How a collaboration on imperfect drug penetration got started

Almost three years ago, in early 2012, I attended a talk by Martin Nowak. He talked about cancer and one of the things he said was that treatment with multiple drugs at the same time is a good idea because it helps prevent the evolution of drug resistance. Specifically, he explained, when treatment is with multiple drugs, the pathogen (tumor cells in the case of cancer) needs to acquire multiple resistance mutations at the same time in order to escape drug pressure.

As I listened to Martin Nowak’s talk, I was thinking of HIV, not cancer. At that time, I had already spent about two years working on drug resistance in HIV. Treatment of HIV is always with multiple drugs, for the same reason that Martin Nowak highlighted in his talk: it helps prevent the evolution of drug resistance.

However, as I read the HIV drug resistance literature and analyzed sequence data from HIV patients, I found evidence that drug resistance mutations in HIV tend to accumulate one at a time. This is contrary to the generally accepted idea that the pathogen must acquire resistance mutations simultaneously.

There seemed to be a clear mismatch between data and theory. Data show mutations are acquired one at a time, and theory says mutations must be acquired simultaneously. One of the two must be wrong, and it can’t be the data![1]

Interesting!

After Martin Nowak’s talk, I went up to him and told him how I thought data didn’t fit the theory. Martin’s response: “Oh, that is interesting!” (Imagine this being said with an Austrian accent). “Let’s meet and talk about it.”

So, we met. Logically, Alison Hill and Daniel Rosenbloom, then grad students in Martin’s group, were there too. I had already met with Alison and Daniel many times, since they were also working on drug resistance in HIV.  John Wakeley (my advisor at Harvard) came to the meeting too.

Between the five of us, we brainstormed and fairly quickly realized that one solution to the conundrum was to assume that a body’s patient consisted of different compartments and that each drug may not penetrate into each compartment. Maybe we found this solution quickly because Alison and Daniel had already been thinking of the issue of drug penetration in the context of another project. A body compartment that has only one drug instead of two or three would allow a pathogen that has acquired one drug resistance mutation to replicate. If a pathogen with just one mutation has a place to replicate, this makes it possible for the pathogen to acquire resistance mutations one at a time.

We decided to start a collaboration to analyze a formal model to see whether our intuition was correct. Over the following three years, there were some personnel changes and several moves, graduations and new jobs. Stefany Moreno joined the project as a student from the European MEME Master’s program when she spent a semester in Martin’s group. When I moved to Stanford, Dmitri Petrov became involved in the project. Next, Alison and Daniel each got their PhD and started postdocs (Alison at Harvard, Daniel at Columbia), Stefany got her MSc and started a PhD in Groningen, I had a baby and became an assistant professor at SFSU. No one would have been surprised if the project would never have been finished! But we stuck with it and after many hours of work, especially by the first authors Alison and Stefany, and uncountable Google Hangout meetings, we can now confidently say that our initial intuition from that meeting in 2012 was correct. Compartments with imperfect drug penetration indeed allow pathogens to acquire drug resistance one mutation at a time. And, importantly, the evolution of multi-drug resistance can happen fast if mutations can be acquired one at a time, much faster than when simultaneous mutations are needed.

Our manuscript can be found on the BioRxiv (link). It is entitled “Imperfect drug penetration leads to spatial monotherapy and rapid evolution of multi-drug resistance.” We hope you find it useful!

[1]Of course, it could be my interpretation of the data!

Stefany Moreno (in large window), Alison Hill, Daniel Rosenbloom and myself in one of the many Google Hangout meetings we had.

(Almost) 100 things we did to make the BAPGX conference a success

(Also posted on http://stanfordcehg.wordpress.com/)
I love working with a team to organize an event. The tenth Bay Area Population Genomics conference (BAPGX) was a fun event to organize. It is part of a successful series of conferences and there was plenty of support, both at Stanford and from the community, to organize it. Five Stanford postdocs volunteered to help out and did a great job.

I think the conference was a success. Here are some of the things we did to make it that success.

How it got started

1.     Dmitri Petrov (who initiated the BAPG series) asked me (Pleuni) if I could organize the conference.
2.     Dmitri and I picked a date (not realizing it was Memorial day weekend!) and after that I was free to organize it the way I wanted.
3.     I asked the CEHG mailing list for volunteers and –within 10 minutes!– found five postdocs who were willing to help me organize the event. We were ready to get started!

