Wednesday, September 02, 2015

From 1988 to 2015 - how Jennifer Doudna shaped my career (and now science and society)

Well, yesterday was really fun.

In college, I switched from being an East Asian Studies major to being a Biology major in my sophomore year but had no idea what aspect of biology I might focus on.

Then I took a course that changed my life. The course was taught by a PhD student at Harvard and it was a kind of supervised reading class. The course was a full year class with weekly meetings to discuss various papers and news stories and such.  The topic was "The Origin of Life: Catalysis in Evolution" and it covered things like chemical evolution, catalytic RNA, the RNA world, introns, Lamarck vs. Darwin, and more.   The course syllabus is posted below:


 
This course changed my life in multiple ways.

First, in the course I learned how to critically read scientific papers. A very important skill. And also I got introduced to the world of catalytic RNA and also the world of "Cairnsian Mutation" which became the topic of my grad. school applications, my NSF predoctoral fellowship application, and the first two years of my PhD work. And I also got introduced to the work of Norm Pace.

This led me to seek out ways to combine my interest in ecology and evolution with molecular biology, which in turn led me to joining the lab of Colleen Cavanaugh and starting work on culture independent DNA studies of microbes.

Anyway, I could go on and on. But this course was transformative. Over the years I had heard about the student who had taught the course and her work, but had not actually seen her in person until yesterday.

The course instructor was Jennifer Doudna. And yesterday I got to see her talk about her work on CRIPSR and CAS9 systems. She has already won a large number of prizes for her work on this, and likely more to come. I cannot say I am surprised. Though I had many teachers at Harvard who were famous, and some of whom were also great teachers and researchers, I can say without a doubt that the one who impressed me most was Doudna. Her passion for science, for biology, for teaching, for being critical while reading articles, and for just wild things that organisms do, was contagious. So cool to see what she is doing now.

Anyway - I made a Storify of the Tweets (mostly mine) from her talk. Check them out below:

UPDATE - found my term paper from the class . posting it here.

Thursday, August 27, 2015

A worthy cause: Help fund a "Patient Centered Probiotics Reference"

UPDATE 8/27/15 - May have had a brain cramp on this.  See comment from Richard Jefferson.  Not sure this is in fact a worthy cause.

As many know I expend a lot of energy railing against overselling of the microbiome. And one aspect of this is the misinformation that is out there regarding probiotics. Well, this looks like it might help provide an antidote to some of the BS that is out there: This is a crowdfunding effort to create a curated resource with information on scientific studies of probiotics.
Powered by FundRazr
From their site:
In his book, "Follow Your Gut", Dr. Rob Knight cited several examples of how your gut microbes can affect your mood, the functioning of your immune system and inflammatory diseases. He suggests that you consult your physician or pharmacist to recommend probiotics that have randomized, placebo controlled trials backing them or failing that, you can survey the latest research published in scientific journals yourself. I know this is not a simple task for the regular consumer. A master reference of probiotics that you can refer to when making decisions on what products to purchase would be a handy thing. Dr. Knight notes in his book, that "...no patient centered resource exists that compiles this data." If someone were to go ahead and do a google search for this information, you'd have to wade through a lot of marketing material from companies trying to sell you stuff. By focusing on the peer reviewed scientific literature, we eliminate all the marketing material. The research reports are then read and summarized by our scientists (curators) who put it in our reference database in a language you don't need to be an expert to undestand. My colleague, Dr. Stephan Schurer, of the University of Miami Medical School, and I have built databases as tools for researchers to search for new drugs. We built these by extracting & summarizing research published in scientific journals. We propose to use a similar approach to build the probiotics reference. The money we raise will go to purchasing subscriptions to the scientific journals (like Journal of Gastroenterology and Gut Pathology) so that we can download the relevant research articles. It also goes to pay the part time curators who will read the journals and enter the key information into the database and lastly it goes to the costs of hosting a website and licensing of necessary softwares. Please help us in any way you can. We greatly appreciate monetary pledges, but also we need you to tell your friends and spread the word about our project.
Definitely seems like a worth project

Wednesday, August 12, 2015

TWIMO: This week in microbiome overselling - how the microbiome destroyed the Ego, Vaccine Policy, and Patriarchy

Well.  I guess thanks are in order to my friend and colleague David Pollock who pointed me to this on Facebook and asked if it fit the mold for an Overselling the Microbiome Award: How The Microbiome Destroyed the Ego, Vaccine Policy, and Patriarchy.  And, well, it certainly does.  This is just so so so so so painful I do not really even know what to say.  So I am just going to quote some of the worst parts here for everyone to think about



A bold beginning

The relatively recent discovery of the microbiome is not only completely redefining what it means to be human, to have a body, to live on this earth, but is overturning belief systems and institutions that have enjoyed global penetrance for centuries.
 And more boldness

