Drugging the “undruggable”

In conventional medicine, a small molecule, known as a drug, will bind to the protein responsible for disease and, if all goes right, alter the undesirable behavior of that protein.  You might remember the “lock-and-key” pictures from high school biology, where the drug is the key and the protein is the lock.  The “lock-and-key” concept has grown more complex since coined in 1894, but the basic principle remains:  A protein needs a drug that can fit tightly within it.  The problem?  Up to 85% of proteins in the human body are deemed “undruggable”, according to a recent episode of the podcast “Stereo Chemistry”, produced by Chemical & Engineering News.  I was moved by the advances in chemistry, biology, and drug discovery presented on this podcast and am excited to share a summary here.

What makes a protein “undruggable?” A lack of clear pockets, indentations, or other topographic features a small molecule can fit into.  According to the podcast, emblematic of an undruggable protein is the protein KRas, which tops people’s lists for what to attack.  Why? It is one of the most commonly mutated proteins in cancer. 

The KRas protein
The protein KRas. Credit: C&E News; Kevan Shokat

On the challenges posed by KRas, the podcast interviewed one of my old chemistry professors, Kevan Shokat.  (Hi, Professor Shokat!)  Professor Shokat talked about how significant it would be to attack KRas with a standard small molecule drug, versus newer forms of medicine, like gene therapy for example, that are not as well understood or as easily executable.  

Here are some strategies being used to approach “undruggable” targets:

1.  Keep the undruggable protein from ever being made.   messenger RNA (mRNA) contains instructions for making proteins, but before doing so, exists in a variety of shapes as the molecule twists and turns.  If a target could be designed to “trap” the mRNA in one of these pre-instruction shapes, the mRNA couldn’t go on to direct protein synthesis.  

2.  Catching transcription factors in action.  A transcription factor is a protein that controls the rate of passage of information from DNA to RNA, and thus along to making proteins.  They are like regulators of protein synthesis.  Sometimes, the transcription factor cMyc becomes stuck in the “on” position, promoting genes that allow cancer cells to multiply.  Traditional structural analysis has shown cMyc devoid of any nice pockets to which a small molecule can bind.  In the words of Angela Koehler directing the MIT group working on this, the cMyc proteins “lack shape”.  However, in the cell when they are working, they do not.  Dr. Koehler’s group has found a way to take the proteins as they behave inside the cell and explore them against a library of potential drugs to test for binding.  This approach catches the proteins in action, rather than as static structures outside of their typical surroundings.  

3.  Harnessing the power of mass spectrometry.  Unlike conventional approaches, no structural information about a protein is needed beforehand.  A protein is thrown in with potential drugs, and the output analyzed by mass spectrometry.  Mass spec can determine what stuck on the protein and where.  According to Dan Nomura of UC Berkeley, this method has identified 100,000 “druggable hotspots” across 20,000 protein targets.  One potential problem: do the druggable hotspots actually influence protein behavior, and therefore, affect disease? That’s where the next idea comes into play.

4.  Using the new “druggable hotspots” to simply destroy the protein.  If the new hotspot does not affect protein activity, you attach a complex of molecules that will go on to destroy the protein.  Once the protein is destroyed, that same complex can perform the task again.  This approach is called “Protein Degradation”.  

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Schematic of protein degradation. Credit: Novartis.com

In sum, scientists are taking creative and bold approaches to attacking this huge swath of formerly elusive proteins.  I’m excited to see where this goes.  

Maybe I Should Stop Eating Candy Corn


From today’s WSJ piece on the LD50 of sugar

As an older generation might say, this fall has been a doozy over here.  One unexpected twist was that since September 28, one month ago today, I’ve been to the dentist seven times.  Yes, that’s right.  Seven.

A routine cleaning on September 28th revealed a back upper molar missing part of an old filling.  This led to the placement of a temporary crown on October 2.  On October 9th, the temporary crown was re-positioned with sedative cement due to intense pain I’d been feeling the prior three days.  On October 10th, after taking one bite of a delicious dinner I made — an occurrence almost as rare as a total solar eclipse — I found myself crunching on the temporary crown.  So, on October 11th I went in to get the temporary crown reset, but luckily the permanent crown was ready! Happy Day!

Except two days later, on my birthday, I began to feel intense pain.  So, I went back to the dentist on October 19.  And on October 20, I was sitting in the endodontist’s chair, having a root canal.  On October 24, while eating a protein bar at my desk, I bit into what felt like a rock.  So I was back at the dentist today, thinking I’d lost part of a filling in another tooth.  The good news is the filling is intact.

