Laura Ranum to the Rescue

I previously mentioned that several different C9ORF72 ALS-FTD groups have published that there is an antisense transcript at the repeat region, but only used FISH targeting the antisense transcript.  I was surprised that the claims made it through the review process, given my experience in the trinucleotide repeat field.  More specifically, my most recent grants were returned with harsh reviews suggesting that antisense transcripts at repeat regions are spurious and unimportant.  But the ALS-crowd embraces the prospect whole heartedly.  Additionally, the ALS-crowd embraces Repeat-Associated Non-ATG (RAN) translation, a story that should be solely credited to Laura Ranum.  OK, I am certain there are others who suggested non-ATG translation is possible.  However, Laura realized it was a critical feature of trinucleotide repeat expansion diseases.  As the repeat expands, there is a longer transcript generated from the repeat region.  This transcript can generate longer or more polypeptides, in multiple frames. Dr. Ranum took a great deal of heat for this line of research, but she opted to move through the critiques rather than give up.  Here is a link to a great review by John Cleary and Laura Ranum.

Why is RAN-translation important?  It opens a window to a new field of study.  An important window.  There have been mumblings about "aberrant" peptides that are generated by our cells.  Of course, they are passed off as unimportant.  After all, if something does not adhere to the central dogma:

DNA->RNA->Protein

it cannot be real/important/possible/likely/useful (pick your favorite word).

What is wrong with scientists?  It seems as though there is a great population of scientists who cannot think outside of the core classes they took as undergrads or graduate students.  I am always puzzled.  In a discipline with a history of searching for the novel, the current "research-leaders" shun the brilliant observations and celebrate the popular studies.  Of course, as a scientist, it is as much my responsibility to highlight good science as it is to recognize the bad.  On that note: here is another paper on C9ORF72 ALS-FTD, this time from the Ranum lab.  Because it is from a veteran repeat-expansion disease lab, there is actual analysis of the sense and antisense transcripts.  Note: while my work on the antisense transcript at the C9ORF72 locus is still not published, I will point out that I have different results. Of course, I am fairly sure I know why and I am looking forward to addressing the question myself.

Laura's paper is a reminder of what I find interesting about bidirectional transcription, as well as a reminder to not give up on a pursuit that is important.

Focusing on the Important Things in Life

I planned to write about duons and John Stamatoyannopoulos, at the University of Washington. A UW press release this past week set off quite a discussion on twitter (#duons).  More haters than supporters, and the hate is directed at the premise that the Stam lab was the first to discover duons.  Of course, this is not true on many levels.  I suspect John Stam did not claim to be the first.  Instead, this is a genome-wide approach to unify what many other researchers have demonstrated.  Is this the real reason for the outcry? Numerous researchers feel slighted when a big project does not effectively acknowledge the history of a project.  Press releases are meant to be hype, as there is a great deal at stake to make your University seem like it has the most brilliant and innovative scientists.  Want to poke fun at the most hyped press releases? Visit Eisen's blog.  Perhaps there is more to the outcry than I appreciate.  Is there something about UW Genome Sciences or John Stam himself?  If there is, spit it out. If not, talk about the science.  Anything in between is troll-like, which is more harmful to science than a hyped press release.

Unfortunately, I was distracted this week by a struggle of a family in the midwest.  A heartbreaking death of a child from cancer.  No, they are not the first family to cry for a child, nor will they be the last. And I know that there are many causes of childhood death, including infectious disease, accidents, as well as inherited disorders.  Like so many other researchers, I entered this field to try to understand and ultimately help those who are suffering.  During the past few years, I have been distracted by the fraud and egos in biomedical research.  After reading about this family's loss, I realized that I am no longer focused on the important aspect of science, namely, discovery.

Breakthroughs are still needed for metastatic cancers, drug-resistant infections, and degenerative disease.  Working towards these breakthroughs are more important than discussions about a press release.  New motto: read the report, evaluate the science, glean important knowledge, move forward.

Can you remember your original goals?

I have a hobby, knitting.  I have been knitting since I was an undergrad at Indiana University, School of Business.  One of my marketing professors suggested that we teach ourselves something new.  Part of the goal was to demonstrate that we had reached a point in our academic careers that we could teach ourselves. Of course, he suggested that we continue to teach ourselves something new for the rest of our lives.  The objective is to increase our ability to converse with our customers.  As we broadened our experiences, we had greater subjects to be able to discuss.  Ultimately, this approach resulted in my returning to school to become a scientist.  I actually only intended to take 1-2 courses to learn some chemistry.  My first chemistry course was so interesting that I read the entire chemistry book by the middle of the semester.  My professor took be aside and asked me whether I was working in the right field, reminding me that life is more interesting if we are passionate about our work.

Fast forward, and I have a PhD in Biochemistry.  I love the work that I have done and I want to do more.  But a few years ago, I started knitting again.  At first I thought my desire to knit was to create things for my young son, but I did finally realize that something was missing in my work life.  I was not asking the questions that I wanted to ask. Actually, let me clarify, my then boss had a habit of using my projects as the platform for recruiting new students or postdocs. Countless times, when I interviewed a postdoc or grad student for the lab, the person would say: "I was told to get the details of what you are working on right now, as I will take over the project". Thus, I was never able to complete a story. So I turned to knitting, where I could control the project.

I joined an online knitting community "Ravelry".  It is a fantastic community where you can join sub-groups based on your interests.  One of the groups I joined was "Scientific Knitters".  We discuss knitting, but mostly we discuss science, career, co-workers, experiments, etc.  Currently, we have a very young member of the group who is just learning about chemistry, biology, physics, and experimentation.  This member is actually a high school student, thus very young.  For the rest of the post, I will call this person "Y" for young.  Y wants to be the first person to create a eukaryotic cell, from scratch.  Seems that Y is enamored by synthetic biology (and knitting).  But what has made Y so interesting is the pursuit.  Like any new student, Y has just enough information to ask great questions, but not enough experience to understand how to perform the work.  This is typical of a student.  I was at that stage once.  But we change during training.  We learn to dig deeper to fully understand to science behind our results.  We question everything, so that we can provide well informed answers to reviewers.

However, there is another change that takes place.  During graduate school, we have requirements that must be met, course work, qualifying exams, committee meetings, and more.  A labmate called these things "hoops" and suggested to all graduate students: "just jump through the hoops" "do not protest, as the hoop will remain until you finally jump, so jump and get it over with".  This was the best advice I was given in grad school.  I did as I was told and advanced to graduation fairly easily.  But I was surprised that during my postdoc, I was expected to jump through "postdoc-hoops" AND additional, non-training hoops.  My mentor would throw out this odd hoops that were not informative, instead, obstacles to slow me down.  I realized that most of the postdocs had these extra hoops thrown in the way, as did new faculty.  Not everyone jumped, some resisted, some found ways around the hoops.  It seemed that postdoc and beyond was more of a lesson in learning which hoops were important.  Great lesson, but it changes our thinking.  We expect our trainees to jump through hoops to satisfy our requirements.  Ultimately, we spend too much time thinking about hoops rather than about science.

As a result, I am ignoring hoops.  Fortunately, I joined a great lab, with talented, goal-oriented individuals and a PI insatiable curiosity.  It is refreshing and a wonderful reminder of why I am a scientist.  Of course, Y reminds me of my original goal to become an experimentalist.  I want to understand how alterations in a cell's transcriptional identity leads to disease and how we can characterize and monitor these changes.  I want to touch the transcripts, read the sequence, and see the changes in function.  I want to understand how the transcriptome is regulated, temporally, spatially, and developmentally.  There is so much to do, way to too much work to be bothered by extraneous hoops.