Oct 292012

Many expecting parents make the decision to store their cord blood at a blood bank with a fee (~$2000). The rationale is that if their child develops childhood leukemia in the future, the stored cord blood will have healthy stem cells that could be used for bone marrow transplantation.

Last Friday I talked to two colleagues who are rheumatoid arthritis doctors. They mentioned that for childhood leukemia, no doctor would recommend using the child’s own cord blood, since the stem cells stored may contain the same genetic defect that caused the childhood leukemia. In addition, it is unclear whether the stem cell in storage is still in good enough shape to make good transplantation. Instead, they should use the stem cells from normal kids with good matches. So the value of privately stored cord blood is only applicable for one kid to save his/her sibling, and only if the storage condition is good enough. In China where most families have only one child, this would totally void the value of storing cord blood.

Therefore, the best way to help future leukemia transplantation is to donate the cord blood to a public blood bank. It is usually free to the donor, with just some paperwork for registration. This way, your child’s cord blood could be used to save other kids, and vice versa. Most OBGYNs don’t tell parents this option, since they get paid from private cord blood banks (for paid storage), but not for public cord blood banks (for donation). This link contains the list of public blood banks.

I was shocked by this information! How many parents have been cheated of their $ to think that they could save their own child by paying to store their cord blood. These companies play on parents’ fear, and to me are quite unethical not to tell parents the truth. I hope to tell as many expecting parents about this in the future: donate cord blood, save your money and help other kids.

Oct 212012

I heard another wonderful talk by Stephen Baylin at the Hopkins epigenetics meeting. First they treated cancer cell lines with 3 days of minimum dosage of 5-aza, then compared the untreated and treated cells for xenograft tumor growth and sphere assays. Interestingly the treated cells have much slower growth. Then they treated cancer patients with 3 days low-dose 5-aza, which are very well tolerated by patients without much toxicity. These are patients who have failed multiple drug treatment and already have metastasis. Patients with 5-aza treatment showed clear and durable response, and some metastatic tumors shrank over 4 years. Patients who later had other drugs also had better response if pre-treated with 5-aza, and only 25% of their patients died. This is truly amazing, and some of the results were published (Tsai et al, Cancer Cell 2012)!! It prompted me to also look at Jeff Settleman’s cell paper (Sharma et al, Cell 2010), where HDAC inhibitor treatment could be used with targeted cancer therapy to reduce drug resistance. These findings, in addition to the the recent bromodomain inhibitors, are extremely promising development for epigenetics cancer treatment.

Interestingly Baylin and team found that the 5-aza treatment could induce immune response. I asked him after the talk whether this is increased immune on the cancer cells or host normal cells, since in the cell line experiment they were pre-treating cancer cell lines and putting them in SCID mice with compromised immune system. He suggested and those SCID mice still have residual levels of immune system, and suspected that the boosted immune on the cancer cells is interacting with the host cells. In addition, he showed that by DNA methylation pattern before treatment, they know which patients could benefit from the 5-aza. Basically if the immune genes are methylated, then 5-aza could activate these genes and the patients could respond. What was really impressive is that Baylin, turning 70 this year, is taking a sabbatical to learn immunology to better understand the molecular response of 5-aza treatment. What motivation and scientific curiosity!!

I am trying to write more blog articles, without worrying too much about grammar and structure. Hopefully this will make writing a bit easier.

Oct 202012

I just came back from a Hopkins epigenetics meeting and heard a keynote talk from Bert Vogelstein. They have a robust way to finding real cancer drivers, which he believes is much smaller a set than other annotations. The rule is: > 5 interagency mutations, Tumor suppressor gene > 15% of mutations be inactivating, Oncogenes: > 15% recurrent activating mutations. Many well known cancer drivers have 80% mutations, so he believe this is a pretty reasonable criteria.

By this criteria, they only detected ~120 cancer drivers (~70 tumor suppressors and ~40 oncogenes). It is very hard to target lost tumor suppressors, so oncogenes are better drug targets. All rivers can be organized into 12 core pathways: TGF, Wnt, Hedgehog/GLI, HIF1A, JAK/STAT, NOTCH, G1/S transition, DNA damage, Apoptosis, Chromatin, PI3K/PTEN, RAS/RAF. Interestingly he believes that whole genome or exome sequencing are showing plateaux in terms of finding new driver genes, and many new drivers are related to epigenetics. The next step is to develop early detection method and understand what these drivers are really doing. In addition to understanding cancer drivers that his lab has been doing for years, they are recently looking sensitive biomarkers and techniques to detect early cancer mutations from blood, urine or stools.

