Xiaole Shirley Liu is Professor of Biostatistics and Computational Biology at Dana-Farber Cancer Institute and Harvard School of Public Health. She works on computational genomics and epigenomics, and applies her expertise to understand gene regulation in cancers. She likes reading (actually listen to audible) non-fiction books, traveling, gardening, playing sports (but not watch) and classical music (and listening too), and having fun with her sons.

Feb 122017

During the Christmas and New Year holidays, I read two books: The Miracle Morning and The One Thing. I tried to combine their recommendations in my daily activities, and the results have been quite impressive. I will start by explaining the The Miracle Morning first, which encourages people to establish a morning routine. There is a recommended routine, but the author encourages people to try different things to find something that fits them well. So here is mine:

1. Before going to bed at night, be determined to get up at a certain time in the morning. Depending on the time I go to bed, I decide the specific time I need to get up, but this doesn’t need to be crazy early, although going to bed early and around the same time daily helps.
2. Put the alarm away from arms reach, so I can really get up as soon as the alarm sounds.
3. Put on my fleece jacket, use the bathroom and brush my teeth. I feel much more refreshed after brushing my teeth.
4. Drink a cup of water I put next to my bed the night before. I put lemon juice and honey in the water which helps hydration in the morning.
5. My husband always takes a little longer, so I sit in bed, look over my new year resolution and the schedule for the day to wait for him (for meditation and exercise together). The new year resolution reminds me of my priorities, so I feel better saying no or delaying response to low priority activities. Checking my daily schedule ensures that I don’t forget important meetings that day. Also each day I give myself the top 1-2 things I need to get done (more details about The One Thing later).
6. Do 10 min meditation using Headspace or InsightTimer on my iPhone. Ariana Huffington recommended Headspace although there are many other mediation apps available. The Miracle Morning recommended “Affirmation” (kinda like going over our priorities) after meditation. However, if I don’t go over my priorities and schedules, my mind keeps on wandering over my priorities and schedules during the meditation. So I decide to mediate after I set my goal and schedule for the day.
7. Exercise for 30 min on yoga mat. We used to follow Sworkit, but recently we just sample some exercises from Sworkit ourselves. This really gets us warm and awake.
8. Take a shower, get dressed, do my writing. My husband gets the kids to school in the morning, while I pick up the kids in the afternoon. Depending on the time I have, this could be a productive time to get grants / papers written. No email at this time, although I need to be more disciplined here!
9. I take my vitamin and calcium pills and drink my breakfast while doing my writing. I prepare my breakfast the night before: add mixed bean porridge (16 mixed-bean bags from MarketBasket, cooked with high pressure cooker), yogurt, frozen fruits and vegetables, some nuts, and water, blend it into a fine mix. It looks disgusting but tastes great!
10. Go over my 3 daily SCRUM project meetings on Skype: 8am on immunology, 8:30am on CRISPR screens, and 9am on epigenetics. I am grateful to the dedication and hard work of my team, so we make progress every day!
11. Get more writing done alone at home, or prepare teaching on Tue / Thur teaching days.
12. Drive to work when there is no traffic, and listen to audiobooks on the drive. I don’t schedule meetings in the morning, so can drive in late. The Miracle Morning book recommends reading before writing, but writing is more important for me to get done in the morning, so I only “read” (aka listen) on my commute. Unfortunately audio books can’t be too serious (e.g. you can’t read scientific papers), but still could be very enlightening and fun.

The real “miracle” I have learned from this book is that these items (especially 5, 6, 7, 8) don’t always need to be the same length. Ideally, I get up at 6am and start my writing at 7am. However, if I sleep late and get up later in the morning, then I can shrink all the activities roughly proportionally: e.g. 1 min priorities, 3 min meditation, 10 min exercise, 15 min writing; or 30 sec priorities, 1 min medication, 5 min exercise, and 7 min writing. Even 5 min exercise is still better than no exercise. The key is to keep this routine every day! The habit, once established, could be very effective in making the whole day productive. Keeping the schedule makes me feel really good in the morning, so I am motivated to continue the habit. So now I really need to go to bed, so I can get up early to start My Miracle Morning tomorrow.

