Black Lives Matter

The murders of George Floyd, Ahmaud Arbery and Breonna Taylor have once again reminded us that our country is built on racism and hate. It reminds us that the policing system targets and murders Black people. It reminds us that, despite the fact that Black people’s free labor was used to build this country, they are denied equal access to freedom and justice.

For many, it has been an intense week filled with anger, rage, confusion, and fear. It is OK to have these feelings. It is OK to feel angry at our country, our government, and the police. It is OK to feel angry that your Black friends and family members have never experienced the freedom that you experience. It is OK to feel rage that the system never changes. It is also OK to feel fear as you watch things burn and turn violent. As with most things, the current unrest will calm down – but that is when the real work begins.

We cannot return to a society that accepts the status quo of where Blacks are second-rate citizens. We cannot return to a status quo where we don’t stand up for every injustice. We cannot return to a status quo where we don’t hold the government and police accountable.

Science is no different. Every facet of modern science is tainted by discrimination and racism towards Black scholars and students. Grant funding, publishing, and hiring are all documented to be biased against Black scientists. Black scholars deal with racism from colleagues and other faculty on a daily basis. Black academics aren’t afforded institutional support from their departmental and university leaders. This is the hostile environment in which our Black colleagues are forced to try to thrive. This is unacceptable.

As your PI and mentor, I am fiercely dedicated to equality in science and academia. I promise to create an environment where the most disenfranchised can thrive and feel welcome. I promise to call out hate and biased speech in our halls. I won’t stand for discriminatory behavior or attitudes in the lab. I will try to model unity and acceptance on a daily basis.

We must work together to eliminate and dismantle the oppressive powers in society, academia, and science that do not value Black lives.

A new rare disease project: modeling PIGA mutations

When I attended the Rare Disease Day event hosted by Sanford Burnham Prebys Medical Discovery Institute, NGLY1.org, and CDG Care, I met a number of inspirational families. Families who have been struggling to find resources, help, and ultimately a cure for their child with a rare congenital disorder of glycosylation. These families are incredibly resourceful – because they have to be – at finding experts and coming up with out–of-the-box ideas. 

I met Ann and Steve Nguyen and their son, Emmett, during this visit. Emmett is a sweet boy who was born with a mutation in the PIGA gene (follow their journey here and here). Patients with mutations in PIGA, like Emmett, have a devastating metabolic disorder that involves infantile spasms and intractable epilepsy. This, of course, impacts all aspects of development and everyday functions. This was the Nguyen’s first CDG meeting and first rare disease day event, but they showed up with a poster for the scientific poster session. With the help of a friend, the poster presented a multipoint plan on potential therapeutic interventions that might work for Emmett. I looked it over and it seemed quite reasonable and could be successful. After chatting with them, I did a simple Pubmed search on PIGA biology. What was missing, however, was an animal model and some basic understanding of the physiological consequences of losing PIGA function. I continued to chat with the family throughout the meeting and it quickly became clear to me that we could use some of our approaches studying Drosophila models of other rare diseases to work out the effects of PIGA mutations. 

What is PIGA? Phosphatidylinositol N-acetylglucosaminyltransferase subunit A (PIGA) protein is a subunit of a larger complex involved in the synthesis of N-acetylglucosaminyl phosphatidylinositol (GlcNAc-PI). The production of GlcNAc-PI is the first step in the biosynthetic pathway generating the GPI anchor. The GPI anchor is a glycolipid that serves to anchor proteins on the cell surface. PIGA functions on the cytoplasmic side of the endoplasmic reticulum (ER) membrane. While this biochemical function is well understood, there is little known about the physiological consequences of loss of PIGA function (except we know the null mouse is early embryonic lethal). This is where we can step in and try to work out what might be happening in a Drosophila model.

                                                                      &nbs…

                                                                          modified from Brodsky, Blood 2014 124:2804-2811.

