Thursday, May 24, 2012
Climbing, April-May 2012
Just a placeholder to say that I'm a climbing trip behind on posting pictures and that I'm going to Bishop right freaking now!
Wednesday, April 11, 2012
Epigenetics and magical thinking
[updated to correct typos, clarify and add a link to the article I disagreed with]
Someone sent me a link to Dr. Mecola's website, in which he argues that because epigenetics exist, we are free from the Overlord of Determinism and can think our way out of cancer. Or something. I found the article to be carelessly written, misleading and just plain wrong about a lot of the science. So I wrote a rebuttal and tried to post it in the comment section. Have a look at the article - it's a short read.
The article reminds me of "The Princess Bride." One of the characters keeps saying "inconceivable!" to things that actually happened. Another character says, real quiet, "You keep on using this word. I do not think it means what you think it means." That's my initial reaction to this article. It's interesting to see how people are trying to apply and misapply concepts like epigenetics. It really speaks to how badly we as scientists convey the beautiful insights of the field effectively and accurately.
As a side note, the article seems to deeply confuse DNA sequence vs. DNA expression.
Here are my main responses. Article quote appears first, then my response to it.
--"Epigenetics Shatters "The Central Dogma""
I have no idea what this statement means :-) The central dogma hasn't been "shattered," nor would it be a bad thing if it were. Scientists have made careers and even won Nobel prizes characterizing apparent exceptions to it (we have one of these here at UCSF). In order for the central dogma to be "shattered," it would have to have been replaced with a theory that has better predictive power. Epigenetics doesn't do that; it explains a set of apparent anomalies by tacking on an additional mechanism for transmitting information in the form of DNA "marks." It's actually a pretty cool story.
--"The ramification of buying into the central dogma is that it leads to belief in absolute determinism, which leaves you utterly powerless to do anything about the health of your body; it's all driven by your genetic code, which you were born with."
Maybe for this guy, that statement is true. And in fact I do think "determinism" is probably the most accurate description of what's happening here, at the end of the day. But epigenetics is simply another causally-based mechanism to explain observations. For instance, epigenetic modifications can happen for all kinds of reasons, both those reflecting conscious changes to lifestyle and those reflecting exposure to environmental factors of which one is completely unaware :-)
--"'Cairns took bacteria whose genes did not allow them to produce lactase, the enzyme needed to digest milk sugar, and placed them in petri dishes where the only food present was lactase [I think they mean lactose here]. Much to his astonishment, within a few days, all of the petri dishes had been colonized by the bacteria and they were eating lactose. The bacterial DNA had changed in response to its environment.This experiment has been replicated many times and they have not found a better explanation than this obvious fact – that even primitive organisms can evolve consciously.'"
The experiment demonstrates natural selection in action, a process that for 150 years or so has proven to be very good at predicting things like speciation. Bacteria do have processes to acquire or reshuffle genes in times of extreme stress like starvation. It's their version of sex, a process which most eukaryotes use to generate diversity in populations. That some organisms "win" using this strategy demonstrates why it's been conserved in one form or another for billions of years: at the population level, diversity works. So yes, in a sense you could call this "evolving consciously," meaning that an active process exists to generate diversity within populations, but I don't see how that "shatters" the central dogma, nor does it in itself imply consciousness (although I do believe in a kind of consciousness across all life), any more than being hungry and seeking food does. These are evolved responses to stress, and they were selected because they worked.
--"What this all means is that you are not controlled by your genetic makeup. Instead, your genetic readout (which genes are turned "on" and which are turned "off") is primarily determined by your thoughts, attitudes, and perceptions"
This would be cool if true, but nothing in the previous text actually supports what he just said here. It's also kind of ridiculous in a way surely the author didn't intend. First of all, the entire question of whether "you" are being "controlled" by a genetic program seems deeply misleading. Who are "you?" in this scenario and who are the nefarious "genes" seeking to control you? But more seriously, of course you are "controlled" by your genes in the sense that the information you need to respond appropriately to the environment is encoded within them! Africans have a set of gene encoding melanin production that protects them from solar radiation. Are they "controlled by their genes" when they activate melanin production constitutively? There's a well-defined genetic program that's required to accurately separate chromatids during meiosis. are these genes "controlling you" when you activate them to make offspring? This makes no sense.
--"Now here's where epigenetics comes in … certain foods, such as broccoli and other cruciferous vegetables, garlic, and onions contain substances that act as histone inhibitors, which essentially block the histone, allowing your tumor suppressor genes to activate and fight cancer. By regularly consuming these foods, you are naturally supporting your body's ability to fight tumors."
Surely the author realizes that all genomic DNA (in eukaryotes anyway) is packaged in histones. Therefore eating foods that, if such activity resided in the food itself, "block the histone" would, in the logical extension, prevent any cell from accessing virtually all of its DNA. Therefore what's being suggested is that food can promote the appropriate acetylation of histones, driving a packaging configuration that prevents transformation (making cancer cells). While that may be true, and would be wonderful as preventative therapy, it's of course also true that the enzymes enacting this acetylation are responding to many cues. Some are environmental (and we can change that!) while some are coming from the hundreds of other proteins encoded by the genome. Shifting the emphasis entirely onto epigenetic modifications, as this article does, is just misleading.
"So the good news is that you are in control of your genes … You can alter them on a regular basis, depending on the foods you eat, the air you breathe, and the thoughts you think."
This is false. Your body does have ways to modulate the expression of your genes - true. "You" are not able to "alter them on a regular basis" in the sense implied here. The primary known ways that gene sequences are altered "on a regular basis" is in the immune system, where B and T cells induce hypervariability in antibody regions to create the ability to bind antigens (a cool story), during meiosis, when chromosomal arms cross over to generate diversity in offspring (also a cool story!) or for instance due to repair after oxidative damage to DNA.
Probably there are other ways that human cells change their own DNA sequence and expression, and it will be great to discover them! But framing the effect of epigenetics as a "little guy beats back mean old determinism" and blandly telling people they can think away their cancers, if only they just think the right thought! - is badly misinformed and borderline irresponsible. What if every reader took that as their new reality? They go off, change their thoughts, eat broccoli and decide what the hell do I need checkups for? I'm thinking fine and eating miracle epigenetic diets!
Someone sent me a link to Dr. Mecola's website, in which he argues that because epigenetics exist, we are free from the Overlord of Determinism and can think our way out of cancer. Or something. I found the article to be carelessly written, misleading and just plain wrong about a lot of the science. So I wrote a rebuttal and tried to post it in the comment section. Have a look at the article - it's a short read.
