Students Brief Senate, FDA, & Personalized Medicine Coalition

By Nonie Arora

Duke students and faculty brief Senate staffers, Pictured left to right: Allison Dorogi, Nonie Arora, Robert Cook-Deegan, Samantha Phillips, Jenny Zhao, Elisa Berson. Credit: Robert Cook-Deegan

Duke students and faculty brief Senate staffers, Pictured left to right: Allison Dorogi, Nonie Arora, Robert Cook-Deegan, Samantha Phillips, Jenny Zhao, Elisa Berson. Credit: Robert Cook-Deegan

The week of April 13, at the height of cherry blossom season, Duke students traveled to Washington, D.C. to brief senior staff members of the Senate, Food and Drug Administration (FDA), and the Personalized Medicine Coalition (PMC). Over the spring semester, five students in the Genome Sciences & Policy Capstone course (including myself) studied the regulatory framework of laboratory developed tests (LDTs).

LDTs are tests developed for use in a single laboratory. The clinical laboratories that develop LDTs are considered to be medical device manufacturers and are therefore subject to FDA jurisdiction. The FDA exercises “enforcement discretion” over LDTs, which means they choose when to regulate these tests.

Duke students in Washington, D.C. Credit: Robert Cook-Deegan

Duke students in Washington, D.C. Credit: Robert Cook-Deegan

Under the supervision of Duke professor Robert Cook-Deegan, we dove into five case studies regarding different types of LDT tests.

The case study that I focused on was the differential regulation of two tests used for breast cancer patients. The two tests, MammaPrint and Oncotype Dx are regulated differently even though both aim to help doctors understand when patients should have follow-up chemotherapy after surgery. The company that markets MammaPrint, Agendia, chose to obtain FDA clearance for their test, but the company behind Oncotype Dx, Genomic Health, chose against it. Surprisingly, this decision did not substantially increase the number of patients who receive Oncotype Dx relative to MammaPrint.

Furthermore, the two tests do not always produce the same result, according to a research study. Several key question remain, such as:

  1. Is the FDA-regulated test more accurate?
  2. Does the more accurate test get more market share? Does FDA approval make a difference?
  3. How should these tests, and ones like them, be regulated to reduce harm to patients?

The students hope that their case studies will serve as illuminating examples for stakeholders and help guide the conversation regarding federal regulation of LDTs.

 

Joining the Team: Anika Ayyar

By Anika Ayyar

Hi! My name is Anika Ayyar and I am currently a Duke freshman. I grew up in warm, lovely Saratoga, California, where I picked up my love for long distance running, organic farming, and the ocean. When I was 14, I moved to across the country to Exeter, New Hampshire to attend a boarding high school, and here I developed a deep interest in biology and medicine. Exeter’s frost and snow were far from the Cali weather I was used to, but my fascinating classes, caring teachers, and wonderful friends more than made up for the cold.

My sophomore semester abroad program at The Island School, on an island called Eleuthera in the Bahamas, certainly provided a welcome change to East coast weather as well. At the Island School I studied marine biology and environmental conservation, earned my SCUBA certification, and spent time with the local middle schoolers refurbishing a library and stocking it with books. I was also part of a research team that studied species richness and diversity on patch reefs off the coast of the island.

Dissecting fruit fly larvae under the microscope at the Seung Kim Lab at Stanford.

Dissecting fruit fly larvae under the microscope at the Seung Kim Lab at Stanford.

My marine research stint in the Bahamas drove me to join a molecular biology lab the summer after I returned; a decision that transformed my passion for science. At the Seung Kim Lab for Pancreas Development at Stanford University, I worked on a project that used binary systems to study the expression of specific genes related to insulin production and diabetes in fruit flies. I soon grew so immersed in my work that I wanted to share the project with others in the scientific community at Exeter, and my research mentors, biology professors, and I worked to create a novel course where other students could take part in the project as well. This unique research collaboration, called the “StanEx” project, proved to be a huge success, allowing other students to experience the trials and joys of real-world research while also generating Drosophila fly strains that were useful to the larger scientific community. If you are interested in reading more, check out my website about the StanEx project!

While my current interests lie more at the intersection of technology and medicine, I hope to be involved in equally compelling and fulfilling research here at Duke. Hearing about the various projects my professors are working on, and reading about the discoveries made in labs on campus, I have no doubt that this will be the case.

Outside of classes and research, I enjoy being part of the Duke Debate team, and Lady Blue, one of Duke’s all-female a cappella groups. You can often find me on the trails on a long run, or trying out a new dessert recipe I found on Pinterest. I am beyond excited to be a part of the research blogging team, and can’t wait to start attending talks and interviewing research personalities whose stories I can share with our readers!

Is the “Wizarding Gene” Dominant or Recessive?

