Thanks to an incredible effort and an amazing team, especially my co-lead authors Bruna Paulsen, Silvia Velasco and Martina Pigoni, our paper is out in Nature! Great work has been done to shine light on the genetics of autism spectrum disorder, and we know that your risk of ASD is influenced by variants in *hundreds* of genes. We focused in on 3 of them - SUV420H1 / KMT5B, ARID1B, and CHD8. These genes influence your risk of ASD, but why? How do they affect the brain during development? To find out, we leveraged a reproducible lab-grown model of human cortical brain development. My colleagues created heterozygous mutations in each one of these three genes in stem cell lines, and grew them along with isogenic controls, over several months, into brain organoids. The organoids grow the same kinds of cells that would appear during human cortical development. We used single-cell RNA sequencing (& more) to compare the mutated and control organoids. We found that mutated ones grow certain cell types at different times. In this figure, organoids with SUV mutations have accelerated development of Immature Deep Layer Projection Neurons. Sometimes the direction was the opposite – i.e. in ARID1B mutated organoids, there was a *delayed* differentiation of those same neurons. But the types of cells where we saw a shift was the same across all three genes: deep layer projection neurons, and early GABAergic neurons. One major finding here- although these effects were consistent, which cell line you use for organoids matters for how big the effect is. A lot! This means that researchers need to consider the cell lines they use – and how many! – when drawing conclusions about complex disorders. We’re left wondering what differing speed of neuron development affects downstream. For the first clue, Sung Min Yang used calcium imaging to look at the neuron’s activity in the organoids, and found changes in circuit activity in SUV420H1 mutants. Tantalizing results… This was a huge project with SO many moving parts & great teamwork! It started years before I joined the lab and I'm so glad to see it out in the world.
0 Comments
"The biologist gathers knowledge, will often describe his or her work as if telling a story, strives to draw conclusions and construct models, and appreciates that exceptions are just as common as rules in our biological world. Compare this to the logic and process-oriented computer scientist, for whom rules and optimization are the goals... We have found, though, that this is where the strength of interdisciplinary research shows its full potential." -Jennifer Gardy and Fiona Brinkman, Science I recently wrote a guest blog post for the Broad Institute's Terra Blog. Terra is the Institute's cloud platform for biological researchers. I wrote about how their Terra-backed tool, the Single Cell Portal, can be used to smooth over the divide between computational and wet-lab researchers. Check it out here. Tools like this one are an important part of my field of research. A lot of attention, deservedly, is paid to new technology, such as the development of of single-cell RNA-seq assays, which has enabled us to measure and predict more things more accurately in biological research. But it's also incredibly important to have smart people building tools like this, which connect researchers across their various expertise. As I say in my post, "It's been amazing to experience first hand how emerging technology can help us not only to improve assays and analysis of biological data, but also to bridge the gap and facilitate hand-offs between data-producers and data-analyzers, and ultimately speed up and amplify the discovery process." There's a growing list of great tools like this - which can range from using Google Drive and GitHub in your research, to large-scale cloud-based platforms like Terra which are built with biological researchers in mind. I'd love to hear about your favorite tools and platforms that make your collaborative work easier. "If I hadn't had mentors, I wouldn't be here today. I'm a product of great mentoring." -Indra Nooyi, CEO of PepsiCo I'm so excited to say that I will be working at the Broad Institute after I finish my PhD this summer. I'll be a part of the Stanley Center researching psychiatric disorders as a staff scientist. I could not be happier.