The article reminds me of "The Princess Bride." One of the characters keeps saying "inconceivable!" to things that actually happened. Another character says, real quiet, "You keep on using this word. I do not think it means what you think it means." That's my initial reaction to this article. It's interesting to see how people are trying to apply and misapply concepts like epigenetics. It really speaks to how badly we as scientists convey the beautiful insights of the field effectively and accurately.
As a side note, the article seems to deeply confuse DNA sequence vs. DNA expression.
Here are my main responses. Article quote appears first, then my response to it.
--"Epigenetics Shatters "The Central Dogma""
I have no idea what this statement means :-) The central dogma hasn't been "shattered," nor would it be a bad thing if it were. Scientists have made careers and even won Nobel prizes characterizing apparent exceptions to it (we have one of these here at UCSF). In order for the central dogma to be "shattered," it would have to have been replaced with a theory that has better predictive power. Epigenetics doesn't do that; it explains a set of apparent anomalies by tacking on an additional mechanism for transmitting information in the form of DNA "marks." It's actually a pretty cool story.
--"The ramification of buying into the central dogma is that it leads to belief in absolute determinism, which leaves you utterly powerless to do anything about the health of your body; it's all driven by your genetic code, which you were born with."
Maybe for this guy, that statement is true. And in fact I do think "determinism" is probably the most accurate description of what's happening here, at the end of the day. But epigenetics is simply another causally-based mechanism to explain observations. For instance, epigenetic modifications can happen for all kinds of reasons, both those reflecting conscious changes to lifestyle and those reflecting exposure to environmental factors of which one is completely unaware :-)
--"'Cairns took bacteria whose genes did not allow them to produce lactase, the enzyme needed to digest milk sugar, and placed them in petri dishes where the only food present was lactase [I think they mean lactose here]. Much to his astonishment, within a few days, all of the petri dishes had been colonized by the bacteria and they were eating lactose. The bacterial DNA had changed in response to its environment.This experiment has been replicated many times and they have not found a better explanation than this obvious fact – that even primitive organisms can evolve consciously.'"
The experiment demonstrates natural selection in action, a process that for 150 years or so has proven to be very good at predicting things like speciation. Bacteria do have processes to acquire or reshuffle genes in times of extreme stress like starvation. It's their version of sex, a process which most eukaryotes use to generate diversity in populations. That some organisms "win" using this strategy demonstrates why it's been conserved in one form or another for billions of years: at the population level, diversity works. So yes, in a sense you could call this "evolving consciously," meaning that an active process exists to generate diversity within populations, but I don't see how that "shatters" the central dogma, nor does it in itself imply consciousness (although I do believe in a kind of consciousness across all life), any more than being hungry and seeking food does. These are evolved responses to stress, and they were selected because they worked.
--"What this all means is that you are not controlled by your genetic makeup. Instead, your genetic readout (which genes are turned "on" and which are turned "off") is primarily determined by your thoughts, attitudes, and perceptions"
This would be cool if true, but nothing in the previous text actually supports what he just said here. It's also kind of ridiculous in a way surely the author didn't intend. First of all, the entire question of whether "you" are being "controlled" by a genetic program seems deeply misleading. Who are "you?" in this scenario and who are the nefarious "genes" seeking to control you? But more seriously, of course you are "controlled" by your genes in the sense that the information you need to respond appropriately to the environment is encoded within them! Africans have a set of gene encoding melanin production that protects them from solar radiation. Are they "controlled by their genes" when they activate melanin production constitutively? There's a well-defined genetic program that's required to accurately separate chromatids during meiosis. are these genes "controlling you" when you activate them to make offspring? This makes no sense.
--"Now here's where epigenetics comes in … certain foods, such as broccoli and other cruciferous vegetables, garlic, and onions contain substances that act as histone inhibitors, which essentially block the histone, allowing your tumor suppressor genes to activate and fight cancer. By regularly consuming these foods, you are naturally supporting your body's ability to fight tumors."
Surely the author realizes that all genomic DNA (in eukaryotes anyway) is packaged in histones. Therefore eating foods that, if such activity resided in the food itself, "block the histone" would, in the logical extension, prevent any cell from accessing virtually all of its DNA. Therefore what's being suggested is that food can promote the appropriate acetylation of histones, driving a packaging configuration that prevents transformation (making cancer cells). While that may be true, and would be wonderful as preventative therapy, it's of course also true that the enzymes enacting this acetylation are responding to many cues. Some are environmental (and we can change that!) while some are coming from the hundreds of other proteins encoded by the genome. Shifting the emphasis entirely onto epigenetic modifications, as this article does, is just misleading.
"So the good news is that you are in control of your genes … You can alter them on a regular basis, depending on the foods you eat, the air you breathe, and the thoughts you think."
This is false. Your body does have ways to modulate the expression of your genes - true. "You" are not able to "alter them on a regular basis" in the sense implied here. The primary known ways that gene sequences are altered "on a regular basis" is in the immune system, where B and T cells induce hypervariability in antibody regions to create the ability to bind antigens (a cool story), during meiosis, when chromosomal arms cross over to generate diversity in offspring (also a cool story!) or for instance due to repair after oxidative damage to DNA.
Probably there are other ways that human cells change their own DNA sequence and expression, and it will be great to discover them! But framing the effect of epigenetics as a "little guy beats back mean old determinism" and blandly telling people they can think away their cancers, if only they just think the right thought! - is badly misinformed and borderline irresponsible. What if every reader took that as their new reality? They go off, change their thoughts, eat broccoli and decide what the hell do I need checkups for? I'm thinking fine and eating miracle epigenetic diets!
Monday, April 09, 2012
Climbing: Yosemite and Sonora, April 2012
My buddy Kyle and I travelled to Yosemite to inaugurate this year's climbing season. Getting there wasn't pretty. I had stayed up until 5AM the night before to prepare my lab data presentation, a wholly avoidable tragedy created by my unwillingness to stop collecting data and start making a presentation. I mention this because the sleep deprivation caused me to miss several turns on the way to Yosemite, and we were therefore unable to crash until well after 1AM Friday night.
Kyle volunteers with Bay Area Mountain Rescue Unit. One his buddies who volunteers for the NPS, Blake, was already set up at Camp 4 and kindly let us split the site with him. So we were able to roll in late and get our tents set up without too much trouble. I slept very well!
Saturday morning I roll out of the tent, slap on some shoes and take care of the only thing that matters: COFFEE. We then hook up with several other NPS friends of Blake's (Sebastian, Val and ...?), then all head out to Reed's pinnacle. The more experienced climbers are looking to get some trad crack climbing in there, so Kyle and I bail out to Five and Dime for easy 5.8 warmup sport leads. Here's me trying to do justice to the view from the top of that wall.
