Toxic and toothsome: a tale of two wild Asteraceae

Toxic Interloper:

Not long ago, I planted a bunch of coriander/cilantro seeds in my back yard.  When the seedlings emerged, I found not only cilantro, but also this:

Not cilantro as it should have been, but common groundsel. Don’t try to fool me with your toothed leaves–I can totally see you’re sending up flower buds already.

Senecio vulgaris, known as common groundsel to me, but also as Old-man-of-the-spring. It’s just about everywhere right now–I’m seeing it along roadsides, in gardens, at the park and clawing its way through sidewalk tiles.  It starts off with lobed leaves and an emerging crown of flower buds that’s visible really early, and ends up with nearly-closed yellow flowers, and fuzzy gray seed heads like tiny dandelions (whence the “Old man” name–it looks a bit like a tousled gray head of hair).

Of wild carrots and the death of Socrates

There is a plant I keep encountering, both on foraging trips and while out running, and for a long time I had been entertaining the hope that it was wild carrot (Daucus carota), while secretly suspecting that it was actually poison hemlock (Conium maculatum).  These two members of the Apiaceae/Umbelliferae family look very similar as young plants (and both are sometimes called Queen Anne’s lace), but armed with Samuel Thayer’s “Nature’s Garden” on our recent Redwood Park foraging trip, I was able to pin down once and for all that…dammit, yes: it’s hemlock.

Poison hemlock, Conium maculatum. Not the wild carrot I was hoping for. Photo courtesy of Jen at willblogforfood.

The Apiaceae are a fickle lot of plants: some are friendly foodstuffs (carrot, fennel, celery, parsley, caraway), some are vicious poisons (poison hemlock, water hemlock, fool’s parsley), and some are something in between (like cow parsnip, which is edible but whose sap can be a strong irritant).  Several of them look similar as young plants, too, with rosettes of feathery leaves and umbels of delicate white flowers.

Caraway, Carum carvi. If I hadn’t read the title, I might have thought it was fennel, because all these darn Apiaceae look similar. From Koehler’s Medizinal Pflanzen.

Over the centuries, many people have been poisoned by mixing them up.  A handful of case studies from the last decade of folks who ate a variety of toxic Apiaceae can be found  here, here, here, and here.  For those who forage, wild wood survival offers a sturdy guide to telling tasty wild carrot from its toxic doppleganger.  (Quick and dirty version: hemlock has smooth stems, sometimes speckled purple or with a chalky residue.  It doesn’t smell very good, and its flowers are loosely packed in umbels, like caraway, above.  Wild carrot has fuzzy stems, smells strongly of carrot, and has tightly-packed umbels of flowers with one dark purple flower in the middle.  And if you’re in doubt, don’t eat it!)

Wild carrot, Daucus carota. Similar enough to C. maculatum to give you pause, and make you wish you’d brought some store-bought carrot leaves along for comparison. Photo from Gunther Blaich’s website.

And then, of course, there are the more sinister, deliberate poisonings.

These pink elephants are caused by what part of the absinthe, exactly?

Back in 2002 I went to Prague, where I was able to legally sample that storied vice of brooding 19th-century artists, absinthe.  The preferred method of preparation was to pour some of the liquor into a large spoon, add a pinch of sugar, and heat it over a candle flame until the sugar dissolved.  It was a ritual that added to the sense of participating in a dangerous, clandestine tradition, and coupled with the pre-Industrial-era architecture and cobblestone streets, I would leave the pub fully expecting to run into a Van Gogh-like figure, or at least hallucinate one.

"The absinthe drinker" being visited by the green fairy. By Czech painter Viktor Oliva, 1901.

Somewhat disappointingly, I never hallucinated any depressive one-eared artists.  Or anything else for that matter.  In fact, despite the 120-proof alcohol content, I only got modestly tipsy, thanks to the absinthe’s bitter, anise-y flavor (the origin for the word “absinthe” is likely the Greek apsinthion, which means “undrinkable”).  The one time I followed the absinthe up with a couple glasses of red wine, I did end up with a headache that might have inspired some gruesomely morbid poetry, but I wasn’t feeling moved by a creative impulse so much as by the impulse to find out what had happened to my Advil over the course of 3 flights and two layovers.