I learned a lot throughout this job search process. From practical things (my last interview was so much better than my first), to surprising things (turns out I don't want to work in pharma? ...yet?). But the most important thing I learned should not have been surprising to me: I learned about the importance of mentors. When I first started thinking practically about what I wanted to do after graduation, I tentatively sent word out that I was looking to get coffee with people in different careers. Suddenly, it was like a swarm of supportive people came out of the woodwork to share their stories and their advice with me. A high-up exec shared her life story with me over an hour-long meeting. A friend I hadn't seen in a year gave me salary negotiation advice (including divulging her salary - it is so helpful!). A woman I met once at a conference has now met with me several times, and periodically texts me thesis-writing encouragement. The enthusiastic mentorship I've received from these women made me feel like I had my own personal executive board behind me, cheering me on. In fact, my entire life story thus far has truly been one about generous and ardent mentorship. I attribute my intellectual curiosity to my grandfather, and our sessions of "Grampy's College of Knowledge." A small man with an enormous capacity for imagination, who never graduated from college himself, he would sit me in his room and encourage me to ask questions. "How do clocks keep time?" "Who is the man on the moon?" "Why are there wars?" There was no Google then - he either knew the answers, or together, we guessed. I referred to him, with his winking encouragement, as "the smartest man in the world." He told me I would one day be smarter than him, and I think in that one instance, he was wrong. There was the middle school math teacher who taught me that math could be a passion. The life science teacher who taught me that science could help people - and that I was worth helping. The guidance counselor who valued my kindness over my grades. The internship supervisor that told me to never lower my aim. And - of course - Dr. Don Elmore and Dr. Ernest Fraenkel, my advisors at Wellesley and at MIT. I could not have asked for better academic sponsors. Scientifically, I learned powerful techniques and even more powerful methods of inquiry and ways of thinking from both of them. Personally, both have, in their own ways, been immeasurable sources of support. So I should not have been surprised when, as it came time to decide between the jobs I interviewed for, mentorship was so important to me. The Broad offers so much value in that regard. The Institute is an amazing place for a computational biologist, hosting hundreds of colleagues I will learn from. And I will be working directly under three amazing scientists whose work I respect deeply, and who all, in my conversations with them, emphasized their commitment to mentorship. Joshua Levin, Paola Arlotta, and Aviv Regev. During one of my meetings before my job search, one woman told me, while refusing to let me pay for even my half of a dinner bill, that the only payment she wants is for me to do this for someone else in the future. Having a chance to mentor undergrads and other grad students during my PhD has been one of the more rewarding activities I've taken part in, but I have a lot to pay forward. "Behind every successful woman is a tribe of other successful women who have her back." Last week, Graduate Women at MIT held their annual Leadership Conference, with the theme "Lady Bosses: Women in Leadership and Entrepreneurship." We had a blast organizing and attending this conference. The conference committee, led by the fearless Chairs, Nil and Mahsa, was a great group of grad and post-doc women who poured their heart into this awesome week of events. The week started with an opening keynote by Christine Souffrant Ntim, a fabulous entrepreneur featured in this year's "Forbes 30 Under 30", among other accolades. She had some beautiful advice for us, including her main tagline - not "Follow Your Passion", but "Follow Your Patterns". She advocates auditing your life to find out where your true strengths and interests lie and letting those lead you to your next goal, whether for a new business or any venture. Other events included Movie Night, with PBS documentaries about Women in Politics and Women in Business, panels on "Succeeding in Male-Dominated Fields" and "Changing the World Through Entrepreneurship", popular workshops with knowledgeable mentors on "Taking Control of a Meeting" and "Negotiating Your First Job Offer", and a mixer with MIT alumnae. In fact, alumnae were involved in almost every event during the conference. We sent an email out to members of Alumnae Association's and AMITA's email lists, and we were shocked at the number of responses we got from amazingly qualified women who wanted to help us! It makes me excited about the culture of MIT and the appeal of