The BAPGX committee, Pleuni Pennings (@pleunipennings), Maria Avila (@maricugh), Carlo Artieri (@Carlo_Artieri), David Enard (@DavidEnard), Dave Yuan (@13bee_slurpee), Bridget Algee-Hewitt (@BridgetAH), Dmitri Petrov (@PetrovADmitri, not in the picture).

The BAPGX committee

4.     The BAPGX committee met 3 times. The first meeting was mostly to brainstorm, the other meetings were more focused on logistics.
5.     We sent many (many!) emails within the committee.
6.     We kept notes and files in a shared folder on Google Drive.
7.     We split tasks: Bridget was in charge of communication with speakers and participants.
8.     Carlo was in charge booking the location, catering, and poster boards.
9.     Maria was in charge of mugs and name stickers.
10. David was in charge of the logo and photography during the event.
11. Dave was in charge of wine and cheese and printing the schedules and signs.
12. Pleuni was in charge of the website, Facebook, twitter and the money.
13. We decided on the program (and many other things) together.

There was a BAPGX mug for every participant.

Logistics

14. We looked at several lecture halls at Stanford and chose M106 in the Alway building, even though it wasn’t fancy, because it had the right size (140 seats) and was adjacent to a courtyard (great for registration, breaks and posters). It was also good because people could take their coffee with them into the room and because we could order food from an outside vendor.
15. We decided to start the conference at 10AM, so that it was convenient for people who wanted to take the Caltrain (the first arrived at 9:17 in Palo Alto).
16. We put travel instructions on the website and also sent them by e-mail:http://evolgenomecehg.wordpress.com/bapgx-map-and-travel-instructions/
17. We put up some signs to make it easier for people to find the Alway building.
18. We encouraged people to ride share and included a column in the registration Google doc with ride share information.
19. We had two of our committee members (Maria and David) in and at the Caltrain to guide people to the lecture hall.
20. We made sure the lecture hall would be open on the day of the conference.
21. Two of us washed all the mugs and four of us went to Costco two days before the conference.
    

    Dave and David are preparing the registration area.

Registration

22. Registration was free and open to all.
23. We decided to cap participation at 150 (even though we had only 140 seats) under the assumption that some people would cancel or not show.
24. To sign up, people simply added their name, email, affiliation, food preference, whether they’d bring a poster and ride shareride share info to a Google doc.
25. A few days before the conference we “locked” the Google doc and asked people to email us instead.
26. We reached 150 registrations around one week before the conference. After that approximately 10 people canceled and around 5 additional people were admitted. A few people didn’t show up and a few crashed the conference, but this was no problem as we had enough seats and food.

A full lecture hall.

Using social media to build momentum

One of the great things about working with an active community and a motivated committee is that we could build a lot of momentum before the conference.

27. We had a simple website (http://evolgenomecehg.wordpress.com/bapgx/)
28. The committee communicated with the community through emails (to individual people, to the speakers and the poster presenters and to the BAPG Google group).
29. We hoped for participation from many different universities and made additional efforts to encourage people from SFSU, Santa Clara and UCSC to sign up. We also had participants from UCSF, UC Davis, UC Berkeley, the Cal Academy of Sciences, Ancestry.com, Stanford and a few other institutions.
30. We used twitter (all committee members are on twitter).
31. We decided on a twitter hashtag early on (#BAPGX).
32. We used Facebook (through the CEHG Facebook page).
33. We tried to keep everyone updated on the program and everything else we were working on (logo, mugs, cheese etc.) to show that we were working hard and that we were excited about the conference.
34. We asked three active tweeters from the community to live-tweet the conference (@razibkhan, @mwilsonsayres and @JeremyJBerg)
    

    One of many tweets on the day of #BAPGX

Money

35. We received financial support from Ancestry.com and from CEHG (thank you!!).
36. For the CEHG money we had to write a short proposal, but basically used the same text as we already had on the website.
37. We spent money on food and coffee ($2,266), water, juice, soda, wine and grapes ($711), cheese ($430), mugs ($715), and name stickers ($76).
38. We saved money by buying water, juice, soft drinks, wine, crackers, grapes, paper plates and plastic cups at Costco.
39. We also saved money by using stickers as badges (instead of more fancy badges).
40. We saved money by not video-recording anything.
41. We decided not to spend any money on inviting an outside speaker or gifts for speakers.
42. We got help with the financial administration from CEHG (Cody Sam) and from Elena Yujuico (Dmitri’s admin).