A paradigm shift has occurred, so immense in implication, that the entire frame of reference for our species' self-definition, as well as how we relate fundamentally to concepts like "germs," have been transformed beyond recognition
Got to invoke some Copernicus

a Copernican revolution when it comes to forming the new center, genetically and epigenetically, of what it means in biological terms to be human
A little side throw at vaccines

This concept is of course intellectually infantile, and if you do some investigating you'll find it was never quite grounded in compelling evidence or science.
And of course, the patriarcy must be attacked too

The microbiome has also fundamentally displaced a latent patriarchal prejudice concerning the relative importance and contribution of the man and woman towards the health and ultimately the continuation of our species.
And the microbiome is clearly trying to counter the patriarchy

it follows that most of our genetic information as holobionts is maternal in origin. 
and



if 99% of what it means to be human is microbiome-based, and if the mother contributes most, if not all, of the original starting material, or at least the baseline and trajectory of future changes in the inner terrain, then her contribution becomes vastly more important than that of the father.


This is perhaps the best part:



In other words, being born in a hospital via C-section and vaccination, will produce, genetically and epigenetically, a human that is so different – qualitatively – from one born at home, naturally, that they could almost be classified as different species, despite sharing nearly identical eukaryotic DNA (remember, only 1% of the holobiont's total). 
And let's attack men some more

In light of the new, microbiome-based view, the male role in protecting the health of women and children will be irrevocably downgraded in importance, not just professionally and medically, but biologically.
And then, well, this

The birth process, also, has been described as the closest thing to death without dying (it is ironic that anesthesiology, which could also be described in the same way, makes obstetrical interventions like C-section and epidural possible, at the same moment that it negates the spiritual experience of natural birth/women's empowerment we are describing), offering women a window into the 'in between' and a direct experience of Source that men, less likely to experience it naturally would later emulate and access through the various technologies of shamanism.
And all of this then justifies environmental protection



This means we can't simply live in a hermetically sealed bubble of shopping for organic, non-GMO certified foods at Whole Foods, while the entire planet continues to go to post-industrial hell in a hand basket.  Our responsibility becomes distributed across everything in the world, and every impactful choice then becomes relevant to the fundamental issue and imperative at hand. With the microbial biodiversity in Big Ag, GM-based agricultural zones fire-bombed with biocides, by the very same corporations that either own or distribute the "organic brands" we all love to think will save our bodies, if not the planet, we need to step deeper into our activism by stepping out of the diversions and palliative measures that don't result in lasting change.
 I think the words speak for themselves.  But not for me.  Or my microbes.

Tuesday, July 28, 2015

YAMMA - Yet Another Mostly Male Award - AAAS Public Engagement Award

So - I saw an post on Twitter about the AAAS Public Enagement with Science Award






And I went to check it out since, well, I wondered - how could I win that.  And so I thought - I should look at how I compare to previous winners.  And in one way I compare really well. I am male.

Below is a list of past winners (via AAAS). In yellow I highlight those that appear to be male and green those that appear to be female. I note I base my assignment on appearance and names and descriptions of the people including the descriptions from AAAS. I realize that determining someone's gender is not always straightforward and that there are people who do not fit into this binary gender division and I apologize for any mistakes made.
  • 2014 James Kakalios 
  • 2013 Steven Strogatz
  • 2012 Richard B. Alley
  • 2011 Nalini Nadkarni
  • 2010 J. John Cohen
  • 2009 May R. Berenbaum
  • 2008 Kenneth R. Miller
  • 2007 Neil deGrasse Tyson
  • 2006 S. James Gates, Jr.
  • 2005 Jane Lubchenco
  • 2004 Eric S. Lander
  • 2003 John Allen Paulos
  • 2002 Bassam Shakhashiri
  • 2001 Ian N. Stewart
  • 2000 Vaclav Smil
  • 1999 Lawrence Krauss
  • 1998 Christopher Wills
  • 1997 Barry T. Peterson
  • 1996 Alan J. Friedman
  • 1995 Carl Sagan
  • 1994 Edward O. Wilson
  • 1993 Science Theatre
  • 1992 Farouk El-Baz
  • 1991 Stephen H. Schneider
  • 1990 William L. Rathje
  • 1989 Robert D. Ballard
  • 1988 Anthony M. Fauci
  • 1987 Philip Morrison
The totals are 24 men and 3 women (and one group).  Or, for those assigned to a gender, 89 % men and 11 % women.  Could this all be about merit?  I don't think so.  I think there are many examples of areas in which AAAS has problems with gender bias.  For example, consider the recent letter (of which I am a cosigner) regarding AAAS' reinforcement of "damaging stereotypes".


Sunday, July 26, 2015

Possibly the worst press release on the microbiome ever: Greenlaw and Ruggiero and the third brain.



Well, this is a combination of horrendous, frustrating and painful: Discovery of Microbiome “Third Brain” Confirmed by Scientific Research in Japan | Business Wire. This is a press release that focused on Peter Greenlaw and Marco Ruggiero so I assume it came from him.