GWAMIT to know how involved our alumnae are. Finally, the week ended with a closing keynote by (another alumna!) Nidhi Kulkarni, Co-Founder and CTO of Spitfire Athlete, a strength training app for women that focuses on helping women achieve their athletic goals (no weight loss talk here!). Nidhi's talk was one of my favorites - she went into some real detail about the process of building her company from the perspective of an engineer-turned-entrepreneur. She talked about the decisions she and her co-founder made along the way, from business models to growth rates, and about the culture for women entrepreneurs in tech in Silicon Valley. After her talk, we hosted a strength training class with MIT Recreation and all got a little bit stronger. I hope some of you were among the hundreds of people who attended our conference! GWAMIT has been one of the most rewarding experiences I've had in graduate school, and I loved hosting these events for my fellow students, and showcasing some incredibly awesome women! "It’s about helping people. It’s about smart people coming together. It’s about having just enough energy to create a spark to change the world." –HD2016 attendee This past week, I had the inspiring experience of attending the Hereditary Disease Foundation’s biannual conference, HD2016. It was three days of talks and conversations with scientists dedicated to Huntington’s Disease research. One the things that struck me most at this conference was how collaborative and supportive these scientists are. The HD scientific community is, as many attendees said, a family, and we are dedicated to finding a cure. There are many ways that science can work, but it cannot work in a vacuum. The experience of placing my work, which is already extremely collaborative, in the context of an entire field of research on this disease was invaluable. One of the many things I learned at this conference was the rich history of HD research. From Dr. George Huntington describing the disease in 1872 because of its prominence in the small community where he grew up, through the establishment in 1980 of an incredible coordinated effort to study a highly affected community in Venezuela, to the discovery of the mutated gene in 1993 due to that study. We are still reaping the benefits of data collected from that Venezuelan community today. The meeting started off by grounding us in our purpose - an incredible visit from an HD patient and his family. Their creativity and bravery in dealing with his disease, and in talking so candidly about it to a room of strangers, were so inspiring. The patient's perspective is critical for researchers, and in answering questions like "which symptom of your disease would you cure first?" (Answer: memory loss, when many people think of HD as a movement disorder), it gave us indispensable insight. The first talk shared the exciting news that, 22 years after the discovery of the mutated Htt gene, a clinical trial is underway for a drug that will silence that gene. It is an exciting advance for the field, though it will be years before these drugs enter regular use in the clinic, if it proves effective. I also appreciated the reminder that this treatment, even if it works, will be expensive and require the kind of hospital infrastructure that not everyone has access to. The field won't consider the problem solved until we have a solution that we can bring back to Venezuela and all communities in need of it. The rest of the conference underscored how far we have to go. Despite 20 years of study, we are still learning of new functions of the Htt protein - in autophagy, development, DNA repair, and more - and debating whether that protein is the only important target in this disease. Because of the huge variety of molecule and pathways affected in HD, we still need to work out which are drivers of disease, and to determine what the best biomarkers are to test if a treatment is working. And there was much talk of new and better models for lab research of HD, from neurons in a dish created from patient skin samples, to mice, flies, and sheep. There were stimulating talks from leaders in the field of genome editing discussing how exciting new technology could be put to use for these patients. I wish I could do justice to all of the amazing science presented at the conference. But there is one important message I got from this conference that takes precedence: We can solve this, but we aren't done. Get back to work. I recently had my first grad school paper published! This paper describes software that my colleagues and I created for integrating high-throughput biological data, or "omics" data. The software is called Omics Integrator. The bulk of this work was done when I first joined the lab, in the summer of 2013, and the intervening years have involved a lot of tweaking, improving, and paper submitting. Biologists have a habit of labeling assays which measure a whole species of molecules "omic" assays. You've