The 2016 graduates: Congratulatory tributes
During the Convocation ceremony, Rockefeller faculty commended their students for their scientific contributions, untiring work, and unique skills. Here are the congratulatory tributes given to each of the 2016 graduates (including students in the Tri-Institutional M.D.-Ph.D. Program, denoted with an asterisk).
[ezcol_1half id=”” class=”” style=””]Rachel L. Belote
Daniel Blanco Melo
Peter C. Fridy
Nicholas David Gulati*
Joshua A. Horwitz
[/ezcol_1half] [ezcol_1half_end id=”” class=”” style=””]Corynn Kasap*
Maxime Jérémie Kinet*
Constantin Nicolae Takacs
Melanocyte–Keratinocyte Interactions and Intercellular Communication in the Skin
She comes from Rutgers, she’s got Jersey pride
Though she works up here the Upper East Side
She came to study and work alongside
Scientists she felt were most qualified
Her studies were on the melanocyte
Cells throughout the skin that block the sunlight
So the UV does not over excite
The DNA of keratinocyte
Skin must be healthy for work to begin
But there’s her problem, a tale hangs therein
‘Cause she had to go with a sheepish grin
To find the parents, to ask next of kin
Would you please help me? I need the foreskin
For a Ph.D., was it dignified?
But work must be done She swallowed her pride
Filled IRB forms, she followed the guide
All human subjects, rules must be complied
Cells were kept healthy to grow and divide
Glucose and peptide, carbon dioxide
Staining was vital, no formaldehyde
Results were startling but most bona fide
Their dendrites had spines, things seen in the brain
Synaptic proteins were in the membrane
And calcium sparks in local domains
In skin can this be? Please help me, Elaine!
That skin was like nerve cells could not be denied
From neural crest cells they are derived
What are their signals? What do they provide?
This must be resolved, studied, clarified
So for the moment she’s unsatisfied
She’s stayed in my lab, trying to foresee
What kind of comments from the referee
Today she is here with her family
President, chairman, and all honoree
Here’s Rachel Belote for graduate degree
B.S., Universidad Nacional Autónoma de México
Paleovirological Analyses of Endogenous Retroviruses and Host Innate Immune Effectors
Retroviruses are special among viruses in that they deposit a copy of their genome in the DNA of the cells they infect. When their targets include cells of the germ line, viral DNA can become heritable, like genes. Over time, fragments of retroviral DNA accumulate in genomes, to the extent that many modern organisms (you included) have significantly more viral DNA than genes. You are descended from viruses as well as from apes.
The viral DNA fragments in our genomes are a rich fossil record of ancient viral infections. Daniel Blanco Melo joined my lab to study this fossil record. His particular goal was to understand how ancient viruses shaped the intrinsic defense mechanisms that cells deploy to block viral attack.
First, Daniel developed new bioinformatic tools to mine and catalog retroviral fossils, and then he used the fossils to deduce and synthesize ancient viral sequences. ln one case, Daniel could functionally reconstitute part of an ancient retrovirus that repeatedly infected our primate ancestors over millions of years. He used it to identify the cell surface receptor that the ancient virus used to infect cells. Then, amazingly, Daniel found that our recent great ape ancestors apparently co-opted part of the ancient virus that had been inserted into their genome, and used it to block the receptor. This event likely contributed to extinction of the virus.
In another remarkable set of experiments, Daniel described how natural selection by pathogenic viruses, over hundreds of millions of years, has, apparently repeatedly, taken a copy of a gene that ordinarily makes a gate that guards pores in cell membranes and fashioned it into a gene whose product instead traps virus particles as they depart from the surface of infected cells.
Daniel was a wonderful student and is embarking on a great career as a postdoc and beyond. He is one of a new breed of scientists who is equally adept with a computer keyboard at his fingertips as with a pipette in his hand. He is full of insight and determination and goes about his work with an unwavering enthusiasm and cheerfulness. He is also among the most unselfish scientists I have encountered. As my lab has struggled to grasp the opportunities that a deluge of sequence data can provide, Daniel has been our point person and teacher, impacting many projects in addition to his own. So today, I offer him both my congratulations on his graduation and my deepest gratitude for all his contributions to our work.
The Genetics of Mosquito Heat-seeking Behavior
Right now, all of you sitting comfortably in your seats are releasing the cues that drive mosquitoes wild. Roman Corfas is interested in your body heat. He was the first in my group to measure exactly how mosquitoes detect heat, and showed that a gene called TRPA1 helps them hone in on the temperature of human body heat, and also to avoid higher, more dangerous temperatures. In a series of elegant experiments, Roman demonstrated that mosquitoes pay attention to relative differences in temperature, allowing them to hunt humans at a range of ambient temperatures. This work is important because these animals are currently infecting hundreds of millions of people with Zika, dengue, and other dangerous viral diseases.
Roman was born in Rehovot in Israel, grew up in Boston, and was an undergraduate at Oberlin College. There, he majored in neuroscience and was something of a bohemian scientist and scientific bohemian. As an undergraduate, Roman practiced science in the labs of a “Who’s Who” list of neuroscientists: Michael Greenberg, Tom Schwarz, Howard Eichenbaum, Morgan Sheng, and Lorna Role, to mention just a few. Roman came to Rockefeller to carry out basic research in neurobiology and behavior. His thesis work beautifully captures his interests at the intersection of genes, behaviors, and circuits.
Perhaps no one better than Roman himself can introduce his passion for science, and I quote from the essay he wrote for his graduate application to Rockefeller:
“For myself, there is no field in science as thrilling as neuroscience—there are no questions as fascinating as those asked in neuroscience research. How are memories made? How are sights, sounds, and smells sensed? How do neurons communicate through simple chemistry to produce such complex phenomena? After years of studying and working in science, I’ve come to realize that the most satisfying answers to these difficult questions are found at more concrete levels—cells, molecules, action potentials, and behavior.”