By Nonie Arora

Dr. Spana explains the wizarding gene to eager students. Credit: Arnab Chatterjee

Dr. Spana explains the wizarding gene to eager students. Credit: Arnab Chatterjee

How do recessive alleles and the world of Harry Potter connect? Some students found out last week from Dr. Eric Spana, a faculty member in the Biology department.

He started off by explaining how a mutation in the MC1R (melanocortin 1 receptor) gene causes red hair in humans because of the way it affects a pigment called eumelanin. He added that MC1R is a recessive gene, and showed a pedigree of the Weasley family tree. Professor Spana pointed out that J. K. Rowling had gotten the genetics right. The Weasley clan has red hair and so does Harry’s daughter Lily. This makes sense because Harry must have a recessive allele for red hair since his mother, also Lily, had red hair. Whether this is intentional or just fortuitous casting, who can really say?

He then explained some potential retroactive genetic “crosses” that could be done to determine whether the “wizarding gene” was dominant or recessive. As a quick refresher, recessive alleles require both the mom and dad to pass on the same genetic sequence to the child for the condition to occur, while dominant alleles require only one copy.

According to Professor Spana, Step 1 was to check whether a witch and a muggle who mated ould produce a wizard. Indeed, this is possible, and the evidence is Seamus Finnigan, a half-blood wizard. Due to these results, the gene could still be dominant or recessive.

In Step 2, he explained, you mate a wizard to someone who could not have the wizarding gene. Fridwulfa, the giantess, married Mr. Hagrid, a wizard, to produce our beloved Rubeus Hagrid, who was a wizard. Since giants cannot have the wizarding gene, but Hagrid is still a wizard, the wizarding gene must be dominant!

Crowd of students ask provocative questions about squibs and recessive vs. dominant inheritance. Credit: Arnab Chatterjee

Crowd of students ask provocative questions about squibs and recessive vs. dominant inheritance. Credit: Arnab Chatterjee

You’ll have to stop by Dr. Spana’s office to ask him more about where muggle-borns and squibs come from. There’s a few different genetic explanations, and I encourage you to do some thinking and exploration.

Outside of his work on the genetics of Harry Potter, Dr. Spana also researches and teaches Genetics & Developmental Biology at Duke.

iGEM: An Exciting Way to Merge Biology and Engineering

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Duke iGEM 2014 team with faculty advisors Nick Buchler, front left, and Charlie Gersbach, front right. Mike is behind Dr. Gersbach.

by Anika Radiya-Dixit

The International Genetically Engineered Machine (iGEM) competition is dedicated to education for students interested in the advancement of synthetic biology, in other words, taking engineering principles and applying them to natural sciences like biology.

Students in the competition explored using a gene or series of genes from E.coli bacteria to create biological devices for applications such as dissolving plastic or filtering water. In November 2014, the Duke iGEM team took part in the annual competition in Boston, proudly leaving with a gold medal on their work in 3D printing technology and DNA synthesis protocol.

This week, I contacted the iGEM team and had the opportunity to talk with one of the members, Mike Zhu, about his experience in the competition. Mike is currently a junior from Northern California studying Biomedical Engineering and Computer Science. He is enthusiastic about researching how biology and computer science interact, and is conducting research with Dr. John Reif on DNA technology. Mike is also involved with the Chinese Dance team, and enjoys cooking, eating, and sleeping. Below is an edited transcript of the interview.

 

How did you get interested in your project topic?

We wanted to build a binary response platform that uses logic gates or on-off switches in E. coli to make it easier to regulate genes. We used the CRISPr/Cas9 system that allows for specific targeting of any gene, and that enables synthetic biologists to create more complex gene circuits. Personally, I was interested in developing an infrastructure that allows engineering concepts to be applied to cells, such as creating code that allows cells to do arithmetic so they can keep track of the cells around them. I think applications like these open doors to a really cool field.

 

What was your best moment during the Boston competition?

The competition was four days long, but we had to come back early due to work and midterms, so we missed the last dance and dinner, but overall it was a lot of fun. There were multiple workshops and talks, and the one that stood out most to me was one by someone from MIT who designed a ‘biocompiler’ to take code specifying the behavior of cells [1]. It was essentially like creating a programming language for cells, and I thought that was really cool.

Tell me about someone interesting you met.

There were a lot of people from the industry who came by and asked about our project, and some of them wanted to recruit us for internships. At the competition, there were people from all over the world, and I liked best that they were friendly and genuinely interested in developing tools to work with cells.

 

Experiment work in a biology lab.

What was the hardest or most frustrating part of working on the project?

Lab work is always the most frustrating because you’re dealing with microscopic parts – things easily go wrong and it’s difficult to debug, so we ended up repeating the experiments over and over to work through it.

 Are you continuing with  the competition this year?

I’m working for Caribou Biosciences in Berkeley, one of the companies that wanted to recruit us during the competition. They are developing tech similar to what we did, so I enjoy that.