It starts off discussing a new paper from
"the prestigious peer-reviewed scientific Journal “Anticancer Research
which according to the PR:
"describes the properties of a food product that is reminiscent of the “super food for the third brain.”  
Note - no link is provided to the paper.  Not surprisingly, the PR then transitions to being something else - in this case a new book by Greenlaw:
 "this finding supports the discoveries revealed in the book “Your Third Brain,” co-authored by Peter Greenlaw, Dr. Marco Ruggiero and Drew Greenlaw, with the forward written by author John Gray, Ph.D." 
So this is not really about the new paper - this is a kind of bait and switch. Then comes one of the doozies "
Four and a half years ago, a huge discovery was made. In 2010, a team of researchers discovered a new organ that had gone undetected for more than 3,000 years in Human Anatomy. They called this newly discovered organ the microbiome.

What?  The human microbiome was discovered four and a half years ago?  That is of course complete BS.  I note - there is something a tad bit off here with the "3000 years too".  Is this a religious reference of some kind?

Then comes another amazing section.  Underlining by me
The microbiome is much more than the gut microflora. It is a complex organ that is responsible for the development and function of all the other organs and systems, from the brain inside our heads to the immune system. The influence of the microbiome, that is located all over our body and not only inside the gut, on our behavior and intellectual functions is so significant that it can be aptly named “the third brain” as it is described in the book.
Wow.  I mean sure there is some evidence that the human microbiome can impact the brain.  But first of all, it is ridiculous to consider it "the third brain".  Also, to say it is responsible for the development of the rest of the body is just plain silly.

How about this next section?
Dr. Ruggiero’s team is working hand in hand with the complete cooperation and unprecedented collaboration of medical doctors, with the goal of extending the highest possible quality of life for their patients for as long as possible. And although Dr. Ruggiero did not personally discover the microbiome, he did identify it as the third brain.
OK - so is this meant to imply other people don't collaborate with medical doctors?  And other people do try to extend quality of life for parients?  

So many other bad sections I am not sure which other ones to point out.  How about this:
Before this book was written, man did not know that his thoughts, feeling, emotions, behaviors, his supposed free will were under the control of a non-human organ whose existence had gone undetected until very recently, the microbiome.
This sounds like the voice over you might have in a science fiction horror movie.  Except - this is real fiction and from a horror show of a press release. 

I must say - Greenlaw and Ruggiero are clearly very proud of themselves.  I will just leave everyone with the last paragraph for people to ponder how humble and understated it is.
This book describes what is and how we can take control of this non-human third brain and aspire to bring out the superman that is inside us. As the Philosopher wrote: ‘Let your will say: the overman shall be the meaning of the earth... Man is a rope, tied between beast and overman—a rope over an abyss ... what is great in man is that he is a bridge and not an end.’ Thanks to the information contained in this book, for the very first time in the history of mankind we can transform ourselves and reach this end
I am hereby awarding Greenlaw and Ruggiero an "Overselling the Microbiome" award.  But that seems too small for them.  They deserve some sort of "Biggest pile of BS ever" award.  I will consider starting such a new award series in their honor.

Friday, July 24, 2015

A Phoenix Rises from the Ashes: A new discovery emerges from the 2009 retraction.


This is a post in my continuing series of the "Story Behind the Paper." series. This post is from Benjamin Schwessinger, Pamela Ronald, Rory Pruitt, Anna Joe, and Ofir Bahar.


A Phoenix Rises from the Ashes: A new discovery emerges from the 2009 retraction.

A phoenix depicted in a book of legendary creatures by FJ Bertuch (1747–1822).
Via Wikipedia Commons - based on this

This is the story behind our report published today in Science Advances.

The Background

In Science Advances we report that one class of bacteria produces a previously undescribed, and long sought after, molecule recognized by plants carrying a specific receptor.

The story began in the 1970s, when Professor Gurdev Khush and colleagues demonstrated that a wild species of rice was immune to most strains of the Gram-negative bacterium Xanthomonas oryzae pv. oryzae (Xoo), causal agent of a serious disease of rice globally. In the 1990s Ronald began studying the rice/Xoo interaction. Because both rice and Xoo are genetically tractable, the rice/Xoo biological system proved to be an excellent system for studies of the molecular mechanisms governing the plant immune response. In 1995, two postdoctoral fellows in Ronald’s lab at the University of California, Davis- Guoliang Wang and Wenyuan Song-reported that this rice immune response was controlled by a single receptor kinase, called XA21.

The predicted structure of the XA21 protein, with a predicted leucine rich repeat extracellular domain and an intracellular kinase domain, suggested that XA21 could sense a secreted microbial molecule and then activate an immune response.

A few years after the discovery of the XA21 receptor, the fly Toll and mouse Toll-like receptors (Tlr4) were shown to share striking structural similarities with XA21 and other plant receptors. The animal receptors also recognized and responded to microbial molecules. Together these discoveries demonstrated that plants and animal use similar mechanisms to protect against infection. Professors Bruce Beutler and Jules Hoffman were awarded the 2011 Nobel Prize in Physiology or Medicine for their important work.

