A new year…a new life

My post-doc, as rewarding as is was, is officially over.  After much soul searching, I accepted (and recently started) a position with Cell as a scientific editor.  Some of you may know Cell as the high impact journal that competes with Science and Nature for the most interesting studies in biology.  To me, it has always been the most recent addition, but probably most important and well-respected member of the trinity – Science, Nature, and Cell.  These the three journals comprise the top of any biologist must read list (or should I say, must skim list, since we are all so busy doing experiments and writing grants and supervising students and teaching classes and thinking about data and giving talks and presenting posters) to stay in the know about the newest and most important discoveries.

Cell was originally founded in the early 1970s by Benjamin Lewin, the Cambridge University trained molecular biologist who has been accused of intensifying the pressure and competition associated with scientific publishing, but who has also been praised for infusing scientific editing and publishing with high standards for production values and intellectual rigor that are now universally associated with cutting edge scientific papers.  Cell is the mother of the Cell Press family of journals, including some that I used to read as regularly as I looked at Cell, Science, and Nature, such as Neuron, Molecular Cell, and Developmental Cell.  Cell Press is now a subsidiary of the Dutch-based Elsevier, a long standing publishing house that takes it name from 16^th century Elzevir family of booksellers and publishers.

What does this decision mean for my life? for my blog?  Change.  In a new city and in a new role, I have to figure out how to reconcile who I have been for the past 12 years with who I am now becoming.  I miss the actual discovery process of bench research and I miss my friends and colleagues from lab, but I enjoy reading and thinking about science; I love learning about how to make decisions and how to put new discoveries in their appropriate context, and I feel nothing but satisfaction when I edit and write about cutting edge discoveries.  Although this transition from scientist to writer/editor is challenging and a bit scary, I take comfort in the company motto, Non Solus.  This latin phrase means “not alone”.  In my new job and my new life, I am not alone.  I have fantastic new colleagues who are helping me make this transition; I have the privilege of working with brilliant and kind-hearted scientists, and, as many grad school and post-doc friends can attest, I am not alone as I join the growing ranks of Ph.D.’s making a transition from academic research to different and exciting careers.

The Elzevir family’s mark, which graces the websites and documents published by Elsevier, shows that scientists and publishers are interdependent, leaning on each other to help promote the fruits of scientific research.  The official Elsevier sentiments is that Non Solus highlights the mutual effort required for promoting scholarly (scientific) research.  To me, the robed scholar examining the tree branches and those two simple words, non solus, go beyond science or publishing and say that no matter what, none of us is ever alone.  And with that I must say adios and good-bye.  I no longer can provide a post-doc perspective on science, and so, as all good things, this particular blog must come to an end.  While londonkara is no more, stay tuned for a new web presence, cambridgekara.  Thanks for reading.

Post-doc Development

The intellectual and practical development of a post-doc.

Intellectual: When a newly minted PhD chooses a post-doc lab, he/she has the opportunity to change fields, learn new ways of thinking, and explore different areas of science.  I definitely made a leap when I started my post-doc – moving from yeast cell biology to zebrafish developmental biology.  After a bit of frustration and feelings of “lostness”, I realized that I was building on a very firm foundation of knowledge and critical thinking skills gained in grad school.  I took more ownership of my new research and I’ve now established my own unique experimental repertoire – based on my various experiences and interests – so that I can design and perform experiments to address interesting questions about cell behaviors including proliferation, differentiation, and migration.  By choosing to pursue a post-doc in a new and different field in a new and different place, I’ve grown personally and intellectually.  I’m happy to report that I’ve become a scientist who loves reading papers, who enjoys thinking about all the stuff that we still don’t understand, and who can generally hold her own in many different scientific discussions and debates.

Practical: In addition to the basic wet-bench experience you gain as a post-doc, the most essential part of post-doc training is the opportunity to develop what I call “scientific ESP”.  This extra sense enables you to know when projects should be pursued and when they should be dropped faster than a stinkbug.  It helps you discern which is the “killer experiment” – the one experiment that will let you know if your research is destined for publication in a top journal, a respectable journal, or the rubbish bin.  And it reveals which areas in your particular field are ripe for investigation.  Some may also say that “scientific ESP” helps you seek out the departmental seminars where gourmet snacks are served.

Skills gained through activities like talking with experts, thinking, teaching, mentoring, and organizing journal clubs are sometimes are called transferrable skills since they can be applied to anything and everything.

