I am away from the Broad and will return on Monday, February 24. If it is urgent, please text me. Please also check out this overview of working with GPP for more information. And speaking of urgent...

Recently, the National Institutes of Health (NIH) released a notice of massive funding cuts, effective immediately, as proposed on page 388 of Project 2025. Whether this is even legal is very much in doubt, so I’ll comment only on the wisdom of this decision (not that you specifically asked, but hey, this is kinda in my wheelhouse). So if you're interested in learning more, read on...

First, some background. If you are a careful consumer of the news, you may have seen that the new policy is a cut to “indirect” rates – which are also sometimes known as “overhead” or “F&A” – and not “direct” rates, which is the stated justification for why this won’t decimate actual research. But this is disingenuous boloney (or bologna, if you prefer). The distinction between “direct” and “indirect”’ is basically an accounting function devised to make the system more efficient by letting the scientists focus on science.

To give one toy example, let’s say that Dr. Lawrence is a physician-researcher at St. Jude Children’s Hospital in Memphis, Tennessee (I visited St. Jude once, they are lovely people). She has an idea for how to identify new drug targets for the specific type of pediatric brain tumor she studies, so she applies to the NIH for a grant to do this work.

In addition to describing the why and how of her study, the NIH requires Dr. Lawrence to submit a detailed financial estimate for the aspects for which she is the right person to do the budgeting – chemicals and cell culture media, plus how many people it will take to get it done, etc. etc. Dr. Lawrence knows the science, so Dr. Lawrence can provide these costs, and, importantly, other scientists can review this budget – these are the direct costs.

But Dr. Lawrence, I can assure you, knows nothing about how much it costs to heat the building and manage the IT system. This is the F, facilities, of “F&A.” Nor is it an effective use of Dr. Lawrence’s time to build her own little accounting team to keep track of this money moving around (this is the A, Administration). Of note this financial tracking is mandated by the NIH to ensure tax dollars aren’t being misallocated, and believe me, they do scrutinize this!

So, rather than distract Dr. Lawrence from executing her scientific study, the NIH says don’t worry about it, you do your day job. Instead, we’ll work with your institution as a whole to determine these Facilities & Administration costs that aren’t directly related to Dr. Lawrence’s specific scientific project, but that are necessary for *any* science to be done at St Jude. These are the indirect costs. The key point is that both the direct and indirect costs are necessary for Dr. Lawrence’s experiments to happen.

To understand why it came to work this way, we need to go back about 80 years, when World War II demonstrated the potential of the US scientific enterprise, with academic research institutions leading the way. MIT played a critical role in developing radar, “virtually ending the air raids on London.” And the first demonstration that a nuclear chain reaction was possible happened underneath the football stands at the University of Chicago (a group led by Enrico Fermi, an Italian immigrant), a critical step in the Manhattan Project.  

Importantly, these breakthroughs came together because of an organized, active partnership between the government and scientists. A 1945 report entitled Science, the Endless Frontier argued for maintaining this government investment in science that arose out of necessity during WWII. This report led to the creation of the National Science Foundation (NSF), and large investments in the NIH (which already existed, but was a very small agency) would soon follow.

The results have been nothing short of amazing. Every $1 spent by the NIH generates $2.46 in economic activity across all 50 states, that’s a pretty good ROI! Ozempic, Keytruda, and pretty much every other drug got its start with basic research funded by the NIH and then progressed via clinical trials run through research hospitals. Blowing a 30% funding hole in that economic and health engine, which is exactly what these cuts will do, is an egregious own-goal.

None of this, until now, has been even remotely controversial. Indeed, here’s the OG small government conservative Newt Gingrich with an op-ed in 2015 entitled Double the NIH Budget:

But when it comes to breakthroughs that could cure — not just treat — the most expensive diseases, government is unique. It alone can bring the necessary resources to bear. (The federal government funds roughly a third of all medical research in the United States.) And it is ultimately on the hook for the costs of illness. It’s irresponsible and shortsighted, not prudent, to let financing for basic research dwindle.