(Almost) glitches

43. We didn’t realize until fairly late that we planned the conference in Memorial Day weekend.
44. We didn’t think about Wi-Fi access for guests until the night before the conference. On the day itself we created a guest login for the Stanford network and that worked.
45. We were not consistent about the length of the normal talks. We originally announced that they’d be 12 minutes (+3 minutes for questions), but then this somehow became 15 minutes (+5 minutes for questions).

Talks

46. We allowed for normal talks (15 min) and mini talks (5 min) and got an equal number of abstracts for both.
47. We set a deadline for talk submissions (4 weeks before conference) and another deadline for registration (one week before conference).
48. We asked people to submit abstracts (this was not done for previous BAPG conferences. At previous BAPG conferences, people were encouraged to add their name in a Google doc to sign up for a talk, but we thought that making the process a little more formal would get us different speakers and potentially more well-prepared speakers).
49. We accepted all talks that were submitted before the deadline (but none that were submitted after).
50. Our program was a bit longer than previous BAPG programs, because we decided to accept all submitted abstracts and because we wanted to be sure there was ample time for questions.
51. We asked speakers to send us their slides (only Powerpoint or PDF allowed) a few days before the conference (in the end we had all files before the start of the conference!)
52. We organized a practice-your-talk session for the speakers from Stanford.

Posters

53. Participants were encouraged to bring a poster. No titles or abstracts needed, just a “yes” in the right column in the Google doc.
54. 11 People signed up to bring a poster, in the end there were 9 posters.
55. We borrowed simple poster boards from the Beckman center and brought pins and tape (We considered higher quality poster boards, but they would have cost around $500 rental fee at Stanford).
56. Posters were up the whole day (from the coffee break in the morning).
    

The day itself

57. All of the committee (except Maria who was on the Caltrain) met at 7:30 to set up everything for the day.
58. We made sure we each had all the other phone numbers.
59. We brought several computers, VGA cables, thumb drives etc (but in the end all worked from the computer that was already in the lecture hall).
60. We brought plates and knives for the cheese and grapes.
61. We asked Dmitri Petrov to say something at the start of the conference.
62. We split chairing between three members of the organizing committee (Carlo, Maria, David).
63. Bridget and Pleuni “manned” the registration table from 9 till 10:30 and explained to everyone how to indicate their affiliation on their name sticker.

Name sticker with associations indicated (a yellow dot at the approximate location of Stanford and a green dot at the location of SFSU).

64. We had fairly long breaks and allowed plenty of time for questions. Each session ran a few minutes late, but we caught up during the breaks.
65. Each of the members of the organizing committee missed at least one of the sessions to be outside to handle food.
66. Our three designated twitter volunteers did a great job live-tweeting the conference and many others joined in. The result was storified here: https://storify.com/mwilsonsayres/bay-area-population-genomics-x
67. David brought his camera (photo’s will follow!).
68. Originally we had someone (not the chair) assigned the task of keeping track of time during the talks, but in the end we decided that it worked better if the chair did it him/herself.

After the conference

69. We all stayed till the end and cleaned up the mess.
70. We found a home for the leftover mugs & the leftover wine and cheese.
71. We wrote this document.
72. We sent an email to all participants to thank them for coming & for great talks and posters & to tell them about the storified tweets.
73. We plan to have a nice lunch or dinner with the committee to celebrate the success of the conference.
74. We’ll publish the photos.
75. We’ll round up the financial administration.

Other notes

76. The talks were of very high quality (thank you, speakers!!). The fact that we asked presenters to send us their slides beforehand may have contributed to that.
77. We got a lot of positive feedback about the mini talks (lightning talks), so it may be a good idea to keep that as part of BAPG.
78. Many people stayed for the posters and cheese. The cheese may have helped with that; we had a Toma (cow’s milk cheese from Pointe Reyes), Comte (cow’s milk cheese from France), Brabander (goat’s milk Gouda from Holland) and Casatica (buffalo milk soft cheese from Italy).