tag:blogger.com,1999:blog-25085966118648010792024-03-13T17:34:12.519-07:00PLadd SciencePLaddhttp://www.blogger.com/profile/11315143719078119070noreply@blogger.comBlogger13125tag:blogger.com,1999:blog-2508596611864801079.post-66312731797745801592013-12-29T14:09:00.000-08:002013-12-29T14:11:30.019-08:00Laura Ranum to the RescueI 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 <u>R</u>epeat-<u>A</u>ssociated <u>N</u>on-ATG (RAN) translation, a story that should be solely credited to <a href="http://neurogenetics.med.ufl.edu/faculty/dr-laura-p-w-ranum/">Laura Ranum</a>. 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 <a href="http://www.ncbi.nlm.nih.gov/pubmed/23918658">review</a> by John Cleary and Laura Ranum.<br />
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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:<br />
<div style="text-align: left;">
<b><span style="color: #990000; font-size: x-large;">DNA->RNA->Protein</span></b></div>
it cannot be real/important/possible/likely/useful (pick your favorite word).<br />
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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 <a href="http://www.ncbi.nlm.nih.gov/pubmed/24248382">paper</a> 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.<br />
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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. <br />
<br />PLaddhttp://www.blogger.com/profile/11315143719078119070noreply@blogger.com2tag:blogger.com,1999:blog-2508596611864801079.post-12849617911060581452013-12-15T11:42:00.000-08:002013-12-15T11:46:35.509-08:00Focusing on the Important Things in LifeI planned to write about duons and John Stamatoyannopoulos, at the University of Washington. A UW <a href="http://www.washington.edu/news/2013/12/12/scientists-discover-double-meaning-in-genetic-code/">press release</a> this past week set off quite a discussion on twitter (<a href="https://twitter.com/search?q=%23duons&src=typd">#duons</a>). 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 <a href="http://www.michaeleisen.org/blog/?p=1516">Eisen's</a> 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. <br />
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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.<br />
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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. <br />
<br />PLaddhttp://www.blogger.com/profile/11315143719078119070noreply@blogger.com0tag:blogger.com,1999:blog-2508596611864801079.post-56282374806896734102013-12-01T12:11:00.002-08:002013-12-01T12:14:12.164-08:00Can 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. <br />
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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.<br />
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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. <br />
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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. <br />
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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. <br />
<br />PLaddhttp://www.blogger.com/profile/11315143719078119070noreply@blogger.com0tag:blogger.com,1999:blog-2508596611864801079.post-29812209565903458262013-11-23T10:39:00.000-08:002013-11-23T10:40:30.904-08:00Hazy Dreams, Productive ThoughtsThere has been a bug in my household, not surprising when there is a 7 year old living in the same space. He seems to bring home new viruses each week. This one did not hit me as hard as some of the others, but I have been tired, very tired. The downside of each new bug is the time lost in "recovery". I hate giving up this time to a virus, especially if I have viruses at work that need my attention. Of course, I am referring to actual viruses in the -80°C freezer that are waiting for me to interrogate.<br />
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The upside of sleeping a little bit more each morning (instead of working out) is that I have let my mind wander to what I really want to accomplish professionally. A few years ago, I attempted a search for a tenure track position. To my surprise, I received several personal notes from search committee members expressing some interesting points. What was particularly interesting is that these were notes that were in addition to the rejection letter and generally unsigned. The notes were complementary, and pointed out what I would have needed to advance in that round. Almost always, the missing item was NIH funding and obvious independence. Neither is a big revelation. <br />
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As a problem solver, I have thought about this issue a great deal, not only for myself, but for future scientists. The reality is that not every postdoc has the opportunity to submit grants to the NIH. Seriously. Sometimes, it is the PI who is the roadblock, other times it is a dynamic of the lab. In the end, the actual issue is that a postdoc lives in two worlds. One world is the lab setting based by a PI, who has a particular agenda. The other world is the research community, which has "committee" based criteria for the postdoc deemed hirable. Many others have discussed the inequality of academic hiring, including fantastic, well spoken, bloggers, tweeters, etc. I cannot do this topic justice. Instead, I will point out the math: if there is one job and 300 applicants, 299 people are not hired. Many of them are qualified, but some criteria, fair or not, stood in the way. This does not mean the other 299 applicants are not hard-working, accomplished scientists. So why do we treatment as losers?<br />
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I am hungry for a change, another path for the career scientist. The biggest hurdle is knowing how to exit the current academic setting and still maintain health insurance and income. Of course, every self-employed individual struggles with that hurdle! The difference is that a scientist does not always have a "sellable" product. At least, we do not understand what the sellable product really is. In hindsight, I now realize that the postdoc effort was the sellable product. It is the relationship between PI, postdoc, and University that needs to change, and postdocs need to demand greater ownership of their data. <br />
