Lease renewals in State College happen earlier than probably any other place in the world.  The other day I was required to decide whether to extend my current lease that ends in July.  When I went to the rental office to sign the renewal agreement, I noticed that the rent was $215 per month less than what I was expecting it to be ($2580 over the lifetime of the lease).  How did I react?  I didn’t say anything, signed it, and requested a copy.

Two hours later, I received an email explaining that the rent was listed incorrectly, and requesting that I sign an updated version of the renewal agreement.  The renewal agreement states very clearly that it is a legally binding document.  As such, I’m pretty sure that I’m in the position of power here.  I get to determine what happens moving forward.  I thought about it for a while, and I’ve determined what I’m going to do.  My question for you is, what would you do?  And I don’t mean in the abstract case, I mean in the very real case where the difference is $2580 in your pocket.

For anyone curious, my plan is to let the gods decide.  Go to a casino, and bet it on red.  Re-sign if it hits; everybody wins.  Also, because tone doesn’t always come across in text, that is a joke.  I’m going to sign the stupid thing.  Very reluctantly.

Just thought I would post some high points from a lunchtime discussion on the stressful but character-building exercise of developing an elevator pitch to present at our six month review lab meeting. It makes sense to have a plain-language summary of one’s research, but it’s impossible to make a single pitch for a wide range of potential audiences. As noted in the links from Eleanore’s blog post, the pitch should change depending on the audience. We give our elevator pitches to the lab group–and believe me, I really appreciate having a kind audience already familiar with my research–but it doesn’t necessarily prepare us for the terrifying reality of elevators.

So here are two terrifying potential solutions:

(1) Rather than having a single pitch we give to the lab group, how about making cards with a potential target audience and each drawing one from a hat? Perhaps along the lines of “skeptical member of the public”, “family member”, “visiting seminar speaker” or more optimistically “Bill Gates”, or “talk show audience”. The upside is that we could have a lot of fun with the names we put in the hat (and I already have the hat), but the downside is that we would have to invest a lot of prep time.

This elevator contains only three people, rather than an entire lab group.

(2) Another option would be to draw names of fellow lab members and give an elevator pitch on their research. For one thing, it’s a lot easier to sum up others’ research, but for another, it would be nice to get an outside perspective on what research questions are most memorable and exciting. One possible downside: if it’s embarrassing to give a bad elevator pitch on my own research, it would be worse somehow to give a bad summary of lab mate’s research.

Or perhaps elevator pitches are an activity best practiced in the pub (and in small groups), in which case, the curly fries are on me.

Drug resistance is a problem. We can measure the devastation multi-drug resistance causes in financial figures and mortalities, and they all drive home the same point we focus on in our research day-to-day and which Andrew brings up in his class and TED talk: evolution is killing us. Antibiotics, antimalarials, cancer drugs, antiretrovirals, all have the same story. In malaria, it is a problem that has rapidly emerged after implementation of every drug we have ever brought to market. It seems like the explanation is simple: human intervention via drugs exerts selection pressure on bugs. The more drugs we use, the more pressure we are putting on bugs to evade them. But here is something I don’t understand: many, if not all, of these drugs were developed to mimic active ingredients in medicinal plants that we used centuries before the existence of big pharmaceutical companies. Why did resistance to the plants (and their active compounds) not develop over this time and interfere with their functionality before we brought them to market via big pharma?

Artemisinin has been in use for 2,000 years. We have found “prescriptions” for artemisinin in malaria cases from the notes of Chinese herbalist Li Shizhen — in 1596 he wrote that fevers should be treated as follows: “take a handful of sweet wormwood, soak it in a sheng of water, squeeze out the juice and drink it all,” (Meshnick 2002). Sweet wormwood, qinghao, is the same plant source we use in modern day artemisinin therapies: Artemisia annua. Evidence of artemisinin (ART) resistance and treatment failure is recent, with WHO issuing an official emergency response for containment of ART-resistance in 2013. Two thousand years of herbal use led to no problems, but less than 30 years of pharmaceutical production, and we have huge problems with resistance.

Artemisinin is not the only antimalarial that has this story. Quinine resistance also followed from the introduction of pharmaceutical production despite having long-term use as a traditional medicinal in its plant form. Why this trend?

I can come up with several possible explanations:

1. Maybe the concentration of active compound in plants is much lower than the concentration put in a pill that we can pop. That would translate to a lower selection pressure and a lower probability for resistance to emerge.