The Ronald laboratory then spent twenty years trying to identify the microbial molecule that is recognized by XA21. The research led to the identification of a number of microbial genes that are required for activation of XA21-mediated immunity (rax genes). These genes encode a tyrosine sulfotransferase, RaxST, and three components of a predicted type 1 secretion system: a membrane fusion protein, RaxA; an ATP-binding cassette transporter, RaxB; and an outer membrane protein, RaxC. raxST, raxA, and raxB are located in a single operon (raxSTAB). Based on these findings, we hypothesized that the activator of XA21-mediated immunity is a tyrosine sulfated, type 1-secreted protein.

We were excited about this idea because sulfation has emerged as an important posttranslational modification controlling receptor-ligand interactions. It is a common posttranslational modification of eukaryotic proteins and plays important roles in regulating development and immune responses. The importance of this area of research to biology and medicine is reflected in the recent report of a novel drug that blocks HIV infection. To achieve this breakthrough, the researchers exploited the observation that HIV binds tyrosine sulfated amino acids for cell entry (Gardner et al., 2015).

Despite a clear model and diverse supporting data suggesting that Xoo secretes a sulfated peptide, the identity of this molecule remained elusive.

In 2009, the Ronald laboratory reported that XA21 recognized a sulfated peptide. However we later discovered major errors in this work and in 2013, we retracted the paper. We discussed these mistakes in several lectures, post and articles including a Keystone symposium, Scientific American, Nature, and Schwessinger’s blog (here and here). The process with which we addressed the problems was highlighted as “Doing the right thing” by Retraction Watch, a blog that reports on retractions of scientific papers. The retraction was included as one of the top 10 retractions of 2013.



The new Discovery

Today, in Science Advances, we are delighted to report the identification of the microbial molecule that activates XA21-mediated immunity. As predicted, it is a tyrosine-sulfated protein. We named this microbial protein RaxX.

The rice immune receptor recognizes the bacterial molecule RaxX and initiates an appropriate immune response. Illustration by Kelsey Wood.



To isolate this molecule, postdoctoral fellow Rory Pruitt systematically created bacterial mutants carrying deletions near the RaxSTAB operon. He showed that one of the deletion mutants lost the ability to activate the XA21-mediated immune response. The deleted region encodes a small open reading frame that we named RaxX. Xoo strains lacking RaxX and Xoo strains that carry mutations in the single RaxX tyrosine residue (Y41) are able to evade XA21-mediated immunity. Postdoctoral fellow Anna Joe, together with collaborators at the University of Texas, Austin and at the Joint Bioenergy Institute in Emeryville, showed that Y41 of RaxX is sulfated by the prokaryotic tyrosine sulfotransferase RaxST. Postdoctoral fellow Benjamin Schwessinger, graduate student Nick Thomas and collaborators showed that sulfated, but not nonsulfated, RaxX triggers hallmarks of the plant immune response in an XA21-dependent manner. A sulfated, 21–amino acid synthetic RaxX peptide (RaxX21-sY) is sufficient for this activity. Xoo field isolates that overcome XA21-mediated immunity encode an alternate raxX allele, demonstrating the co-evolution of host and pathogen. RaxX is highly conserved in many Xanthomonas species.

Our results indicate that the presence or absence of sulfation is decisive for the ability of RaxX to trigger XA21-mediated immunity.

The new insights gained from the discovery and characterization of RaxX may be useful for the engineering of resistant crop varieties and for the development of therapeutic reagents that can block microbial infection of both plants and animals.

The rice XA21 receptor kinase, the first innate immune receptor discovered in plants or animals, provides resistance against Xanthomonas oryzae pv oryzae through recognition of RaxX, a tyrosine-sulfated protein secreted by the bacterium.

Illustration by Maurice Vink


Notes on the publication process

The scientific life is the most complex of all to write about. In the case of scientists, impulse becomes compulsion”. -- Carol Shields

After we discovered mistakes in our previous paper, we spent several years correcting the scientific literature both by retracting the original Science paper (Lee et al. 2009) and by following up with publications to further correct the literature (Bahar et al. 2014). We made extra efforts to control the results in this current report.

Wrestling with the retraction and discovering the new molecule in rapid succession was an enormous challenge. Here we share some of the lessons learned.




Pamela Ronald, Professor, Department Plant Pathology and the Genome Center, UC Davis; Director of Grass Genetics, the Joint Bioenergy Institute:

I would not wish a retraction on anyone. Scientists are supposed to catch their mistakes before publication. Still, I am astonished to conclude that the process has in some ways been positive.

On an administrative level, the lab is running more efficiently. I have instituted new practices for the lab: created duplicate stocks of key strains (validated and maintained by the lab manager), mandated electronic notebooks for each lab member and required that all new assays be independently validated by three independent researchers before publication.