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Just consider what a postdoc does for the PI. In a typical lab, the postdoc does the manual labor, trains grad students, writes protocols, research updates, papers, and lab maintenance. This is not to say the PI does not work, on the contrary, the PI is working on administrative aspects of the lab. Having a postdoc in the lab means more data is generated, more students are trained, and projects run smoothly. However, there is no safety net under the postdoc, who is bound by the constraints of the PI when it comes to grants and papers. A better system is one where the postdoc has a 3 yr contract. Year one, the postdoc contributes 80-90% effort on the PI's project and 10-20% effort on a personal project. This could be a literature search, small grant or crowd funded proposal, or basis of a larger project. The second year, this changes to less effort on the PI's project and more effort on the personal project, perhaps a 60-40 split. Finally, the third year is flipped, where the postdoc spend greater than 50% effort on a personal project. This is what "payment" means. Postdocs should not be service providers as much as they should be scientists. <br />
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Now, most PIs and postdocs would say that they need to give 110% for 2-3 years just to get a project started. In that case, the payment is ownership of the data generates, meaning that as a postdoc advances each year, the postdoc acquires greater ownership of the project. For those who say that we already have this system, I love that there are already PIs who think this way. But it is not the norm, at least not in my experience. <br />
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After 3 years, a postdoc really is independent and should be treated as such. Does this mean a 4th year cannot be a staff scientist? No, it means that we need to make distinctions much earlier. At the 4th year, academia needs to be responsible for all of the researchers in the department, meaning that postdocs are hired by the University rather than the lab. This is a very important change that serves to add respect for a postdoctoral position. Give all postdocs equal footing in the academic landscape and allow all to be responsible for their scientific portfolio. Open the door to allow cross effort on another PI's grant, a bit of internal freelancing. <br />
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Finally, allow these postdocs freelance space. There are so many ways for a University to capitalize on the independent scientist, without providing them long term contracts. The greatest reward to a University is the great science that is produced by highly creative and intelligent people. It makes no sense to discard superdocs at the current rate. Why not recoup the investment?PLaddhttp://www.blogger.com/profile/11315143719078119070noreply@blogger.com0tag:blogger.com,1999:blog-2508596611864801079.post-30098027818744890482013-11-17T12:07:00.000-08:002013-11-17T12:07:25.227-08:00Bidirectional Transcription, Tandem Repeats, ALS, and Competition
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<span style="font-family: Arial; font-size: 11pt;">When I started my postdoc position at the <a href="http://www.fhcrc.org/en.html">Fred Hutchinson Cancer Research Center</a> in 2004, I had the great opportunity to identify an antisense transcript at the FMR1 CGG repeat region <a href="http://hmg.oxfordjournals.org/content/16/24/3174.long">(HMG, 2007)</a>. Better yet, I was able to interact with Diane Cho as she finished her story on antisense transcripts at the DMPK locus (<a href="http://www.cell.com/molecular-cell/retrieve/pii/S1097276505015996">Mol Cell, 2005</a>). The only other group actively looking at antisense transcripts was the Ranum lab, who was in Minnesota at the time (<a href="http://www.nature.com/ng/journal/v38/n7/full/ng1827.html">Nat Gen, 2006</a>). We had so much to do as we navigated the skeptical mRNA-centric world. As a consequence, we had to characterize the antisense transcripts using the tools and questions that we would use to analyze coding transcripts. Were the antisense transcripts polyadenylated? Capped? In the nucleus or cytoplasm? Spliced or unspliced? RNA pol II or III? There were so many preconceived notions about the extra transcription exhibited by a gene locus that we had to overcome with careful characterization. Ultimately, we defined the appropriate way to characterize antisense transcripts at repeat regions.</span></div>
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<span style="font-family: Arial; font-size: 11pt;">But, publications and grant applications were not easy to obtain. Most reviewers hated the notion of antisense transcript. A major assumption was that the transcripts we identified were "spurious", a term that I have come to realize is tossed around to mean: NOT REAL. My other favorite critique was the statement "you do not know if the antisense transcript causes disease". All of the genes we characterized had a repeat expansion associated with disease. I find it incredibly short sighted to think that the antisense transcript somehow was independent of the sense "disease-causing" transcript when both harbored an expansion from the same region.</span></div>
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<span style="font-family: Arial; font-size: 11pt; margin-left: 1em; margin-right: 1em;"><b>A representation of strand-specific interrogation of transcripts at a CAG repeat region</b></span></div>
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<span class="Apple-style-span" style="font-family: Arial; font-size: 15px;">As a consequence, it is difficult to publish noncoding transcriptional activity at a locus. Basically, the transcriptome is an uncharacterized frontier, largely due to lack of interest by genomics field and lack of research funding for the transcriptional regulation field. The tenuous relationship between the transcriptomics field and what seems like the rest of science is best depicted by the public distain for the</span><span class="Apple-style-span" style="font-family: Arial; font-size: 15px;"> </span><span class="Apple-style-span" style="font-family: Arial; font-size: 15px;"><a href="http://www.genome.gov/10005107">ENCODE Project</a></span><span class="Apple-style-span" style="font-family: Arial; font-size: 15px;">. I would rather not spend time on discussing the merits of either side of the argument, rather I want to focus on what I have seen, touched, sequenced, characterized, and understood about bidirectional transcription at unstable tandem repeat loc.</span></div>