Fast forward to this past St. Patrick’s Day, when my friends brought over a bottle of appropriately green absinthe made and sold just a few miles away at our local distillery, St. George’s.  While the mystique was not so pronounced in my living room as it had been in a Czech pub, the product was definitely the same: the bottle confidently proclaimed that it contained extracts from wormwood (Artemisia absinthium, the plant that gives absinthe its distinctive flavor and color).  Ten years ago, I had to go to Europe for this stuff.  Why is it legal here now?

Why “Natural” isn’t always better: almond extract and cyanide

Right now the various species of Prunus are in flower all over northern California; the ornamental plums that are so popular as sidewalk decor are shedding petals everywhere, apricot blossoms are peeking out from yards, and the almond trees that crop up as renegades from the big orchards near Davis and in the central valley are covered in popcorn-y pinkish white flowers.  With constant reminders of stone fruit everywhere but none actually in season to eat, I’ve been doing a lot of baking with almonds and almond extract.

A sprinkling of wild plum blossoms (Prunus americana) on my way to lab.

Prettiest Plant in the Lab: Foxgloves, Digoxin, and Digoxigenin

A while ago I posted about oleander and the structural similarities between the oleander cardiac glycoside oleandrin and the foxglove cardiac glycoside digoxin.   But foxgloves express enough biologically useful (and harmful) molecules that they’re worth showcasing.  Plus they’re such nice eye-candy!

Gloves that pack a punch

The various members of the Digitalis genus, which include the gardener’s favorite foxglove Digitalis purpurea and a range of other Digitalis species, are favored ornamental plants for their tall showy flower spikes and bright colors.  A disputed but appealing origin for the name was advanced by William Henry Fox Talbot, who proposed that the whimsical ye Olde English people imagined fairies wearing the deep cone-shaped flowers for gloves, and called them folks’ gloves.  Very cute.  But given that fairies were famous not only for being adorable but also for other light-hearted mischiefs like stealing babies and poisoning livestock, it’s perhaps fitting that their pleasing-to-look-at gloves come barbed with a heavy dose of serious poison.

Enough folk's gloves for a children's book full of fairies. Digitalis purpurea, by Ferdinand Bauer.

Foxgloves are poisonous because they contain two cardiac glycosides, digoxin and digitoxin, which are found in all parts of the foxglove plant but are most concentrated in the leaves.  There are a few ways to poison yourself with foxgloves by mistake: the flowers have some appealing similarities to honeysuckle, which might lead the unwary to try to suck nectar from them.  Because the plant is still poisonous when dry, a hapless gardener might inadvertently inhale foxglove plant matter when digging or replanting near an old foxglove bed.  The leaves of foxglove (especially before it flowers) resemble and have sometimes been mistaken for comfrey, which is benign and a common basis for tea (here’s an article about several people poisoned this way).  Never fear though, ehow has a handy how-to on distinguishing comfrey from foxglove leaves; the clearest difference might be that foxglove leaves are finely toothed while comfrey’s are smooth.

Leaf of comfrey, Symphytum sps. Good for tea, beloved by herbalists, and pretty easy to confuse with foxglove leaves, pictured in the illustration above. Photo courtesy of Heather at ahandmadelife.blogspot.com, which is also a pretty nifty blog.

Finally, one of the side effects of digitalis poisoning is strong hallucinations, so there may be a handful of people out there ingesting it deliberately…but I doubt the visuals are worth the heart arrhythmias, severe nausea, fainting, coma and possible death that come with them.