Roman has moved on to postdoctoral training at Caltech in the laboratory of Michael Dickinson, where he will undoubtedly provide his unique insights into the mechanistic underpinnings of complex behaviors.
B.S., Duke University
Nanobody-based Interactomic Studies of Single Transcripts during mRNA Maturation
It’s my very great pleasure to say a few words introducing Peter Fridy on his graduation. Quite simply, Peter is a shining example of the outstanding caliber of our students.
For a few years, Peter has essentially worked on two thesis projects for the price of one, which has been a bargain deal for me! However, Peter took this in his stride, and the interconnected projects were both highly successful.
First, he was instrumental in developing a new way of making “nanobodies”—tiny, artificial antibodies—from immunized llamas. Peter really threw himself body and soul into this project, even going as far as to personally visit the llama farm in the Berkshire Hills to make sure our llamas were well looked after and happy. After this, llamas may have become a bit of an obsession with him, and he even knows our llamas by their first names—Barbie, Blossom, and Marley. How Peter got on a first name-basis with llamas, I didn’t enquire.
Not content with working on a hugely impactful new way to make reagents that could become important diagnostics and therapeutics, he turned to use these reagents as a stepping-stone to developing a second powerful new methodology—this time, one to isolate single RNAs at different stages of their assembly. This new approach promises to open the door on whole new avenues of discovery for how exactly genes translate and regulate their information into encoding the proteins that build cells, and how this can go wrong in various diseases.
During his time in the laboratory, it became clear that Peter has a blend of talents that together add up to a first-class scientist. He is both intelligent and thoughtful, and he is an excellent experimentalist. Because of his dedication, his projects have grown into major pieces of work.
M.CHEM., University of Oxford
A Census of Human RNA-binding Proteins and Characterization of the DEDDh RNA Exonuclease NEF-SP in the 3′ End Maturation of 28S Ribosomal RNA
I apologize, Stefanie, for not being here in person, and I regret very much to miss this important celebration. Stefanie, I congratulate you on your well-deserved doctoral degree.
Stefanie was part of the Tri-Institutional training program in chemical biology, which she entered after obtaining a master’s in chemistry and molecular and cellular biology from Oxford University in England. Stefanie has always been an exceptional scholar, and she won prestigious fellowships, including the Oxford Domus Scholarship and the Boehringer Ingelheim Ph.D. fellowship.
Her thesis project was composed of two parts. First, she conducted a genome-wide census of human RNA-binding proteins, analyzing their evolution, abundance, and tissue-specific expression patterns. It was a large computational project but also required reading countless biochemical papers. She showed that RNA rules in cells, and that RNA-binding proteins represented the most abundant and numerous group of human gene products: over 1,500 proteins directly interacting with coding and/or non-coding RNAs and coordinating the expression of our approximately 20,000 genes. When her census was published, she received the following email: “You don’t know me, but I’m a Ph.D. student in Gene Yeo’s lab at UC San Diego. I’m preparing for my advancement to candidacy in a month and wanted to let you know that I can say for certain that your analysis, ‘A census of human RNA-binding proteins,’ is the single most helpful piece of literature I’ve encountered about RBPs.” This is the nicest compliment one can receive for a research publication.
Project number two was much more experimental. Stefanie had to select one of the proteins from her census for further study. It should have been an easy choice: with a complete table built from a complete genome, there could be no second thoughts about anything missing. But then she was faced with the difficult choice between the most conserved protein, the longest or the shortest, the most cell-type specific, or maybe the most abundant, or maybe one that has not been studied before. I vividly remember this period of discussion. At the end she picked an unstudied but conserved protein, an exoribonuclease with unusual high abundance in gonads. She started functional analysis in fruit flies guided by Hermann Steller’s group, which became her second home. To keep it short, she solved a long-standing puzzle of how the 3′ end of the largest ribosomal RNA was matured; yet her work raised a new question of why such a universal protein was so dramatically overexpressed in the testis and developing ovary, and required for normal gonad development and germ cell maintenance.
For Stefanie, the next adventure is already waiting as she is joining the three-year Ph.D.-to-M.D. program at Columbia University. We wish her well, and we will miss her.
presented by Michel C. Nussenzweig, Zanvil A. Cohn and Ralph M. Steinman Professor and head of the Laboratory of Molecular Immunology
A.B., Harvard College
Selection Dynamics in the Germinal Center during Antibody Affinity Maturation
Alex Gitlin hails from Mexico and Palo Alto, California, where he grew up in a family of engineers. Although Stanford was just next door, Alex left California for Harvard, where he majored in chemistry and physics and worked in Stuart Schreiber’s laboratory. Despite the background in chemistry, Alex became interested in problems in biology, and from Harvard Alex joined the Tri-Institutional M.D.-Ph.D. program. He came to my laboratory to work on the question of how antibodies develop affinity during the immune response.
Our immune systems have to be ready to respond to anything that nature comes up with, which of course is a nearly impossible task. So what our immune systems do is start with the best thing available, and then refine it to make it better. For antibodies, this means introducing mutations and then selecting the mutations that increase antibody affinity for the pathogen. The biological reaction responsible for the selection process is called affinity maturation, and how it happens has been a bit of a mystery. Alex came to the lab to study affinity maturation and devised a series of elegant experiments to try to solve this problem. He discovered that affinity maturation is an iterative process and defined how it is regulated. His work has been much appreciated by scientists in a number of different disciplines and led to his being awarded the prestigious Weintraub Award, which is a national prize for outstanding achievement during graduate studies.
I will miss having Alex barge into my office with his constant canine companion Noodle to spend time discussing yet another brilliant idea or debating the result of an interesting paper. Alex is completing his medical training at Cornell before moving on to residency and postdoctoral training.