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<span style="font-family: Arial; font-size: 11pt;">To
date, only a few gene regions have been characterized well enough to understand
the consequence of a repeat expansion. This includes the FMR1, SCA8, DMPK, FRDA, SCA7, HTT, loci, plus a few more. However, there are ~30 known unstable tandem repeat regions associated with neurodegenerative, developmental disorders, and muscular dystrophy. The repeats are tri, tetra, penta, hexa, and dodeca repeat regions found near promoters, introns, and exonic regions of gene loci. A quick glance of any human gene of interest on the <a href="http://genome.ucsc.edu/">UCSC browser</a> reveals higher transcriptional activity near repeat regions as demonstrated by deposited ESTs. Note, this activity is in both directions. Comparison of the human genome and other organisms, such as mouse, reveal that in many cases, there are overlapping genes at the repeat regions. A huge question is whether the antisense transcripts we have identified are actually remnants of genes no longer in play due to the formation of a true repeat region or whether the antisense transcripts represent regulatory elements, not yet fully appreciated. </span></div>
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<span style="font-family: Arial; font-size: 11pt;">Ideally, I would like to continue to explore bidirectional transcription with the goal to provide a clearer picture of the
transcriptional activity at tandem repeat gene loci. This is primarily due to the number of diseases associated with repeat expansions. When a repeat region expands, additional and potentially
toxic RNAs are generated. These transcripts could also be utilized as locus-specific biomarkers for the associated disease
pathogenesis</span><span style="font-family: Arial; font-size: 11pt;">. </span><span class="Apple-style-span" style="font-family: Arial; font-size: 15px;">With an increased focus on therapeutic agents, such as ASOs that target expanded sense
transcripts for degradation, it is imperative that we understand what transcripts
are generated from expanded disease-associated alleles. </span></div>
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<span class="Apple-style-span" style="font-family: Arial; font-size: 15px;">Unfortunately, as a senior scientist in some one else's lab, I did not have my own funding. The years of work to break down the barriers to even recognize antisense transcripts are perhaps wasted for my career, as I could not hang on long enough to acquire funding. However, there is some light at the end of the tunnel. The Amyotrophic Lateral Sclerosis (ALS)</span><span class="Apple-style-span" style="color: #444444; font-family: arial, sans-serif; font-size: x-small; line-height: 16px;">,</span><span class="Apple-style-span" style="font-family: Arial; font-size: 15px;"> community seems to have embraced bidirectional transcription, as well as another controversial topic, <a href="http://www.plosgenetics.org/article/info%3Adoi%2F10.1371%2Fjournal.pgen.1002018"><u>R</u>epeat-<u>a</u>ssociated <u>N</u>on-ATG (RAN) translation</a>. RAN translation was first described by <a href="http://neurogenetics.med.ufl.edu/faculty/dr-laura-p-w-ranum/">Laura Ranum</a>, another pioneer in bidirectional transcription at repeat regions. In fact, the ALS community is incredibly competitive about the sense, antisense, coding, non-coding, toxic, non-toxic, RNAs and transcripts and the C9ORF72 gene. It is a thrill to read each paper, each perspective, and each interpretation. There seems to be little room of critique of antisense transcripts in their world, instead they seem to be focused on using every bit of evidence they can find to characterize the molecular mechanisms underlying this disease. </span></div>
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<span class="Apple-style-span" style="font-family: Arial; font-size: 15px;">Make no mistake, I do not support some of the underhanded competition that has occurred in this field. Even I have been taken advantage by a few members of the C9ORF72 community, but I stand firm that the outcome will benefit the patient community, so it is worth it. I have faith that the researchers are close to having viable and realistic therapeutics for ALS, something that is truly needed. But I chuckle at how easily authors have claimed to "demonstrate" bidirectional transcription at C9ORF72, such as the <a href="http://www.mayo.edu/research/labs/neurodegenerative-diseases/overview">Petrucelli Lab</a>, where the evidence is basically in vitro analysis of transfected constructs or <a href="http://www.biochemie.abi.med.uni-muenchen.de/edbauer/index.html">Edbauer Lab</a>, where evidence of antisense translation is the proof. This is liberating for the field, where scientists with expertise in disease characterization do not have to spend 3-5 years characterizing the transcript boundaries, localization, and processing prior to addressing impact on disease. </span></div>
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<span class="Apple-style-span" style="font-family: Arial; font-size: 15px;">There is time and space for researchers such as myself, who can more quickly address the RNAs generated at the locus. I hope the recent body of work at the C9ORF72 locus will make it easier to address bidirectional transcription at the remaining 20+ unstable tandem repeat genes, all associated with equally devastating disease. Nonetheless, I wish that I could have a conversation with the reviewers of my grants, papers, and research proposals and ask them why they rejected the validity of bidirectional transcription. What did they gain by blocking progress? There was never a consequence for them, instead the ultimate burden is on the individuals who harbor repeat expansions and suffer from disease. These individuals continue to wait for someone to be interested in their gene mutation. It pains me that I came so close to being able to advance understanding of the gene loci associated with 20+ unstable repeat regions, but the road block of grant review did not see these diseases as important.</span></div>