After that we headed over to Pat and Jack's to meet up with Blake and friends. Kyle and I tackled the first pitch of this 5.9 - at least I think that was the route:
That's Kyle at the top. Beyond him is a technically beautiful - I mean really stunning - trad 5.10b that I got to climb with a top belay, following Sebastian after those guys arrived. Surprising moves, everything you needed but none of it obvious. Really nice climb.
When Sebastian led the route we had just done, he took two 9.8-ish mm ropes with him in order to top-belay me. Once I was up there, he set up a rappel and went to take off. I stopped him, looking at the "excuse-me-is-that-a-granny-knot?" overhand knot he had used to tether the ropes to one another.
Me: "uh...so, yeah. How sure are you that this knot is safe?"
Him, in thick German accent: "I am glad you asked! Never take anything for granted! It is an overhand knot that will not capsize [come undone under tension] under loads up to (...5?) kN! Also, look how its asymmetry makes it roll over rocks. This knot won't get stuck when you pull rope, and that is what ["vat"] makes it so useful!"
He was very enthusiastic about his knot. I, on the other hand, was enthusiastic about letting him be the first to rap down on his knot. Ultimately it worked fine for us both.
Once down, Blake and Kyle kept referring to this knot as an EDK. This, Sebastian discovered, is short for European Death Knot. He laughed and laughed at this, bending himself over in giggles the whole hike back every time he said "EDK."
We got back and were invited to a potluck with some of the NPS/BAMRU folks. That was great fun until the last two days came down on me like a sandbag. Kyle and I hiked back to our tents. It was a full moon so I stopped to admire El Capitan and the frozen-but-moving ghostliness of Bridalveil Falls in the half light. And then I slept. And slept.
Lucky for us on the way to Yosemite, one of the wrong turns I took led us near signs for Sonora. Sonora! That was where I first climbed outdoors, under the guidance of many of my then climbing buddies/mentors: Brian and Nick (who went on to climb El Cap together the next year), Joel ("It's a video") Tornatore and Annika before she abandoned us all for New Zealand. There's a secret-feeling place there called The Grotto, at the end of a rocky and pastoral approach, and it is truly gorgeous.
Once there, we hooked up with a sarcastic and fun group of climbers - and, alas, engineers - from the Bay Area. Kyle and I warmed up on a juggy 5.9. Here's Kyle doing what turned out to be his most skilled activity that day - hangdogging:
After playing belay monkey and smack talking some more, the alas-engineers were nice enough to let us toprope some of their sport- and trad-led routes. Here's me working on another excellent, technical 5.10 (c?) with a super-fun crux about 2/3 of the way up. Everyone else went left to a side pull, then back over. I tried to, and eventually managed to, go straight up after learning how to trust my feet on all that smeary goodness. The crux is just below the small outcropping directly above my head in this shot:
And here's me waving from the top:
After that we exchanged emails with the alas-engineers, talked about future climbing adventures together and then Kyle and I hiked back out. Traffic was light and before I knew it, I was happily back home with wife and cat.
As usual, I couldn't wait to get back into lab :-)
Kyle volunteers with Bay Area Mountain Rescue Unit. One his buddies who volunteers for the NPS, Blake, was already set up at Camp 4 and kindly let us split the site with him. So we were able to roll in late and get our tents set up without too much trouble. I slept very well!
Saturday morning I roll out of the tent, slap on some shoes and take care of the only thing that matters: COFFEE. We then hook up with several other NPS friends of Blake's (Sebastian, Val and ...?), then all head out to Reed's pinnacle. The more experienced climbers are looking to get some trad crack climbing in there, so Kyle and I bail out to Five and Dime for easy 5.8 warmup sport leads. Here's me trying to do justice to the view from the top of that wall.
After that we headed over to Pat and Jack's to meet up with Blake and friends. Kyle and I tackled the first pitch of this 5.9 - at least I think that was the route:
That's Kyle at the top. Beyond him is a technically beautiful - I mean really stunning - trad 5.10b that I got to climb with a top belay, following Sebastian after those guys arrived. Surprising moves, everything you needed but none of it obvious. Really nice climb.
When Sebastian led the route we had just done, he took two 9.8-ish mm ropes with him in order to top-belay me. Once I was up there, he set up a rappel and went to take off. I stopped him, looking at the "excuse-me-is-that-a-granny-knot?" overhand knot he had used to tether the ropes to one another.
Me: "uh...so, yeah. How sure are you that this knot is safe?"
Him, in thick German accent: "I am glad you asked! Never take anything for granted! It is an overhand knot that will not capsize [come undone under tension] under loads up to (...5?) kN! Also, look how its asymmetry makes it roll over rocks. This knot won't get stuck when you pull rope, and that is what ["vat"] makes it so useful!"
He was very enthusiastic about his knot. I, on the other hand, was enthusiastic about letting him be the first to rap down on his knot. Ultimately it worked fine for us both.
Once down, Blake and Kyle kept referring to this knot as an EDK. This, Sebastian discovered, is short for European Death Knot. He laughed and laughed at this, bending himself over in giggles the whole hike back every time he said "EDK."
We got back and were invited to a potluck with some of the NPS/BAMRU folks. That was great fun until the last two days came down on me like a sandbag. Kyle and I hiked back to our tents. It was a full moon so I stopped to admire El Capitan and the frozen-but-moving ghostliness of Bridalveil Falls in the half light. And then I slept. And slept.
Lucky for us on the way to Yosemite, one of the wrong turns I took led us near signs for Sonora. Sonora! That was where I first climbed outdoors, under the guidance of many of my then climbing buddies/mentors: Brian and Nick (who went on to climb El Cap together the next year), Joel ("It's a video") Tornatore and Annika before she abandoned us all for New Zealand. There's a secret-feeling place there called The Grotto, at the end of a rocky and pastoral approach, and it is truly gorgeous.
Once there, we hooked up with a sarcastic and fun group of climbers - and, alas, engineers - from the Bay Area. Kyle and I warmed up on a juggy 5.9. Here's Kyle doing what turned out to be his most skilled activity that day - hangdogging:
After that we exchanged emails with the alas-engineers, talked about future climbing adventures together and then Kyle and I hiked back out. Traffic was light and before I knew it, I was happily back home with wife and cat.
As usual, I couldn't wait to get back into lab :-)
Tuesday, March 27, 2012
Impressive paper on control of message activity during meioisis (Saccharomyces)
Link to article, for those with access: http://www.sciencemag.org/content/335/6068/552.abstract
I'll have more to say about what was reported in this paper - which I consider a landmark piece of work - as well as a layperson's summary...later. Right now I gotta head over to the Fischbach lab and run some preparative HPLC. Super exciting day.