Extra nitty-gritty: Digoxin as heart medicine

Cardiac glycosides like digoxin and oleandrin work as sodium-potassium ATPase inhibitors, which means that they interfere with the balance of ions inside cells. The muscle cells of the heart are particularly vulnerable to changes in sodium concentration, because sodium concentration is coupled to calcium export, and the calcium concentration inside the muscle cell is what regulates how strongly or quickly the muscle cell can contract.  When there’s too much sodium, the cell can’t efficiently export calcium, and the cell contracts too strongly as a result.  Erratic muscle contractions are certainly bad news for a healthy heart.

Digoxin: sometimes a help and sometimes a hindrance to heart function.

Unlike oleandrin however, digoxin has considerable utility as a medicine: the same calcium ion hoarding effect that’s so dangerous in a healthy person can be used to combat heart failure by promoting stronger contractions in a damaged heart, and digoxin gained FDA approval as a treatment for chronic heart failure and some kinds of heart arrythmias in 1998.

The initial use of digoxin came before beta-blockers were used to manage heart failure (HF), and there is ongoing study as to whether digoxin remains valuable as an HF management strategy in concert with other therapies. A recent article in the International Journal of Cardiology has undertaken a multivariable regression approach to attempt to classify which categories of patients are more likely to suffer higher mortality or further hospitalizations for heart failure following digoxin use.  Their meta-study combined cases of over 7000 patients, and found that higher mortality and hospitalizations for heart failure were correlated with groups of patients that were female and had high blood pressure.  Studies like this one may help identify which groups of patients can still benefit from digoxin and which groups should avoid it.

Extra nitty-gritty II: Digoxigenin as molecular label

Apart from its cardiac glycosides, Digitalis also harbors a supremely handy steroid, Digoxigenin (DIG), which I use routinely to label RNA molecules.  Digoxigenin is a fairly small little molecule that can be coupled to the nucleotides that make up DNA or RNA (nucleotides=letters: A,G,T/U, and C), and there are specific antibodies for DIG that can be used to detect it anywhere it’s bound in a cell.

DIG-UTP. This labeled "U" is incorporated into RNA molecules just like regular UTP.

So when I want to find which cells in my tissue sample are making a certain RNA, I can make a probe with a complementary sequence and some of the U’s labeled with DIG.  Then I can use anti-DIG antibodies (conjugated to an enzyme that makes a purple color under the right conditions) to look for the probe, with a technique called in situ hybridization.

A little how-to for using DIG-labeled UTP to find a target RNA by in situ hybridization.

Want more details?  Here are references for the articles mentioned:

Ather S, Peterson LE, Divakaran VG, Deswal A, Ramasubbu K, Giorgberidze I, Blaustein A, Wehrens XH, Mann DL, & Bozkurt B (2011). Digoxin treatment in heart failure – unveiling risk by cluster analysis of DIG data. International journal of cardiology, 150 (3), 264-9 PMID: 20471706
Lin, C., Yang, C., Phua, D., Deng, J., & Lu, L. (2010). An Outbreak of Foxglove Leaf Poisoning Journal of the Chinese Medical Association, 73 (2), 97-100 DOI: 10.1016/S1726-4901(10)70009-5

Oleander: backyard killer has a softer side?

A murderer lurks in your neighborhood.  It’s Nerium oleander, and it’s everywhere. Great swaths of it envelop LA freeways.  It’s littered across backyards, and encircles parking lots.  And it’s deadly poisonous to humans, animals and especially kids so don’t taste it, don’t sniff it, don’t even touch it, OMG I brushed against it AAAHHHH!!!

Don't be fooled by the sweet pink exterior. It's totally out to get you. (Photo by Servophbabu, Creative commons attribution 3.0 unported license)

Actually, it may not be quite that big a deal.  Although all parts of the oleander plant are toxic, and quite a lot of people are treated for oleander poisoning in the US, there have actually been only a handful of adult deaths from oleander poisoning in the last 25 years.  Most of these were deliberate self-poisonings, with the exception of a young couple of vegans who got lost while hiking and ate a whole mess of oleander leaves.  Estimates I’ve seen suggest that a lethal dose to a child would be about one whole leaf, and several leaves for an adult, and the potential for poisoning by skin contact is minimal.  So, while you should definitely watch out for your kids around oleander, you don’t have to be quite as afraid of it as I always thought. The urban legend about a troop of boy scouts who died after roasting their marshmallows on oleander sticks, for example, is almost certainly bunk.