The bad news is I’m terrified of eating any Halloween candy this year.  An non-candied apple is kind of as far I’m willing to go with my mouth full of time bomb silver fillings from the early 90s.  So maybe it was a blessing-not-in-disguise to see today’s article in the Wall Street Journal on the LD50 of various popular Halloween candies, a chilling reminder of sugar’s murderous behavior.

The LD50 is the dose of a substance lethal to half of a test population, typically rats.  Every substance has an LD50, even water!  Sucrose, the main sugar in candy, has an LD50 of 13.5 grams per pound of body weight.  For a 125-pound person, this translates to about 200 fun-size candy bars, 250 gummy worms, and just over 1,000 pieces of candy corn.  I LOVE candy corn — I know, it’s disgusting, but I love it — though don’t think I’d ever eat 1,000 pieces in one sitting.  Gummy worms on the other hand?  I kind of could picture mindlessly munching 250 of them, if I were watching a gripping enough movie.  For now however, I will sit longingly staring at the bin of candy corn, wondering if I’ll be brave enough to take a handful and possibly end up at the dentist again next week.

My favorite part of this article?  The personalized equation they offer:

(Your weight * 13.5)/9.3 = the number of fun-size candy bars that would kill you

This equation takes the LD50 of sucrose (13.5), multiples it by your weight, and then divides it by 9.3, which is the number of grams of sugar in an average fun-size candy bar.  Go ahead, give it a whirl.  Maybe this can inspire the next blockbuster murder mystery — was it death by fun-size Milky Way or Three Musketeers?

To Sit Or Not to Sit . . . Or to Sit.

The online science publication Ars Technica came out with a piece today entitled, “The new study suggesting sitting will kill you is kind of a raging dumpster fire.”  The title alone fills me with glee!  Debunking science!  Using “kind of” in the title!  And, it’s OK to sit again!!!!

In truth, the study today’s article alludes to completely freaked me out.  It had me googling “treadmill desks” and envisioning doing squats during nighttime TV watching.  But the sun has come out today — the Ars Technica authors poke enough holes in this study to put me back on good terms with our couch.

The particulars on the beef the authors have with the original study, which appeared in the Annals of Internal Medicine:

  1. The study was funded in part by Coca-Cola.  The authors find fault with this saying that rather than focus on unhealthy consumption, Coca-Cola funds studies like these to shift the conversation to focusing on unhealthy behaviors.  Personally, this doesn’t bother me that much.  I feel like most people interested in heath — i.e., the people who are interested in these studies — already know drinking sugared sodas isn’t a great choice.  The “conversation shift” certainly won’t lead me to begin chugging sugared soda after a workout.
  2. The study didn’t actually measure sitting.  OK, getting warmer.  Researchers did not rely on subjects’ reports of sitting times, as these are notoriously error prone.  So, they used something called an Actical accelerometer, mounted to one’s hip, which tracks the amount of oxygen a person uses in various activities.  Unfortunately, it cannot distinguish between sitting and standing.  Or lying down and light movement.  So, in this study, working at a standup desk is lumped into regular old sitting.  As the authors point out, nuance is severely lacking here.
  3. The study demographics are problematic.  A bunch of people dropped out early, leaving the more sedentary participants to complete the study which lasted a week only.  Also, the more sedentary groups in the study were on average ten years older than the least sedentary groups.
  4. Statistical challenges.  Once the data were in, the researchers broke the participants into four groups, those who:
    1. rarely “sat” (or did something else of low intensity), and when they did, “sat” in short bursts
    2. rarely “sat”, and when they did, “sat” for long durations
    3. “sat” frequently, in short bursts
    4. “sat” frequently, for long durations

The numbers of participants in the middle groups, as well as mortality rates, were      not high enough to permit any statistically significant conclusions on the effects of sitting in short or long bouts.  The researchers themselves cap off the study with a statement on the difficulty of drawing any conclusions due to issues with statistical significance.

The problem is that while this disclaimer appears in the actual research paper, how many of us read that?  Rather, we tend to read the news summaries, which are often based off of summaries like this, which appears in Science Daily.  And according to this summary,

“A new study founds that sitting around for 12 or more hours per day, particularly if accumulated during 60- to 90-minute periods, increased the risk of early death — even in those who exercised.”

With no mention of the above limitations.  So a big thank you to Ars Technica for probing deeper!

No really, have a seat.


Green Roofs

Last night Eric and I went to an Empiricist League event — one of regular nerdy dates.  The Empiricist League describes itself as “a creative community for those who believe in evidence, observation, and experiment”.  In other words, science.  A few times a year, the Empiricist League holds an event with 3 speakers focusing on some aspect of science, at an area bar.  Last night we funneled end-of-the-week alcohol at Union Hall while learning about “The History of the Future: Steampunk, Spacesuits, and Beyond”.