It’s a good thing to get into bioengineering. People are trying to make  tech cheaper and easier so we can potentially do experiments in our garage – sort of like ‘biohacking’ or do-it-yourself-biology – and this still has a long way to go, but it’s really cool.

MikeZhu

Mike Zhu, wearing the competition shirt.

Now that you’ve gone through the competition, what would you like to say to future students who are interested in applying their knowledge of BME  learned at Duke?

There are a lot of clubs at Duke that are project-based, but these are primarily in Electrical Engineering or Mechanical Engineering, so the iGEM competition is – as far as I know – the only project-based club for students more interested in biology. You get funding, lab space, and mentors with a team of undergraduates who can work on a project themselves. It’s pretty rare for both PIs [Principal Investigators] to give the undergrads free reign to work on what they want, especially compared to volunteering in a lab. You also get a chance to present your project and meet up with other people, and you’re exposed to topics most students get to experience only in senior year classes. Overall, the club is a great way to be introduced to cutting edge research, and it’s a good opportunity for freshman to find out what’s going on in BME.

Learn More about the Duke iGEM team and project

[1] More about MIT’s Biocomplier can be read at http://web.mit.edu/jakebeal/www/Talks/IBE12-BioCompiler-Feedback-abstract.txt.

 

Pain-Sensing Gene Named for Rocky

Guest Post By Sheena Faherty, graduate student in Biology

How do our neurons discriminate between a punch to the face or a kiss on the cheek? Between something potentially harmful, and something pleasant?

A new study published this week in Current Biology offers an answer by describing a previously uncharacterized gene required for pain sensing.

This work comes out of Dan Tracey’s lab at the Duke Institute for Brain Sciences. They named the gene balboa in honor of fictional prizefighter Rocky Balboa and his iconic immunity to pain.

Stallone as Rocky

Float like a drosophila, sting like a …oh, never mind.

The researchers found that the balboa gene is only active in pain-sensing neurons and is required for detection of painful touch responses. Without it, neurons can’t distinguish between something harmful and something pleasant.

Does the ultimate prize of naming of the gene inspire any boxing matches between lab mates?

“In the fly community, we are allowed to have these creative gene names, so discussions about the decision on naming are more fun than argumentative,” Tracey says.

Tracey’s lab is concerned with sensory neurobiology, the study of how neurons transform cues from the surrounding environment to signals that can be interpreted by the brain. Ultimately, the lab group hopes to identify the underlying molecular mechanisms that are involved in our sense of touch.

Pugilistic fly artwork designed by Jason Wu, a neurobiology graduate student in Jorg Grandl's lab

Pugilistic fly artwork designed by Jason Wu, a neurobiology graduate student in Jorg Grandl’s lab

“It’s unclear what happens during that moment of touch sensation when sensory neurons detect and convert a touch stimulus into a nerve impulse,” said graduate student Stephanie Mauthner, who is the lead author on the Rocky paper. “It’s also ambiguous how nerves are capable of discriminating the threshold of touch intensity.”

Although the fruit fly has a relatively simple central nervous system, Tracey’s group uses it as model because it has many of the same neural circuits that the human brain has.

“[Our goal was to figure out] what molecular components are required for pain neurons to detect harsh touch responses and what is the mechanism for performing this task,” Mauthner said.

Using fluorescent cells, their study also shows that balboa interacts with another protein of the same family named pickpocket. They’re hopeful that this gene duo can be a potential target for pain medications that could discriminate between different sites of pain throughout the body.

Pain relievers such as aspirin or ibuprofen work broadly throughout the whole body—with no discrimination to where the pain is actually occurring. But, by working towards the exact molecular mechanism of pain signaling, genes like balboa and pickpocket are potential candidates for more targeted therapeutics.

Grad student Stephanie Mauthner, hangs out with one of her many vials of flies (courtesy of Stephanie Mauthner)

Grad student Stephanie Mauthner hangs out with one of her many vials of flies (courtesy of Stephanie Mauthner)

CITATION: “Balboa Binds to Pickpocket In Vivo and Is Required for Mechanical Nociception in Drosophila Larvae,” Stephanie E. Mauthner, Richard Y. Hwang, Amanda H. Lewis, Qi Xiao, Asako Tsubouchi, Yu Wang, Ken Honjo, J.H. Pate Skene, Jörg Grandl, W. Daniel Tracey Jr. Current Biology, Dec. 15, 2014. DOI: http://dx.doi.org/10.1016/j.cub.2014.10.038

Pursuit Of Bird Brains Takes Researchers Back 66 Million Years

A handful of bird species survived the K-T extinction. Chicken genomes have changed the least since that terrible day.

A handful of bird species survived the K-T extinction. Chicken genomes have changed the least since that terrible day.