probably heard of "genomics." Well, there is also "epigenomics" ("over the genome", or measurements of marks and structure of the DNA), "transcriptomics" (measurements of transcripts of RNA), "proteomics" (measurements of proteins), and many more. All of these assays result in hundreds of thousands of data points, and biologists nowadays often do more than one of these assays. That's often too much data for a human brain to make sense of, and even when you can, the different assays can often disagree with one another, since they are interrogating different parts of the system within a cell. Enter Omics Integrator. The software is designed to take in data from several kinds of omic assays, and to output a "network". In this case, networks are made of "nodes" that stand for proteins, and "edges" that connect proteins which physically interact inside the cell. Omics Integrator outputs nodes and edges which were implicated by your input omics data. These networks are a lot easier to understand. They also often include new nodes - hidden nodes - which didn't show up in your omic assay, but may be very relevant to the cells you were studying. In many cases, you can use these networks to find novel pathways of interacting proteins which are important to your system, whether that system is cells with a human disease, mice which were raised in different environments, or any experiment you've done in your lab. Finding pathways of interacting proteins is a good way to identify which processes have changed in your experiment, and to focus future experiments on that process. If you're studying a disease, pathway identification can help you decide on a drug to try in that disease, or on a drug target. We've tried to make this software as flexible as possible so that it will be useful for any biologist with too much omic data and not enough results. If you want more details on all the math and computation in the software, read our paper (it is published in an Open Access journal, which means you don't need to pay to read it. Open Access publishing could probably be another blog post of it's own). If you're a scientist who wants to try out the software, check it out on our lab website or GitHub page! "Why should girls miss out on the joy of adventure?... I'm not against fear, but I am pro-bravery." - Caroline Paul, author of The Gutsy Girl I recently joined the executive board for Graduate Women at MIT (GWAMIT), and we just wrapped up our Spring Empowerment Conference! The theme of this years conference was Be Gutsy, inspired by our keynote speaker Caroline Paul, who recently wrote a book for pre-teen girls about the value of adventure and bravery. Paul talked about how we condition young girls to let their fear keep them from having adventures, all while encouraging young boys to be brave. "When girls become women, this fear manifests as deference and timid decision making" (NYT). She talked about her joy in having adventures, from firefighting to skydiving to writing a book. The rest of the Empowerment Conference week was filled with events designed to empower and inspire the grad women of MIT to Be Gutsy. We had a movie night featuring a 14 year old girl who traveled around the world alone. We had a belly dancing class. We had a panel of women at MIT who do "Extreme Science" (including two of my great friends/rolemodels, Laura Stevens and Mariana Matus, and two of my science heroines, Susan Solomon and Nergis Mavalvala). And much more. It was incredible. I was inspired by the speakers and workshops at the conference - and by the amazing group of women who helped plan and put on the conference - to be more gutsy in my own life. Despite my fear of public speaking, I participated in the conference events twice. I was a panelist in a Women in STEM panel, and I moderated the Extreme Science panel. It was a wonderful experience both times. And yesterday, after the conference, I invited my fellow GWAMIT Board members to volunteer with me for MIT's CityDays. We were assigned to Habitat for Humanity and, incredibly, we actually helped to build a house. I learned a lot about this amazing organization which provides affordable homes for low-income families. And by the time we left, there was wall sheathing and housewrap on a home that had not been there before. I am so proud of that. I encourage you all to Be Gutsy, and seek out adventure. It is such a rewarding way to live. "I thought that looking presentable, having clean hair, and never letting myself cry until after I left the doctor’s office would get me better treatment. So I continued to smile through my numb face." -Ana Saldamando, "What It's Like When No One Believes You're Sick" As a molecular scientist, I like to deal in well-defined questions, quantitative data, evidence. I like to find answers. As the family member of someone with chronic health issues, there are usually no answers. I am happy just to have a medical professional take us seriously.