2. Maybe drug resistance did exist in populations chewing on cinchona bark (the source of quinine), etc., but without the abilities we have now to document treatment responses and genotype parasite profiles, we lack historical evidence for resistance to medicinal plants.

3. Maybe access to medicinal plants and the knowledge base of what plants to use was not widely spread, consequentially there wasn’t the same degree of pressure for parasites to evolve resistance as there is now. (This seems doubtful. If you have ever traveled to an area where traditional healers are more common than allopathy, the knowledge is as widespread as our use of chicken soup for a cold.)

4. Maybe plants and their synthetic or pharmaceutical derivatives from geographic regions more distant from a population are more effective than that population’s native plants and derivatives. For example, we could ask: have areas where the cinchona tree is native developed resistance to quinine more rapidly than areas where the plant is not native? If the answer is yes, than resistance to quinine may have already been developing under use of the plant, and thus emerged quicker where the trait was already present in the parasite population at the time of quinine introduction.

5. Maybe there are other compounds in medicinal plants besides the one active ingredient we tend to isolate that make plants “evolution proof.” Could medicinal plants be similar to combination therapies and we are not considering all possible components plants contain in terms of their antiparasitic abilities? Are we missing something when we isolate an active component?

6. Maybe synthetic versions are less potent than the natural plant because of differences in d vs. l enantiomer concentration. In vitamin E we know that the vitamin extracted from the plant is much more potent than the synthetic version because of differences in stereochemistry. It has so far been impossible to make a synthetic version that is not a racemic mixture. If the body recognizes synthetics vs. natural forms of the same compound differently, maybe synthetic antimalarial compounds could also be exerting a different selection pressure on parasites, leading to drug resistance?

A recent article in PLOS ONE may convince you that hypothesis #5 has some validity for explaining why artemisinin resistance appears to be a recent development despite long-term use of the natural plant. The study by Elfawal et al compared treatment responses between whole plant powdered leaves of A. annua (14.8 mg artemisinin per gram of dried leaf) and a comparable dose from pure drug. The results showed an obvious discrepancy in effectiveness, with whole plant treated mice having lower parasitemia and faster parasite clearance. Only when the dose of pure drug was at a dose five times higher than the dose of whole plant was the outcome of treatment comparable (24mg/kg artemisinin in whole plant treatment had the same outcome as 120 mg/kg of artemisinin pure drug).

This result suggests that either artemisinin in whole plant form is more potent or there are other compounds in A. annua that act synergistically in treatment accounting for the reduction in efficacy of the artemisinin pure drug.  The authors provide evidence that either possibility could be occurring, citing work that has shown that artemisinin in plant form is more bioavailable and that there are also particular flavonoids in the whole plant that could contribute to synergism. If flavonoids or other molecules in the whole plant are contributing to the enhanced potency, the authors suggest that whole plant therapy may be more similar to combination therapies currently in use rather than monotherapy with artemisinin.

Our current understanding of resistance suggests that resistance is less likely to emerge to a particular drug when used in combination with other drugs as the likelihood that resistance to multiple selection pressures occurs at once is less than the likelihood of resistance emerging to just one selection pressure, particularly if there is a fitness cost to resistance mutations. This has led to current implementations of combination therapy in treatment for HIV/AIDS and malaria. It looks like nature may have come up with this idea well before our antimalarial combo drugs. Is A. annua the original combination therapy? And is that what delayed resistance to artemisinin compounds for 2,000 years?

Seems to me like plants may be smarter than we think.

Source: Meshnick, S. R. Artemisinin: Mechanisms of action, resistance and toxicity. International Journal for Parasitology 32 (2002): 1655-1660.

I often complain about the cold weather, but I keep finding little elements that make life in the frigid cold bearable and at times increasingly beautiful.  I’ve become fond of going out on a run in the middle of a light snow at a nearby trail that runs through a wooded area near where and I live, and listening to the shockingly quiet landscape, or marveling at tree branches encased in ice after a freezing rain.

More recently, I discovered an extra treat that really appeals to the five year old in me. If you haven’t thrown a rock at a frozen pond, you need to do it promptly because the sound that comes from the act is devilishly satisfying.

I’m not the only one to think so. Check this soundclip out.

It did feel slightly blasphemous to have my first experience of this be at Walden Pond. I could just see Thoreau shaking his head in annoyance, “Darn kids!”.