What are we going to do? My lab uses the Drosophila model to try to understand the pathogenesis underlying rare diseases and also to identify genetic modifiers of these diseases. So, we can apply these methods to model the effects of PIGA mutations. While we are still in the planning phases of this project, we do have some rough plans on what we will pursue:

1)    Generate a fly with a PIGA null mutation using CRISPR
2)    Study both the CRISPR null and the RNAi knockdown fly models
3)    Study consequences of loss of PIGA function in the nervous system (seizures are associated with PIGA mutations).
4)    A natural genetic variation modifier screen (modifiers are good therapeutic targets)
5)    “Rescue” the null fly with transgenes expressing mutant PIGA proteins from the patients.


There’s a lot of interesting biology here, but more importantly, we can make a lot of progress on this understudied rare disease using the powerful Drosophila model. We hope to stay in touch with the Nguyen family and others impacted by PIGA mutations and test some of their ideas and experiences in our lab. 

Open science is critical to rare disease research

All research needs to be open. But especially for making progress on rare diseases, research needs to be open. In most cases, there are so few stakeholders (patients, physicians, families, and scientists) that any barrier to open science will be especially damaging. Here are two broad ways that we need to be more open in rare disease science:

Findings and publications don’t belong to (well-funded) scientists and journals. 

For science, the paywall and delay to publishing can mean that it is months or years before other groups learn about important findings. This results in duplication of effort (different from replication) and even going down the wrong road. A nice solution to this is posting all work on BioRxiv, an open access preprint server. Because of the broken publishing system and broken incentive system in academia, it’s not always possible to publish in an open access journal, but if the work is posted on a preprint server, then it is still accessible. 

For patients, open access means they can read the science for themselves. It no longer needs to go through the paternalistic filter that most scientists use when speaking with patients. Access to the most recent research allows patients to make connections to real life experiences that may inform the science and the development of therapies. Don’t forget that patients are tax payers and they have the right to tax funded research. 

For physicians, especially those treating patients with rare diseases, staying on top of the science could be critical for treating the patient. Again, physicians may be able to make connections that scientists just aren’t aware of. 

All stakeholders need to be open to communication and collaboration. 

In almost any scientific advance, collaboration and openness speeds discovery. This is especially important for rare diseases. Collaborations across nontraditional aisles will need to occur. Scientists should move away from tribalism and protecting unpublished data, but be open to all who are seeking the information. Meetings, especially disease focused ones, should make every effort to include physicians and patients. Sharing data among scientists is great, but the information is only useful if it’s shared with the people actually impacted by the disease.

One particularly exciting collaboration that is now occurring is between Retrophin, NCATS, and NGLY1.org to find small molecule therapeutics for NGLY1 deficiency. A collaboration between a company, an NIH institute, and a patient advocacy group to bring together the strengths of all three, to speed discovery. This is the model for rare disease. In small communities, all parties need to be working together. It’s not a race to find a cure first, it’s a race to find a cure. Period. 

So, moving forward, what will the Chow Lab do to try to improve this for the rare disease community? 

1)    We will always post our work on BioRxiv and whenever possible, publish in open access journals. We haven’t always done this, but to improve access, we will also post PDFs of all our papers.

2)    We will share unpublished data. If you ask, we will share findings (with whatever caveats).

3)    We will participate in more patient centered meetings and interact with more physicians and patients.
 
4) We will be open to collaborations from any angle. 
 

Open science is important to all of science, but especially to advances that need to happen for rare diseases.

Rare Disease Day 2018

With the NGLY1 deficiency community at the SBP Rare Disease Day Symposium in San Diego.

With the NGLY1 deficiency community at the SBP Rare Disease Day Symposium in San Diego.

This is the first installment of a number of blog posts about rare diseases (here, here, and here).

This past month I spoke at two different Rare Disease Day events about how we are using model organisms to move towards therapies for rare diseases. I attended the 9th Annual SBP Rare Disease Day Symposium & CDG Family Conference in San Diego and The 5th Annual Rare Disease Genomics Symposium at UAB. 

These were incredibly eye-opening experiences. Both have given me a lot to think about, especially regarding the direction of the lab and the relationship that science has with patients. I hope to write a bit more about these ideas over a few posts. For this post, I'll write a little about what these meetings were about and some quick lessons I learned.