Jan 152017

In the last decade, Chinese government has drastically increased investment in education and research. One important initiative is the Chinese Scholarship Council (CSC) which sponsors graduate students to study for 1-2 years at top foreign research institutions. Our laboratory has hosted a number of talented visiting students, many of which achieved impressive research results during their visits. In Dec and Jan right before these scholarship applications are due, I often receive many email requests from candidates. Quite a few read something like this:

Dear Professor Xiaole Liu,

My name is AB, and I am 2nd year PhD student from C University in China. I work on the mechanism of X gene / complex in the Y developmental stage of Z organism. From my previous studies, I know techniques D, E, F and G and have published a paper in H, I, J journals. From your website, I read that you are a cancer and bioinformatics expert, and I really hope to learn more about both. Recently I have been awarded the CSC scholarship, which will sponsor me for travel and living cost to study in the US for one year. I hope to have the opportunity to study in your lab, so I urgently need to get an invitation letter from you.

I look forward to working with you!


Is there anything wrong with such a letter? Let’s analyze:

1. People usually say Dear Professor (or Doctor) Lastname, not first last. So I should be addressed as: Dear Professor Liu.

2. In most cases, the XYZ research has nothing to do with what my lab is doing. The applicant is just interested in learning cancer or bioinformatics, or both, but why would our lab be interested in hosting them? This is the same with postdoc applications as well. Is there something that the applicant could contribute, e.g. certain experimental technique, qualitative skills, biological knowledge, clinical sample resource, etc, which might be valuable to the host laboratory?

3. Usually the first letter just explores the possibility that a is interested in hosting his/her visit. The invitation letter request should be mentioned after the host lab has agreed to host. It is inappropriate to ask for the letter in the first email, let alone to ask for it “urgently”.

4. Every graduate student (of course postdoc and faculty as well) should actively maintain and update a CV, and include the CV in the attachment of such an email. Resume and CV are used for industry and academic job applications, respectively, and they have different lengths and formats. CV gives the host laboratory a lot more concrete ideas about the candidate, his educational histories, test scores, publications, awards, and other professional experiences, etc. Many people put their CV online, so it is easy to find good CV online and see how they are written. I often look at the CV of really successful experts in my field, and see what areas I need to grow. For example, seeing what papers these big shots published, grants and awards they obtained, courses they taught, other professional experiences they had at my stage is very inspiring. Anyway, always include CV when applying for PhD, postdocs, visiting scholarship, etc, which greatly increases the chance the application will be considered seriously.

Jan 082017

Recently, as I was looking up some answers to an immunology question, I came by this great YouTube Playlist of 35 short immunology videos by Armando Hasudungan. I will certainly be viewing all of these lectures!

From there, I also found the Aims Education list of 7 good BioMedical YouTube sites. Over the years working at DFCI, I have grown to admire doctors more and more, at least the Harvard MDs that I have worked with. I have meant to take some courses to learn more about medicine, such as the Harvard Medical School crash course to help physicians prepare for the board exam, but really haven’t found the time to do so. I guess this is a quick and easy start.

Technology is great, and god bless the people who spent the time to create educational resources for the world (e.g. contributors to Khan academy and Wikipedia).

Dec 152016

In the Dec 15, 2016 issue of Cell, three papers from Jonathan Weissman, Aviv Regev, and Ido Amit described this really cool technique called Perturb-seq. This is a technique to do focused CRISPRi screen (of ~100 sgRNAs) followed by Drop-seq. Basically they use CRISPRi to knockdown different genes in different cells, then examine the transcriptome outcome of the different knockdowns through single-cell RNA-seq. Very often after a genome-wide CRISPR screen, you often have many hits, so they can use CRISPRi to validate each hits and explore the mechanism of the KD effect. Although single-cell readout from Drop-Seq could be noisy, they sequence ~500 cells per CRISPRi, so the average from the ~500 should give a much more robust expression readout. Perturb-seq doesn’t have to be a validation step of a CRISPR screen, as I would be totally excited to see the transriptome in MCF7 after knocking down 100 different transcription factors, chromatin regulators, and kinases, as Aviv’s paper beautifully demonstrated. This is super cool!! For a long time we have been searching for a proper application for single-cell RNA-seq in translational cancer research. Perturb-seq really sold me on the practical value of Drop-seq.

Now, before we get too excited, we should examine the raw data from Perturb-seq. Seeing is believing! If the data quality is indeed excellent, then there will be opportunities to develop computational methods for the systematic modeling of gene regulatory networks. Aviv’s paper has some cool informatics modeling, but I am sure there are still good opportunities!!