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<!--EndFragment-->PLaddhttp://www.blogger.com/profile/11315143719078119070noreply@blogger.com0tag:blogger.com,1999:blog-2508596611864801079.post-35388937434993343512013-11-02T17:49:00.001-07:002013-11-02T17:52:03.236-07:00Reveal, Reclaim, Reform The 3 R's in Modern Science<span class="Apple-style-span" style="font-family: Cambria;">
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</span><br />
<div class="MsoNormal">
<span class="Apple-style-span" style="font-family: Cambria;">On the blog front, I have been suffering from a bit of
paralysis.<span style="mso-spacerun: yes;"> </span>My intent for this blog is to
focus on my field of interest: transcription, transcription regulation, and
transcriptomics. However, my focus has been diffuse and scattered lately.<span style="mso-spacerun: yes;"> </span>In the past few weeks, I have been caught off
guard by the number of bloggers, columnists, and science writers who have been
critical of the waste, fraud, and misconduct in science.<span style="mso-spacerun: yes;"> </span></span><br />
<span class="Apple-style-span" style="font-family: Cambria;"><span style="mso-spacerun: yes;"><br /></span></span></div>
<span class="Apple-style-span" style="font-family: Cambria;">
</span>
<div class="MsoNormal">
<span class="Apple-style-span" style="font-family: Cambria;">Let me clarify: I am not taken back by the comments that
have been made.<span style="mso-spacerun: yes;"> </span>Instead, I am surprised to
see more scientists be open about what is happening in academic science.<span style="mso-spacerun: yes;"> </span>In the past 4-5 years, when I openly expressed
my concerns about the state of academic science, I was accused of not being a
team player or worse, not being competitive.<span style="mso-spacerun: yes;">
</span>Seemingly, by pointing out the failings of academic science, I was seen
as someone who could no longer compete with my peers.<span style="mso-spacerun: yes;"> </span>The hesitation to be as corrupt as my
competitors suggested I was not a strong scientist. <o:p></o:p></span></div>
<span class="Apple-style-span" style="font-family: Cambria;">
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
What troubles me most is how my silence enabled continued
misconduct.<span style="mso-spacerun: yes;"> </span>Now I feel compelled to
share my experiences and support those who dare to challenge the status quo.<span style="mso-spacerun: yes;"> </span>It is time to “<b>reveal</b>” the bad behavior of
scientists so that collectively we can decide how to recognize and discourage underhanded
behavior.<o:p></o:p></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
Misconduct is not a new problem, thus pointing my finger at
individual scientists is hardly productive.<span style="mso-spacerun: yes;">
</span>Instead, I want to speak up to say misconduct, whether deliberate or
careless, gender and ethnic disparity in career advancement and funding, as
well as exploitation of students, technicians, and postdocs are all important
topics that should no longer be ignored.<span style="mso-spacerun: yes;">
</span>I witnessed this behavior at every level of my training from
undergraduate to project scientist.<span style="mso-spacerun: yes;"> </span>Like
most trainees, I tried to steer clear of those who were blatant frauds, but
eventually ended up in an area where inappropriate behavior was considered
smart and competitive.<o:p></o:p></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
During my second postdoc, I was surprised by the number of
graduate students and postdocs who could relate multiple, unique, and
individual stories of scientific misconduct by their PIs, collaborators, or lab
mates.<span style="mso-spacerun: yes;"> </span>Worse, I met a number of newly minted
(and inbred) postdocs who supported underhanded approaches to double salaries,
honorary authorship, and un-reproducible results.<span style="mso-spacerun: yes;"> </span>Their objective was to increase authorship
and grant funding.<span style="mso-spacerun: yes;"> </span>I encountered the
attitude that most of our work is obsolete in 5 years, so why worry about the
integrity of science? Keep your head down and worry about the paycheck and the
number of publications on your CV, it is the only way up the career ladder. <o:p></o:p></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
Initially, I was outraged.<span style="mso-spacerun: yes;">
</span>When I witnessed a postdoc who sabotaged the research going on around
her, I encouraged one of the victims to speak up.<span style="mso-spacerun: yes;"> </span>To my disgust, the victim was reprimanded and
later fired, for revealing a problem in the lab.<span style="mso-spacerun: yes;"> </span>The saboteur was rewarded for being
competitive and given a raise.<span style="mso-spacerun: yes;"> </span>The rest
of the lab was told to never speak up again, as it will not be tolerated.<span style="mso-spacerun: yes;"> </span>It was then that I felt defeated.<span style="mso-spacerun: yes;"> </span>Once again, the whistle blower was punished.<o:p></o:p></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
Scientific misconduct is most insidious when it is from a
person of power, who controls references, publications, grant and paper
reviews.<span style="mso-spacerun: yes;"> </span>As a result, we cannot put all
of the responsibility on those who have been victimized.<span style="mso-spacerun: yes;"> </span>However, this power is reduced when their misconduct
is revealed. <span style="mso-spacerun: yes;"> </span>As members of the
scientific community, it is our responsibility to speak up for those who do not
have voices.<span style="mso-spacerun: yes;"> </span>Of course, keep in mind
that graduate students have a department chair, and committee members to look
out for them.<span style="mso-spacerun: yes;"> </span>Technicians,
undergraduates, postdocs, and senior scientists do not have this type of