B.A., Columbia University
Characterization of Skin Immune Reactions Induced by the Contact Sensitizer Diphencyprone in Healthy Volunteers and Metastatic Melanoma Patients
Nick joined the Tri-Institutional M.D.-Ph.D. program after undergraduate training at Columbia University. He had a demonstrated interest in cancer biology and thus joined my laboratory that is focused on skin diseases (skin is the organ with the greatest number of cancers in humans). Nick is my first student to complete a series of projects that spanned the full spectrum of translational research—often characterized as bench-to-bedside and back again.
His thesis project involved molecular characterization of immune reactions in patients with metastatic melanomas that were created to induce immune-mediated cancer regression, but his project extended into normal volunteers so that he could study differences in immune responses in normal individuals versus cancer patients. He also performed basic studies of cellular and molecular composition of melanomas and benign pigmented tumors versus normal skin using laser capture microdissection of skin sections coupled with genomic profiling. Nick was prolific as a writer and has at least 22 papers published or accepted for publication as of today from his graduate studies.
I wish Nick the best of luck in a future career likely to be centered on skin biology and skin disease when he completes his medical training.
B.A., Rutgers University
Plasticity of the Nuclear Pore Complex Revealed with Proteomics
It gives me a great deal of pleasure to introduce Zhanna Hakhverdyan today, another first-class example of the superb young scientists we are lucky to have making up our graduate program.
As well as her brilliance and thoughtfulness, Zhanna has a strong sense of dedication and perseverance. I discovered this early, when I found out that one of Zhanna’s hobbies is paragliding. It seems that the skills needed for paragliding are analogous to those needed to do research; that is, before you can soar into the sky, you need to do a lot of running along and falling flat on your face.
Zhanna’s fearlessness led her to work on two difficult and related projects. She was first instrumental in developing a straightforward method to isolate and preserve the dynamic macromolecular complexes in our cells, so they could be analyzed by a variety of techniques to learn how they’re put together and how they function.
She then used this technique to isolate and preserve the nuclear pore complex. This is among the largest complexes in the cell, responsible for transporting materials into and out of the cell’s nucleus. She used this as an example to learn how huge cellular machines such as the nuclear pore complex are assembled and maintained. For this, she has developed some of the most painstaking and careful assays to gather the data she needed.
In doing so, she has addressed crucial questions about the living cell: How are its component complexes formed? How are they repaired? Does our inability to replace or repair some of these complexes lead to issues, including diseases like cancer and aging?
In summary, Zhanna’s work has been a fascinating and highly impactful tour de force, from a very talented young researcher, and has given us some fundamental insights and raised some important new questions.
presented by Michel C. Nussenzweig, Zanvil A. Cohn and Ralph M. Steinman Professor and head of the Laboratory of Molecular Immunology
B.S., M.ENG., Cornell University
Dynamics of HIV-1 Infection and Therapy In Vivo
Joshua Horwitz grew up in sunny Los Angeles, California, and much to his parents’ dismay—and my great pleasure—he somehow lost his way and ended up exactly where both of his parents had met, here at Rockefeller on the opposite coast. Josh earned his undergraduate degree at Cornell, and then spent two years in Charlie Rice’s laboratory while deciding about graduate school. In Charlie’s lab, Josh became a card-carrying virologist and also contributed very significantly to the development of mouse models for hepatitis infection.
Josh’s work in virology led him to join my laboratory that was just beginning to work on the HIV problem. He was the first person in my lab with any virology background, and in addition to his own projects, he played a major role in helping to establish the virologic assays we now take for granted.
HIV-1 is a chronic disease affecting millions here and abroad, and although we can now control the disease, we have no vaccine and no cure. Our laboratory has been investigating rare individuals who fight the virus by producing antibodies that are broadly neutralizing. After we cloned the antibodies, Josh was one of the first to investigate their activity in animal models. He came up with and tested the idea of combining the antibodies with standard therapy in animal models to great effect. His success at the bench led us to perform clinical trials here at Rockefeller that are modeled on his earlier experiments. Josh has taken the lead on these trials and, like his mouse experiments, the clinical trials have also been successful and will soon be published.
Josh is a fabulous individual who will be very much missed by me and by his colleagues in the laboratory, not just for his scholarship, but also for his culinary skills at our annual barbeques. Josh will continue his training in virology and begin to learn structural biology in his postdoctoral fellowship at Harvard with Stephen Harrison.
A.B., Harvard College
Natural Products from Functional Screening of Soil Metagenomic Libraries
It is my great pleasure today to introduce to you Hala Iqbal. Hala was a student in our Tri-Institutional chemical biology program. She came to Rockefeller from Harvard University where she majored in biochemical sciences and worked in Kami Ahmad’s lab at Harvard Medical School. Before that she worked as a research technician at King Abdulaziz University in Jeddah, Saudi Arabia.
Hala’s graduate thesis work has focused primarily on developing improved methods for accessing new small molecules from uncultured bacteria. As you may know, the majority of medicines we use to treat ailments as diverse as cancer and bacterial infections are derived from molecules produced naturally by bacteria. Unfortunately, in recent years it has become clear that most bacteria present in nature are not readily grown in the laboratory, and therefore we cannot identify the additional, potentially useful, molecules they might produce. The Brady lab’s research program is primarily focused on developing and implementing new approaches for accessing biologically active small molecules from these bacteria that we cannot culture in the laboratory. Although it is not yet possible to easily culture these bacteria, it is possible to extract microbial DNA directly from the soil where these bacteria live and clone this DNA into cultured bacteria to allow us to characterize the molecules they encode.