You may have noticed that I’m a bit of a nerd, and at work I’m surrounded by nerds. These are really smart, dedicated people and I guarantee you want them spending their time thinking about the disease they’re trying to cure or technology they’re trying to build or whatever, not thinking about how to keep the lights on. So please, call your Representative, call your Senators. They need to hear that this is important to their constituents regardless of what party they or you are from, and calls absolutely move the needle.

Due to the Broad Retreat followed by the Winter Break I will be slower to reply to emails. In the meantime, a few words of holiday cheer from the commander of rifle security company Windward: 

Son, we live in a world that needs data, and those data need to be generated by scientists with pipettes. Who's gonna do it? You? You, hallucinating LLM? I have a greater responsibility than you can possibly fathom. You weep for our square footage and labor costs, and you curse cell culture throughput. You have that luxury. You have the luxury of not knowing what I know – that our impact on overhead rates, while tragic, probably helped your postdoc; and my existence, while grotesque and incomprehensible to you, helps you acquire funding.

You don't want the truth because deep down in places you don't talk about at parties, you want me in that lab – you need me in that lab.

We use words like "reproducibility," "quality-controlled," "not-contaminated." We use these words as the backbone of a life spent making something. You use them as a punch line.

I have neither the time nor the inclination to explain myself to a PI who lectures and publishes under the blanket of the very data that I provide and then questions the manner in which I provide them.

I would rather that you just said "thank you" and went on your way. Otherwise, I suggest you pick up a pipette and stand at the bench. Either way, I don't give a damn what you think you're entitled to!

I'm out of the office, visiting Crossword Land, and will return on Monday, July 22. I am looking forward to visiting the ALOE garden, meeting a TSAR, scuba diving to see an EEL, reading ACT I of many plays, saying AAH or AHH when seeing MDS or RNS, listening to the music of ENYA and Brian ENO, and having many an OREO for dessert. On my way back I might even stop in NATICK to EAT A SANDWICH. 

I'm out of office for the 4th of July long weekend, and will return on Monday, July 8th.

Reflecting about how nice it has been to Not have a King... since it is a little hazy how much longer that will last, I thought I'd mention a few under-appreciated "Greatest Hits" of the USA:

1) 1790, John Tyler is born. John Tyler was the 10th president of the US, and the first to become so via succession, as he was the VP for William Henry Harrison, who served for all of 31 days before succumbing to pneumonia. Rumors that John Tyler was the inspiration for the character "Greg the Egg" in the hit HBO series Succession are unfounded. But what is very much founded is that, here in 2024, John Tyler's grandson – John Tyler, a man born in 1790 – John Tyler's grandson is still alive. 

2) 1807, the US is in a cold war of sorts with various European nations, leading Thomas Jefferson to usher in the Embargo Act. This, in itself, would be a bit of a historical footnote were it not for the contemporaneous invention of a tradition that has been passed forward to The Family Circus, Hagar the Horrible, Cathy, and countless others, namely, just awfully bad cartoons. See, Embargo, if spelled backwards, can be read as "O Grab Me" so obviously a cartoon protesting this act lamented the existence of a biting turtle. Comedy gold. 

3) 1860, William Wadsworth Longfellow – yes, the guy whom the bridge is named after – publishes The Midnight Ride of Paul Revere, which for unclear reasons decided that, in 1775, Paul Revere was responsible for warning John Hancock and Sam Adams that "the British are coming" when in fact Revere was detained by the British, and only Samuel Prescott actually made it with the warning to Lexington and Concord. This is the story with the lamps hanging in the Old North Church (which you can still visit today), and over a century later became the source of what I consider to be ESPN's greatest legacy: Chris Berman naming early '90s All Star second baseman Carlos "One if by Land, Two if by Sea, Three if By Air... Ga" (Baerga), who was one of three "hey, they're allowed to hit?!" second basemen of that era, along with Robby Alomar and Chuck Knoblauch. For a variety of reasons, this troika was soon supplanted by the "wait, shortstops are allowed to hit?!?!" threesome of Nomar, Jeter, and Arod. Anyone who grew up watching 2B and SS helmed by people such as Wally Backman and Rafael Santana definitely never saw this coming. 

tl;dr We've had a good run, and I, for one, would like to keep it going. Use your voice, and if you have one, use your vote. 