But the best part of this bad situation has been working with this particular team. It has been an immense privilege to watch each person work through the situation in their own way, collaborate, and make new discoveries. Respect for each other and for the scientific process was paramount. After figuring out what went wrong (no easy task), they tried not to look back. They did not give up, even when it would have made sense to do so. Their persistence and optimism in face of this daunting challenge buoyed all of our spirits. I will always be in awe of their work and will always be grateful.

Equally stunning was the supportive and kind response from the scientific community. We received many letters of encouragement - even from complete strangers. It helped us keep going.

There are still hills to climb. Some scientists may be extra skeptical of results from my lab for a long time to come. For example, in a critique of our submission, one of reviewer’s asked, “how do we know the strains weren’t mixed up again this time?”


Rory Pruitt, postdoctoral scholar in the Ronald lab.

I was only a few months into my postdoc when I became convinced that the majority of the Ax21 story was incorrect (Ax21 was the proposed elicitor of XA21-mediated immunity in the retracted papers). My mind was filled with questions. How could this happen? What results can I believe? Admittedly, the biggest question that hounded me was “Should I be looking for a new job?” There were a few key factors that led to my decision to stay in the lab. I think these factors were also critical to this story working out as a “success.”

Early on, I went to Pam with some of my doubts. It was terrifying to approach my new boss and I say I didn’t believe some of her published work (including a Science paper!). But I needed to know that I could be honest with her and not feel pressured into only showing results that fit the established model. Pam listened to my concerns and those of others in the lab. Most importantly, she showed that she was committed to getting the story right and correcting the literature if need be.

In addition to Pam, there was a great team of postdocs and graduate students who were equally devoted to correcting the science. At times it seemed a long, painful process with little reward (there’s not a good space on a CV for working towards a retraction). Nevertheless, it needed to be done so that we and other labs could move forward. I was encouraged by Ofir, Ben, and others who worked persistently on this.

A final factor in my decision to stay is the prospect of new discovery. If Ax21 isn’t the activator of XA21-mediated immunity, what is? Maybe we can find it! It’s that hope of new discovery that keeps us coming back to the lab bench. My postdoctoral experience has had some highs and lows, but I am glad I stuck it out. With persistence, enthusiasm, and a good team committed to reliable science, we were able to not only correct earlier mistakes but also move forward.


Benjamin Schwessinger, former Ronald Laboratory postdoctoral scholar and now independent research fellow in Australia, at the Australian National University in Canberra.
You have much to lose as an early career researcher if you are thrust into a situation where results cannot be reproduced. In a hyper competitive environment irreproducible results you are trying to build on are a big problem, no matter how smart, privileged, and gifted you are. Lengthy delays in publishing as a postdoc can cause great harm to a career. Here are the main factors that made us successful in the face of adversity.

(Be lucky) have your own funding

Your own funding makes you financially and also scientifically more independent. It ensures your academic freedom. I was grateful to have been supported independently by the Human Frontier Science Program. It made me bolder and braver in speaking out. I was able to choose to stay or go. Because of the team I believed in I decided to stay!

Get confidential outside advice

Getting some outside confidential impartial advice on how to approach this problem is very important. Many senior figures have most likely seen similar cases in the past and have more insight. Following through with this advice is a total different matter. I decided to stay!

Collaborate

Work through it together as a team. Build on each other’s strength and talk about all possibilities. Repeat each other’s experiments with all required controls. Invite well respected figures in the field to independently test (and confirm) core experiments.

Admit mistakes and retract
Everyone makes mistakes. They are part of the scientific discovery and science has to be self-correcting. Retractions are an integral part of this process. Not to retract is NOT an option! It obstructs all future progress in the subject matter.

Follow the data

Do controls, repeats, and repetitions of conclusive experiments. Seeing is better than believing.



Ofir Bahar, former Ronald Laboratory postdoctoral scholar and now principal investigator, Plant-Microbe Interaction Research Group, the Volcani Center, Israel,

I remember the day, early 2013, when we were driving back to Davis from a happy and relaxed baby shower at Benjamin’s place in Oakland, Rory mentioned to me “you know, I deleted an upstream and a downstream region to raxSTAB. The downstream mutant was no different than wild type, but the upstream mutant forms long lesions on XA21 plants…”

This was the turning point; I immediately knew this was a big discovery and a major break through for the lab.

But before that moment, we were a bunch of enthusiastic post docs that just loved doing science. We wrote these nice proposals to get our fellowships, based on the amazing story of the rice immune receptor XA21 and its (thought to be) elicitor Ax21.

It was a fascinating story we were all so excited about having read it in Science. Of course we joined the Ronald lab to follow up on this initial discovery, but well… the building upon part did not work as we all might have wished. We had to dig deep, real deep, to figure out what was going on and what went wrong before our arrival to the lab. So, a year….. year-and-a-half in our new positions we finally reached the ultimate conclusion that there was a big hole in the model – there’s no elicitor! Or, there is, but it’s not Ax21 and we don’t have a clue what the identity of this molecule might be. It felt like we were thrown back 10 years, to 2004 with the da Silva paper just published describing the requirement of the three Xanthomonas genes RaxST, RaxA and RaxB for XA21 immune activation.