During her time in the lab, Hala became particularly interested in expanding the diversity of model bacterial hosts available for use in the cloning and expression of DNA extracted from soil. She astutely realized that the best model systems available for studying DNA from uncultured bacteria were completely inadequate. Existing models were unlikely to express genes that encode for the production of new small molecules. Hala reasoned that it would be much better to identify new model bacteria that had naturally high propensities to make drug-like small molecules.
During her graduate studies, Hala established improved methods for building libraries of environmental DNA in cultured Streptomyces species. This project has been very challenging. Many other research groups have tried these experiments but failed. The key factor that resulted in her breakthrough method for library construction was a very careful attention to detail during the movement of large insert clones into her preferred model host. Her work is very exciting, as it has led to the discovery of the first truly novel complex metabolites to arise from functional screening of soil DNA libraries.
Hala has not only been a very active member of the Brady lab, but she has also participated in a number of social movements during her time in New York City. She is a through and through “99 percenter.” In fact, during the peak of the Occupy Wall Street movement, the lab was never sure whether she would be at work in the morning or if someone would be visiting her at Rikers Island in the afternoon. Hala is a remarkable and earnest young woman who challenges those around her to question and be more introspective. Her sincerity and honesty has contributed to making the Rockefeller community more socially aware, and for that I would like to thank her.
Hala’s options are numerous, and she is now faced with the difficulty of figuring out what to do next with her life. Whatever that is I am sure she will be successful, and I wish her the best in all of her future endeavors.
B.S., Binghamton University
CRISPR-CAS: From a Prokaryotic Immune System to a Genome Editing Tool
Wen is the first student that will graduate from my lab. He joined my group shortly after I arrived at Rockefeller and was fundamental to the launch of my laboratory. Over the past five and half years, Wen has distinguished himself as both a technological guru and a passionate, curiosity-driven scientist. Shortly after he came to my lab he had the vision to use CRISPR-Cas systems for genome editing, a technique that today is revolutionizing biomedicine. He thought of this before anybody else I know. Although I made the debatable decision of not encouraging him too much about this technology, he trusted his intuition and pioneered the development of microbial genome-editing techniques in my lab. At the same time, he followed his interest in basic science and elucidated how a special set of CRISPR-Cas systems defends the bacterial host by degrading viral transcripts. He has also built numerous genetic tools that he very generously shared with his labmates, facilitating their successes in their projects. Perhaps I can summarize all of Wen’s qualities just by telling you that in the five and half years that he has been in my lab, he has published 11 papers, five of them as first or co-first author. This sets the bar really high for my next students!
Having Wen around the lab has been a delightful experience, and I will very much miss working with him in the future.
When a lab is being born, the people working in it have its future in their hands. I could not have been luckier to have had Wen in the genesis of my research group.
presented by Marc Tessier-Lavigne on behalf of Cori Bargmann, Torsten N. Wiesel Professor and head of the Lulu and Anthony Wang Laboratory of Neural Circuits and Behavior
S.B., Massachusetts Institute of Technology
Aversive Olfactory Imprinting in Caenorhabditis elegans
In 1583, the Jesuit missionary Matteo Ricci was invited to Zhaoqing, China, to share his expertise as a mathematician and cartographer—perhaps the earliest formal scientific exchange between Chinese and European cultures. Ricci had prodigious memory skills, which enabled him to master written and spoken Chinese, and write the first European-Chinese dictionary. In the international scientific exchange that has continued since then, Rockefeller graduate Xin Jin has honored Matteo Ricci by providing new insight into the way that the brain forms memories.
The brains of humans and animals have a special ability to form memories during certain stages of life called critical periods. Human language development has a critical period; so do certain olfactory memories, like a salmon’s memory of the home stream to which it will return to spawn. Traumatic memories formed early in life are also particularly strong and long-lasting. Xin discovered that the tiny worm Caenorhabditis elegans has a critical period for traumatic olfactory learning, which causes it to form a lifelong aversion to bacteria that made it sick when it was young. She used this discovery to learn about the cellular and molecular mechanisms of long-term memory.
Xin discovered neurons and genes required for long-term memory, and delicately disentangled those that were only required for the long-term, and not for shorter-term memories. From these studies, she learned that different neurons are required to form the memory and to retrieve it. She showed that the link between these two groups of neurons is provided by an adrenaline-like learning molecule called tyramine, which is made by a learning neuron and sensed by a retrieval neuron that encodes the memory. The transient tyramine signal is converted into a long-term change in the retrieval circuit that maintains the preference.
Remarkably, the rules that Xin discovered in aversive olfactory imprinting in worms bear similarities to the rules for long-term memory in more complicated animals, including ourselves. From its origin, the brain has been a learning machine that enables individuals to generate appropriate behavioral responses based on their own experience. Xin Jin’s work shows that learning and memory are fundamental features of all nervous systems, derived from their earliest evolutionary history.
presented by Tarun Kapoor, Pels Family Professor and head of the Selma and Lawrence Ruben Laboratory of Chemistry and Cell Biology
B.S., University of Michigan
DrugTargetSeqR: A Genomics- and CRISPR/Cas9-based Method to Analyze Drug Mechanisms of Action
We continue to search for new therapies to treat diseases such as cancer. There are now several technologies to discover new candidate therapeutics—crucial first steps. However, sorting out how these potential therapies work in our cells remains very challenging. Without this understanding, the development of a new therapeutic agent can be severely restricted.
Corynn Kasap, an M.D.-Ph.D. student, has devised a powerful new approach, named DrugTargetSeqR, to address this major challenge in drug discovery. She sets up “crash tests” in the laboratory and systematically analyzes how the drug fails. She then combines genome editing, cell biology, and biochemistry to identify the genetic alterations that cause the drug to fail. These data can establish a “gold standard” proof for how the therapeutic agent works. Corynn applied DrugTargetSeqR to dissect how an anti-cancer agent that recently entered clinical trials works, revising the accepted hypothesis and providing valuable insights for further studies.