This semester I have been lucky enough to get a glimpse of the medical field from another perspective. As part of my Graduation Education in Medical Sciences program, I am shadowing Dr. Anne Louise Oaklander, a neurologist as Massachusetts General Hospital, as she see patients and runs a lab researching their disease. Dr. Oaklander studies Small Fiber Polyneuropathy (SFPN), a disease that causes pain and other symptoms because the small nerve fibers in the skin are damaged or dead. This disease is hard to diagnose and hard to treat. Dr. Oaklander is one of the foremost experts on this disease. Patients travel from all over to see her, usually as part of a long journey seeking relief, and for the past weeks I have been in the room while she see them. I have learned so much during this time, but one of the things that strikes me the most is the story I hear over and over again - the struggle to find a diagnosis. The struggle to make anyone believe they are sick at all. Doctors that have never heard of SFPN, doctors that don't believe it's real, doctors that send these patients home with no help after the third, fourth, fifth time they come in weeping with pain, assuming they are just seeking drugs. These patients are so relieved once their pain has a name and, now, a face in Dr. Oaklander. "I see so many doctors, but I only cry when I see you" said one young woman, "because you understand the disease." (She was a grad student before her condition forced her to drop out, my age.) Being in Dr. Oaklander's clinic can feel a little like emotional whiplash. In one appointment a patient told us they think about suicide every day of their life. In the next a patient told us that the latest treatment had completely changed their life, that they felt like a new person. SFPN, like many diseases, is very different for each individual patient, so there is no such thing as a one-size-fits-all cure. Humans have a tendency to push away anything they don't understand. When patients with an invisible disease come into their office and no lab test they can devise points to an answer, some well-meaning doctors decide there must not be a disease after all. They refer their patients to psychologists and move on. SFPN is just one of several real conditions that often get ignored. We have to educate our doctors better. That is one of Dr. Oaklander's missions - in many parts of her crazy schedule she is speaking at conferences, publishing papers, making connections like no one's business. But, increasingly, there is another angle of attack - educating the patients. Many of the patients that have come into the clinic have done reams of research on their condition. Some of them were the first to utter the term SFPN to their doctors, having found it on the internet. They come to Dr. Oaklander with questions on everything ranging from acupuncture to stem cell therapy. They carry binders with medication lists, dates of treatments, forum posts, scientific papers. They put me, the student ostensibly studying this disease, to shame. It's a revolution. It's invaluable. It's intimately familiar to me from my own experiences with my mom. But it's not enough. How many patients don't have the privilege of the time, resources, and education necessary to take control of their own health? Or just don't feel they have the authority to question their doctors? How many are falling through the cracks of our deeply broken healthcare system? And what can we do to fix it? "The search for fundamental knowledge, motivated by curiosity, is as useful as the search for solutions to specific problems" -C.H. Llewellyn Smith This week, my Molecular Medicine seminar was lucky enough to hear from Dr. Bob Horvitz, a Nobel prize winner in Medicine in 2002. His story has me thinking about the usefulness of basic research. Dr. Horvitz studies C. elegans, a tiny worm that serves as a common model organism in biology labs. I have fond(ish) memories of long hours spent staring at these little guys through a microscope in undergrad lab classes. But although their ease of use recommends them as a lab model, you might wonder how useful these microscopic worms could be. Dr. Horvitz told us the story of how he began studying cell death in C. elegans. The worms are so tiny they only have 959 cells in their whole body (for reference, you have about 50 trillion). But, 131 other cells are created, and never make it to the final adult worm. Some cells die off as the animal develops. Until then, biologists mostly thought about cell death as something that happened when things went wrong. But it seemed like these cells were dying in purpose. Dr. Horvitz' lab used genetic studies of C. elegans to discover several genes that were responsible for "programmed cell death"- a purposeful, important biological process, now termed apoptosis. Cells need to die at the right time in order for worms to develop normally. And, it turns out, the same holds true for you and I. Some cells need to die off for you to stay healthy. There are some diseases that involve too much cell death (for example, neurodegenerative diseases like Huntington's), and some diseases that involve too little (for example, cancer is an outgrowth of cells that won't die off). Healthy bodies have to create a balance. Some time after discovering the cell death genes in C. elegans, Dr. Horvitz noticed human genes that were very similar to his worm genes. He and his colleagues started companies to study these human genes in more detail. It turns out that these genes act very similarly to their C. elegans counterparts - by causing (or preventing) apoptosis. Years later, those companies now have Phase II and III clinical trials in humans going on, testing drugs that target these genes in order to treat diseases of apoptosis gone wrong. It's one of the most direct stories I've heard about translating basic scientific research to human medicines. Nobody predicted that by counting all the cells in microscopic worms, they would one day invent a drug to treat leukemia. And yet, without the discovery of programmed cell death in C. elegans, it would have taken untold years before we could appreciate its importance in humans. It is a potent reminder that, although I am passionate about research with the explicit goal of curing diseases - and specifically looked for PhD projects that would allow me to do so - basic science for science's sake is just as useful an undertaking. Scientists' curiosity about C. elegans has led to countless important discoveries. Whether you like it or not, we owe a lot of thanks to a bunch of worms. "The best career advice given to the young is, 'Find out what you like doing best and get someone to pay you for doing it.'" -Katharine Whitehorn, journalist In addition to the awesome science that was presented at the two conferences I went to last weekend, which I talked about in my last blog post, both conferences featured speakers who offered us their perspectives on what to do after grad school.