Those were ‘dark ages’ and difficult times. Understanding that most of the time you invested so far was, at least in practical terms (e.g. publications), for nothing, and that there is no biological model to work on, but that it needs total reboot. To be honest I was feeling a bit worried at that time for my scientific career. But then, a series of exciting discoveries (including some that are not published yet) gave me hope again. Well… isn’t this how science goes, bad, bad, bad, bad, good, bad, bad, bad, good and so on. I remember Pam telling me: “you know why I love a big group? There has got to be some positive results coming all the time”

Later, a few months after Rory shared with me his finding, we already knew what it was, and we were very certain, this is the ONE. Unfortunately, or luckily, I got a position offered at my home country and I gladly accepted it. So I actually wasn’t there for the flower stage (you know… the decorations), but I was very happy to have been there when the bud of this beautiful flower to be emerged. Every time I think of this story its like, WOW, can you believe all this has happened in just 3-4 years, unbelievable.

My lesson is, never lose hope, be critical, believe it when you see it, work on multiple projects, enjoy science and openly share science



Anna Joe, postdoctoral scholar in the Ronald lab.

I was in my final year grad school and looking for a postdoc position in early 2013. The Ronald lab was on the top of my wish list because I was fascinated by the Ax21 story in Science 2009. But just before I applied for a position in the Ronald lab I learned that something went wrong with Ax21 and that the original paper would be retracted. Many thoughts crossed my mind. Main one was “Do I still want to join the Ronald lab?”. Actually it was easy to answer the question once I spoke with Pam about it and talked with her lab members during the visit for my formal interview. “Yes, I’d like to work in the lab which just retracted two papers”. This for sure sounds crazy to most people. However, the whole experience of my visit gave my many reasons to join the Ronald lab. Correction of errors is a part of science (I knew this because I also had difficult time to track down a mix up plants problem before) but not many people are brave enough to admit mistakes. Pam and all lab members honestly, clearly stated to me what the errors were and how they verified the problems. They communicated well with each other, shared idea freely and respected other’s opinions. Their open mind and transparency attracted me.

On top of that I was very curious about the unexplored, new Xa21 activator. All other lab members might have felt the same curiosity and channeled its energy to continuously work through the problems during last several years. Although I did not share the “dark period”, I could see everybody in the lab was persistent with the common effort to correct the science. I experienced incredibly good teamwork and great collaboration. All of those are the driving force of our success. Finally, I’d like to mention that we could not make it without the support and encouragement from the scientific community. Many scientists shared their thoughts and advice and were rooting for us. Most collaborators unhesitatingly complied with our requests for assistance. They helped us not only “do the right thing”, but also do better science.


Wednesday, July 22, 2015

Should I testify in German court about how there is no such thing as the measles virus?

I could use some help from the crowd. I got this email a few minutes ago. Am wondering what people think about this? Should I testify in German court about how there is no such thing as the measles virus?
Dear Prof. Eisen,

my name is Dr. Stefan Lanka from Germany and in 1987, as a jung student of biology I isolated the first so called giant virus out of the sea, the Ectocaropus siliculosus virus with its circular 335 kbp dsDNA genome.

Would you be so kind as to help me in my issues?

In searching the origins of viruses, me, my professors and others realised that so called human viruses never were isolated and typical molecules of cells used in the protocols to "isolate" them were mistaken as viral.

Since then I successfully did research what are the real causes of so called human viral diseases.

In a court case on the existance of the so called measles virus, a jung medical doctor claimed that in six publications there is the scientific proof of the existance of the measles virus.

In reading the six papers you will realise that in these papers (and others) there is no such thing as a measles virus.

My question: Would you act as a referee in this court case in Germany?

If yes, here you will find the six papers:

1: https://archive.org/details/EndersPeebles1954

2: https://archive.org/details/BechVonMagnus1959

3: http://jvi.asm.org/content/3/2/187.full.pdf

4: http://www.sgmjournals.org/docserver/fulltext/jgv/65/9/JV0650091535.pdf?expires=1437587740&id=id&accname=guest&checksum=B3FFF42F7406C335DB55C79251B73210

5: https://archive.org/details/HorikamiMoyer1995

6: http://www.osaka-med.ac.jp/deps/b-omc/articles/532/532daikoku.pdf

Thanks a lot!