support under our current system, where the University has a vested interest in
the PI’s career rather than the careers of those in the lab.<span style="mso-spacerun: yes;"> </span><o:p></o:p></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
We need to “<b>reclaim</b>” our voices, expertise, and
experiences.<span style="mso-spacerun: yes;"> </span>Too many postdocs leave their
field of research taking with them all of the knowledge they amassed from
undergrad to postdoc.<span style="mso-spacerun: yes;"> </span>As a result,
experiments are never published, shared, or further explored.<span style="mso-spacerun: yes;"> </span>What a waste of time and effort.<span style="mso-spacerun: yes;"> </span>How do we capitalize on this obviously
untapped source of knowledge? Macro or micro-blogging coupled with
open-notebooks or mandatory raw data sharing is probably the best way to
establish an area of expertise.<span style="mso-spacerun: yes;"> </span><o:p></o:p></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
A little chatter about the relative levels of
scientific integrity at different Universities, departments, and lab groups
should be expected.<span style="mso-spacerun: yes;"> </span>I know this makes
some people uncomfortable, but our silence only aids the misdeeds of
others.<span style="mso-spacerun: yes;"> </span>We should have a greater fear of
tarnishing our reputations than fear of not getting funding.<span style="mso-spacerun: yes;"> </span>We should have greater pride in publishing
sound, reproducible data than pride in a mega-paper in Science, Nature, or
Cell. <span style="mso-spacerun: yes;"> </span><o:p></o:p></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
I challenge everyone who became a scientist to satisfy
curiosity and to advance a particular scientific question to reclaim positions
as mentors, investigators, and experts.<span style="mso-spacerun: yes;">
</span>Grant funding and academic positions are very slim for early career
investigators, but that does not mean we must stop being scientists.<span style="mso-spacerun: yes;"> </span>There are other outlets, including using
social media to advance a scientific question.<span style="mso-spacerun: yes;">
</span>We may not have the means to perform experimentation, but we can read,
evaluate, and question the published work of those in our fields.<span style="mso-spacerun: yes;"> </span>Ultimately, to blog, tweet, and comment our
critiques of the work is the best type of peer review, as it gives us the
opportunity to have on-going conversations about the science.<span style="mso-spacerun: yes;"> </span>In doing so, we will reveal who among the authors
understood the experimentation and experimental question from those who were
mere middle-managers, assembling the story.<span style="mso-spacerun: yes;">
</span>Our voices are the strongest tools we have to work against the rise in
scientific fluff, particularly un-reproducible or highly improbable
research.<span style="mso-spacerun: yes;"> </span><o:p></o:p></div>
<div class="MsoNormal">
<br /></div>
<span style="font-family: Cambria; font-size: 12.0pt; mso-ansi-language: EN-US; mso-ascii-theme-font: minor-latin; mso-bidi-font-family: "Times New Roman"; mso-bidi-language: AR-SA; mso-bidi-theme-font: minor-bidi; mso-fareast-font-family: "MS 明朝"; mso-fareast-language: EN-US; mso-fareast-theme-font: minor-fareast; mso-hansi-theme-font: minor-latin;">Better yet, as outside voices, we can champion
good science, even if it is not published in a top-tier journal.<span style="mso-spacerun: yes;"> </span>Good science should be publically acknowledged,
and social media provides an excellent platform.<span style="mso-spacerun: yes;"> </span>Furthermore, social media is a platform that
provides all of us the opportunity to establish an expertise in a field of study.<span style="mso-spacerun: yes;"> </span>Ultimately, using our voices to share our
knowledge is the best way to “<b>reform</b>” science, as we know it.<span style="mso-spacerun: yes;"> </span></span><!--EndFragment-->
</span>PLaddhttp://www.blogger.com/profile/11315143719078119070noreply@blogger.com0tag:blogger.com,1999:blog-2508596611864801079.post-68918853038540371062013-09-22T16:26:00.003-07:002013-09-22T16:26:48.462-07:00What is your passion?Do you know what you want to do the rest of your life? I do. I want to be a working scientist. Better yet, I want to be a productive scientist, meaning that I want to contribute good science and good training for the betterment of my field of study. I really do not care if the science is published in a glam journal, as long as the data is accessible. I do not care where I do the work, as long as I can provide for my family. <div>
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<div>
Like any postdoc or senior scientist, I have taken time to prepare job applications for tenure track positions, or even lecture positions. I have gone through the process a couple of times, but fell short of a faculty position. This is disappointing, but there is an odd sense of security in the realization that most of my former co-workers are not in faculty positions. Some realized that they were not willing to move to another city or state, others just grew tired of the time spent marketing themselves. Like myself, they hated giving up the time needed to look for a job, when there are so many experiments left to do. </div>
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My friends who have found positions, have done so with a price. Either they moved to cities that were less desirable, or took a position that offered less salary, bench space, and/or more teaching than they really expected. I am proud of them for their sacrifices. Unfortunately, I have reached a point in my life where the family's happiness is more important than my title. I can no longer move from city to city chasing a tenure track position that will likely never happen for me. </div>
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<br /></div>
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Does this mean I have given up? No.....it means that I have changed my focus. For years I believed that my only options were industry or academia. But I now see there are many more options that scientists do not consider, including freelance, consulting, and commercialization. Another option is to be independent, really independent. No academic affiliation, no industrial application. The appeal is the freedom. The fear is the lack of a safety net, which includes retirement, health insurance, and a dependable salary. </div>