I got an email the morning after I posted this blog, from my Stanford labmate Serge Saxonov. Turns out he is the CEO of 10X Genomics, the technology platform that enabled the Drop-seq part of Perturb-seq. What a happy surprise it is! I haven’t see Serge since I graduated. He started 23&me right after PhD, and now is the CEO of 10X Genomics, wow!!

Dec 082016

When I was traveling this fall, I watched the movie Me Before You over two flights. A dashing rich young Will Traynor became paralyzed from a car accident. Despite his family members and caregivers trying to cheer him up, he didn’t see his condition improving so asked his family to end his life (sorry for the spoiler). The ending was a surprise, which really got me thinking. Recently I also had a good discussion about it with my girlfriends. They thought Will was good and real, but I didn’t think very highly of him. His brain was still very sharp, and he had good connections to make a difference in the world. If he wasn’t so rich, had a wife and kids to support, could he afford to die?

Today at the San Antonio Breast Cancer Symposium, Eric Winer gave the William L. McGuire Memorial Lecture. He discussed the recent development and challenges of breast cancer treatment. At the end he talked about his own history. He was born with hemophilia and frequented hospitals as a child, at a time when the life expectancy of hemophilia patients was 20. When he was 13, Factor VIII became available which with injections every 5 days, he could be symptom free. This motivated him to be a doctor. Since Factor VIII was isolated from blood donors, he got HIV infection in 1989 and was kicked out by his dentist. With the development of HAART, a cocktail taken daily for HIV patients, he can live with HIV. Then it turns on HIV infection from blood donors also often accompanies hepatitis C, so he had to take 2 more years of interferon and ribaviron to treat hepatitis C. In 2003, he got GI vascular shunt from the HIV treatment and liver necrosis, which he had to take a surgery to bypass. Despite these harrowing experiences, he now has a lovely family with 3 successful kids, and appears as healthy and energetic as ever. He thanked biomedical research, also the US healthcare system for giving him access to newest drugs to treat his conditions. So the hope for cancer patients, at least in US, is also that with advances in biomedical research, cancer treatment will advance significantly in the coming years.

It was such a moving and motivational talk! Before I only knew Eric as the preeminent breast cancer oncologist, the head of our breast cancer SPORE, who always appears happy and confident. I didn’t know he had to live through so much, and even now has to regularly take the Factor VIII injection and HAART medication. He has all the excuses in the world to complain about his fate, and yet he has the optimism and grit to achieve so much in life. Actually looking around, many of my very successful relatives and colleagues have had personal or family tragedies, divorce, illness, or death (of loved ones), etc. And yet they had the optimism and grit to pull themselves together and try their best. Eric mentioned that growing up with hemophilia shaped him, so he was able to deal with later challenges in life. Compared to them, I feel so lucky and want to give my best to my work and the world.

So now I am even more convinced that Will should not commit suicide. Christopher Reeve didn’t commit suicide, instead he made his last 9 years of paralyzed life worthwhile and did so much good to the world. Even though Will’s illness was not curable at the time, there is always hope that a cure will be found with new biomedical research and development.

Dec 012016

Just finished NIKE founder Phil Knight’s book Shoe Dog. An absolute must read, not only for its content, but also for its humor! The true stories about real people are infinitely more fascinating than novels, you see the laughs and the tears in their experiences.

When I read books about Steve Jobs, Jeff Bezos, and Elon Musk, I felt that these people are geniuses way beyond my league. They knew exactly where they want and are going from the start. But Phil Knight is more like us mortals, improvising as he went along, and just trying his best. His advice was quite intriguing: “Let everyone else call your idea crazy, just keep going. Don’t stop, don’t even think about stopping until you get there, and don’t give much thought towards where there is.” Indeed, in work, I wish we plan strategically and do the right things towards the goals, but very often we end up in a different place from where we thought there is.

NIKE was able to keep most of its founding team for many years, especially those who love sports or running. It boosted my respect for runners who have that grit and optimism. I bought new NIKE free running shoes. Time to get back to regular exercise!