-If you can explain your science to a non-scientist, you might convince them to vote for more science related funding.  Ok.  That might be wishful thinking, but at least you might convince some kid that learning and exploring the microscopic world can be a really cool (and a way to know more than their parents).

-If you can plan your experiments and budget your time so that you get a result each week (not necessarily a good result or a very meaningful one…but a result or a pretty picture), then you might just be able to plan other aspects of your life.

-And most importantly, if you can follow a protocol, you can learn to follow a recipe and cook yourself a decent meal.

Being a post-doc provides all kinds of learning opportunities.  For this post, I’ve  highlighted some of the good learning experiences I’ve had as a post-doc.  But, in the interest of full disclosure, being a post-doc is not always fantastic.  For some insight into that matter, I refer you to the cartoon below and others from a former post-doc, Alexander Dent.

Thinking about the next step...

zeptoliters and a bit of etymology

Since a bolt-cutting lock-breaking thief misappropriated my bicycle several weeks ago, I’ve been hoping that he (or she) would return it.  Until then, I’m riding the bus.  Time on the bus gives me the opportunity to eavesdrop and read – both activities provide ideas and inspiration for my writing.

Just the other night, when the bus was on diversion, which means that it takes nearly twice as long for me to get home, the upper level was quiet, with only a few of us heading home after a long day at work.  I was paging through at the latest issue of Nature Methods and began to read a News and Views article about a recent advance for detecting epigenetic marks while determining the sequence of a piece of DNA.  I could write an entire post on epigenetics – what it is and how important it is – or even what an important breakthrough this new technique (SMRT) is, but when I read about the latest progress in detecting methylated Adenosines and Guanines what stuck with me an obscure word – zeptoliter.  This word conjured up all kinds of images, the most vivid was a space age zeppelin that delivers small squirts of liquid.  A zeptoliter is actually 10^-21 of a liter, a billionth of a trillionth of a liter, a very, very small volume that can be measured and delivered by a miracle of nanoscale engineering, a zeptoliter pipette.

The word zeptoliter got me to thinking about and searching for other interesting but obscure words.  I’ve included several words with links to their dictionary/wiki page that I’m going to try to use in conversations over the next few weeks.

Oxyopia describes a condition of heightened visual acuity, which comes from increased sensitivity of the retina.  It is a word with very old origins:  Oxy, meaning sharp or acute, can be traced to ancient Greek, and Opia is a Greek suffix with Indo-european roots meaning sight or vision.  If only the linesmen and referees in some of the recent world cup games were oxyopic.

Schizothemia has nothing to do with the craziness associated with schizophrenia and everything to do with being unable to sustain a thought or theme in an oral or written conversation.  When you speak with someone who suffers from ADD or ADHD you may experience schizothemic conversations.  Schizothemic stories are convoluted and lack focus; they are the evidence of a writer trying to cover too much.  I might even be tempted to describe my scientific career as schizothemic as I’ve jumped from field to field:  autoimmunity as an undergrad, glycobiology as an undergrad and pre-grad student, the cell and molecular biology of mitochondria dynamics and inheritance in yeast as a grad student, and finally cell and developmental biology study of eyes in zebrafish to examine how cells transition from proliferation to differentiation.

Arcology is a portmanteau word that combines architecture and ecology describing a futuristic form of building design that encloses enormous habitats that maximize human interactions, minimize the use of resources like energy and raw materials, and practice the principles of reduce, reuse, and recycle, sort of like a massive scale Eden project.  Arcology developments are popular in science fiction, but there are real life examples too.  Arcostani is a planned community in Arizona for 5,000 people designed by Paolo Soleri, the Italian architect who coined the term and popularized the concept of better urban living through arcology.  Like other suburbs and planned communities, construction of Arcostani began in the early 1970s and is still on-going.  Unlike those other developments, Arcostani is self-contained, relying on new technology and smart design principles to not sprawl into the surrounding open space.

A little self-promotion

Euphoric moments of discovery are few and far between.  As a scientist, I’m lucky enough to witness them every now and then.  Even luckier still, I combined the evidence of some of those exciting moments to form a scientific publication.  My latest scientific publication has appeared in the July issue of Development and it even warranted an “In this Issue” summary.  For those of you who aren’t scientists (and even for those of you who are), I’ve included the lay summary of the paper that was the culmination of nearly 5 years of work.