Career advice in science often tends to boil down to one central question: Academia or Industry? Students are encouraged to choose either the "tenure track" and become professors at Universities, or the "industry route" by applying for jobs at businesses in pharmaceutical companies or the biotech industry. The unfortunate fact is that the two sides tend to denigrate each other - academics might think of going to industry as "selling out" or becoming a corporate drone, while industry workers tend to think of academia as out of touch and slow to change. At the HHMI Symposium we got the valuable opportunity to hear from someone who has done both. Dr. Morris Birnbaum was a professor at the University of Pennsylvania for nearly 20 years before changing track and joining Pfizer as the chief scientific officer for cardiovascular and metabolic disease research. He presented a salient list of "myths" about industry he heard while he was an academic. Some rumors about industry, he says, are simply false (people are less engaged in science and work less collaboratively). Some myths are semi-truths (there are a lot of meetings, you get told what to work on). And finally, there were the myths that are just true (the goal of the company is to make money, and having an advisor or department head is not like having a boss). Dr. Birnbaum's talk encouraged us to think of industry not as the "evil" alternative to academic jobs (although I think this type of thinking is becoming less and less common), but to think of it as a choice that may or may not fit with your personality. He also encouraged both sides to try and reach a better understanding of the other, so that collaborations between academics and industry will go better. The theme of finding a fit for your individual personality was also discussed at the CSB retreat, where we had a fascinating panel of former MIT CSB grad students talk about their careers in the few years since they got their PhD. It was an uncommon opportunity to hear from people in between - after grad school, but before establishing a full career and reputation. The alumni panel had a great representation of different career paths. Albert Cheng is just starting up his lab at the Jackson Laboratory, after a post-doc at the other campus of the same organization. Alex Robertson works as a Software Engineer at Counsyl, a biotech company that does clinical genome sequencing, and Robin Friedman is the very first employee at a new start-up called VL34. For me, this panel showed the futility of the simple divide between academia and industry. The job that Dr. Birnbaum did as a professor at UPenn was very different from the one Dr. Cheng will do as head of an academic lab at a smaller institution not connected with a traditional university. And his job at the Pharma giant Pfizer would be unrecognizable to Dr. Robertson working at a biotech firm in Silicon Valley, and they are both a world away from Dr. Friedman's work with a nascent start-up company. Condensing all of this career information over the past week and a half has been an experience of further subdivision past "academia vs industry." I have gone from "leaning towards industry" to thinking about whether I would fit in better with a small start up or a huge pharmaceutical company, with more tech-minded businesses or bio-focused drug discovery ventures. Each of the alumni emphasized the importance of passion for what you do. Despite the very different environments where they work, they each seem to love their jobs, as they went the route that felt right to them. One piece of advice that I found particularly memorable was Robin's urging to take a post-doctoral position after grad school only for the "right reasons" - not to simply move along the trajectory of "what comes next" but to gain an experience you will treasure along the way. I have always felt that it is important to prize each step along your life's path, and never treat years of your limited lifespan simply as a tool to get from point A to point B. |
AuthorAmanda Kedaigle's work in the Broad Institute focuses on leveraging brand new biological data modalities to study novel models of human brain development. Archives
February 2022
Categories |