Sep 282016

When I was a graduate student at Stanford, fellow graduate students hang out together all the time, going to social activities, consulting on class or research projects, or gossiping about different advisors or laboratories. One topic we discuss often is how long it takes for our respective advisors to revise our manuscripts. A common complaint from students is, “I have sent this manuscript to my advisor for two weeks, and still haven’t heard a word from my advisor about it. What is s/he doing??”. Having been a faculty for 14 years, I finally understand the answer to this question.

First of all, I appreciated how busy a faculty’s schedule is, and it gets busier as the faculty becomes more senior. Since I wrote the “Fit Tasks to Schedules” blog, I feel much less guilty saying No to people who requests me to review papers / grants or write letters of references / evaluations on a short notice. Also, I now categorize manuscripts from my trainees into 4 categories based on how important and well written the ms is.

A. For ms that is very important (clever method, significant finding, potential for high profile publication) and well written, I am extremely motivated to revise it as soon as I receive it. I am very happy to use my skills and knowledge to improve the writing of the ms, and check it off my to-do list.

B. For a ms that is well written but not very important, or not so central to the research program in my group, I usually take a quick look and give some brief feedback quickly, and mostly rely on the first and senior authors to revise the ms in detail.

C. For a ms that is very important and yet not so well written, I feel strongly that the ms has potential but also the pain associated with the revision / rewriting. It would take the trainees persistence to find time and work with me on the revision, and my perseverance to revise the ms to a good shape in a couple weeks or months.

D. For a ms that is not so important and not so well written, it usually languish on my computer for months. The ms is often not in shape for submission but it will take too much time and efforts to revise it.

So when trainees wonder why their advisors still haven’t revised their ms, it is often because their ms is in category C or D. When this happens, the trainees often feel that the ball is in the court of the advisors (I already give the ms to her, and it is her responsibility to revise it), but in fact it is still in the court of the trainees (I better revise this ms myself more so it is in better shape for my advisor to revise). So trainee should take the initiatives and schedule a time (e.g. 30-60 min) to talk to the advisors about the ms to get some quick comments, or to sit and work on the revision together with the advisor. After all, if a ms drags on too long or never gets published, it probably hurts the trainees more than the advisors.

Sep 232016

Recently I went on a seminar trip, and happened to discuss DNase-seq data analysis with colleagues. I realized that many people didn’t know about our paper on the potential issues with DNase-seq footprint analysis.

After our original paper, the Stam lab submitted a correspondence to Nature Method challenging our study, and we were asked to submit a response. Both were submitted to reviewers, who turned out to be overwhelmingly supportive of our study. Unfortunately based on these reviews, the editor decided not to publish the correspondence and our response, which could have been informative to the research community. I still see people toil with DNase-seq footprint analysis now, only to reach similar conclusions as we did in 2014. So, instead of a lengthy blog about our original paper, I would like to include this response we wrote, which clearly summarized the technical issues with DNase-seq footprint analysis. I apologize for not being able to include the original correspondence from the Stam lab, because I don’t have their permission to post here, but I hope the readers can guess.

Overall the DNase-seq data from the Stam lab has been very high quality and extremely valuable to the community, and is one of the crowning successes of the ENCODE project. However, we cautioned the liberal calls of DNase-seq footprints, due to DNase I cutting bias and over dispersion of sequencing noise. Similar caution should also be given in ATAC-seq footprint analysis, in fact we see even stronger cutting bias in ATAC-seq. Instead of footprint analysis, we believe DNase/ATAC-seq peak heights (or read count in the peaks) with motif hits could better predict TF binding.

Youthful Explorations

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Jul 152016

I recently finished reading Robb Lowe’s autobiography Stories I Only Tell My Friends. It is a pretty fun read, and as he talked about the movies he made, I started checking out many movies in the 80s which lead to the Brat Pack. The brat pack kids were crazy in the 80s. You kinda wonder what they did everyday except drinking, smoking, drugs and sex. But many of them, after having “been there, done that”, like Robb Lowe and Andrew McCarthy (although many never came back), really got themselves back together and are leading very purposeful lives.

After reading the book, I started discussing with my husband and other friends about raising kids. This generation of kids, especially those grown up in China, are so busy with their daily school and extra curricular activities, that they have very little time to free play and explore the world at their pace. Needless to say how much homework Chinese elementary, middle and high school students have every day, so they really don’t experience the world. College life could be interesting, but many are starting to think about going abroad or making money. Graduate student life could be monotonous (unless they find excitement in research discoveries), and students seem to have limited interactions with people outside their academic environment. After graduation, many will be busy with work to buy a house and raise a family. It is around the time when they are in their 40s when many people had a stable job, house, and family, when suddenly mid-life crisis hits. They look back and regret not having a wild youth and have worked too hard that their youth is now behind them.