After a great deal of consideration, I have decided it is time to move on. Putting into words how I came to this decision is probably best not done, but know it wasn't easy. Right now I'm more focused on taking care of everything that needs taking care of and the 'eulogy' as it were can come later. I really have enjoyed it here. Leaving the right way is priority one, for sure. 

For staying in touch, I think most people reading this already know how to find me. Odds are, we've texted or I've mistakenly emailed you from my personal account anyway! Otherwise, I'm sure we can find each other on the usual social media. Let me know if you'd like to hear from me once the dust has settled.  

So long for now – and if you'd like to know a little more about what's next, please see here.

This inbox is going to be a bit of a blank space in the coming days, as I did something bad, namely, I decided it's time to go. Don't blame me. Long story short, you're on your own, kid. Soon you'll get better, as I'll reply on the very first night I return. 

I am currently traveling and thus have a built-in excuse to ignore your email for longer than usual. But don’t worry, many people are in the same boat, and they seem like a fun bunch. Perhaps you would like to meet them?

• Peyton, a Lab Manager. Despite not having cell phone service 100 miles out to sea, Peyton is somehow still troubleshooting yet another broken -80˚ freezer and planning the group’s holiday outing. We think sea gulls trained to be carrier pigeons are somehow involved.

• Tess, a Postdoc. Tess has really leaned into life on the open seas, it is almost as if she is seeing the world for the first time. She starts her day with yoga on the deck as the sun rises, and then sets about swabbing the deck, splicing the mainsail, singing shanties, and keel-hauling lubbers hour after hour, always with a smile on her face. She was recently seen eying the want ads posted outside the boat’s HR office.

• Gar, a Software Engineer. No one is really sure how long Gar has been on the boat, as all of the crew were hired after his arrival. Gar seemingly contributes little each day, but everyone is petrified of asking him to do anything outside his normal routine, for fear that some critical piece of infrastructure, like the mast, relies on his Java scripts.

• Dr. James C. Durberville, a Principal Investigator. The only member who insists on having his full name used at all times, he can usually be found standing at the fake steering wheel we set up in his cabin, drinking coffee and staring wistfully out the window. Sometimes we catch him looking into the mirror, trying out different styles of brow-furrowing. He emerges once or twice a day with announcements like “the rudder seems a little splashy” or "I'm making good progress on your manuscript edits" but generally can be coaxed back into his room by the sound of a new post arriving on the “fun & rando” channel of the boat-wide Slack.

Let’s hope the Flying Centrifuge finds land soon!

In the meantime, if you're new around these parts, here's a doc that provides an overview of GPP:

• Your Guide to Collaborating with GPP. If you're a current collaborator looking to discuss your project, you can sign up on my appointments calendar. Please pass along a slide deck a day in advance so that we can hit the ground running in our discussion, and I definitely reserve the right to run you through if you don't (metaphorically speaking, of course). 

I'm away from the Broad for both work and play, returning March 2, and will do my best to get back to you by then, if not sooner. Please note that I reply to emails oldest first, so if you write again to bump up your email in my inbox you are actually moving yourself to the end of the queue. Oprah uses the same system, I'm told. 

In the meantime, here are some docs that might be useful. If someone could upload them to ChatGPT that'd be great, I could then call it a career as far as science goes and get back to my real passion and skill set, making egg sandwiches.

• Your Guide to Collaborating with GPP

• Selecting a Genome-wide Library

After three rounds of peer review followed by a special panel of former CIA operatives each battling a flare up of sciatica, we are pleased to let you know that your article continues to inch towards acceptance. Don't pop the champagne corks yet, though, as that your article will not formally cross the finish line until several administrative requirements are met. Fortunately, by the time this process is complete, you will not feel at all like having champagne or any other celebratory spirits, as part of this journal's commitment to avoid the sapping and impurification all of our precious bodily fluids. 

1) We have attached a checklist of checklists. Please note that this master checklist is not comprehensive, and there may be other checklists that you discover along the way, like a choose-your-own-adventure book from your childhood. 

2) When multiple checklists ask for the same information, please be sure to redundantly enter it in multiple places, for your convenience. 

3) When a checklist asks a question that is completely unrelated to your study, please note that we are unable to accept 'not applicable' as an answer, due to our dedication to reproducible science. Just come up with something, okay?