Below are my notes for the presentation, for the aficionados who want to scan them. I was going to upload my slides, but they contain images from this and other non-open-access works. Not sure it's OK for me to present them here without the express permission of their authors and publishers (the latter, of course, sucks).
Brar et al (2012) JC presentation
Introduction
1. Lots of data in paper
Not going to be able to get through all biological and technical developments in 1 hour
Will focus on interesting biological questions answered
With technical review necessary to understand results
And biological review of context
Cell cycle control
translational control
Ambitious project yielding high-resolution data set that authors will be able to explore over several careers
2. Meiosis
Specialized developmental process yielding haploid germ cells from diploid progenitors
Chromosomal DNA is compacted by factos up to 1:10,000 relative to vegetative state
Transcription globally silenced
TFs and histones have been shown to exchange into/out of chromosomes
Mammalian mitosis: RNA Pol II excluded from mitotic chromosomes (Parsons & Spencer MCB 1997)
How is highly coordinated, precisely-timed process regulated?
Majority of DNA is tightly packaged and less accessible.
What role does translational regulation play during meiosis?
Authors wanted unbiased, high-resolution view of transcription and translation during cycle
3. History of relevant systematic approaches
1998: Ira Herskowitz (along with Joe DeRisi, Michael Eisen and Pat Brown) inventory changes in message levels
through meiosis in yeast. Develop basic structure echoed in current paper:
=> identify stages cytologically
=> Cluster genes by expression pattern
=> relate to cytological stage
=> use functional annotation to predict and mutagenesis to validate
2003: Current co-author Ghaemmaghami (here at UCSF with O'shea and Weissman) attempts to define
global protein expression in yeast.
2003: Pat Brown and Dan Herschlag labs collaborate to assess # active ribosomes assoc with all transcripts
microarray based
had to physically bin polysome peaks, leading to steps in data
2009: Landmark paper from Weissman lab. Used RNAseq to define ribosome footprint of each transcript.
Now able to precisely quantify # ribosomes per transcript, # transcripts and ribosome position on transcript
"Ribosome profiling"
2012: Using ribosome profiling approach, Weissman lab returns to 1998 Herskowitz project
Goal: precisely define transcriptional and translational activity using RNAseq sensitivity
Mitosis/meiosis review
Allows sexual reproduction, genetic recombination
In yeast, gametogenesis (sporulation) -> sexual spores
Two distinct processes: meiosis and cytokinesis
Meiosis: faithful replication of parental DNA, controlled recombination (crossover), separation 2N -> 4N -> 1N
Cytokinesis: physical separation of cells
Highly regulated, precise timing
A. Review meiosis in yeast
1. Overall process (basic)
2. Features specific to Sc
Induced by lack of glucose and nitrogen, + nonfermentable carbon source
IME1 = master regulator
NDT80 induces, requires Ime2 kinase (and Ndt80 accumulation) for activation
Ime2 phosphorylates Ime1 => degradation and Ndt80 => activation of meiotic progression
(Sopko et al MCB 2002)
3. Meiosis in Sc
Pre-meiotic DNA replication (S phase) resembles pre-mitotic in many ways
but is slower and requires different factors like MUM2.
Passage through meiotic S-phase required for DSBs, meiotic recomb and Synaptonemal complex formation
Pachytene checkpoint: after DSB/crossover => is damage repaired?
Questions:
How is segregation of organelles regulated? When does segregation happen?
Check claim that clustering of genes recapitulates cycle phasing
review staging controls used
good review of uORF regulation/activity
why didn't authors co-IP ribosomes?
review mitotic checkpoints to explain YDR506 and YLR445W experiments
how did they differentiate between protection by ribosome and protection by secondary structure, stress granules, etc?
monosome cut (RNase I treated vs. ctrl) then resolved by gel and excised 28 bp region.
Methods
1. RNA prep
+CHX: Harvest cells by filtration; drip into liquid nitrogen; pulverize
Take total RNA aliquot, treat w/ RNAse I vs U/T ctrl
sucrose gradient, monosome cut, excise 28bp region from polyacrylamide gel
add poly-A tail to 3' end
ss cDNA amplification; circularize; cut with ApeI; now do PCR to amplify from both ends
2. RNA sequence mapping
seq = variable mRNA read + polyA sequence
Align w/ up to 3 mismatches
If aligned seq matches region with AAA... then ambiguous
Resolved by using shortest and longest fragment w/ highest score
Degenerate reads (>= 18 of first 22 nucleotides were ’A’ bases) were eliminated.
rRNA hits were discarded
(Ingolia 2009; in present paper rRNA sequences experimentally subtracted)
Align all reads independently against:
yeast genomic sequences,
yeast processed protein-coding genes
yeast processed non-coding RNAs
if no alignment, then:
processed protein-coding transcripts
Then filter out low-complexity mappings:
discard >2 mismatches, <18 bp alignment against genome
Start codons were called by:
AUG and "initiation context score" >0.001
non-AUG (1 bp difference) and "initiation context score" >0.01
context score came from sequence matrix derived from AUG region of highly expressed genes
Ribosome density correlates better w/ protein abundance than does mRNA abundance (Ingolia et al 2009)
More later!
Wednesday, March 14, 2012
Talk summary: human vs. viral genetic arms race
The speaker at yesterday's microbial pathogenesis series (UCSF) was exceptional. Harmit Malik spoke about viral co-evolution with (primate) host
defense responses, casting the process as a genetic arms race. Using signature gene sequences and mining available genomes, he traced HIV, hepatitis
C, etc. back to various stages in primate evolution. Because retroviruses
insert their DNA into ours (sometimes becoming part of our germ line), by looking
for signature viral genes one can type the viral burdens of our
ancesters back in some inferred cases by hundreds of millions of years. Harmit then went into case studies showing how a virus acquired
functions to subvert host defenses and described the host response to
that - all at the amino acid level of key proteins over evolutionary time. His lab
further showed that if you reversed a host mutation back to its
"ancestral" state, it lost the ability to block viral activity. The research article is unfortunately closed access, so I won't link to it.
Anyway it was a fun morning. If you ever get a chance to hear Harmit speak I strongly recommend taking it; we see many speakers at UCSF and he was a stand out example of how to give a talk.