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A few people have been public in their independent pursuit, including the <a href="http://www.perlsteinlab.com/">Perlstein</a> and the <a href="http://letolabs.com/">Leto</a> Labs. <span class="Apple-style-span" style="font-family: Times, 'Times New Roman', serif;">Perlstein has trumpeted crowdsourcing as a way to fund his research, while Leto's motto, as taken from his website: "We fund ourselves, so that we do not have to worry about being ignored or constrained by those who do". I am certain there are other independents, who fashion an approach that works for them. In fact, I think the independents have always been around, just largely ignored. </span></div>
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<span class="Apple-style-span" style="font-family: Times, 'Times New Roman', serif;"><br /></span></div>
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<span class="Apple-style-span" style="font-family: Times, 'Times New Roman', serif;">I will stress that I plan to do something a little different. I want to provide a PATH for other independent scientists. My personal struggle to create an independent, productive lab is not interesting enough unless I help the future independents. It is time to provide reasonable competition to the current academic model. I predict that a new wave of independent scientists are coming.</span></div>
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PLaddhttp://www.blogger.com/profile/11315143719078119070noreply@blogger.com0tag:blogger.com,1999:blog-2508596611864801079.post-9614995800747321052013-09-14T22:55:00.004-07:002013-09-15T15:47:06.986-07:00A Visit to the Home LabI spent Friday night with old friends (and a few new) at the <a href="http://www.fhcrc.org/en.html">Fred Hutchinson Cancer Research Center.</a> Friday evenings are generally celebrated with a beer hour to discuss science (or more often--weekend plans to hike, kayak, or ferry somewhere in the beautiful Pacific Northwest). Each week, as different lab hosts the beer hour with a keg or two of beer and some yummy snacks. But the highlight for each beer night is the poster that the host lab puts up to announce their intentions. My good friend Steph in <a href="http://research.fhcrc.org/geballe/en.html">Adam Geballe's lab</a> is the master at these posters. My favorite is when she photoshopped Adam's head to Psy's for a Gangnam style Hutch beer hour. But she really topped herself with a "3D poster", which was basically a bust of Adam on a "keg" pedestal. This bust is now called the "<a href="https://www.facebook.com/photo.php?fbid=10201530836448526&set=bc.AboLhwfnONyjZd4T7z4ANX6vsBJo34oGEQC3Zv17qZFIB3g2dgzCRO7FqxhL_nHfp_uKzhD5cpabXEGkOlX7oWyo5NsjVtPE7xj2kZaiNM4AOSa4k0j7Dhzssvbx6v1z6sU&type=1&opaqueCursor=Abr-9pyjHc6EICMkY2CjwJFBjkgr_Ory-ZkkB429JqM7mz4f1idor726i-28wbrHM56tzAD4HId5aqXHZYqG9-sz-TruM-FKqMk5JC5ctyhitiE8t6h4hVzn5FuftZGXYwOOdNSYYe7Z7L33ZGIrOLrXRrq9ccYj9gU7vejTYksz1e9A7K6oORczy9k_hGdMpsXULSwy4H0g1vFbfYoN5rtupmpeP0KcimcXvOPA7Io3xqZmxNMG2c-LUNYHBK59wKY&theater">Geballus</a>", hopefully it will be awarded internally to other labs when they do something <i>GREAT, </i>like an outstanding lab halloween costume theme or spirited Christmas decorations. <br />
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<div>
It is silly fun, I know. How could this possibly be important in the grand scheme of things? Well, it is a morale builder. It is a safe place to discuss the week-to-week, day-to-day trivia of life at the Hutch. I have solved many experimental problems after discussion with other talented postdocs or faculty. This is a place where science is the focal point of the day and night. The Hutch is large enough to have research diversity, but small enough for most people to know one another. Graduate students and Postdocs come and go, but they typically leave reluctantly. Is everyone happy at the Hutch? Probably not. But I do not recall many people who were eager to leave the place, as it is truly an inspiring place to work. If anything, I am one of the people who complained the most, about someone with whom I worked. </div>
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I did not feel a similar magic when I moved to UW in 2008 or UCSD in 2009. In fact, I met many postdocs at UCSD (2009-2013) who were far more unhappy than I was. The competition for grants, papers, and their PI's attention seemed too great for most postdocs to remember the joy of science. This is why I left. This is why I took a job that on the surface does not seem to be the type of job that will help me get to my career or science goal. (My gut still says it was the right decision.) </div>
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The benefit of my current position is that I am close to my Postdoc "home", The Hutch. I feel a little more centered having made a visit to the campus and spoken with the great scientists who stopped by the beer hour for a little conversation. I am ruminating a number of things that I <i>want</i> to do for my current project, that I <i>need </i>to do for the previous project, and that I <i>hope</i> to do for a future project.</div>
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I wonder....is it the independent spirit of the Hutch that makes it magical? </div>
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PLaddhttp://www.blogger.com/profile/11315143719078119070noreply@blogger.com0tag:blogger.com,1999:blog-2508596611864801079.post-82925116281938632022013-09-08T10:48:00.000-07:002013-09-08T10:51:46.941-07:00Lead or Follow?The twitter feed for many of the people I follow is often filled with critique of other scientists. Typically, the tweets are critical of the process of science, with a little self-rightous tone. Nothing that I take too seriously, but I know there is an underlying reality to the criticism. From where I stand now, as there is a conflict between my early training (undergrad and graduate school) and my later senior postdoc experiences. Much of the conflict has to do with scientific integrity, reproducibility, and authorship. <br />