Yours sincerely,

Dr. Stefan Lanka

Tuesday, July 21, 2015

Story behind the paper: Backbones of evolutionary history test biodiversity theory for microbes


This is a guest post in my series "The Story Behind the Paper".  Post is by James O. Dwyer about his paper (coauthored with Steven Kembel and Tom Sharpton) in PNAS entitled "Backbones of evolutionary history test biodiversity theory for microbes


Backbones of evolutionary history test biodiversity theory for microbes

Prehistory

This paper has its roots going back a few years, and it all started off fairly innocuously.  A previous collaboration with Steve Kembel and Jessica Green resulted in this earlier paper, where we had the lofty goal of encouraging microbial ecologists to throw out slightly less data, and also attracted Jonathan’s attention for our microbiome figures.  One of the central questions in ecology is to explain and understand patterns of biodiversity: for example, by quantifying the diversity of a local community (“alpha” diversity), or similarity between multiple local communities (“beta” diversity).  In microbial ecology it is common to use evolutionary history to quantify these measures. But both phylogenetic alpha and beta-diversity tend to change systematically with increasing sample size, making it difficult to compare results for samples of different sizes.

Our idea in the earlier paper was to generate a fast way to compute a null prediction for these metrics for phylogenetic alpha and beta diversity—i.e. this would provide a way to standardize the results for sample size, and hence we could use full samples rather than smaller, rarefied samples.  The solution is relatively simple, and involved a phylogenetic analogue of the Species Abundance Distribution (SAD), which we called the Edge-length Abundance Distribution (EAD).  In comparison with the SAD, this distribution replaces species units with subclades of a phylogenetic tree, replaces species abundances with subclade size, and inserts branch length weightings in a specific way.

The present day

Job done.  So how did this lead to a new paper?  Well, this first study generated something slightly mysterious to us.  In theory, the EADs we computed from empirical data could have taken any form they wanted to—and yet for various microbiome habitats, they all seemed to display a very distinct power law scaling. Translated into a more concrete consequence, the form of the EAD was such that phylogenetic diversity typically increased as a power law function of sample size.  There’s a history in ecology of looking for (and sometimes finding) behavior that both takes on a power law scaling, and is also universal across multiple systems, fitting with a general sense that some patterns may be emergent and independent of much of the underlying variation between communities. There’s also a history of looking for (and sometimes finding) power law scaling in evolutionary trees, for example in the number of species per genus, which has often been claimed as a power law.  Here we had found a link with these older ideas, with a nice combination of new factors.  First, we weren’t relying on human definitions of species, which could certainly be biased towards generating power law scaling artificially (e.g., the principle of balance).  Second, we had large numbers, so that these scaling behaviors spread over multiple orders of magnitude.  Third, there was an untapped world of microbial sequence data to look at to see whether these patterns extended into microbiology.

With Tom and Steve, we combined these ideas to set up the empirical side of this new paper: expand the original study across a broader range of habitats, test whether the patterns are robust to different alignment and inference methods, and see whether the same scaling behavior holds up for this new range of samples.  Which indeed it did---Figures 1 and 3 in the new paper show that this power law scaling is present across multiple microbial habitats.  

 Just knowing that this distribution takes a power law form is already useful on its own, because (again) it defines the null expectations for the way phylogenetic alpha and beta diversity change with sample size.  But these results still left a number of open questions, centering around whether this could also give us some insight into what models of biodiversity could be consistent with what we were seeing.  Could these scaling patterns provide evidence for whether a given ecological and evolutionary scenarios had strongly influenced a community?

Coarse-graining: reducing the resolution of phylogenetic trees

The first modeling approach we considered is neutral theory. Neutral models have provided the basic null models in fields stretching from population genetics and ecology to cultural evolution and the social sciences. In common is the key assumption that selective differences are irrelevant for predicting large-scale patterns. If the power law scaling is just an inevitably--an ecological version of Benford's law--it seemed likely that it might be just a consequence of neutrality, with all of the variation and mechanism somehow washing out.  Is it possible that these observed phylogenetic patterns are driven by this most basic, neutral model of biodiversity?  The answer turns out to be no---at least using the vanilla version of the neutral theory, we don't reproduce these scaling behaviors.

Next, we got a little creative. When working with trees generated by neutral processes, we were thinking of the Kingman coalescent. I.e. a model of tree structure that works backwards in time, coalescing pairs of lineages at each node.  There's a one-parameter family of coalescent models generalizing the Kingman coalescent, with the unifying feature that more than two lineages can coalesce at each node.  Viewed forward in time, one lineage can burst into many. This generalized family, the Lambda-coalescent, produces precisely the power law EAD (known in that context as a site-frequency spectrum) we were looking for.

These generalized coalescent trees have previously been used to understand population processes with a skewed offspring distribution, where there is a significant probability that an organism has a large number of offspring, and this matches the idea of multiple lineages coalescing. But for our evolutionary trees that idea of instantaneous, multiple branching seemed unlikely. At a fine-grained level, branches in our evolutionary trees ought to split into two, driven by cell division and subsequent diversification. This is also what our tree inference algorithms are designed to find, even when our sequence data likely isn't sufficient to resolve all polytomies.  So how could these generalized coalescent trees possibly be consistent with our empirical trees?  