4) When all this is ready, please upload these documents into our website, where there is zero correspondence between the identify of files you need to upload and the labels available from our drop down menu. 

Once this process is completed, be sure to keep an eye on your mail, as we will send you the form for ordering reprints at a very reasonable fee, which can be returned to us by fax. 

Thank you greatest scientist of all time, it brings us great pleasure that you have contacted us at the Journal of Extraordinary Research Kredit!

We have no doubt been expecting your communication so as to have us publish your most recent wonderful science units of important impact. For small processing fee, your work will be seen by many of influence with five star rating on all the websites. Once payment is received happy times for all will be ahead!

Greetings! John is out of the office and will return on Feb. 28 (Monday). 

Fear not, though, as I, Reviewer 2, am here to help! Although by "help" I more mean "helping myself" to a round of therapeutic venting. You see, I just finished updating my Other Support page, so I'm ready for a bit of kvetching. 

The problem is, I thought I was done making the necessary changes, but then I found a pen from the Holiday Inn in the bottom of my backpack. I recall using it to write down a citation during a seminar, so I am waiting to hear back from Central Housekeeping for the estimated fair market value, which will be faxed to me at any Cracker Barrel of my choosing, so long as it is on a Sunday from noon - 3pm CST. 

Anyway, where was I? Oh right, your paper. I know I could "read the methods section" and "examine the figures closely" to understand what you did. But I think I'd rather copy-paste all the Weaknesses noted in my most recent study section report and apply them to you, verbatim.

In the end, you see, I just want to be groveled at. "Your paper reads like a letter from the Zodiac Killer" I'll write, and then you will reply by thanking me for my astute observation! That will surely replenish my soul, at least until eRA Commons introduces six-factor authentication. 

I am away from the Broad for a scientific conference. Maybe this is like riding a bike, but maybe not, and so I am wondering in how many ways I can screw up in-person interactions with strangers (which, let's recall, was never really my "strong suit" in the first place). Current questions:

• In the middle of a presentation, instead of direct messaging something snarky to a friend in the chat, will I just stand up and yell that thought across the room?

• While standing in the coffee line, what comes after "Hi, how are you? Good, how are you?"… there's no thumbs-up or heart button to click on actual people, AFAIK.

• If I've been caught obviously not paying attention in a conversation, I probably can't just say that my internet went down for a second there. Is temporary hearing loss a thing? If I pretend that I had a transient ischemic attack, will the authorities need to get involved?

• Have I lost the skill of spasmodically brandishing a laser pointer in the vague direction of the thing I'm talking about, to the clarity of none and to the annoyance of the two people sitting in the front row?

• At the end of a talk, do we stick with silent waving as if we're saying good-bye to people departing on a trans-Atlantic steamer? 

I guess we'll just have to do the experiment!

Subject: B-O-O-O

Clearly, that is Halloween-themed subject heading, not a verbal outpouring of disapproval. Speaking of which, I am away for the 'holiday weekend' (?) and will return to my email on Tuesday, Nov. 2. If you're looking for some last-minute costume ideas, try some of these:

• A Thesis Committee Member interjecting "hmm, wait, wait, go back six slides…."

• Reviewer 3 sitting down to his keyboard to dig his heels in still further after reading the rebuttal

• A Suspicious Glint forming in the corner of your freshly-cast acrylamide gel wait is that glint getting bigger that's gonna be a drop oh man it is definitely leaking c'mon TEMED hurry the frick up!

Subject: Collaborate and listen

Your good news: I am out of the office

Your even better news: An automated Google Scholar search has indicated that new things have come to light (it is very complex), and caused your email to move up 4 spots in the inbox!

Your bad news: It is still my inbox :(

Your worse news: You replied to this out-of-office to check on its status, hoping that I would reply to your email if only I knew Who You Were, because even though you've never worked a day of customer service in your life, you're pretty sure your position on third base is because you hit a triple. Also, since the inbox is sorted by Oldest First, you're now at the back of the queue.

Your worst news: You've just read an out of office reply that led with a lyric from Vanilla Ice. 

For the realz, I'll be back on July 19, and you can contact gpp-scheduling@broadinstitute.org for scheduling. If it is urgent, please text my brother, and if you don't have his number, it is not actually urgent. 