Vogelstein mentioned that many cancer mutations that might cause drug resistance actually were already present when patients are first diagnosed with cancer, although they are only present a tiny percentage of cells. Some people call cells harboring these mutations tumor initiating cells or cancer stem cells, but they might just mean cancer heterogeneity (this is my interpretation). Unfortunately, most of cancer research is focused on treating patients at the last stage which is too late. He recommended the following about cancer treatment:
1. Treat tumors when they are as small as possible
2. Use combination agents
3. Is it ethical to use single agent drugs in Phase II/III trials? Phase I is OK, but Phase II/III with single agent would do patients harm, since patients are almost certain to develop drug resistance later.

I heard that Vogelstein rarely travels to present at conferences or seminars, and he refuses most of the meeting requests from speakers presenting seminars at Hopkins. He stays focused on important cancer research areas that he believes will make long term impact. But surprisingly when I email him to request reagents or information, he always replies by himself very quickly. I really admire this level of focus and science-driven curiocity. This was the first time I heard his talk (I unfortunately wasn’t there when he came spoke at DFCI in April 2012 when his postdoc trainee Nelly Polyak got tenured at Harvard) and I was totally inspired by his knowledge and dedication. I actually shed some silent tears afterwards and got a little distracted from Doug Higg’s talk afterwards which was also quite interesting (will have to read his papers to catch up). I hope we could do some solid cancer work deserving the inspiration he gave me.

Oct 182012

When I started writing blogs, I decided not to write negative things. Today, we did a journal club of all the transcriptome studies in ENCODE, and I just can’t bear it any more. It is mind boggling how much resources were wasted on ENCODE transcriptome. First of all, very little RNA-seq has been generated (~4 cell lines / year). In addition, different companion papers use different GENCODE versions (v7 and v8, mind you the current GENCODE is already v11!), could I trust their annotations, if so which version? The companion paper on lncRNA is especially shocking, and all the findings could be explained by an alternative hypothesis: that all the lncRNA they predicted are transcriptional noise. I actually liked the Mortazavi paper on RNA editing which I think are very carefully done, but he is probably not really in the transcriptome group.

For ENCODE to really generate useful resources to the community, why bother asking experts to review the proposals and NHGRI program officers to select grants for funding? I heard that the funding decisions were not really agreeing with review scores anyways. Instead let the community vote, every scientist could vote, and their vote could get higher weight if they could show that an ENCODE dataset is used to publish their own paper. I think the wisdom of the crowd will motivate the funded groups to consciously generate more useful and high quality data to the community.

Update: We were looking at annotations on transcription start sites of microRNAs. You would think after so many years of ENCODE $, GENCODE has some annotations on this, based on DNase-seq, pol2 / H3K4me3 ChIP-seq, conservation and some other sequence features. But nope, they only have start sites of mature miRNAs. Sigh!!

Oct 172012

Recently I went to PSU for a seminar and a junior faculty asked me about picking future research directions. It reminds me of the Harvard course taught by Tal Ben-Shahar on happiness. Basically to be happy, pick a direction based on three principles:

Interest: I found reading papers, listening (I only have time to “read” audio books on my commute, scientific and non-scientific) to books, and going to conferences a great way to refine my interest. I go to conferences not only to learn more science and people, refine my research interests, but also to help me find out which direction I definitely do not want to get into. Interest could change and evolve over time. There are cases when I was totally confused and frustrated by a speaker in my early career, only to find the same speaker absolutely fascinating a few years later because I knew more.

Advantage: This includes your natural abilities, previous background, expertise, connections, any available resources (天时,地利,人和) that give you a unique advantage. Actually advantage could stimulate interest. E.g. I get more motivated to improve our algorithm when I found it outperforms others.

Fulfill your social value: Find a research direction with a big picture goal that is appealing not only to your colleagues, but also to your family or the president. You could define short term directions towards the long term goal and make slight adjustment of your long term goals, but stay on course. Dedicated focused efforts over a long time could build your expertise and reputation to gradually fulfill your social value.