Anyway this led to a discussion with down-the-hall colleague Suzanne Noble in which she pointed out that viruses are thought to be most
virulent when they hop to a new host species, decimating it because no host-pathogen equilibrium has yet been established. Over time, the host
evolves a response and the virus becomes more stably integrated within the population. So is the end "goal" of a (retro)virus to not
be a virus at all, but to be a heritable genetic element in the host
genome? Another colleague in our lab, and always-fun-discussion partner, Mark Voorhies, pointed out that the
best of all worlds is to retain the ability to synthesize virions and induce lysis, such that if the host runs into trouble the latent virus can
jump ship. Such a strategy is well-characterized in bacteriophages and is called lysogeny. However in this case I suspect it's more complicated. For instance, the less frequently a virus escapes its host, over evolutionary time, the less
capable it will be to successfully escape. The requisite genes, having been isolated from selective pressure while dormant and transmitted, will not necessarily be competent to escape the host.
Anyway it was a fun morning. If you ever get a chance to hear Harmit speak I strongly recommend taking it; we see many speakers at UCSF and he was a stand out example of how to give a talk.
If you have any comments or want to set me straight on retroviral evolutiion and its consequences, please comment away.
update: here's the PLoS Biology comment introducing Harmit's publication:
update: here's the PLoS Biology comment introducing Harmit's publication:
Sunday, March 11, 2012
Future scientific advances and the United States
Small comment inspired by this article:
Great read. Sad that the US is falling behind, although maybe inevitable given the national arrogance that always accompanies hegemony. You start to take success and power for granted while listening to your own misleading stories of intrinsic greatness. Aside from that, one quibble is that he's predicting future accomplishments based on what Americans/westerners have generally emphasized. If we're diminishing as an innovative force due to loss of infrastructure and investment, then the conceptual flavor of innovation will also change as different cultures take the lead in asking the big questions.
Great read. Sad that the US is falling behind, although maybe inevitable given the national arrogance that always accompanies hegemony. You start to take success and power for granted while listening to your own misleading stories of intrinsic greatness. Aside from that, one quibble is that he's predicting future accomplishments based on what Americans/westerners have generally emphasized. If we're diminishing as an innovative force due to loss of infrastructure and investment, then the conceptual flavor of innovation will also change as different cultures take the lead in asking the big questions.
Saturday, March 03, 2012
A statement on nonviolence
This arose from an offline conversation with someone advocating - or for the purpose of debate pretending to adocate, I can't tell - for violence in civil rights movements, "Occupy Wall Street" included. Anyway here's my response to him, which predictably comes down on the side of nonviolence but for reasons that surprised me when I ended up writing this response, edited to correct grammar and typos:
" I think the heart of my reaction boils down to believing that almost anyone has the capacity to respond with empathy when presented with a more complete description of the world's dynamics. Even the most rabid conservatives who call for wholesale slaughter of brown people in the Middle East will respond with empathy and concern when someone they know is in trouble - even if responding with help and support violates every principle they spent years espousing or even enforcing. I call this one's "empathy radius" and use it to distinguish those who end up being (a modern United states) conservative from those who become progressive: what is your capacity to identify with others?
I agree that credible threats of force contribute to behavioral change in others, which I take it underlies your invoking the Black Panthers and the "Arab Spring" in Egypt. But let me ask you this: what changes in those others and what are the consequences of those changes? It's pretty well-established that strong emotions and credible threats are very effective in shutting down large portions of human brains while they resort to limbic-based reasoning. Therefore, by invoking violence credibly, you are diminishing the humanity of your "opponent." You also accept the terms of their end of the debate by acknowledging their "otherness." That may, as you indicate, result in short-term successes but does absolutely nothing to address the root cause - the willingness to see and treat others as outside of one's empathy radius. When people say that the enemy has won because you started acting like them, they may mean that you have debased youself. That's not what I hear. I hear that "they" have won because you have done nothing to substantively advance and change how conversations about power are constructed. You are now playing their game on their terms by having accepted their propositions so fundamentally that the acceptance defines everything fundamental about your response. They're not winning by eliciting a violent response from you; they're making you into them."
Monday, February 06, 2012
Duckicorn compression wave
Duckicorn standing compression wave. Spontaneously forming, barely had time to whip out the camera!
My favorite run in San Francisco
Last year, at the urging of my awesome lab mates, I ran my first half-marathon (Feb 2011) and full marathon (July 2011). After that, I decided to give running a rest and focus more on climbing, working, getting married...you know. The usual. Anyway last weekend it was time to start again so I had a nice run/hike, following my favorite path through this beautiful city. I live in Potrero Hill, so I first ran to the top of nearby Bernal Hill. View of downtown:
From Bernal I ran along 26th/25th street and found a cool park I'd never seen before, Douglass Dog Park. There's a bonafide if short class 4 scramble at the back end. I went up it and onto what was probably the less-than-legal side of a fence to catch a view of the next destination!
From there I scrambled down to Clipper Street, probably screwing up lots of people's anti-erosion measures. Not recommended if you want to avoid my accidental dickishness. From there I hit Twin Peaks blvd (mostly hiking now, some running):
Nearing the top, I saw some beautiful native poppies and lichen (possibly also native, but with lichen you never know. I consider them untrustworthy characters).
And of course, views from the top! Tons of people up there already, waiting to see the sunset.
On the way back down, there were some beautiful rock formations left over I imagine from the blasting they did to make the road.
Then over Mt. Sutro to drop by lab and pick up my bike. It had been stranded there since I went to the Keystone conference in Santa Fe, and had started talking smack about me to the other bikes. On the way I saw this cool tree. Its beauty almost makes up for my wife's current bad allergies; somehow I know it's this particular tree, halfway across the city, that's causing all the trouble. I mean, just look at that face. 100% trouble.
And then a nice bike ride home from Parnassus to Potrero. Great day! And if you're looking for an enjoyable run through/over the city, I highly recommend this route. I've also added in Mt. Davidson but the ugly postwar developments on its skirts make it nonawesome. However if there's daylight I strongly recommend adding in the forested paths over Mt. Sutro (behind UCSF). Gets up to about 7 miles and is pretty grueling.
From Bernal I ran along 26th/25th street and found a cool park I'd never seen before, Douglass Dog Park. There's a bonafide if short class 4 scramble at the back end. I went up it and onto what was probably the less-than-legal side of a fence to catch a view of the next destination!
From there I scrambled down to Clipper Street, probably screwing up lots of people's anti-erosion measures. Not recommended if you want to avoid my accidental dickishness. From there I hit Twin Peaks blvd (mostly hiking now, some running):
Nearing the top, I saw some beautiful native poppies and lichen (possibly also native, but with lichen you never know. I consider them untrustworthy characters).
And of course, views from the top! Tons of people up there already, waiting to see the sunset.
On the way back down, there were some beautiful rock formations left over I imagine from the blasting they did to make the road.