The SBP event was focused on bringing together physicians, patients, foundations, and scientists working on Congenital Disorders of Glycosylation and NGLY1 Deficiency. We had scientific sessions where we shared the most recent advances in our labs. I spoke about advances we've made with our model of NGLY1 deficiency. We also had an open sessions where we spoke with families and kids with rare diseases - listening to their experiences and answering questions about the basic biology and potential therapeutic advances. Finally, the scientists spent time brainstorming and sharing unpublished data, to pull together connections that may not be apparent to any one lab. The most effective part of this meeting was that patients participated in all of the events, including the scientific brainstorming session. This video captures the excitement of the meeting.

The UAB event was quite different, focused on therapeutic advances and management of rare diseases. I spoke about how model organisms can really help advance therapeutic development in rare diseases. There were also sessions on challenges of finding appropriate care and how to advocate for your child with a rare disease. 

I learned a number of really important lessons during these trips:

1) Hud Freeze told me that meeting the patients changes your life. This is absolutely true. Meeting the brave kids and adults battling rare diseases was inspirational, especially learning about the strength that they have to fight for their lives. Putting a human face on science is important. 

2) Scientists need to talk to patients. Patients and parents understand a lot more than we give them credit for. They've often read all the research and followed the science. It turns out, if you aren't trained in science, you can come up with really good out-of-the-box ideas that aren't filtered out by years of scientific training. 

3) Scientists need to talk to patients. Patient experiences matter. Hearing about the conditions and struggles that they go through may give you ideas that can be pursued in the lab. Often, these anecdotes won't be documented in the literature, but reflect real experiences. 

4) Basic science is essential to finding therapies for rare diseases. Because the communities are so small, patients, physicians, and scientists HAVE to work together. 

5) Science needs to be open access. Patients and physicians need to be able to read the current literature. Patients are taxpayers and voters. They have a right to access work that may impact their lives. 

These are just a handful lessons I learned. The real highlights were the personal connections I made with patients and parents. I encourage scientists and trainees working on disease models to attend patient meetings and events. You never know how it might change your life and impact your science. And if you're lucky, you might meet someone amazing like Emily Kramer-Golinkoff, who started a foundation and is fighting for a cure for her rare disease. 

Grants and what we'll do with them

We’ve been incredibly fortunate lately. Our lab has received two grants which will help fund us for the next five years. Grants help to fund our science by paying the salaries of the people in our labs. The majority of a grant is salary support, unless it’s been otherwise designated. Grant money supports the livelihood of people working in the lab. Here is a quick summary of some of the work that these to grants will support:

NIH/NIGMS MIRA R35 - Investigating the Impact of Genetic Variation on ER Stress Response and Disease

This grant differs from the standard NIH R01 in that it is meant to fund multiple projects that fall under a common theme in a particular lab. For us, this was really nice, as we have common thread of understanding how genetic variation impacts disease. This grant will support three projects:

Project 1: Understanding the underlying genetic architecture that contribute to differences in individual ER stress responses.
Project 2: Understanding how genetic variation affects Retinitis Pigmentosa, a retinal degeneration disease.
Project 3: Understanding how genetic variation affects NGLY1 deficiency, a rare metabolic disorder of deglycosylation.

You can read a more formal summary of this grant here.

Glenn Award for Research in Biological Mechanisms of Aging

Again, our lab is broadly interested in understanding how genetic variation impacts the ER stress response. This grant will allow us to begin studies where we introduce a new dimension to this work – age. We are interested in understanding how the role genetic variation on the ER stress response changes as an individual ages. This has important implications for age related diseases like cancer and dementia.

These grants will go a long way in advancing the work in our lab. We have a talented team of excited techs, students, and postdocs working hard on these projects.

Science is for everyone.

Science is a human pursuit. Science should be a safe space. Science is for everyone.

Recent political developments have put everyone on edge. 

No matter how you feel, or how you voted, or how you identify, you should be welcomed into this grand pursuit we call science. 

People should feel safe in the lab and in the field. 