For Christmas this year, my cousin bought me a rubber chicken.  It’s a great gift, as evidenced by the fact that I brought it into work my first day back and it’s been on my desk ever since.  But it also made me realize that I need a better way of communicating what I do to a non-academic audience.  In my cousin’s eyes, I currently work on chickens; I used to work on caterpillars; I might work on fish, or pigs, or (my mother’s fingers are crossed) humans in the future.  And my cousin’s view isn’t unique.  My family and most of my non-academic friends see me as a chicken biologist or an entomologist, even though I have never and would never describe myself either way.  I’m a disease ecologist.  I study the mechanisms that drive infectious disease dynamics.  Only by exploring multiple host-pathogen systems can generalities be made, and in my personal opinion, making correct generalities should be the goal of research.  I need to find a better way of getting that across.

On Wednesday, Andrew showed me a secret message. Well, ……… “secret” might be a slightly fantastic representation of the truth. The message is in plain view for all to see. It’s printed in large colored blocks on the carpet of a room on the 3rd floor. This message, however, IS written in code. Binary code to be exact.

At first I was a bit concerned that I’d been misinformed. There are 5 different colors arranged in what may or may not be considered a pattern. This led me to briefly consider some kind of “pent-ary” code but then I decided to focus on why five variables might be required to represent a binary code. Writing a full message in binary code would require a lot of carpet, so perhaps the 5 variables are used to compress the code into something that will fit in the room?

Now, looking at the carpet it seems safe to assume that the color brown is used as a spacer to mark where a word begins and where it ends. This leaves 4 colors: red (r), light blue (l), dark blue (d) and green (g). One possibility is that instead of printing all the 1s and 0s, only the 1s are recorded. In this case the colors could indicate the position of the 1 in a byte. This would allow long strings of binary like “00110” to be represented with the spatially more efficient “gd”. (Here I’ve assumed that green (g) is the 3rd position and dark blue (d) is the 4th position, which gives 2^3+2^2=12. The 12th letter being L.) Four colors allows us to represent 15 letters and since the final 11 letters of the alphabet are “pqrstuvwxyz”, it seems conceivable that a message could be written using only the first 15.

The code I’ve just constructed has a number of short-comings ………. the most important one being that it doesn’t seem to be the solution! But, now that I’ve spent a few minutes thinking about this I’m rather curious as to what the actual solution is and would welcome suggestions. Stop by my office (W244A) and let me know if you have any thoughts ………… I might even buy you a coffee!

I spend a lot of time worrying about what programs I use. Am I using the best programs for the job? Is it worth paying for a better program? Will people judge me harshly if I code in a less-than-optimal programming language? Some programs can be looked down upon (“why would you have chosen to write that code in Mathematica? It’ll take forever to run…”, and so on), perhaps for good reason, perhaps not. For example, I started out running models in Excel, and I still think it can be a relatively painless way to start out in programming. Unfortunately, it’s really hard to input complex models and error check, to make visually-appealing graphs, but people make do. Some use Excel by default, and some choose to challenge themselves by doing their work in Excel.

This Powerpoint rendition of malaria parasites bursting out of a red blood cell took a long time to make, but it was totally worth it.

As I’ve learned from Penny Lynch’s impressive Christmas cards, Excel can be used to create complex visual art too. In fact, there’s a contest for visual art in Excel, and the winning artist takes it to a whole new level. If Tatsuo Horiuchi can create exquisite art pieces in Excel (not Powerpoint, but Excel!), surely I can spend a little extra time refining the visual representations of my research. I’ve come across a few blogging scientists who take their presentation-style very seriously (fun blogs to follow: Neurodojo and Better Posters), and who feel that it’s very difficult to create good presentations and posters in Powerpoint. They’re right of course, but rather than invest in Illustrator, I think I’ll take a cue from Tatsuo Horiuchi and learn how to work magic with the programs I’ve got. It’ll be character-building, I’m sure.

It is cold today. It is single digits cold in Fahrenheit, or double-digit negative numbers if you measure how cold it is in Celsius. Here’s a silver lining; if you go for a walk you’re not going to be bitten by mosquitoes. Mosquitoes are typically active above 50°F – what do they do in weather like this?

They have three options for overwintering. 1) as an adult 2) as an embryo from an egg laid in wet mud 3) as a larva in water (plus option 4 – don’t live in a cold climate).

Option 1 only works for female mosquitoes – apparently the males either can’t store up enough fat reserves to go into diapause through the winter, or it isn’t worth it from an evolutionary perspective if females can bite and make eggs in the spring without them. It seems that if the males don’t make it that females must be storing sperm during this time too, at least some of them, or winter would solve our mosquito problems for at least some species. Females will switch their food source from blood to sugar-heavy nectar and rotting fruit in the fall to start building up winter reserves. Then, they hide out in woodpiles, under rotting leaves, in tree holes, nooks and crannies along riverbeds, anyplace out of the way where they won’t be disturbed. If they are really cold they won’t move at all when disturbed but reanimate when it is warmer.