Instead of trying to resolve as many polytomies as possible, we decided to go in the other direction. We imagined reducing the resolution at which we could distinguish the order of branching events. Applying this `coarse-graining', we would certainly generate polytomies, as fast bursts of branching and multiple nodes collapse. Still, much like the EAD, there was no guarantee for what the distribution of polytomy sizes would be after this coarse-graining, or whether it would match these theoretical models. So our second surprise is that the distribution of burst sizes is also a power law---qualitatively consistent with the same distribution in the Lambda-coalescent.

Outlook

So this seems to be the beginning of a very nice story, with a lot of open questions.  Empirical trees display bursts of branching, which quickly collapse to polytomies under coarse-graining, and the distribution of sizes of these bursts is a power law.  The Lambda-coalescent is likely not the end of the story, but at least suggests that this distribution is tied together with the scaling behavior of phylogenetic diversity.  

What's next?  Certainly lots of empirical questions.  Does this behavior extend over an even broader range of samples?  And will it still hold if we have better, longer sequence data?  There are also theoretical questions, mostly centering around whether we can relate parsimonious but mechanistic models to the bursty tree structures, and how best to evaluate and compare these models.  One take-home message stands out for me.  Simplified models of biodiversity, like neutral models and their generalizations, likely won't ever capture the fine-grained dynamical behavior of an ecological community. But they might just tell us something about coarse-grained dynamical behavior, and coarse-grained phylogenies could be a nice part of this story.  Let's see if coarse-grained patterns can be matched with coarse-grained process.

Wednesday, July 15, 2015

Medical Informatics World Conference - bringing you men, men and more men

Just got this email

Cambridge Healthtech Institute and Bio-IT World are happy to announce the 4th Annual Medical Informatics World Conference 2016 to be held April 4-5, 2016 in Boston, MA. The web site is now posted and features summaries of the five conference tracks and highlights from the 2015 gathering. We are now accepting speaking proposals via the web site’s online submission form.

Medical Informatics World Conference 2016Improving Outcomes and Delivery Value with IT Innovation
April 4-5, 2016 • Seaport World Trade Center • Boston, MA
www.medicalinformaticsworld.com
ONLINE SUBMISSION FORM
http://www.medicalinformaticsworld.com/hit_content.aspx?ekfrm=140243
Track #1: Value-Based Delivery Models and Cross-Industry Data Collaboration: Integrating Data Analysis to Manage Costs and Improve Outcomes in the Health Care Ecosystem
 Track #2: Coordinated Care, Patient Engagement and Connected Health: Delivering Care to Patients and Consumers in all Settings to Improve Outcomes
 Track #3: Population Health Management, Risk Modeling, and Patient Stratification: Using Technology and Analytics to Predict Outcomes, Target High-Risk Populations and Improve Quality
 Track #4: Achieving Global Interoperability in Healthcare Datasets and Systems: Delivering Data-Driven Infrastructures to Support Clinical and Financial Transformation
 Track #5: Quantitative Imaging, Radiomics and Advanced Medical Image Analysis: Functional Imaging and Integration of Imaging, Genomic and Other Datasets to Improve Outcomes
 Please feel free to share this announcement with your peers and please do submit a speaking proposal for review by August 19.

Kind regards,
Micah

Micah Lieberman
Executive Director, Conferences
Cambridge Healthtech Institute (CHI) & Bio-IT World

Sounded possibly interesting.  So I checked out the meeting site and then looked up the speakers.  For example here is a link to the Keynotes.

(UPDATE - THE LINK FROM THE MEETING PAGE GOES TO KEYNOTES FROM THE 2015 MEETING, WHICH ARE LISTED BELOW.  NO INFO IS POSTED FOR 2016 AS FAR AS I CAN TELL)

Here are the speakers on Day 1


  • Micah LiebermanMicah Lieberman
  • Tariq Abu-Jaber, MA, MPH, Vice President, Medical Informatics, Harvard Pilgrim Health CareTariq Abu-Jaber
  • Phil PolakoffPhil Polakoff, 
  • Steven StackSteven Stack, 
  • Jason BurkeJason Burke,
And then a discussion session

  • Tariq Abu-JaberModerator: Tariq Abu-Jaber,
  • Jason BurkeJason Burke
  • Stanley Huff, M.D., Chief Medical Informatics Officer, Intermountain Information SystemsStanley Huff, 
  • Steven StackSteven Stack
  • Phil PolakoffPhil Polakoff,
Day 2

  • Micah LiebermanMicah Lieberman,
  • Stanley Huff, M.D., Chief Medical Informatics Officer, Intermountain Information SystemsStanley Huff, 
  • John HalamkaJohn Halamka
  • Jonathan WeinerJonathan Weiner,
  • StephenWarrenStephen Warren
And then a discussion
  • Eric GlazerEric Glazer, 
  • Gowtham RaoGowtham Rao,
  • Jason BurkeJason Burke,
  • StephenWarrenStephen Warren
  • J.D. WhitlockJ.D. Whitlock,
  • John HalamkaJohn Halamka,
Isn't that awesome.  21 slots for presenters for the Keynote sessions.  And all of them are men.  Sorry, but I will not be going to this meeting nor should anyone else.