In my lab, you will be welcomed and you will feel safe. I will be your mentor and ally. I will support you and advocate for you.

I will not tolerate harassment.

You can come to me and I will listen. 

We can make science an example for our society.

The Chow Lab is heading to ASHG

The Chow Lab is heading to ASHG this coming week. Here’s what we’re doing at the meeting:

Thursday 11:30 in room 302 - PgmNr 183: "Diet rescues lethality in a model of NGLY1 deficiency, a rare deglycosylation disorder."
-    Clement will be discussing this exciting new project in the lab. Come hear about how we use model organisms to learn about rare diseases.

Clement will be co-moderating a session on Saturday morning at 10:15 in room 119: “Session #84: Novel Discoveries in Mendelian Disease”
-    This will be great. Come hear about recent advances and new discoveries related to Mendelian disease.

Josh Lowry, one of our postdocs, is attending as a first timer to ASHG! If you see him, say hi!

And…We are looking for people interested in working on rare disease. If you’re interested, find Clement or contact him. 

Summer wrap up.

Summer is always too short. But we managed to still get a lot done. I'm very proud of the lab! The lab is growing and I’m excited that our team is made up of people with diverse experiences and backgrounds.

Some highlights:

  • It was very exciting to have Shani join our lab this summer. Shani is an undergrad at UCLA and she has made some incredible progress on our retinits pigmentosa project.
  • Josh and Becky joined this summer as postdocs. They have both hit the ground running and are moving forward quickly.
  • We attended GSA’s TAGC meeting in Orlando.
  • We celebrated new lab members with lab lunch.
  • We celebrated birthdays with donuts.

That’s a lot!

We wrapped up the summer with a lab dinner together.

Clement, Shani, Elaine, Josh, Demi, Katie, becky

Clement, Shani, Elaine, Josh, Demi, Katie, becky

We’re so excited to see what this year brings!

 

 

The Chow Lab heads to TAGC16

I will be heading to GSA’s The Allied Genetics Conference next week in Orlando (AKA TAGC16). It’s unique in that, for the first time, GSA is attempting to bring together all the model organism genetics under one roof. THERE WILL BE A LOT OF SCIENCE! 

This is especially exciting for the Chow Lab because this will be the first national meeting where we present our own science. Our work spans multiple model organisms and crosses functional and quantitative barriers. This made TAGC16 especially exciting for us, but also like Sophie’s Choice, trying to decide which project to present. Rather than choosing, we submitted two abstracts!

Our mouse project was chosen for a talk. We have been investigating the effects of ER stress on the placenta. We are using RNAseq and small RNAseq to explore how ER stress reorganizes transcriptional networks in the placenta. I will be giving the talk during the Mouse Development session on Thursday from 4-6PM. Talk M272

Our fly project was chosen for a poster. We have been exploring the pathogenesis underlying lethality in a Drosophila model of NGLY1 deficiency. This is mostly the work of our tech, Katie Owings. It’s turning out to be a really interesting story! Please drop by and check it out. Poster D1331

I also contributed to a talk and a poster from my postdoc with Andy Clark and Mariana Wolfner: 
1.    D121: Investigating the female’s role in sperm competition in Drosophila melanogaster.
2.    D1408: Male genotype-specific transcriptional responses to mating in female Drosophila melanogaster.

I will also be moderating the "Comparative Genomics, Computational Methods and Evolution" session on Thursday morning with Steve Munger. 

Finally, I am particularly excited to be a mentor at the “Mentoring Roundtables” event on Thursday from 12:30-1:30. I will be at the “Transition to Independence” table. Come hear about what has worked for me (so far) in my transition.

I hope you find me and say “hi”, but more importantly, I hope you’ll look for our science and give us feedback!

On science communication

Science communication is an important part of a scientist’s job. It’s an opportunity to tell the public about how awesome and spectacular your work is. I recently recorded a podcast on The Scope about some of our work on genetic variation and disease. It was really fun. I was able to think about how to distil my science into just the essential non-jargony points.