After completing her thesis research, Corynn is now back at medical school continuing her training. We all miss her and thank her for her numerous contributions to our research. We valued her advice and benefited from her deep understanding of topics that ranged from chemotherapy to exotic cocktails. We wish her all the best in continuing to bridge the gap between basic research and clinical work.
B.A., Columbia University
Regulatory Architecture of a Non-Apoptotic Cell Death Program in Caenorhabditis elegans
It is a great pleasure for me to be here today to participate in Maxime’s graduation. Maxime is a creative, innovative, and adventurous scientist, and it has been very exciting to see him through his discoveries. Maxime is an M.D.-Ph.D. student, and he joined the lab after spending some time doing human disease–related work. Our lab focuses on understanding basic principles of living things, and this doesn’t always turn out to have immediate medical relevance. However, Maxime, either because of perseverance or because he possesses a sixth sense, not only made strides to understand basic biology, but has informed us on normal and disease physiology.
It was immediately obvious from my first discussion with Maxime that he was deeply thoughtful, seeking overarching principles that govern biology. He joined my lab with a keen interest in understanding a mysterious cell death form we uncovered that plays a role in the development of the nematode C. elegans. At the time we also had morphological evidence that this process may be conserved across animals, and that seemed to have been enough to whet Maxime’s appetite. The lab had identified a number of candidate genes involved in the process, and Maxime began characterizing a set that appears to regulate gene expression. This was a difficult project, as mutations in these genes were lethal, and Maxime had to develop clever tricks to examine their functions.
He did so with aplomb, and sought constantly to extend the gene list, to reveal the principles behind this new cell death program. This persistence bore fruit. Not only did Maxime discover that a key cellular gene involved in protecting cells from stress actually had the opposite capacity to kill cells, but he generated reagents that allowed us, for the first time, to test the order of action of the various genes we identified—transforming our knowledge from a simple list to a logically organized gene network.
This work was recently published in the journal eLife, and a second manuscript has been submitted. Maxime also wrote a thorough review of the field of alternative cell death programs, which was published a couple of years ago.
Besides being the consummate scholar/scientist, Maxime was an amazing presence in the lab. He is a generous, kind, and collegial team player, and he helped to instill an atmosphere of openness and friendliness in the lab.
Maxime is back in medical school, where he is finishing his training. (We are lucky that he was allowed to take today off from his hospital duties!) He is now contemplating his career options, and it is my great hope that he will in some way be involved in academic research—he certainly has both the talent and temperament.
B.S., Duke University
Qualitative and Quantitative Regulation of the Leptin Gene In Vivo
Life is not always easy for Yi-Hsueh Lu. You see, Yi-Hsueh is outstanding at everything she does, and this often makes it difficult for her to choose from among the many different paths that she could pursue with precision, passion, and excellence. Yi-Hsueh hails from Taiwan, where she established herself as one of the most promising chemistry students nationwide. She was valedictorian of her high school class and was the top-scoring female in the nationwide chemistry olympics. She was then accepted into the chemistry program at Duke. There was, however, a small problem; she arrived in Durham speaking little English. She doesn’t recall knowing how to say much beyond “thank you” and “please.” Despite her steep language learning curve, Yi-Hsueh finished at the top of the class of chemistry majors and graduated summa cum laude.
She then entered the Rockefeller Ph.D. program and joined my laboratory, where she studied the molecular mechanisms that control the expression of the leptin gene. Leptin is a hormone made by fat tissue that regulates appetite and body weight. When fat mass expands, leptin levels increase, resulting in a decrease of appetite. By this mechanism, each individual’s weight can be stably maintained within a narrow range. Key to this mechanism is that when weight is gained and fat cells get larger, they in turn make more leptin. There is a mystery, however. How does the fat cell know it has accumulated more fat and gotten larger? To answer this, Yi-Hsueh set out to study the mechanisms that control leptin production with the aim of identifying the responsible DNA sequences and protein factors.
In her thesis, she identified the key DNA sequences that control leptin production and characterized one of the key protein factors that interact with these DNA elements. Thanks to her efforts, our laboratory is well on its way toward solving this mystery.
In addition to her inestimable academic skills, Yi-Hsueh takes great pride in everything she does, setting the highest standards for herself. She is also an extraordinary baker. The lab would often wait with great anticipation for the appearance of her latest creations that from time to time, and I kid you not, included recreated images from our papers in cake form.
After completing her thesis, Yi-Hsueh was unsettled about the direction in which she should move and asked for my advice. Unsure of what advice to give, I searched the web using the phrase, “What’s a good job for someone who’s good at everything?” It turns out this question has been addressed in a chat room, and some of the less-than-helpful suggestions include: become a consultant, do technical pre-sales, become a monk, become a pirate, and “I’ll give you a dollar if you’ll mow my lawn.”
Despite the abundance of these attractive options and others, Yi-Hsueh decided to enter Stony Brook Medical School after, not surprisingly, receiving near perfect scores on her MCATs. And to no one’s surprise she is excelling there, as she has everywhere else. Her plan is to become an orthopedist in an academic department.
It has been a privilege and pleasure to work with Yi-Hsueh. She has been a wonderful colleague, and everyone in the laboratory will miss her greatly, none more than me.
B.S. Tufts University
Tracking the In Vivo Dynamics of Antigenic Variation in the African Trypanosome
When students ask me for advice regarding the presentation of their thesis, I usually tell them to imagine presenting it as a before-and-after picture—that is, presenting clearly the state of knowledge in the field before one started, and the state of knowledge now, after the student’s contribution. That makes it very clear what their contribution has been.
Very frequently, that contribution is small, all things considered, and that’s fine. But sometimes, there really is a huge difference between the before and after, and a person’s thesis stands as a landmark in the field.