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When I was an early post-doc, one of my dual mentors warned me about sharks in the water. "Learn to swim with them while you are a fish" my mentor would say, "but do not trust them not to eat you". I resisted this advice early on, not wanting to be distrustful of my fellow scientists. After all, our efforts at the bench speak for themselves. But it seems that our field has bottomed out in integrity. I am not certain that we value bench work. Instead, we reward the project manager approach, where a theorist gleans the experimentation in the lab, department, university, or field of study. <br />
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When experimentation is undervalued relative to interpretation, we lose the fundamental aspect of research, namely "observation". Very little space is allocated to <a href="http://www.the-scientist.com/?articles.view/articleNo/37382/title/Many-Papers-Lack-Detailed-Methods/">experimental methods</a> in many high impact journals. Details are very brief and reagents are hard to track. Worse yet, in silico data is harder to track when much of the bioinformatics are in-house and code is guarded closely. How can we advance a field of study without discussing the methods used? How did we get to this place is science? Is experimentation a dirty word or did we become so adept at incorporating so many small projects into one big paper that we lost sight of the individual experiment?<br />
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The knee jerk reaction is to have journals, such as Nature, define <a href="http://www.nature.com/authors/policies/reporting.pdf">policy</a>. But I think the bigger issue is the lack of outrage by all of us in the field. If we want reproducible science from our peers, we need to expect reproducible science from our peers. This means we need to ask for the details when we review papers, attend meetings, and collaborate. We need to take pride in the details rather than hide behind reputation and big stories. When a researcher replies that the experimental method is unimportant, we need to be suspicious that the researcher either does not know the details (thus is actually a project manager not the experimentalist) or is hiding something. We also need to demonstrate good science when we publish our own data. <br />
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Lead by example and the field will follow!PLaddhttp://www.blogger.com/profile/11315143719078119070noreply@blogger.com0tag:blogger.com,1999:blog-2508596611864801079.post-55197061395307364522013-09-01T08:38:00.000-07:002013-09-01T08:38:42.601-07:00<div class="separator" style="clear: both; text-align: center;">
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<b>Transcriptomics</b><br />
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Over the past decade, I have been trying to identify some of the most difficult transcripts, such as the antisense transcripts at the FRM1 (asFMR1) and the Ataxin-7 (SCAANT1) loci [HMG, 2007, 16(24), Neuron, 2011 70(6)]. What is so challenging about these transcripts is the sequence. Each contain repetitive CGG and CAG regions, respectively. However, the biggest challenge has come from the scientific community, which has and absolute aversion to antisense transcripts, bidirectional transcription, and many noncoding RNAs. <br />
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I have read or heard every possible argument as to why these transcripts are unimportant. Yet, more and more groups are finding noncoding or seemingly noncoding transcripts. I have faith that we will eventually have a clear picture of the transcriptome, but the persistent wading through the muck is slowing down progress. I have to ask my scientific peers, why be a road block? At the end of the day, does it make you feel better about your scientific progress to block the progress of others? Or do you hold so dearly the central Dogma DNA->RNA->Protein that you cannot imagine what else is happening in the cell?<br />
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Greater than 90% of the human genome is transcribed, at some point in time. The validity of this observation seems to be one of the hardest to convince non-RNA biologists. There seems to be a disconnect in understanding how our genomic sequence. I am always surprised that there are highly educated scientists who would rather believe that the majority of our genome is nonfunctional, or better yet, unimportant. Yet, we evolved to carry this much genetic information. Of course, I have heard many a technician exclaim that we have not evolved enough, but that is for another day. Instead, I will post one of my favorite figures from a fairly recent publication. Here we see an updated view of the activity at a single gene locus. So much effort from so many research groups! And I know the hurdles faced by all of us to get this information to the masses. If only our "peers" could have had more open minds, we could be further along.<br />
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<br />PLaddhttp://www.blogger.com/profile/11315143719078119070noreply@blogger.com0tag:blogger.com,1999:blog-2508596611864801079.post-25434820199988989112013-03-14T10:46:00.000-07:002013-03-14T12:55:47.978-07:00End of My Hiatus Wow, it has been almost 2 years since my last blog post! <br />
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I did not mean to go this long without blogging, but I have been very busy at work and at home. After my last blog, I took a 3 week vacation with my family. We took a road trip of the Western and Midwestern states. It was an eye opener! I did not realize just how severe poverty was in the US until I traveled through Texas, Arizona, New Mexico, Missouri, Kansas and Illinois. What are the major factors? Weather, drought, industrial collapse, racism? I do not fully understand what has happened in these states, but it is heartbreaking. I have no idea what the solution is, nor do I know how long it will take to turn these areas around. I doubt that casinos, fast food companies, and retail malls are the answer, but these were the only infrastructure remaining in some of these places. This lead me to rethink my priorities, thus I spent the last year and nine months focused on my work and family.<br />