Wythe Marshall (Harvard grad student in History of Science dept) opened the night with a talk on “Cities of Futures Past: Strange historical visions of the urban future”.  He spoke about early visions of green space in city planning, and then posted a striking photo of a colossal green roof which made me wonder where I’ve been — I had no idea this was happening on Randall’s Island!

Wythe Marschall talking about Cities of Futures Past.

The Five Boroughs Green Roof is a green roof on top of the headquarters of the Five Borough Technical Services Division of the NYC Department of Parks and Recreation.  The idea was conceived in 2007.  The before and after photo is striking.

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from nycgovparks.org

At 29,000 square feet, it is the 5th largest green roof in NYC.  (What are the other four?)  I don’t really understand why every roof isn’t green, because the benefits seem so obvious.  I wonder, what are the disadvantages, if any? What specs does a building need to have in place before the roof goes green?  Can anyone recommend a great green roof book/primer?

Dad, One. Frizz, Zero.

It’s back-to-school time . . . and many of us begin thinking of apples, plaid, backpacks, sharp pencils, and smooth, combed out hair.

Image result for frizzy hair stock photo
This is not my baby.  This is the first time I am using a stock photo! 

But what if your kid’s hair is plagued by frizz?  And in fact, the more you comb it, the frizzier it gets?  This happened to one Dad, Biogeochemistry PhD Boyce Clark.  His daughter’s daily battle with frizz pushed him to first research frizz, and then start his own company fighting it.

After experimenting in the kitchen for nine months, Boyce Clark started Lubricity Labs, a company that makes anti-frizz hair products.  According to the company’s About page, the products

“are all made from naturally-derived ingredients, ultra-gentle cleansers and the highest quality bio-compatible proteins. They are vegan, GMO-free, paraben-free, sulfate-free, and cruelty-free — if you don’t count the hundreds of hair washes my daughter had before we had the Eureka moment.”

The two-step anti-frizz regimen changes the structure of hair, smoothing out irregularities that make hair permeable to moisture and result in frizz.  The treatment takes about 30 minutes, and is needed only once or twice a year.

Clark says it changed their morning routine, eliminating the typical 20 minutes of arguments and crying.  Um . . . if only we could end the tantrums here through anti-frizz hair products!

Note 1: I am not affiliated with Lubricity Labs. 

Note 2: A big thank you to Tomoko for sending an article on this my way!

Water to Whiskey

During my McKinsey consultant days, I would often frequent hotel bars in the evenings, hoping at least to take the edge off, at most to meet the cast of the next blockbuster movie.  (You see, one of the consultants I idolized had met the entire cast of Ocean’s 12 at the Amsterdam Four Seasons hotel bar, so I was gunning for my chance, though doubtful I’d find them at places like the Westin hotel bar in Princeton, New Jersey, where I was stationed).

I elevated my taste from my graduate school Jameson to the slew of single malts I could now afford . . . with Lagavulin and Oban as my favorites.  (As I write this, I’m salivating, but it’s only 4 PM! Must make it until the kids are in bed.)  Another consultant taught me to add just the tiniest amount — about 1/2 of a standard straw — of water to my scotch, and revel in the torrent of scents and flavors unleashed.

I’ve always wondered about this significant before- and after-water difference with scotch tasting.  Could it have something to do with hydrogen bonding?  But my inquiry joined the long list of Things to Look Up Someday, until last week, when I saw this headline in the Washington Post: “The best way to drink whiskey, according to science.”

Björn Karlsson and Ran Friedman from the Linnaeus University Centre for Biomaterials Chemistry in Sweden (of course), undertook computer simulations, modeling the molecular composition of whiskey, to investigate why water made it taste better.  The results were published here in Nature last week.

In the Linnaeus University news article, Karlsson explains the taste of whiskey is linked to molecules with a “water-loving” (hydrophilic) and “water-hating” (hydrophobic) part (soap and mustard have these features as well, fyi), such as guaiacol, a compound that forms when the malt grain is dried over peat smoke during whiskey production.

Figure 1
Figure 1 from Karlsson’s and Friedman’s paper, an image of 2-methoxy-phenol, aka guaiacol.  The OH part on the bottom is water loving, since water is also made from H (hydrogen) and O (oxygen).


The scientists studied simulations of a water/ethanol mixture in the presence of guaiacol, and determined that in mixtures containing 45% or less ethanol, the guaiacol was more likely to be found at the liquid-air interface, rather than deep in the liquid.  The presence of majority water seems to “release” that flavor compound.