As a field, parasitologists think of Monica’s work as exactly such a landmark. Monica has devised and used tools to assess how quickly the African trypanosome, which is the parasite that causes sleeping sickness, changes its surface coat composition to evade the immune response. Her work upends a 100-year-old paradigm in the field. But that is only a side note. It also opens the door for mechanistic studies into how the parasite and the immune system interact and, ultimately, for more general studies into how any pathogen interacts with the antibody response.
Monica has garnered a number of professional awards already, but that too is a side note. More important is the respect that she commands in our field. Her thesis defense was attended by a number of parasitology faculty, some of whom traveled from Boston just to hear her talk. She has given invited talks at meetings large and small, and taught courses both locally (e.g., Hunter) and at faraway places (like Ghana).
Most recently, Monica was nominated by Johns Hopkins for an Early Independence Award, given by the NIH Director’s office, as an inducement to universities around the country to hire the most promising young scientists, and allow them to start their own shop right out of graduate school.
B.S., The University of Tokyo
Genetic Dissection of Neural Circuits Underlying Value-based Decision-making
Hiro Nakayama was a superb student at The University of Tokyo, and he came to Rockefeller with a great deal of experience in modern molecular genetics. In my first conversations with Hiro, I was impressed with the depth of his knowledge and his quick mind. So when he decided to join the lab, I knew he would be the kind of person to forge a path into the scientific unknown. I just wasn’t sure which part of the universe he would choose to explore. It has been a true pleasure to watch, and provide a touch of guidance here and there, as Hiro took his journey into the unknown.
As I expected, Hiro chose to address a very difficult problem: identification of brain circuitry involved in complex decision-making. Although a great deal is known regarding innate behaviors in many species, most decisions that we encounter in daily life have predictable yet uncertain outcomes. If the environment changes, so must our actions. The processes involved in this sort of value-based decision-making had already been defined as action initiation, action selection, and learning. When Hiro suggested that we try to dissect the brain circuitry involved in each of these phases of decision-making, I thought, “Why not? Given our facility with the analysis of circuits controlling other aspects of murine behavior, this should be relatively straightforward.” I never stopped to consider just how difficult it might be to assay these processes in a laboratory mouse.
Thankfully, Hiro is intelligent, determined, and independent. With a great deal of ingenuity and effort, he devised a behavioral scheme in which the most talented of these small animals could learn to adjust their behavior based on the probability of reward, and he showed that this task could reveal each aspect of value-based learning. Hiro has demonstrated, for example, that obsessive or compulsive behaviors are defects in action initiation, and that the brain areas and circuitry required for this aspect of behavior are distinct from those involved in action selection or learning. This is a significant accomplishment because it allows one to identify cellular and molecular mechanisms that play key roles in even these very advanced cognitive functions. And it is all due to the talent and dedication of this impressive young man.
In closing, I would like to thank Hiro for educating me during his journey, and for the intellectual and practical generosity he has displayed in all aspects of laboratory life.
presented by Sohail Tavazoie, Leon Hess Associate Professor and head of the Elizabeth and Vincent Meyer Laboratory of Systems Cancer Biology
B.A., University of California, Berkeley
Characterization of Mechanisms That Mediate Cancer Metastatic Colonization
The pace of life was too slow for Zander in California, where he had spent most of his life before starting the Tri-Institutional M.D.-Ph.D. program.
Consistent with this, Zander took on two projects for his thesis work. In the first project, he tested the effects that shutting down each of 15,000 different genes has on the ability of colon cancer cells to spread to and grow in the livers of mice. This allowed him to identify many unexpected genes involved in this deadly process. He then focused on one such gene that is normally expressed in liver cells but turned on, as Zander found, in aggressive colon cancer cells that spread to the liver. He showed that this gene impedes the complete breakdown of the sugar glucose in cancer cells, allowing the atoms of glucose to instead be converted to an antioxidant system that allows cancer cells to survive the damage caused by free radicals generated within the liver.
In his second project, he chose to study how individual cancer cells within a tumor are able to become so different from one another. Such diversity or heterogeneity is a major clinical problem—enabling rare cancer cells within human tumors to resist chemotherapies. Zander discovered rare cells within breast cancer that produce progeny that are very different from each other in the repertoire of genes they have turned on. These rare “diversity-generating cells” were more resistant to chemotherapeutics and better at forming metastatic colonies than other cancer cells. Zander wished to understand how these rare cells produce such diverse daughter cells. He found that the differences between their daughter cells was not caused by different mutations being inherited by individual progeny. Rather, Zander showed that these clever cells achieve such diversification by having faulty machinery for zipping together pieces of RNA messages that code for proteins, leading to the production of gene products that are diverse in their nature and abundances.
Zander has since returned to medical school to complete his clinical training before starting a research-track residency program. There is no challenge big enough for Zander, whether it be competing in triathlons, teaching himself multiple computer languages for analyzing biological data, or substituting for his professor as a speaker at conferences. Zander, I fully expect you to keep pursuing your triathlons both in life and in science.
B.S., Cornell University
Retrograde Activation of a Somatic Transcriptional Program Regulates Distal Axon Degeneration
We’re fortunate, at Rockefeller and in my lab, to have benefitted from the three dimensions of Jason Pitts: Jason the scientist, Jason the colleague, and Jason the citizen. He excels in all three.
A star student, Jason graduated from Cornell with a top-five GPA, and had multiple research experiences, including an internship at the biotechnology company Regeneron. But he was equally focused on community engagement and was named a top-20 graduating senior-in-service for his work on environmental and other causes and for mentoring students. After graduation, he joined Teach for America and taught science in underprivileged schools. But his love of research led him to return to Regeneron as a research associate, and then to join our Ph.D. program.