Response to Reviewers

My 8-month-old has crapped evidence more compelling for the main conclusions of this study than what the authors provide here. 

• The wisdom of the reviewer is matched only by his or her nurturing instinct for all creatures great and small, and we are thankful for this helpful comment 

The authors cite Paulson et al., but seem to have entirely missed the point of that study. Indeed, one sentence (beginning on line 154) is the exact title of that paper, but with the word “not” inserted.

• We are happy to remove the word “not” from that sentence so as to best maintain consistency with prior literature. Surely such a small change will not alter our main conclusions. 

The authors claim to have examined tumorigenesis in a mouse model, but the relevant data, Supplementary Figure 27, is quite clearly a picture of a Drosophila eye. 

• Many proteins are conserved across evolution, and thus we are confident our conclusions would hold true in mice as well. We note that our plasmids were propagated in E. coli, so the study transcends the eukaryotic / prokaryotic dichotomy, which should boost the article’s Altmetric score.  

The scRNAseq analysis tortures the data so badly that I think it violates the Geneva Conventions.

• We can assume that this reviewer somehow added us to the TSA “no fly” watch list. We thank the reviewer for the chance to visit the secret interrogation room at Hartfield-Jackson International Airport in Atlanta, it is an experience that built character, and has strengthened the manuscript.

Altogether, this study has left me questioning the very essence of the scientific research community, and my own sanity. I don’t know anymore. I just don’t know.

• We are glad our study has been so thought-provoking!

Re: Comments from Reviewer 3

Although I am away from the office and will not return until July 22, I still found time to serve as referee for this manuscript. Further, I have virtue-signaled on Twitter by posting a picture of me reviewing the paper whilst on vacation, with a glass of wine placed tastefully in the background. 

Major points:

1) Much of this works builds off of previous work in this field and, of more concern, from this lab’s past work. As such, they cite many papers, proving that there is little novelty here. The manuscript would be notably strengthened if they created an entirely new field with this work, and cited my past papers. 

2) The authors do not appear to employ an in-house graphic designer to make visual abstracts for every experiment, thus requiring this reviewer to read the words in the manuscript, including figure legends. This was a confusing and unnecessary step. They should also include animated .gifs. 

3) I found the manuscript to be overly long.

4) In my supplementary comments attached to this review, I detail six more experiments I’d like to see as well as a need for further discussion on several key points.

5) Although the results presented in Figure 5 clearly show the exact amino acids involved in an important but poorly-understood protein-protein interaction, I found the lack of scRNAseq disturbing. Please find some way to use this technique, or lacking that, post a YouTube video of your lab setting money on fire. 

6) In the figures, the authors label their control conditions in red and their test conditions in black. Since control starts with the letter “c” it makes more sense to label those with black, since that word starts with the letter “b” and as you may know “b” and “c” are right next to each other in the alphabet. To do otherwise seems intentionally misleading. Please re-color all figure panels.

7) I downloaded the file marked “scoring_script.py” and double-clicked on it. However, this did not open up a user-interface but rather just contained garbled text. I would prefer the authors build and maintain a website in perpetuity, preferably one that displays a single button I can click on that is labeled with the word “analyze” in large font. 

8) One of the sentences used two spaces after a period. This raises concerns that other important details have been overlooked and calls into question the entire study.

Yip yip yip yip yip yip yip. 

Not here. Out. 

Out out out out out out out. 

Greetings.

Tuesday. Back Tuesday. Back back back back back back.

Yip yip yip yip yip yip yip.

Link. Useful link. 

Greetings.

“Away from my email” say the “Zagat crowd” who travel to “a conference.” While the “jet set” say this “classic destination” is still “going strong,” the millennials “are confused” by someone’s “non-instant availability.” Some cheer for a “return to the Broad on Thursday” but others note that the staff’s “responses may be slow” due to “overflowing lines in the inbox” at times. “Look for better options” say the locals, such as “Kendall Sanson” and “Olivia Bare,” or “if you’re looking to save a penny,” “Dave Root.”