Sometimes, however, science communication needs to just be the voice of reason. Sometimes you just have to tell a Cosmo reporter that a genetic test won’t help you find a romantic partner. Don’t ask. Just read this.

The lab is growing!

So much excite!

Two postdocs are joining the lab this summer and they are both bringing new skills and talents that will enrich the lab.

As a grad student, Josh Lowry used whole genome sequencing methods to map and identify new C. elegans mutants that affect syncytial membrane architecture in oogenesis (here). In our lab, he will be applying his computational skills to understanding the pathogenesis underlying NGLY1 deficiency. Josh is starting in June.

As a grad student, Becky Palu studied the role of Sir2 and HNF4 in Drosophila insulin signaling and metabolism (here). During her postdoc, she will be using her strong background in functional Drosophila genetics to understand the mechanisms underlying natural variation in Retinitis Pigmentosa. Becky is starting in August.

I am eager to see the lab hum with activity! 

 

What to expect

Whether it is for a career in academics, industry, policy or whatever, grad students and postdocs join labs for training. Working in an academic lab can provide valuable skills for all kinds of careers and I take this responsibility very seriously. Students and postdocs are here to learn, not just work.

I am a new professor. I don’t have a lot experience to draw on. But, I do know that I am successful because of the people that trained me.  Obviously, there isn’t a magic bullet for every trainee, but here are some general lessons I picked up along the way. I will try to implement these in my lab:

1)    GOALS: It’s important that everyone has goals – long term career coals and short term progress goals. I will make sure that we reassess and develop these goals on a regular basis. 

a.    CAREER: Whatever your career goals are, I will try my best to provide the necessary resources you need to reach those goals. If I don’t have the answer, we will find someone who does. 
b.    LAB: We will set project goal posts to shoot for. We will reassess on a regular basis and decide if the goals need to be reset or extended.

2)    WRITING: Nearly everyone is terrible at this when they start and nearly everyone improves with practice. So, I will push you to write. Write abstracts, posters and papers. You will write the first drafts. Then, we will work together to improve it. Rinse and repeat.

3)    SPEAKING: Just like writing, nearly everyone is terrible at first. Unlike writing, nerves are involved and the only way to get over the fear, is to practice. GIVE.LOTS.OF.TALKS. Again, I will push you to present. From the beginning you will be presenting for lab meeting. I will encourage you to volunteer for journal clubs, local talks and national meetings. We will always submit abstracts with talks in mind. PRACTICE putting together a talk and giving a talk.

4)    SUPPORT: My door will always be open. Come to me for support. If something is not working in lab, let’s figure it out together. If you feel you are missing something in your experience, let’s figure out how we can fix it. 

5)    CHALLENGES: Expect to be stretched and challenged intellectually. We have (a true) multidisciplinary research program and that means that projects may extend into realms that you aren’t comfortable with. I expect my trainees to leave my lab with a broad outlook on genetics. 

These are a few of the (many) ways I was mentored and helped me be successful (so far). I am still learning this PI thing and of course I will modify how I think about this as I gain experience. But, if you join us, you can expect that I will try my hardest to ensure that your experience will prepare you for your next step. 

Please chime in and let me know how I can be a supportive PI and mentor. What have I missed?

Why I do science

Human disease isn’t just a cell in a dish or a fly in a vial. This first became clear to me as an undergrad. I had the opportunity to intern at a perinatology clinic that dealt with high risk pregnancies. A large proportion of the cases they saw were due to genetic disease in the fetus or baby. I sat in on procedures and genetic counseling sessions. I saw firsthand what genetic disease does to a family. Pain, suffering and unending questions.

As basic scientists, we often forget this. We tell ourselves that we strive for knowledge and truth. This is true. But, our work has so much potential to provide answers and even transform lives. This is why I do science.

As a grad student I worked on Charcot Marie Tooth (CMT) disease, a severe peripheral neuropathy. This story began with a spontaneous mouse mutant, basic science. I cloned the gene and characterized the mouse. Based on this work, we thought it had a lot of similar neurodegenerative issues as patients with CMT. I screened a number of patients and found several families with mutations in the same gene. When this was reported back to the families, we received notes expressing relief that they hadn’t done something wrong to make their kids sick. Now, there is gene test and numerous other patients have been diagnosed. This is what basic science can do.