Then over Mt. Sutro to drop by lab and pick up my bike. It had been stranded there since I went to the Keystone conference in Santa Fe, and had started talking smack about me to the other bikes. On the way I saw this cool tree. Its beauty almost makes up for my wife's current bad allergies; somehow I know it's this particular tree, halfway across the city, that's causing all the trouble. I mean, just look at that face. 100% trouble.
And then a nice bike ride home from Parnassus to Potrero. Great day! And if you're looking for an enjoyable run through/over the city, I highly recommend this route. I've also added in Mt. Davidson but the ugly postwar developments on its skirts make it nonawesome. However if there's daylight I strongly recommend adding in the forested paths over Mt. Sutro (behind UCSF). Gets up to about 7 miles and is pretty grueling.
Friday, January 13, 2012
We need better biomedical model systems
How can we improve the model systems we use for biomedical research? http://www.slate.com/articles/health_and_science/the_mouse_trap/2011/11/lab_mice_are_they_limiting_our_understanding_of_human_disease_.html (via +Kyle Barbour).
I understand and sympathize with the momentum argument; there really
are a huge number of variables to consider when selecting a model
organism, and leveraging past results lends very powerful support to the
conclusions one wants to draw from current work. That said, it's worth
thinking hard about what better animal models as well as, from a humane
rather than scientific perspective, acceptable in vitro systems with
good predictive power. This is a point raised recently by Don Ganem in a
talk at USCF. We're really bad at working out results in vitro that
are predictive of in vivo activity. After reading the Slate article I'm
left wondering how much that problem stems from inappropriate animal
models and how much from misleading in vitro methods.
(cross-posted from google+)
(cross-posted from google+)
Friday, January 06, 2012
Lessons from the great Burning Man ticket fiasco debate
(Published in 2012 -- edited to correct typos and to improve clarity)
For those of you not affiliated with or remotely interested in the Black Rock Arts Festival (AKA "Burning Man"), the latest raging debate will be as much news to you as it will seem pointless squabbling in an internet back room :-) However, engaging in the controversy was captivating and educational. I'll try to tell the story in ways that highlight why. Bottom line: event organizers massively screwed up, formally endangering the ability of many thousands of its most active contributors to attend. The event will happen, but could be much damaged by a severe talent deficit. When discussing the problem online, a common response was: shut up, what's done is done so make the best of the new reality. This runs counter to everything I value about what the event tries to cultivate - so I picked a fight.
What: Burning Man (BM) is an art festival that happens the week before Labor Day in a high-elevation desert. That desert is empty for most of the year, becoming increasingly populated with temporary infrastructure as the event approaches, then lovingly restored afterwards to an empty desert. The event's focus is broader than making and admiring spectacular art. BM ethics also call participants to self-reliance: creating art, the event, one's community and ideally the world. However, because the event is also a real celebration, that's led to it being viewed as little more than an excuse for a weeklong party. That, combined with the fact that attendance is approaching 50,000, has made BM an irresistible target for scalpers.
A common refrain is that BM doesn't matter, nobody dies if they don't get to go, its not worth all the fuss, what's the big deal. That's a fair point. However, Burning Man (and to a large degree relationships at BM) helped me understand how much change I can create in my life and in my world. I don't participate in the event just to party. I participate to create a better world. That's not hyperbole; I think the event's influence extends far beyond that week in the desert. For example, I've argued that as United States citizens we control a disproportionate amount of the world's wealth per capita and are obligated to live as responsibly as possible. Minimizing waste, voting for people who will make positive changes in the world, etc. So, BM creates positive changes in people who really can make the world a better place. It creates participants and discourages spectating. This is why it matters to me.
The players: As you can imagine, selling tickets for an event of this size is complicated business even without the damaging influence of ticket predation. The BM organization ("the org") wants to get tickets directly to actual participants, as well as to encourage those who come to take an active role in creating the experience. Participants ("burners") also want this outcome, ideally as early as possible in order to facilitate creating large-scale, expensive art projects. Those who view BM as a glorified party, put on for them by others in exchange for the ticket price they paid, are derisively called "tourists," "sparkle ponies," etc, often with strongly tribal and discriminatory undertones. My limited experience has been that those who view BM as strictly recreation are perfectly happy to feed the scalpers. And finally of course there are the scalpers themselves who presumably view the ticketing process as an opportunity to engage in radical self-enrichment. How much of an issue is scalping? I haven't seen any hard numbers, but given the amount of money involved and the fact that BM sold out for the first time last year...presumably it's common. I think the org claims otherwise.
The issue: The org changed its ticketing system. Previously, tickets were released in levels, from the earliest and cheapest (sold in January) to the most expensive and latest (sold after the early layers were exhausted). The rationale, one I agree with, was that people very committed to creating the event would score tickets early in order to make sure they would be able to attend and bring their art. The sliding scale was established as an incentive to commit early. So, on a special day in January, the org's servers would jam and crash with the well-known issue of queueing a gazillion people in real time: a non-malicious denial of service attack made up of eager burners obsessively refreshing their browsers to secure a spot in virtual line. This year, after a couple months of internal deliberation and no public calls for input, the org announced that it would change how tickets were awarded. Instead of a queue in January, they said, would-be burners would instead register their credit cards, say how many tickets they wanted (up to 2 or 4 I think) and at what price level. Then a lottery decided who got tickets and their cards would be charged. 80% of all the tickets to be sold were assigned in this way.
Recently the lottery was enacted. The widely reported outcome among burners, predicted by many of us, was that very few burners got any tickets at all. For example, many camps of 30 or more people have only a handful of tickets among them, whereas this time last year virtually all of them were ticketed (and beginning to plan their projects). So where did all the tickets go? It could be reporting. Maybe most ticket-winners, not wanting to be jerks, are quieter than those who lost the lottery. But this clearly is not the case among camps reporting severe shortages; they polled their members to estimate the damage. And there are a lot of camps in this situation. In order to win a lottery, you need numbers on your side. The org told scalpers exactly how to win this: register lots of different names with different credit cards (or organize large groups of real individuals by promising to share scalping proceeds, or if trusted, hand them money outright to buy you a ticket). Then sit back and wait for the tickets to roll in. Unless a great reserve of "legitimately assigned" ticket purchases are sitting somewhere, it looks like scalpers gamed the hell out of the system. That's speculation; I have no data.
And now comes the topical issue. Epic complaining began on the internet. The org royally screwed up, made a decision without input, didn't listen when the terrible outcome was correctly predicted, etc. Incidence of the annual passive-aggressive responses, e.g., "I'm never going to BM again!" reached epic and early levels. In response, as I said above, were posted videos or statements claiming that the community needed something like the ticket disaster because it represented "chaos" and that we would all benefit from having our "expectations" unmet. People needed to stop "whining" and adapt constructively to the new reality.
