ice cream, chips, and granola bars are my typical fodder.

Food goes mysteriously missing in my house all the time. Cookies and cupcakes don’t last more than a few days, and forget keeping anything chocolate around. The latest casualty was a Costco-sized bag of tortilla chips. The evidence of their demise is scattered around the kitchen in the morning, and on more than one occasion, I have woken surrounded by granola bar wrappers and with chocolate on my face. Despite my best intentions and strictest diet plans, I am undone by the monster that emerges while I sleep. Sleep-me devoured my husband’s birthday cake – by the time I realized what I was doing only one scant piece remained. Sleep eating beleaguers a fair number of people, ranging from total wakefulness and recall (that late night cookie binge I berate myself over even as it’s happening) to waking up in the morning surrounded by chocolate wrappers with no idea what happened. Two different disorders flank each end of the spectrum: sleep related eating disorder and night eating syndrome. Both are chronic, lasting months to years, and often coincide with weight gain obesity.

On the unaware while eating side of the spectrum, you have sleep-related eating disorder (SRED). Patients generally can’t remember their episodes of night bingeing and, like sleepwalkers, are mostly unconscious during the event (my husband calls these episodes “werewolfing”). Other sleep disorders, like sleepwalking, obstructive sleep apnea, and restless leg syndrome, are often present alongside SRED. SRED patients consume food normally during the day, but are driven from their beds at night by an involuntary urge to eat. They make their way to the kitchen where, all while mostly unconscious, they binge on high calorie, high carbohydrate food like peanut butter, bread, and ice cream. They may even prepare an entire meal while asleep – obviously not the safest task with clumsy, sleepy fingers. SRED patients have also been known to eat inedible, toxic, or just plain weird things like soap, raw pasta, coffee grounds, or cat food.

Night eating syndrome (NES) patients, in contrast, are mostly awake during their episodes and can remember them come morning. NES was first brought to light in 1955, in patients with treatment-resistant obesity. It’s is characterized by eating a significant number of calories between dinner and sleeping (at least 25%), waking in the night to eat compulsively, and decreased hunger in the morning. Interestingly, one of the theories explaining NES is a disconnect in sleeping/waking and eating patterns. One study found NES patients had the same caloric intake and bedtime as controls, but their meal times were delayed. Animal studies that disconnected genes controlling sleeping/waking and eating found similar symptoms to NES.

Your sleep/wake and eating cycle are circadian rhythms – physical, mental, and behavioral changes that follow a 24 hour cycle. A short quiz from Phillips.com shows my circadian rhythms are slightly delayed from the norm 

Sleep eating behavior rarely falls neatly into one of these two disorders. It’s a spectrum – patients can have episodes ranging anywhere between full consciousness and sleep – making studying and treating the problem complicated. Night eating disorders do have a lot in common, though. SRED and NES are both found more often in obese populations. Whether sleep eating causes obesity or not is still up for debate, but it certainly make it harder to lose weight (as I can attest). NES also associates strongly with depression or anxiety. Both disorders have a genetic component and can be passed down in families.

Doctors treating a suspected sleep eater (wherever they lie on the spectrum) start by giving the patient a special questionnaire addressing hunger, caloric intake, familial history, sleep habits, and how long the problem has been going on. The doctor can confirm the diagnosis by performing a sleep study. Patients bring in foods they’d normally consume at night to a sleep lab, and their wakefulness and eating habits are monitored overnight. Both disorders can be treated with serotonin modulation, like taking SSRIs (commonly prescribed for anxiety and depression). Serotonin acts on the hypothalamus, which controls sleeping/waking cycles and feeding behavior. The effectiveness of serotonin modulating drugs also ties back to the high carb intake of sleep eaters – high carb food items increase the availability of tryptophan, which the body converts into serotonin. Sleep eaters might eat high carb foods because their serotonin levels are low. Topiramate, an anti-seizure medication that causes appetite reduction, can also be used to treat NES and SRED. However, topiramate comes with its share of unpleasant side effects, including dizziness, headache, nausea, and skin numbness or tingling. SRED is often successfully treated by addressing any other sleep disorders the patient may have (excluding sleepwalking) or discontinuing any drugs that induce night eating as a side effect. Sedatives, unfortunately, can often exacerbate night eating, especially in NES cases.

My most successful treatment strategy is a combination of avoidance and food stashing. I’m (mostly) vegan during my waking hours, but if there’s ice cream in the house when I go to sleep it will be gone by the morning. When I buy snacks for my friends, I have to make them take home the leftovers or buy things I won’t be tempted by. Luckily, my sleep eating self is vegetarian and hates yogurt cluster cereal. The food I can’t live without, I have my husband hide. Somewhere in my house is a host of gourmet dark chocolate bars, safe from my nocturnal rampages. Life’s a little more boring without being able to keep cinnamon toast crunch and gelato in the house, but at least I can wake up in the morning to minimal food casualties.

Sources/further reading:
Howell, Shenk, and Crow – “A review of nightime eating disorders”
Sleep Medicine Reviews (2009) 13, 23e34

Winkelman, Johnson and Richards – “Sleep related eating disorder”
Handbook of Clinical Neurology (2011), Vol. 98 (3rd series)

Circadian Rhythms Quiz