It’s important to remember the human face behind the disease. We recently began a project looking into the biology underlying NGLY1 deficiency. This is a disorder of deglycosylation and patients have developmental delay, movement disorders, and many other symptoms. I recently met the first identified patient with NGLY1 deficiency. This reminded me again, that NGLY1 deficiency is not a project. It’s a genetic disease with a human face and human suffering.

Not every experiment will lead to therapy. Not every experiment will improve humanity. But if one does, then we’ve succeeded. Behind all this biology is human disease. Behind the disease is a human face, human suffering. This is why I do science.

The importance of scientific societies

I was recently profiled as a new faculty member on the Genetics Society of America (GSA) website. For the profile, I was asked what role GSA played in my career. This got me thinking about the important role that scientific societies play in the development of all trainees. 

Travel awards and conference organization are two obvious ways that an organization like GSA might influence training. However, the potential is much greater and I think most scientific societies are untapped resources for trainees. As a graduate student, I joined the American Society of Human Genetics (ASHG) Training and Development Committee. This committee is tasked to help develop resources and programs for students and postdocs. After serving for a few years, I was asked to chair the committee. This was a great opportunity. I learned a lot about how the society functions and how decisions are made. I was able to network with leaders in the field. I was even asked to represent ASHG at a FASEB planning meeting. All this was invaluable experience. 

Most scientific societies work hard to provide trainees with the resources and opportunities they need to succeed. More and more, these societies are developing career resources beyond the typical academic route. The staff care deeply about trainee development. Dr. Michael Dougherty, Director of Education at ASHG, and Dr. Elizabeth Ruedi, Director of Education and Professional Development at GSA, are two stunning examples of society staff who work tirelessly to provide invaluable trainee resources. 

I encourage all trainees to take advantage of society opportunities to serve and lead. Reach out to your society. Don’t wait for an opportunity to come to you.

Mendelian diseases as quantitative traits

I recently gave a talk at the annual American Society of Human Genetics meeting in the Novel Genes, Novel Regulators, and Monogenic Diseases session. I was very pleased by the reception of my talk and of the main message I was trying to convey. I thought I would briefly rehash the main point: Mendelian diseases are not simple and should be viewed as quantitative traits.

I presented our work on identifying genetic modifiers of Retinitis Pigementosa (RP), a heritable form of retinal degeneration. We crossed a Drosophila model of RP onto ~200 wild-derived Drosophila strains. These strains contain genetic variation found in a wild population and were NOT mutagenized. When on different backgrounds, this Mendelian disease presented with a HUGE range of retinal degeneration. In short, the phenotype was quantitative. We went on to identify a list of novel candidate genes that make a lot of biological sense. We used natural genetic variation to show that this Mendelian disease is, in fact, complex.

This message may be obvious. After all, the push behind precision medicine is the fact that every individual is different and may present with slightly different disease outcomes and respond differently to therapies. However, when speaking to other scientists studying Mendelian diseases, genetic background and modifier genes are a pesky nuisance. I challenge everyone to embrace these effects.

In order to fully understand the phenotypic spectrum and genetic architecture of Mendelian diseases, we need to treat them as quantitative traits.

Our logo

You'll notice that our lab is represented by a pretty neat logo. I decided that I wanted a logo designed for the lab because I didn't want my face to be the lab brand. I want this lab to function as a team - I just happen to be the PI. 

Our logo has four symbols, a DNA helix, a human, a mouse and a fly. The DNA helix represents our central theme of harnessing the power of genetic variation to answer the questions we are chasing. The human symbolizes the fact that even if we are doing basic science, we strive to contribute to solving aspects of human disease and contributing to the development of therapies. The mouse and the fly show that we believe strongly in model organism research. Continuing advances in model organism biology make these tools more powerful than ever. We use both the mouse and the fly to study and model how genetic variation can impact human diseases. 

I am hoping that this logo will serve as a good reminder for us as we push forward.