Proliferate, differentiate or die?  Making decisions in the developing eye.

Kara Cerveny, Florencia Cavodeassi and Steve Wilson

June 2010

Nearly 40 years after US President Richard Nixon declared “war on cancer”, researchers around the world are still trying to understand how tumors form and grow.  New insight about how cells can be prevented from becoming cancerous is found in an unlikely place – the eyes of zebrafish.

Zebrafish are small striped fish commonly sold in pet stores, and are valued for their hardy nature.  For scientists, zebrafish are model organisms that can be used to reveal new clues about all things biological including brain organization, immunology, cancer, and developmental diseases.

Zebrafish eyes, like the rest of their bodies, grow continuously.  Each eye grows in a very controlled pattern — new cells are added from a specialized region that encircles the edge of the camera-like part of the eye that senses light (the retina).  In this way, the eye grows much like a tree, adding annular rings of new cells that must integrate into the existing tissue.  Your eyes are different.  They are the same size from the day you’re born until the day you die.

The longer a tissue continues to grow, the more likely its cells are to acquire cancer-like properties.  Continued growth requires specific embryonic-like cells with unlimited growth potential, called stem cells.  Specialized regions that house these stem cells and provide a continuous source of new cells are called stem cell niches.  We can examine how tissues regulate their growth (proliferation) by studying accessible stem cell niches, like those in the eyes of zebrafish.

In this study, we analysed mutant fish whose eyes failed to grow.  Although these fish have small eyes, their stem cells can, counter-intuitively, over-proliferate.  The failure of the eyes to grow happens because the abnormally proliferating cells usually die.  From a series of experiments, we learned that mature nerve cells (neurons), adjacent to the retinal stem cell niche, secrete signals that regulate the number of new cells produced.  This new finding tells us that the environment surrounding a dividing cell may be just as important as its own genetic make-up.

In one key experiment, we transplanted mutant cells into normal (wild-type) eyes and asked how they behaved.  We hypothesized that the mutant proliferating cells might form a small tumor in the host eye or be forced to die.  Neither happened.  Instead we found that the mutant cells behaved like their wild-type counterparts and contributed new neurons to the growing eye.  This surprising result along with other data from our study suggests that the environment can guide dividing cells to differentiate into neurons.

Schematic and Real data from our studies of mosaic retinae in zebrafish

The mutant we studied is named flotte lotte (flo for short).  We compared how quickly flo and wild-type eye cells divide, and found that flo mutant cells divide more slowly.  Because flo eye cells divide slower than normal, they eventually activate a cell-cycle checkpoint that prompts them to commit suicide.  Surprisingly, flo cells in a wild-type environment still cycle slowly, but instead of dying, they survive and differentiate into functional neurons.  Instead of triggering death to remove the mutant cells (which are dividing aberrantly and could potentially contribute to cancerous growth), the environment removes them by coaxing them to stop dividing and differentiate into neurons.  This is an attractive hypothesis for multiple reasons.  It provides one possible explanation for why we find neurons in all vertebrates (including humans) that contain evidence of a history of cell division defects such as an abnormal number of chromosomes.  It also provides an explanation for the organization and self-limiting behavior of the zebrafish retinal stem cell niche.

stem cell progression in the zebrafish retinal stem cell niche

Current and future experiments in our lab will try to figure out the exact molecules that drive flo cells to differentiate in a wild-type environment.  We are also interested in determining if particular types of mutants, e.g., classes of mutants with similar cell cycle defects, are more susceptible to environmental rescue than others.  For more information check out a synopsis of our paper in Development or contact us directly.

This summary will also soon be published on the public outreach section of our lab webpage.  This work was supported by a grant from the MRC and a post-doctoral fellowship from the Damon Runyon Cancer Research Foundation.  Future work on this project is funded by Cancer Research UK.

Newsworthy in May

Mitochondria on my mind.

Mitochondria are amazing little compartments in our cells.  They provide us with the energy we need to run, swim, bike, and think – and they are astonishingly beautiful.  Of course, I’m biased.  I spent the majority of my years as a grad student visualizing, examining, and isolating these remarkable organelles, trying to understand them – how they divide and how they partition themselves between mother and daughter during cell division.