That having been said, getting sick from incidental leaf consumption would be no fun, and oleander really is everywhere, so here’s what to look for:  it’s a tall shrub, 2-6m high, often used in neighborhood hedges.  If you live anywhere in southern California (or some places in northern California, like along the 80 between Davis and Sacramento), you’ve seen it lining the freeways and medians.

A menacing stretch of median oleanders. (Photo borrowed from odock.blogspot.com, but original photographer unknown).

The flowers are vibrantly pink or red or sometimes white, and grow in bunches.  Most distinctive are the leaves, which are dark green and leathery, and shaped like thin daggers about 4-8 inches long (there’s that assassin imagery again).  The leaves and flowers are poisonous because of several compounds, but notably the cardiac glycoside oleandrin/oleandrine and its metabolites.  Cardiac glycosides interfere with the Na+/K+ ATPase pump in heart muscle cells, throwing off the balance of ions inside the cell, and ultimately leading to it contracting faster and more strongly than it’s supposed to.  So oleander poisoning can result in irregular heartbeat, poor circulation, seizures, coma, and death.

Oleandrin. My heart's all a-flutter just looking at it.

Myth busting

While I was in college near LA, I encountered a rumor that oleanders were heavily planted along the local freeways because they were able to metabolize carbon monoxide (CO) emissions from cars, thus cleaning the air.  Turns out, the rumor may have had it exactly backwards.  A whole litany of plants, maybe all of them, can take up and metabolize small amounts of CO from the air—this was determined by Canadian botanists Bidwell and Fraser in the 1970s, who put radioactive C₁₄-labeled CO into the air around plant samples, and recovered the C₁₄ label from the plant later.  But the only study that talks specifically about oleander and CO is by Fischer and Luttge in 1978, who found that oleander was actually a net producer of CO through C₁ metabolism of glucose.  That is to say, they might take up a little CO from the air, but then they actually make more of it in their own metabolism.  So no air-quality help there.

Extra Nitty-Gritty: Plant crossover!

One of the treatments for oleander poisoning is a digoxin immune fab, using antibodies raised against a similar glycoside from the plant foxglove called digoxin.  Apparently, oleandrin and digoxin are similar enough that antibodies raised to the latter will also bind the former.  The antibodies work by binding to the glycoside and preventing it from reaching its target in the body and causing harm–it’s the same principle used to make snake or spider antivenom.

Oleandrin and digoxin. You can see how the pink-highlighted parts are almost identical, so that some antibodies that are made to bind to digoxin will also bind the corresponding parts of oleandrin.

Anything oleander is good for?

In previous centuries, oleander was used as an herbal medicine to treat everything from headaches to eczema, which makes me queasy to think about.  Since digoxin is used therapeutically for some heart conditions, I thought oleandrin might be the same, but its therapeutic index seems pretty limited in that context.  However, it does appear that the same Na+/K+ ATPase pump interfering properties that make oleandrin so dangerous to heart cells also make it effective at killing off some kinds of cancer cells when used in concert with chemo- or radiotherapies.  But a drug based on oleandrin called Anvirzel stalled after Phase I clinical trials in Ireland (due to poor performance–no reduction in solid tumors was seen but side effects were, and at least one company trying to inflate claims of its efficacy and continue to sell it got in serious trouble with the FDA). Now it’s the subject of an alarming cancer home-remedy fad based on making oleander extract at home.  People, please don’t poison yourselves!

Want more detail?  Here are the references:

Fab antibody fragments: some applications in clinical toxicology.  Flanagan RJ, Jones AL. Drug Saf. 2004;27(14):1115-33.

Cardiac glycosides in cancer research and cancer therapy. Winnicka K, Bielawski K, Bielawska A. Acta Pol Pharm. 2006 Mar-Apr;63(2):109-15.