I could not disagree more strongly. Here's a posted facebook response to such calls where I pick a fight (strong language edited out):
"With respect to everyone's touted and requested participation in the event, the arguments here make no sense. 1) "Complaining solves nothing." Feedback from the community means nothing? Then WTF does the event mean by referring to me as a "participant?" A silent one who passively accepts decisions from on high? 2) [My energies are] "better spent on one's project" ... that may never make it out [to the desert] with me? Wait...what? 3) "Passively accept the chaos that other peple's decisions created for you because it's good for you." This is also known as "no really it's awesome that I'm [disrupting your ability to plan] as a result of my [terrible] behavior." OK, dude. When did we decide that this was a fundamentally authoritarian structure in which I adjust to your bad decisions and tell myself that I like it?"
"I'll also point out that the organization has taken the ability to choose to attend, based on intent and commitment, entirely out of our hands. 80% of the tickets were assigned at random. So the event they chose is one that accepts attendees based solely on the criteria of convenience to the event and not on any individual's investment in contributing to the event. The outcome of that strudture is - or should be - painfully obvious.
"[Folks] can try to hide behind calling participants "whiners" ... but it doesn't make them any less a promoter of unquestioning respect for borg [org] authority. "Accept the [huge ticketing mistake] by calling it healing chaos?" Exemplary self determination dude.
"For instance. Can [those saying we should not complain and accept the issue] explain how democracy happens without "whining?" Were civil rights protesters "whiners?" How ...might we dissent from the planned creation of any event without "whining?" Do we politely queue somewhere?"
...and so on. The argument was that we should silently accept this as reality and just deal with it rather than expressing dissatisfaction. I obviously felt otherwise, and strongly.
This leads to to one of two lessons I took from the debate. Some were immediately inclined to accept this outcome as irreversible. As reality. I was not. This isn't bad weather, it's a system we agree to create. The price of my agreement to participate is debate and discussion. Otherwise, how are the ethics of participation and self-reliance being enacted? By passively and silently accepting the decisions other people made that affect my choices. No way. This affects an event I value and therefore demanding change is appropriate. In other words, this isn't complaining - it's political discourse.
The other lesson I drew came from some pushback against my position. As several people pointed out, many people complain with no intention of creating improvement. All this does is create noise without leading to better outcomes. In response, I wrote:
"...that clarifies a lot for me. Thanks for translating. Like you, I don't value straight "whining" if by "whining" we mean "negative feedback not motivated by a desire to improve." And probably like you, I've been in lots of conversations where I'm trying to engage the issues but find I'm trying to hit a moving target because the complainer isn't really talking about the issues. They're upset and venting, or unwilling/unable to get at what's really bothering them. In that case I think the answer is to call out the behavior. [Pro-acceptance friend #1] does this by saying "shut the *&$! up," which [is] ... more direct than what I do, e.g., "I don't think you're upset about these specific issues. Can you identify what the core issue is?" When what I'm often thinking is "you're interacting like a child. Quit wasting my time.""
Bottom line: it's important to refuse passively accepting bad outcomes. "Participating" means calling out bad behavior regardless of being characterized as a "whiner." That said, it's probably appropriate to limit expressions of dissatisfaction that do nothing obvious to help create better outcomes.
So what now? I think my wife Haley was exactly right: scrap it all and do it over. No tickets have been distributed. Refund the charges and do it all over, probably with stying conservative and using the system that was in place for many years. I don't think the org will do this, so we are left with band-aid approaches like setting up aftermarket exchanges and a vague call to "report scalpers." Maybe there will be better solutions proposed, and I will happily promote good ideas whenever I hear them.
This is a classic blunder of having too few, and possibly too arrogant, minds on a problem that affects many people. So I would radically change the way the org conducts itself. Decisions that affect the coordinated efforts of tens of thousands of people need to be transparent. Submit a "request for proposals." Go open source and ask people for suggestions on the best and fairest ways to distribute tickets that adheres to the values we all signed on with. There are a lot of smart people who are heavily invested in making BM a continuing success. Use them!
For those of you not affiliated with or remotely interested in the Black Rock Arts Festival (AKA "Burning Man"), the latest raging debate will be as much news to you as it will seem pointless squabbling in an internet back room :-) However, engaging in the controversy was captivating and educational. I'll try to tell the story in ways that highlight why. Bottom line: event organizers massively screwed up, formally endangering the ability of many thousands of its most active contributors to attend. The event will happen, but could be much damaged by a severe talent deficit. When discussing the problem online, a common response was: shut up, what's done is done so make the best of the new reality. This runs counter to everything I value about what the event tries to cultivate - so I picked a fight.
What: Burning Man (BM) is an art festival that happens the week before Labor Day in a high-elevation desert. That desert is empty for most of the year, becoming increasingly populated with temporary infrastructure as the event approaches, then lovingly restored afterwards to an empty desert. The event's focus is broader than making and admiring spectacular art. BM ethics also call participants to self-reliance: creating art, the event, one's community and ideally the world. However, because the event is also a real celebration, that's led to it being viewed as little more than an excuse for a weeklong party. That, combined with the fact that attendance is approaching 50,000, has made BM an irresistible target for scalpers.
A common refrain is that BM doesn't matter, nobody dies if they don't get to go, its not worth all the fuss, what's the big deal. That's a fair point. However, Burning Man (and to a large degree relationships at BM) helped me understand how much change I can create in my life and in my world. I don't participate in the event just to party. I participate to create a better world. That's not hyperbole; I think the event's influence extends far beyond that week in the desert. For example, I've argued that as United States citizens we control a disproportionate amount of the world's wealth per capita and are obligated to live as responsibly as possible. Minimizing waste, voting for people who will make positive changes in the world, etc. So, BM creates positive changes in people who really can make the world a better place. It creates participants and discourages spectating. This is why it matters to me.
The players: As you can imagine, selling tickets for an event of this size is complicated business even without the damaging influence of ticket predation. The BM organization ("the org") wants to get tickets directly to actual participants, as well as to encourage those who come to take an active role in creating the experience. Participants ("burners") also want this outcome, ideally as early as possible in order to facilitate creating large-scale, expensive art projects. Those who view BM as a glorified party, put on for them by others in exchange for the ticket price they paid, are derisively called "tourists," "sparkle ponies," etc, often with strongly tribal and discriminatory undertones. My limited experience has been that those who view BM as strictly recreation are perfectly happy to feed the scalpers. And finally of course there are the scalpers themselves who presumably view the ticketing process as an opportunity to engage in radical self-enrichment. How much of an issue is scalping? I haven't seen any hard numbers, but given the amount of money involved and the fact that BM sold out for the first time last year...presumably it's common. I think the org claims otherwise.