Here, Jason became fascinated with the mechanisms that control the degeneration of nerve cells, specifically their long thin extensions called axons, through which they connect with other nerve cells. Axon degeneration is a hallmark of neurodegenerative diseases like Alzheimer’s, and Jason wanted to understand the degeneration process at a molecular level, a prerequisite to developing therapies.
A good place to start with a Ph.D. project is to test what seems like an obvious prediction, to see if it either holds up or takes one in a new direction. In Jason’s case, the prediction both held up and took him in a new direction.
Jason knew that axon degeneration was controlled by an enzymatic cascade controlled by a protein called Bax, and the simple prediction was that one or more of the known activators of Bax would be required for the degeneration. He found that one of these activators is indeed required, but then, to his and our surprise, he found that it is not present in the axons that degenerate—instead, it is in the nerve cell body.
Many would have glossed over this seeming discrepancy, but Jason doggedly pursued it, leading to beautiful and unexpected findings published last March in Cell on how the nerve cell body remotely controls the degeneration of nerve fibers.
What stood out in Jason from the start wasn’t just his skill at the bench but also his scientific maturity. He is thoughtful, rigorous, reads widely, and thinks deeply, especially about paradoxical findings—the source of his success.
At Rockefeller, Jason also continued to mentor high school students and served as president of the Tri-Institutional Consulting Club, reflecting his entrepreneurial bent, which also led him upon graduation to join the health care practice of consulting firm McKinsey & Company. In recognition of his combination of scientific accomplishment and community engagement, Jason was awarded the prestigious David Rockefeller Fellowship.
Beyond all that, Jason is a very big personality, engaging, warm, supportive, with a wry sense of humor and an almost Seinfeldian ability to capture and describe the absurdities of everyday lab life. He loves to discuss and debate just about any topic, from politics and financials to television and personalities.
Perhaps his most unique impact on our lab was starting a lab fantasy football league. Attesting to his powers of persuasion, he was able to recruit even the most unlikely lab members, including those from abroad who thought football was played with a spherical ball.
I have no doubt that those powers will stand him in good stead in his new profession, and help him multiply further what I know will be a wonderful and profound impact on the world.
B.S., University of Rochester
Metabolic Regulation of Transcription through Differential Histone Acylation: Regulation and Function of Histone Crotonylation
Not every graduate student enjoys having editors from high-profile science journals describe their work as being “out of this world” or “another classic,” but Ben’s first paper in my lab triggered these words in a preview entitled, “Greetings from Planet Croton” (footnote, not Planet Krypton). Vincent Allfrey, a former Rockefeller head of lab who discovered a similar, but different, chemical modification of histone proteins 50 years earlier, might well have called Ben’s work “stellar.” Ben’s next orbit will take him to Rick Young’s lab at MIT, where he will no doubt enhance, or super-enhance, his career. This is because Ben is not only a super-scientist but also a super-man. I have no doubt that Ben will be a bright star in the Young lab, but I also know that he will remain grounded. In sum, Ben is the “real ticket” on planet Earth and beyond. “May the force be with you, Ben!”
presented by Sohail Tavazoie, Leon Hess Associate Professor and head of the Elizabeth and Vincent Meyer Laboratory of Systems Cancer Biology
B.S., Yale University
Protein Regulators of Phosphoinositides as Promoters of Cancer Metastasis
Caitlin hails from the farmlands of Indiana. Her proud biologist parents recognized her early knack for science and fostered this by exposing her to the lab as a young teenager. From there, she went on to do chemistry and chemical biology research, earning the top chemistry award at Yale.
In my lab, Caitlin studied the mechanisms by which cancer cells spread—or metastasize—to distal organs and how they form colonies in those organs. Caitlin found that in order to metastasize, breast cancer cells must turn on a number of genes involved in the binding or breakdown of certain types of decorated fat molecules within our cells called phosphoinositides. Caitlin found that one of her genes made a protein that binds a specific phosphoinositide that is present on an enclosed compartment within our cells called the Golgi apparatus. The Golgi contains proteins destined to be released outside the cell. She found that her protein, by binding to the phosphoinositide posts on the Golgi, could recruit other proteins to the Golgi that pinch off small packets that contain proteins. These packets are then released outside the cell, enabling cancer cells to chew and travel through tissue and to send recruitment signals to blood vessels. Caitlin found that two of her other genes broke down another phosphoinositide in the cell, which is present in the plasma membrane coat that surrounds the cell. She found that this phosphoinositide normally binds to and inhibits a protein that allows cells to move. The breakdown of this phosphoinositide in breast cancer cells frees this protein, allowing cells to move and metastasize. Caitlin has found that women whose breast cancers have higher amounts of these proteins are more likely to develop metastases.
Given her interest in the intersection of chemistry, biology, and human disease, Caitlin now advises biotech and pharmaceutical companies on research and development as an associate at McKinsey & Company. Caitlin has numerous key traits that will assure her continued success. She is incredibly smart, classy, rigorous, and articulate; but she also knows how to party hard. I fully expect that she will play an important role in guiding the development of our future therapies. Congrats, Caitlin.
presented by Sanford M. Simon, professor and head of the Laboratory of Cellular Biophysics, on behalf of himself and Charles M. Rice, Maurice R. and Corinne P. Greenberg Professor in Virology and head of the Laboratory of Virology and Infectious Disease
B.S., Yale University
Analysis of Hepatocyte Secretion Pathways: A Case Study on Hepatic Apolipoproteins, Serum Albumin, and Hepatitis C Virus
Born in Romania, this promising young cell biologist, after his initial schooling, was encouraged, based on his interests in science, to come to the United States for further training. His career has been focused on the internal life of the cell. Most of his studies have focused on the pathways within the cell—those that crisscross every possible compartment. Using a mixture of experimental approaches and tools, he found ways to dissect these intracellular pathways. His work, here at Rockefeller, brought insight into what otherwise seemed a chaotic mess. After Rockefeller is a move to New Haven. But enough about George Palade.