Option 2 works because eggs laid in the summer aren’t as bulky or as well-provisioned as those that are laid for overwintering. These eggs hatch with warmer temperatures.

I only found one example of Option 3 – which was Wyeomyia smithii, a mosquito where the larval stage uniquely overwinters inside of pitcher plants. Apparently even when they are frozen solid they can reanimate and start feeding with warmer temperatures.

Doesn’t it make you feel all warm and fuzzy inside to know that even in these freezing temperatures the mosquitoes will be okay?

I’d like to send this year out by notifying the group about Andrew’s Big Secret, which I discovered while vacationing in Charleston:

Seems he runs a real estate business directly opposite a bar that serves amazing oyster shots.

Who’d have thunk it.

Happy New Year!

Last week, Katey and Lindsay donned their gowns and got formally Doctored. Katey is my first US PhD graduate; Lindsay was primarily advised by Ottar, but he couldn’t make it. Something to do with being in Perth (the one in Australia). So I escorted them both. After almost two hours of ceremony, we were the last three to go on stage and I was the last to leave it. The applause was raucous. I don’t think I have ever had so many thousands of people so enthusiastic about anything I have ever done before.

Every now and then I think about how much better I would be at grad school if I could do it all over again. But since I have no desire to go through grad school twice, I think it might be better to just send some advice back in time. After some consideration, I’ve decided that the two pieces of advice I would give myself are:

1. There are no perfect experiments.

2. You’re rarely, if ever, going to come up with a truly great idea but you can definitely come up with some publishable ideas. It’s the published ideas that do the most for your career.

These two pieces of advice are both based on the most valuable thing I learned in grad school, which is how to recognize and manage limitations. Unfortunately for everyone, this is something I could only really learn through experience. While I have no single gem of wisdom, an informal poll of the PhDs in my life did reveal that most people have some bit of advice that they would send back in time. This advice includes:

1. Read the [censored]-ing student handbook.

2. Take up a hobby, preferably a contact sport. And get a cat.

3. However bad it gets, don’t be tempted to get a cat.

4. A list of all failed experiments.

5. Get on with it.

6. You’re not as smart as you think you are.

7. Just relax, you’ll finish.

8. You will become better friends with alcohol.

9. Be nicer to your advisor.

10. Never graduate.

As a researcher who works in the Center for Infectious Disease Dynamics, do I have a professional obligation to take advantage of preventative measures to stop the spread of disease, like getting an annual flu shot?

I have to confess, I never got the flu shot before starting at CIDD. I wasn’t in a high-risk group (not very young, nor very old) and never gave it too much thought. Last year I got the shot, and felt like I had done my academic duty.

Since vaccines are available I plan to get it this year too.

The VAX game (developed at CIDD) shows how important vaccines can be to stop the spread of disease. Since CIDD is its own social network, we are in essence protecting each other by getting the flu shot (and washing our hands, practicing good hygiene etc). So, is it just altruistic to get the shot to protect our friends? Are vaccines wasted on our generally healthy population? If everyone got the flu shot in CIDD would productivity increase measurably? Curious to hear your thoughts.

The delicious, though expired, morning beverage.

This morning I woke up and had the best cup of coffee I have ever had in my life. Angels descended from the heavens, the coffee gods and goddesses were smiling over my kitchen, I was drinking Zeus’ ambrosia. (That is the best description I’ve got until we enter the age of internet transmitting smells and tastes — think “scratch n’ sniff” stickers but on a virtual level). If you can imagine coffee, imagine it 150x better than you are expecting it to be and you have replaced the need for a smelling/tasting internet. At first, I thought my year of working as a barista had finally paid off into high quality home brewing skills. Then I reached back into the cupboard to see what beans produced this type of magic and here was the kicker: Chock Full O’ Nuts and the beans were seven months expired. The coffee can was sitting on a shelf above the radiator, hot and musty; this was after they were given to me by my grandmother who gave up coffee five years ago.

That is how I arrived on the subject of coffee dates. *Not the kind that happen with people at places (e.g. with Dave and Laura mid-morning), but the kind that are printed on all our bean bags and coffee cans. For that matter how has it come to be that so many things we use and buy come with a set “best by” or “good until” date? I imagine someone sitting in front of heaps of coffee with a timer tasting it at intervals and am guessing no one at Chock Full O’ Nuts ever sat around for seven months or they would have extended the dating. My cynical side says that expiration dates are financial ploys to ensure a steady demand of new product. Does something vacuum sealed or dehydrated self-destruct when it reaches its sellable death day?