Phase 1 trial of Anvirzel in patients with refractory solid tumors.  Mekhail T, Kaur H, Ganapathi R, Budd GT, Elson P, Bukowski RM. Invest New Drugs. 2006 Sep;24(5):423-7.

Cyclopamine, it’s just what it sounds like

Allow me to paint you a picture:

You’re walking through a meadow in Idaho on a lovely warm day.  The grass waves softly in the breeze, and your picnic basket swings loosely from your hand.  The rolling hills are dotted with sheep and flowers.  You turn a corner, and walk into this:

Nooooooo!!! Get away from my picnic basket!. (Public domain image from the USDA).

GAAAAHHHH!!!! You fling your picnic basket at it, spattering wine all over yourself in the process.  What was that??

It’s a one-eyed sheep of course, and it got that way because its mother ate this plant:

Lovely, no? But deadleah. (Photo by Jerry Friedman 2008, used under the Creative commons attribution-Share alike v3.0 uported license)

Which is the corn lily Veratrum californicum (it grows in the Sierra Nevada and Rocky mountains, but the one-eyed lambs that understandably freaked everyone out were in Idaho).  Also known as false hellbore or cow cabbage, it’s a tall plant, about 4-6 feet high, and the leaves, stems, and especially roots produce a robust amount of this compound,  cyclopamine:

It looks harmless enough.

…so named because…well, yeah.  It was causing the farm animals that ate it to give birth to cyclopic babies.

How does it do that?

A better question is: how do you normally end up with two well-positioned eyes, anyway?  There has to be a signal in early embryonic development to tell your facial organs where and how many to form.  An easy way to do this is to tell cells how close they are to the middle of the face.  It turns out that a major “middleness” signal is a protein called Sonic hedgehog that comes from a structure in the developing brain. (Or depending on context, just Hedgehog.  I swear.  Maybe later I’ll write a post on how genes and proteins get such crazy names).  All the cells nearby have another protein, Smoothened, that relays how strong the Hedgehog signal is to the inside of the cell.  If the signal seems strong to the cell, it knows it’s in the middle of the face (nose territory, for example), and if it seems weaker, it knows it’s off to one side.  But when cyclopamine is around, it interferes with Smoothened, so the cells can’t “hear” the Hedgehog signal. Which means not enough middle-of-the-face forms, and structures that should to be further apart think they ought to form right next to each other in the middle.

Losing Smoothened's activity because of Cyclopamine is a bit like taking a picture of a face, cutting down the dotted lines, and gluing the two halves back together. Without enough middle, the eyes end up too close together, or even fused.

So, voila: the cyclopamine in the lily is eaten by the mother sheep during pregnancy.  It gets in the way of Hedgehog doing its job in the embryo, and the eyes creep too close together, in some cases fusing into just one eye.

Can this happen in people?

Yes.  While humans aren’t likely to be exposed to cyclopamine during pregnancy, there are mutations in the gene that encodes Shh or its partners that can cause exactly the same effect (in humans, the resulting condition is termed holoprosencephaly).

Is that what happened to Leela?

Bus driver: "nice eyeball, eyeball." Leela: "nice ass, ass."

Probably not, because Hedgehog signaling is also used for lots of other things, including making fingers and functional kidneys, which seem just fine on Leela.

So that seems pretty awful.  Does it do anything useful?

As it happens, Hedgehog signaling is crucial for the progression of some cancers, including basal cell carcinoma and medullublastoma.  Blocking Hh signaling through the use of Cyclopamine (either as a direct extract from V. californicum or through its derivative IPI-926), is being tested in treatment of these and other cancers.

Want more details?  Here’s a useful review of Hh, cyclopamine, and cancer:

Targeting the hedgehog pathway: the development of cyclopamine and the development of anti-cancer drugs targeting the hedgehog pathway.  Gould A, Missailidis S.  Mini Rev Med Chem. 2011 Mar;11(3):200-13.