Now, when whiskey is bottled, it is typically already diluted with water so the mixture is 40% ethanol.  The authors suggest the few additional drops of water added just before consumption must further enhance the release of the flavor compounds to the surface.

In the wake of the eclipse, I’ve seen a number of people on social media taking their hats off to SCIENCE.  I think this study is almost as important!


“Someone is Eating the Sun”, and other Eclipse things . . .

The Great American Solar Eclipse is nearly upon us.  On Monday, August 21, a swath of “totality” (complete coverage of sun by moon) will stretch from South Carolina in the South up to Oregon in the West, with all of North America, and some parts of South America, Europe, and Africa in partial eclipse viewing range.  

Total solar eclipses occur about every 18 months, when the Earth, moon, and sun align perfectly and the moon blocks out the sun’s rays.  Most of these eclipses are visible from only some place out in the ocean, making Monday’s land-based viewing opportunity all the more special.

We’ve been reading a few books on the eclipse at home, even though I’m not sure we trust BRK with eclipse glasses and may just wait until the 2024 eclipse, with a path of totality stretching from Texas to Maine, to make this a full family experience.


BRK has fallen in love with “Someone is Eating the Sun”, a lovely picture book published in 1974 by Ruth Sonneborn and illustrated by Eric Gurney.  Several farm animals conclude someone is taking bites of the sun, as it takes on its crescent shape during an eclipse.  A wise turtle explains it is merely an eclipse, and after totality, the animals are relieved the sun has returned.  We also read Eddie’s Eclipse, published this year, by Becky Newsom and Pam Tucker and illustrated by Pam Tucker.  BRK is a bit young for this book and I had to severely live edit as we moved through the pages.  The book had a clear, bright diagram of an eclipse that was helpful in explaining to BRK what an eclipse is.

A page from Eddie’s Eclipse

Meanwhile, Eric and I attended a Solar Eclipse class at Pioneer Works in Brooklyn, taught by Joe Patterson, a professor of Physics at Columbia University.

On the first night, he shared a compelling story he wrote about his experience of totality in 1970, during an eclipse in Virginia Beach.  He shared his skepticism that totality would be “worth it”, as he had already experienced a 90% solar eclipse.  He writes:

“As late as 1:30 PM, at about 96%, there was just no hint of the drama yet to come.  I started looking through my binoculars with about 1.5 minutes to go, when Cal warned, “It’s coming fast now.”  At about 15 seconds before totality, he yelled, “Joe — the fringes!”, and I turned to see light and dark bans moving across the sand at 5 mph.  The bands were 2 – 4 inches wide.  I don’t recall if the light bands were any lighter than the sand before the fringes appeared — it would have been very difficult to to tell anyway since the light intensity was changing very rapidly now.  I watched the fringes for a few seconds, yelling, “The fringes! There they are! The fringes!” or something like that.  Then I ripped off one filter and looked back at the Sun.  In a few seconds the diamond ring effect appeared, the last burst of light from the photosphere.  Then Bailey’s Beads flashed into view, and I lowered the binoculars to rip the last filter off.  I had been lying down to view it comfortably, but by this time I was standing up, though I don’t remember getting up.  In my haste to remove the filter I lost my balance and fell, and in a kneeling position I glanced up to see the corona.  All this took at most three seconds, so the corona must have appeared very suddenly.  I looked around me and saw — if that’s the word — the darkness that had enveloped everything.  I heard myself yelling incoherently, “My God! It’s incredible! Fantastic!” and so on.  I heard Bill yelling similar things and I think I heard Cal, but I had no awareness that anyone else was present — except that I clearly recall wondering why nobody else was reacting to the spectacle, so I must have been aware of their presence.  Later Bill and Cal told me that everyone had reacted with the the same hysteria . . . “

Joe also shared with us Annie Dillard’s account of her experience with the 1979 total solar eclipse.  She wrote:

“I had seen a partial eclipse in 1970.  A partial eclipse is very interesting.  It bears almost no relation to a total eclipse.  Seeing a partial eclipse bears the same relation to seeing a total eclipse as kissing a man does to marrying him, or as flying an airplane does to falling out an airplane.”

(How badly do you wish you were going to totality? If you aren’t going to make it for this one, make your 2024 plans now!)


Beyond the awe and spectacle, eclipses also generate discoveries.  Science magazine did a great piece on what past eclipses have helped us learn.  For example, around 150 BC, a Greek astronomer named Hipparchus of Nicaea used a solar eclipse to calculate the distance from the Earth to the moon.

Finally, there have been some reports of faulty viewing glasses.  If you are in doubt about yours, you can check your brand here.  If you find yourself without protective glasses, here’s a cool workaround from Neil deGrasse Tyson involving a colander.

Happy Eclipse Viewing!