When we talk about coffee, the connoisseurs may think that dating is pivotal, but as scientists, what may be even more pivotal is how dating affects our reagents and how drugs may lose efficacy. Nearly everything we use in lab has a date on it but rarely do we know who calculates that date and how one day could change an end result (does the day before the expiration date significantly differ in product content than the day after?).

As law, most pharmaceuticals have to be sold with an expiration date. If you are a drug producer who recognizes that patients take medications with more gravity than I take my coffee, putting an earlier expiration date than is reflective of biological activity has multiple advantages, especially economic ones in addition to erring on the side of safety without stringent testing of later-dating product. Why would any company test the effectiveness of a 10-year old pill vs. a one-month old pill if being good for 10-years would mean your customer only buys product at that frequency? A 2010 story on National Public Radio (NPR) reported that the Food and Drug Administration (FDA) has never had a case of an adverse reaction from expired pharmaceuticals.

A study on the stability of active drug ingredients was put out by Cantrell et al. in the journal Archives of Internal Medicine last November, showing that even after 30 to 40 years on a shelf, the majority of drugs still had 90 percent of the amount of active compound listed, some having even more than the amount listed, by as much as 110 percent. Most drug expiration dates are one year after production date.

When we consider drug treatments for infectious diseases in areas of the world where transportation and distribution are slow and the time from production to receipt could shorten the window before the expiration date encroaches, would it do harm to extend dates? There may be a tremendous amount of waste due solely to the fact that we are throwing out product based on an arbitrary deadline. If dating needs to be reconsidered, who should do it? Currently, it seems like pharmaceutical companies, like coffee companies, food companies and most marketers of perishable goods, are in control of their own expiration dates which leads to high potential for selfish interests to be determining when customers buy new. If an unbiased third-party is needed for expired coffee testing, I volunteer.

I can be very morbid. Recently, I’ve become interested in epitaphs. These short phrases are chosen by the deceased or their closest love ones to be etched into their tombstones.

They range from depressing to touching to humorous.

Robert Frost: “I had a lover’s quarrel with the world”.
Emily Dickinson: “Called back”
Oscar Wilde: “Alien tears will fill for him/ Pity’s long-broken ern/For his mourners will be outcast men,/and outcasts always morn.”
Winston Churchill: “I am ready to meet my Maker. Whether my Maker is prepared for the great ordeal of meeting me is another matter”
Hank Williams: “I’ll never get out of this world alive”
Virginia Woolf: “Against you I will fling myself, unvanquished and unyielding o Death!”

The poet John Keats, feeling very down on himself, requested that his tombstone be inscribed with, “Here lies one whose name was writ in water”. He believed he had made no impression on the planet. His friends gave him his wish, but they added a qualifier at the beginning, “This grave contains all that was mortal, of a young English poet, who on his death bed, in the bitterness of his heart, at the malicious power of his enemies, desired these word to be engraven on his tomb stone”.

Why do I think these are interesing? They are like a little glimpse into the values of these people and their life philosophies.

The one that particular touches me is the one chosen for Sylvia Plath by her husband Ted Hughs.
“Even amidst fierce flames the golden lotus can be planted”.
What a compliment.

Don’t we just have the best job in the world? Yes, yes, I just passed my comprehensive exam and these could just be the witterings of a sleep-deprived maniac. In my defense, though, I’ve said this in less exceptional circumstances. When I last returned to England those friends of mine that are also PhD students seemed shocked (and perhaps even a little appalled) by how cool I thought my job was.

I lay in bed last night, totally unable to sleep, thinking about what was said in the exam. Briefly, I rested my thoughts on something Andrew said to me as we ‘debriefed’, he had concluded from one discussion that ‘nobody really has a clue what we’re doing’. What an amazing thing! Five professors and I in a room and nobody really knows what the answer is. At moments it felt like we were going somewhere completely new. I was reminded of something my dad, who is a statistician, used to tell me as a child – that mathematics was creative, in spite of the impression I got in the classroom. How true that is for all sciences and how little it is appreciated.

In a thankless effort to put myself to sleep, I read an article in The New Yorker by a journalist who is a restless lover of travel, who, like me, is obsessed with seeing the world. All I could think was what an adventure Science is too.