When mitochondria are labeled with fluorescent dyes or proteins and viewed through a light microscope, they look like thin tubes (or like little snakes squirming around in the cell, as my advisor used to say).  When we view mitochondria with the help of an electron microscope, we can appreciate just how elegant and complicated these organelles are.  Each mitochondrion is composed of two membranes – an outer and an inner membrane.  The juxtaposition of these membranes encloses two spaces – the intermembrane space and the matrix.  These membranes and membrane-bound spaces are uniquely required for a multitude of cellular processes.

Because mitochondria are required for the production of nearly all of the energy that a cell needs (in the form of a molecule called ATP), many people forget that mitochondria are also required for many other essential processes.  They produce some of the building blocks for proteins (amino acids); they buffer the release of calcium within cells (which participates in cell behavior and cell-cell signaling); and they are key players in cell suicide (also known as apoptosis).  This new paper that I’m profiling as Newsworthy for the month of May, shows that mitochondria also contribute some of their own membranes to produce the starvation-induced recycling compartments called autophagosomes (which means, when translated from the Greek root-words, self-eaters).

The May 14^th issue of Cell published work from the Lippincott-Schwartz lab that shows how cells, when deprived of nutrients, mobilize resources from various locations inside the cell and assemble the membrane-bound machines that will recycle nutrients and help keep the cell from starving to death.  In their paper, “Mitochondria Supply Membranes for Autophagosome Biogenesis during Starvation”, Dale Hailey and coauthors combine classic cell biology with photo-conversion techniques to examine the membrane flux between cellular compartments.  Specifically they watched fluorescently labeled lipids move from the Endoplasmic Reticulum (ER) to mitochondria to autophagosomes.  Previous reports that showed connections between mitochondria and autophagosomes attributed these findings to autophagocytic ingestion of mitochondria, a process called mitophagy.  This paper now suggests that mitochondria are not only eaten by autophagosomes, they are also a source of the membranes that make up the autophagocytic mouth.

Earlier work from multiple labs, including the Lippincott-Schwartz lab, suggested the lipids for autophagosomal membranes come directly from the ER or from ER-Golgi derived vesicles (e.g., Axe EL et al., 2008; Young AR et al., 2006; Bernales et al., 2006; Ogata et al., 2006; Sakaki et al., 2008…you can find these papers and more by doing a PubMed search).  Indeed, the field of autophagosome biogenesis has been cluttered with myriad reports, which suggest various origins for the membranes of autophagsomes.  With this publication, Hailey et al., begin to sort through the confusion.  First, they show that mitochondria serve as sites of assembly for starvation-induced autophagosomes.  Next, they demonstrate that mitochondria contribute lipids from their outer membrane (and maybe just the outer leaflet of their outer membrane) to build the autophagosome upon nutrient withdraw.  To support their argument that mitochondrial membranes, but not mitochondrial proteins, form autophagosomes, the authors examine the distribution of mitochondrial outermembrane proteins and find that only synthetic proteins with a peculiar hairpin topology are transferred to the autophagosome membrane.  I don’t think any native proteins are inserted into a mitochondria’s outerleaflet this way, but it would be interesting to see if such a species could be transferred, along with mitochondrial lipids, to the forming autophagosome.  This paper clarifies a lot about the early steps of starvation-induced autophagosome biogenesis, but it doesn’t solve the problem of how particular lipids and proteins are partitioned between the donor mitochondria and the recipient autophagosome.  Given the amount of time this paper spent in review and revision, I would guess that these sorts of experiments are already underway.

Perhaps the most important data from this study are stashed away in Supplemental Material and Data Not Shown.  These data illustrate that other types of cell perturbations that induce autophagy (such as ER-stress), do not require mitochondria or their membranes for the generation of autophagosomes.  These data verify previous claims and suggest that different sorts of autophagosomes are formed depending on the needs of the cell.  These observations also raise lots of questions.  What are the signals that induce the different sorts of autophagosomes?  How do the cytosolic autophagocytic proteins target the correct membranes?  Do autophagosomes generated from different cellular compartments have distinct functions?

Earlier this week, I heard a talk about the metabolic changes and mitochondrial remodeling that occur during the generation of induced pluripotent stem cells (iPSCs), which is a fancy term for taking differentiated cells, generally from the skin, and then manipulating them so that they revert to an embryonic-like state.  It reminded me of how much we still don’t know, how preliminary much of this stem cell work is, and how many more questions are generated each time we scientists start to do experiments.  It also reminded me that it was high time for me to share this blog post about the many roles of mitochondria in cellular life and death.  Thanks for reading.