The issue: The org changed its ticketing system. Previously, tickets were released in levels, from the earliest and cheapest (sold in January) to the most expensive and latest (sold after the early layers were exhausted). The rationale, one I agree with, was that people very committed to creating the event would score tickets early in order to make sure they would be able to attend and bring their art. The sliding scale was established as an incentive to commit early. So, on a special day in January, the org's servers would jam and crash with the well-known issue of queueing a gazillion people in real time: a non-malicious denial of service attack made up of eager burners obsessively refreshing their browsers to secure a spot in virtual line. This year, after a couple months of internal deliberation and no public calls for input, the org announced that it would change how tickets were awarded. Instead of a queue in January, they said, would-be burners would instead register their credit cards, say how many tickets they wanted (up to 2 or 4 I think) and at what price level. Then a lottery decided who got tickets and their cards would be charged. 80% of all the tickets to be sold were assigned in this way.
Recently the lottery was enacted. The widely reported outcome among burners, predicted by many of us, was that very few burners got any tickets at all. For example, many camps of 30 or more people have only a handful of tickets among them, whereas this time last year virtually all of them were ticketed (and beginning to plan their projects). So where did all the tickets go? It could be reporting. Maybe most ticket-winners, not wanting to be jerks, are quieter than those who lost the lottery. But this clearly is not the case among camps reporting severe shortages; they polled their members to estimate the damage. And there are a lot of camps in this situation. In order to win a lottery, you need numbers on your side. The org told scalpers exactly how to win this: register lots of different names with different credit cards (or organize large groups of real individuals by promising to share scalping proceeds, or if trusted, hand them money outright to buy you a ticket). Then sit back and wait for the tickets to roll in. Unless a great reserve of "legitimately assigned" ticket purchases are sitting somewhere, it looks like scalpers gamed the hell out of the system. That's speculation; I have no data.
And now comes the topical issue. Epic complaining began on the internet. The org royally screwed up, made a decision without input, didn't listen when the terrible outcome was correctly predicted, etc. Incidence of the annual passive-aggressive responses, e.g., "I'm never going to BM again!" reached epic and early levels. In response, as I said above, were posted videos or statements claiming that the community needed something like the ticket disaster because it represented "chaos" and that we would all benefit from having our "expectations" unmet. People needed to stop "whining" and adapt constructively to the new reality.
I could not disagree more strongly. Here's a posted facebook response to such calls where I pick a fight (strong language edited out):
"With respect to everyone's touted and requested participation in the event, the arguments here make no sense. 1) "Complaining solves nothing." Feedback from the community means nothing? Then WTF does the event mean by referring to me as a "participant?" A silent one who passively accepts decisions from on high? 2) [My energies are] "better spent on one's project" ... that may never make it out [to the desert] with me? Wait...what? 3) "Passively accept the chaos that other peple's decisions created for you because it's good for you." This is also known as "no really it's awesome that I'm [disrupting your ability to plan] as a result of my [terrible] behavior." OK, dude. When did we decide that this was a fundamentally authoritarian structure in which I adjust to your bad decisions and tell myself that I like it?"
"I'll also point out that the organization has taken the ability to choose to attend, based on intent and commitment, entirely out of our hands. 80% of the tickets were assigned at random. So the event they chose is one that accepts attendees based solely on the criteria of convenience to the event and not on any individual's investment in contributing to the event. The outcome of that strudture is - or should be - painfully obvious.
"[Folks] can try to hide behind calling participants "whiners" ... but it doesn't make them any less a promoter of unquestioning respect for borg [org] authority. "Accept the [huge ticketing mistake] by calling it healing chaos?" Exemplary self determination dude.
"For instance. Can [those saying we should not complain and accept the issue] explain how democracy happens without "whining?" Were civil rights protesters "whiners?" How ...might we dissent from the planned creation of any event without "whining?" Do we politely queue somewhere?"
...and so on. The argument was that we should silently accept this as reality and just deal with it rather than expressing dissatisfaction. I obviously felt otherwise, and strongly.
This leads to to one of two lessons I took from the debate. Some were immediately inclined to accept this outcome as irreversible. As reality. I was not. This isn't bad weather, it's a system we agree to create. The price of my agreement to participate is debate and discussion. Otherwise, how are the ethics of participation and self-reliance being enacted? By passively and silently accepting the decisions other people made that affect my choices. No way. This affects an event I value and therefore demanding change is appropriate. In other words, this isn't complaining - it's political discourse.
The other lesson I drew came from some pushback against my position. As several people pointed out, many people complain with no intention of creating improvement. All this does is create noise without leading to better outcomes. In response, I wrote:
"...that clarifies a lot for me. Thanks for translating. Like you, I don't value straight "whining" if by "whining" we mean "negative feedback not motivated by a desire to improve." And probably like you, I've been in lots of conversations where I'm trying to engage the issues but find I'm trying to hit a moving target because the complainer isn't really talking about the issues. They're upset and venting, or unwilling/unable to get at what's really bothering them. In that case I think the answer is to call out the behavior. [Pro-acceptance friend #1] does this by saying "shut the *&$! up," which [is] ... more direct than what I do, e.g., "I don't think you're upset about these specific issues. Can you identify what the core issue is?" When what I'm often thinking is "you're interacting like a child. Quit wasting my time.""
Bottom line: it's important to refuse passively accepting bad outcomes. "Participating" means calling out bad behavior regardless of being characterized as a "whiner." That said, it's probably appropriate to limit expressions of dissatisfaction that do nothing obvious to help create better outcomes.
So what now? I think my wife Haley was exactly right: scrap it all and do it over. No tickets have been distributed. Refund the charges and do it all over, probably with stying conservative and using the system that was in place for many years. I don't think the org will do this, so we are left with band-aid approaches like setting up aftermarket exchanges and a vague call to "report scalpers." Maybe there will be better solutions proposed, and I will happily promote good ideas whenever I hear them.
This is a classic blunder of having too few, and possibly too arrogant, minds on a problem that affects many people. So I would radically change the way the org conducts itself. Decisions that affect the coordinated efforts of tens of thousands of people need to be transparent. Submit a "request for proposals." Go open source and ask people for suggestions on the best and fairest ways to distribute tickets that adheres to the values we all signed on with. There are a lot of smart people who are heavily invested in making BM a continuing success. Use them!
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