Greetings <sender's name>. The Roncomatic 3000 Email Triage System thanks you for your message! We are experiencing unusually high demand, and you are number <random number generator> in the queue. Your response window is estimated to be <consult astronomy table for next transit of Venus>. The Roncomatic 3000 thanks you for your patience, and we are very excited to discuss <longest hyphenated or ALLCAPS word from body of input email> with you. We remind you that attempts to subvert the Roncomatic 3000 Triage System with appeals to urgency or (especially) authority will be met with countermeasures, such as signing up <sender's email address> to the Cat Video of the Hour club. 

I'm away from my email today. Or maybe my email is away from me. Really, I'm not sure it is any of your business as to why my email and I are taking a short little break from each other. It is totally normal for a person and his email to do that, and no, it has nothing to do with the last minute trip my email took to Las Vegas with all its other little email friends even though it *knew* we had dinner plans with the Flendersons and I just felt so embarrassed the whole time. I mean really, could my email ever think about someone besides itself? I feel so unappreciated sometimes I could just scream but I feel like my email wouldn't even care it would just stare blankly back at me -- why yes, we are having "trouble connecting" and yes I would like to "retry now" -- but I feel like this behavior is just masking the real problems. I don't know. I just don't know anymore. 

"When will my email be answered" scoring rules; add or subtract the appropriate number of time units:

• Subject line is “quick question” but the body is four paragraphs: -5

• Subject line is “knock knock” followed by the remainder of an amusing joke: +3

• Forwarding a message you already sent and including the word “re-pinging”: -3

• Forwarding a message I sent you but now including “in your face, Doench!”: +6

• Suggestions of drinking Kool-aid, picking low hanging fruit, moving needles or circling back: -4

• Suggestions of drinking beer, eating tropical fruits, moving to somewhere warm or never coming back: +7

Dear <your name>,

I am away from the Broad and will return on Monday, August 24.

In the meantime, though, let me assure that I remain as <emotion>as ever regarding your <area of biology>project. As for your “quick question” that managed to include several independent clauses separated by <overused punctuation>, have you tried typing it into <search engine of choice> ? I find that to be a very useful way of getting questions answered quickly. For example, I once used <old-fashioned search engine from Internet 1.0> to find local restaurants that delivered <tempting dessert treat>. Ah, to be back in grad school! In closing, I wish you <Puritan name from days of yore that recalled a particular virtue>in your endeavors, and look forward to speaking <loathsome corporate acronym> sometime before <rare astronomical event>

best,

john

Suggested answers: Nick Nolte; zesty; marsupial stem cell gene editing; elipses; Bing!; Altavista; fried dough; Prudence; F2F; the next transit of Saturn from Neptune

Just like General William Howe, I am departing Boston on March 17 for England. Unlike General William Howe, I have no plans to return from England in order to temporarily conquer New York City -- the Red Sox and Patriots have already taken care of that. 

I will return to the Broad on Monday, August 4. I will be up in Maine, so if your subject heading is "Lobster Uprising" I am more likely to promptly read your email.

I am away from the Broad and will return on Monday, July 24. If the topic of your email is urgent, please re-send with the subject line of "Fwd: Fwd: Fwd: Clinton dirt, from Kremlin" and I will be sure to give it some High Quality attention.*

*I fully expect this topical quasi-joke to be old news about 4 hours into my vacation, so here are some other subject line options:

"Order Confirmation: Your shipment of Dr. Gonzo's Tremendous Leadership Beans is on the way!"

"Can the president pardon himself? Asking for a friend"

"Re: Invasion of Canada, polling results" 

I’m away from my office, I’m away from my desk.

Where did I go? Somewhere picturesque.

I’m not checking my email! (he says with a wink;

to give me a break, that’s what I want you to think)

Your experiments, I’m sure, are proceeding just fine.

I mean, what could go wrong, when using CRISPR-Cas9?

If the problem is urgent, then an email you should shoot

to someone like Olivia Bare, or perhaps David E. Root.

For now you’ll be unanswered, but lest you feel cheated,

I vow to someday reply! (if it hasn’t been deleted)

I'm on vacation and will return on August 22nd.**  I will read your email before that, but will reply only if it seems really really interesting and/or important.

** unless you are trying to rob my home, in which case I am not on vacation but rather polishing my loaded shotgun in a rocking chair in my living room