I want to urge young students and postdocs, especially those in China, to treasure your valuable youthful years and fully explore the world. In additional to your study and research life, try something different and have fun, just so that you don’t have to regret not doing it later. Young people should try wild and healthy experiences like traveling, sports and dancing, building a robot or a car, picking up a new hobby, making a movie / book, learning to sell or negotiate, reading many different types of books, starting a new social group, news paper/blog, or a business startup. I learned a lot from Kaifu Li and Tony Hsieh‘s books, which are good examples. Also try out the 101 things to do at MIT. Many of these are wild, crazy, and fun :). These not only make life a lot more interesting, but also give us valuable experiences that could benefit us in later life. In summary, experience the youthful life to the fullest.

I know some young people also try things that might be considered bad. I am not advocating decadent living, instead just want to say, I am not going to make a big fuss about it if my kids or students occasionally did something wild and crazy. E.g. drinking (my family is quite against the US 21 drinking age, and we tell our kids they can drink a bit at home if they feel like it), smoking (trying a bit is not going to kill you, I heard every BBQ we eat is like smoking 12 cigarettes), drugs (every US president in the last 30 years probably tried weed), sex (be respectful and don’t hurt people, live-in as a tryout for marriage is not a bad idea), video games (I have heard advice on giving our kids enough video games to play now, so they can get over it in high school when they are busier at school), gambling (we turn green if we loose a few hundred dollars during school years; people in their 40s could gamble away millions). Just two things to be careful: try in moderation and don’t get addicted (esp drugs); and don’t leave long term damages (e.g. drug overdose, car accident from DUI, pregnancy or AIDS from unprotected sex, etc).

People in mid-life crisis also try these crazy “youthful explorations”, unfortunately the stakes are higher at this age. Recently I have seen / heard some sad stories of my very respected colleagues whose careers suffer significant setbacks due to midlife crisis. It is sad because I know some of these colleagues to be really brilliant and hard working scientists. Society is a lot more tolerant when young people at their teens or twenties try these crazy things or make mistakes, but society expects people in their 40s not be confused about anything (the Chinese saying 四十不惑), so expects the “youthful exploration” days to be over whether or not they have been there or done that before.

For me, there seem to be 2 things I could do, now that I have passed the youthful exploration age. The first is that, looking at the 80 movie stars turning 50, I found that those staying thin at least maintained some youthful charm, while those growing fat totally lost it. So we need to maintain our weight. The second is that kids are our saviors. As my kids grow older, I have to work hard to keep up with them (in sports, travel, music, etc; my older son has soundly beaten me in 100 meter IM after the last season), and I hope to enjoy some (if not all) fun explorations with them later. Hope my sons won’t mind having a crazy old mom sticking around sometimes :).

Jul 012016

When I was in my thirties, exercise was nice but not as necessary. With work and kids, exercise simply took lower priorities. After turning 40, my hair started to turn gray, I really felt my age but dying my hair is still a quick fix ;). Recently, when I wake up with a stiff back, notice body hair turning gray (how do you dye that?), have chest pain after a long and stressful day, exercise suddenly becomes the necessity! I now know why some of my colleagues in the forties and fifties exercise so much more regularly, because this enables them to work better on a daily basis.

I previously mentioned the very intensive and painful iPhone exercise program 7-min-work-out and how Yoga Studio was better. Recently this program has an upgrade called Sworkit, and I am switching from Yoga back to Sworkit. Instead of just having 14 30-sec exercises, the new program allows users to select many different exercise, each lasting only 30 second. I made a custom collection of ~180 different exercise, some building strength, some aiming at flexibility or relaxation, some on neck, arm, leg, back, etc. Then every day, I just specify the length of my work out (e.g. 20-30 min), the program will randomly sample exercises from the collection, so every day I get a different yet comprehensive workout. In the beginning, my body sores after an exercise, but now every morning after the workout I feel so GREAT! This exercise is extremely efficient and very easy to do during travel (some exercises on the floor and some on the bed, so no need to bring yoga mat).

I wish I had taken better care of my health when I was younger, but it is not too late to start now.