Constantin Takacs, also known as Nick, was born in Romania. This promising young cell biologist, after his initial schooling, was encouraged, based on his interests in science, to come to the United States for further training. His career has been focused on the internal life of the cell. Most of his studies have focused on the pathways within the cell—those that crisscross every possible compartment. Using a mixture of experimental approaches and tools, he found ways to dissect these intracellular pathways. His work, here at Rockefeller, brought insight into what otherwise seemed a chaotic mess. After Rockefeller is a move to New Haven.
Born in Romania, close to the Black Sea
He came to New York as a devotee
Of one of our best, Nobel inductee
A fellow landsman, Doc George Palade
Like George his first love, cell biology
He chose to study the assembly
Of a grim virus, Hepatitis C
To understand it meant he had to see
So he made fusions, all to GFP
And blocked with mutants of Rab-GTP
Informing release of the HCV
Now a postdoc at Yale University
Studying Borrelia burgdorferi
President, chairman and all honoree,
Here is Nick Takacs, for his Ph.D.
presented by Tom Muir
B.S., Peking University
Reconstitution and Mechanistic Studies on the Staphylococcal agr Quorum Sensing Circuit
Boyuan Wang graduated with highest honors in chemistry from Peking University. While in Beijing, Boyuan carried out undergraduate research with the eminent structural biologist Yigong Shi and gained experience in protein biochemistry and x-ray crystallography. Yigong was quite effusive in his praise for Boyuan, noting that he was the strongest undergraduate student he had ever had in his lab. Such a glowing recommendation led me to aggressively recruit Boyuan into my lab. I should say that this was despite his having a slightly menacing, even sinister, appearance. The first day Boyuan walked into my lab, he had hair down to his waist and sported a long pencil-thin moustache. This general impression was not helped by his highly idiosyncratic approach to verbal and written communication. I particularly remember one early example of what would eventually be known as “Boyuanisms,” where he wrote the following in a birthday card the lab gave me, I think for my 40th, and I quote: “Tom, have a great birthday, it may be your last.”
Anyway, we got him a haircut and a shave and sent him off to study how virulence is regulated in the commensal human pathogen, S. aureus, long a focus of my lab. To cut right to it, Boyuan made a very important contribution to this area, one that has rewritten the rules for how we study this system and that has truly exciting implications for our understanding of bacterial two-component signaling in general. In brief, Boyuan succeeded in reconstituting in a test tube the entire quorum-sensing circuit that regulates Staph virulence from purified components—the first time this has been done for any such system. This is a tour-de-force achievement since nearly all of the components are integral membrane proteins! Using this reconstituted system, Boyuan was able to determine the thermodynamic driving force for the biosynthesis of the high-energy peptide pheromone that regulates the virulence quorum-sensing circuit. In the process, Boyuan uncovered, and then verified using clever genetic approaches, a hitherto unappreciated link between protein turnover and quorum sensing. Boyuan also deduced the mechanical motions that accompany natural agonism or antagonism of the key receptor histidine kinase protein by the pheromones. These studies provide the first view of the molecular motions triggered by pheromone binding in an intact membrane-bound RHK in a two-component signaling system. His work also explained how and why Staph virulence is turned off during times of energy stress, and why peptide-sensing RHKs such as AgrC are restricted to Gram-positive bacteria. Altogether, his thesis represents a remarkable body of work, and he has given the community a powerful experimental system that will keep us busy for years to come.
Those early impressions notwithstanding, Boyuan (who was my last Rockefeller student) became a respected and much-loved member of my lab. We will certainly miss the “Boyuanisms,” which endearingly blend Eastern Confucian philosophy with Western Yogi Berra philosophy. Boyuan is currently carrying out postdoctoral studies in Mike Laub’s lab at MIT, where he is pursuing his interests in the evolution of cellular signaling systems.
presented by Howard C. Hang, Richard E. Salomon Family Associate Professor and head of the Laboratory of Chemical Biology and Microbial Pathogenesis
B.S., Tsinghua University
Chemical Tools for Exploring IFITM3 S-palmitoylation and Mechanism
Good afternoon to the family and friends of the 2016 graduates. I’m pleased to celebrate Xiaoqiu Yuan’s graduation and welcome his family today.
Xiaoqiu came to Rockefeller after completing his undergraduate studies at Tsinghua University in Beijing, one of the leading universities in China. He had graduated with honors and already coauthored several research papers when he joined Rockefeller, and I was thrilled we were able to recruit him into our Tri-Institutional chemical biology program and pleased to have him join my laboratory.
My laboratory is broadly interested in how we defend ourselves against harmful viruses and bacteria, and how these pathogens cause disease. To do so, we develop new chemical methods to investigate complex biochemical interactions between our cells and these microbial pathogens. Xiaoqiu’s thesis work played an important role in helping us understand how a crucial protein of the innate immune system, IFITM3, prevents pathogens such as influenza virus from entering our cells. In humans, mutations in IFITM3 have been recently shown to increase the morbidity and mortality associated with seasonal influenza virus infection. Unfortunately, the mechanisms by which IFITM3 prevents virus entry are unclear. By developing precise imaging and protein cross-linking methods for IFITM3 in collaboration with other members of the lab, Xiaoqiu’s thesis work has helped demonstrate that IFITM3 directly engulfs incoming virus particles and targets them for destruction. Xiaoqiu’s thesis helped reveal an important means by which our innate immune system prevents virus infection and should help us design new antiviral therapeutics in the future. I would like to thank him for his hard work and dedication to this exciting project in the lab, and I wish him the best in the future.
Seven students graduated in absentia: Sergio Botero, Debjani Chakraborty, Josefina del Marmol, Lisa Fish, Jia Min Loo, Ryan Quin Notti, and Andrej Ondračka.