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I am rejoining the blogging community! I have so much to say and this is the best format. True to my original intent, I will blog about science. Not that knitting is not interesting..... Instead, I previously used my hobby as an outlet to deal with an ugliness of science that is not easy to discuss. No more hiding behind K1, P2!<br />
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It is tempting to address numerous issues plaguing the scientific community, including misconduct, fraud, plagiarism, retractions, funding inequities, and gender bias. All I can say is "maybe". These are difficult issues, often with no clear answer. And there are some very nice sites such as <a href="http://retractionwatch.wordpress.com/">Retraction Watch</a> that do a much better job highlighting these problems than I could ever do.<br />
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A more progressive approach is to move into open-science, open-access, crowd funding, and independent science. Rather than use my energy to attack what is wrong with the system, I want to walk away from the mess and build a new community. The best part is that I have seen examples of like minded people. <a href="http://www.rockethub.com/about">Rocket Hub</a> and <a href="http://www.petridish.org/">Petri Dish</a> are examples of a movement to use crowd funding to finance science. <a href="http://www.perlsteinlab.com/">Ethan Perlstein</a> and <a href="http://www.brightworkcoresearch.com/author/JacobShiach/">Jacob Shiach</a> are pioneers as independent scientists, flying without the safety net of academia. And the <a href="http://opensciencefederation.com/">Open Science Federation</a> is blazing a path for future scientists. Really, it is more rewarding to redefine a successful science career, than to continue to point out who is unethical, who is cheating, and who is a fraud.<br />
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Coming Soon: new blog layout! And old blog purge........PLaddhttp://www.blogger.com/profile/11315143719078119070noreply@blogger.com0tag:blogger.com,1999:blog-2508596611864801079.post-53161099287392181202009-11-08T10:06:00.000-08:002009-11-08T10:06:05.070-08:00The Scientist's LifeWe have such a strange way of training scientists. First, we get an undergraduate degree, of course, we pay for it and understand that it is a privilege to work in someone's lab. Then we make the choice to work as a technician (paid+benefits) or go to graduate school, again "paid", but no benefits. Graduate school takes anywhere from three to eight years to complete. The programs are not equivalent from school to school or even from department to department. Thus, recently hooded PhDs are diverse in their understanding of how to approach a scientific question. Probably--this is OK. <br />
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What becomes a challenge is that the next step is even more variable. The post-doctoral training!! This can be 3 years or even a lifetime. There are far too many variables at this step. Some can be controlled by the individual post-doc. But there is too much that cannot, such as how the university views their obligation to the post-doc. Typically, universities allow the principle investigator (PI) decide how to train the post-doc. Some decide that the post-doc is cheap labor, some decide that training the post-doc is an opportunity to advance scientific thought. <br />
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I have been in the post-doctoral training stage for 5+ years and I now realize that the process is not quite right. If only I could be in charge! Basically, I feel that the University should be fiscally responsible for all steps--whether technician, graduate student, post-doc or PI. There is too much power at the PI level. Sure, the PI brings in the NIH money (or other funding opportunities). I do think that this is important to the process. But the PI should not have so much power over the rest. Post-docs should have equal opportunity to apply for funding independent of the PI. Technicians should have better opportunity to move from lab to lab, perhaps by being an employee of the department rather than the PI. There are so many abusive PI's because they do not seem to have to answer to the University, as long as they bring in funding.<br />
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I have been thinking about this whole process, because I want to move on to the next level. I wonder if I really have enough time to make the changes that should be made. Probably, I need to start being more vocal to the people around me about a "better" or more equitable way of performing science. Perhaps, a few of my ideas will be transferred to the next generation of scientists. PLaddhttp://www.blogger.com/profile/11315143719078119070noreply@blogger.com0tag:blogger.com,1999:blog-2508596611864801079.post-86151218090624390262009-08-29T15:16:00.000-07:002009-08-29T15:16:34.325-07:00Saturday in the Lab....<div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEh98SpIHVrJlXHhq7dloSWfoz4VbsjDVmcLcXytSKpmtuy-GG_1nmlkTHmAj5XRfcAfGReU5-oiHdHs55GkLPdJaz2Xbu56uH_6_z-Vzym9og5NwM9Ou0zKypcaqLvphsDoH-BMebg5Ejc/s1600-h/images.jpeg" imageanchor="1" style="clear: left; float: left; margin-bottom: 1em; margin-right: 1em;"><img border="0" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEh98SpIHVrJlXHhq7dloSWfoz4VbsjDVmcLcXytSKpmtuy-GG_1nmlkTHmAj5XRfcAfGReU5-oiHdHs55GkLPdJaz2Xbu56uH_6_z-Vzym9og5NwM9Ou0zKypcaqLvphsDoH-BMebg5Ejc/s320/images.jpeg" /></a></div>I am applying for a grant from the National Ataxia Foundation (http://www.ataxia.org/). I am not certain that I am really competitive enough for this award, but why not try? The award is due on Tuesday the first, and I received my mentor's edits yesterday. I am sad to spend the day away from Colten, but we did have the whole day together on his birthday. Also, it is another hot day in San Diego and I am in air conditioning, while my family is not-----that makes me sad. PLaddhttp://www.blogger.com/profile/11315143719078119070noreply@blogger.com0