By Karl Leif Bates

In the beginning was the Chicken. Or something quite like it.

At that moment 66 million years ago when an asteroid impact caused the devastating Cretaceous–Tertiary (K-T) extinction, a handful of bird-like dinosaur species somehow managed to survive.

The cataclysm and its ensuing climate change wiped out much of Earth’s life and brought the dinosaurs’ 160-million-year reign to an end.

But this week, the genomes of modern birds are telling us that a few resourceful survivors somehow scratched out a living, reproduced (of course), and put forth heirs that evolved to adapt into all the ecological niches left vacant by the mass extinction. From that close call, birds blossomed into the more than 10,000 spectacularly diverse species we know today.

Erich Jarvis

Erich Jarvis

Not all birds are descended from chickens, but it’s true that chicken genes have diverged the least from the dinosaur ancestors, says Erich Jarvis, an associate professor of neurobiology in the Duke Medical School and Howard Hughes Medical Institute Investigator.

He’s one of the leaders on a gigantic release of scientific data and papers that tells the story of the plucky K-T survivors and their descendants, redrawing many parts of the bird family tree.

From giant, flightless ostriches to tiny, miraculous hummingbirds, the descendants of those proto-birds now rule over the skies, the forests, the cliff-faces and prairies and even under water. While other birds were learning to reproduce songs and sounds, hover to drink nectar, dive on prey at 230 miles per hour, run across the land at 40 miles per hour, migrate from pole to pole or spend months at sea out of sight of land, the chickens just abided, apparently.

terror birds

Sweet little chickadees had a very big, very scary cousin. “Parrots and songbirds and hawks and eagles had a common ancestor that was an apex predator,” Erich Jarvis says. “We think it was related to these giant ‘terror birds’ that lived in the South American continent millions of years ago.”

The new analyses released this week are based on complete-genome sequencing done mostly at BGI (formerly Beijing Genomics Institute). and DNA samples prepared mostly at Duke. The budgerigar, a parrot, was sequenced at Duke. There are 29 papers in this first release, but many more will tumble out for years to come.

“In the past, people have been using 1, 2, up to 20 genes, to try to infer species relationships over the last 100 million years or so,” Jarvis says. But whole-genome analysis drew a somewhat different tree and yielded important new insights.

More than 200 researchers at 80 institutions dove into this sea of big data like so many cormorants and pelicans, coming up with new insights about how flight developed and was lost several times, how penguins learned to be cold and wet and fly underwater and how color vision and bright plumage co-evolved.

The birds’ genomes were found to be pared down to eliminate repetitive sequences of DNA, but yet to still hold microchromosomal structures that link them to the dinosaurs and crocodiles.

The sequencing of still more birds continues apace as the Jarvis lab at Duke does most of the sample preparation to turn specimens of bird flesh into purified DNA for whole-genome sequencing at BGI. (More after the movie!)

As one of three ring-leaders for this massive effort, Erich Jarvis is on 20 papers in this first set of findings. Eight of those concern the development of song learning and speech, but the other ones are pretty cool too:

Evidence for a single loss of mineralized teeth in the common avian ancestor. Robert W. Meredith, et al. Science. Instead of teeth, modern birds have a horny beak to grab and a muscular gizzard to “chew” their food. This analysis shows birds lost the use of five genes related to making enamel and dentin just once about 116 million years ago.

Complex evolutionary trajectories of sex chromosomes across bird taxa. Qi Zhou, et al. Science. The chromosomes that determine sex in birds, the W and the Z, have a very complex history and more active genes than had been expected. They may hold the secret to why some birds have wildly different male and female forms.

Three crocodilians genomes reveal ancestral patterns of evolution among archosaurs. Richard E Green, et al Science. Three members of the crocodile lineage were sequenced revealing ‘an exceptionally slow rate of genome evolution’ and a reconstruction of a partial genome of the common ancestor to all crocs, birds, and dinosaurs.

Evidence for GC-biased gene conversion as a driver of between-lineage differences in avian base composition. Claudia C. Weber, et al, Genome Biology. The substitution of the DNA basepairs G and C was found to be higher in the genomes of birds with large populations and shorter generations, confirming a theoretical prediction that GC content is affected by life history of a species.

Low frequency of paleoviral infiltration across the avian phylogeny. Jie Cui, et al. Genome Biology. Genomes maintain a partial record of the viruses an organism’s family has encountered through history. The researchers found that birds don’t hold as much of these leftover bits of viral genes as other animals. They conclude birds are either less susceptible to viral infection, or better at purging viral genes.

Genomic signatures of near-extinction and rebirth of the Crested Ibis and other endangered bird species. Shengbin Li, et al Genome Biology. Genomes of several bird species that are recovering from near-extinction show clues to the susceptibilities to climate change, agrochemicals and overhunting that put them in peril. This effort has created better information for improving conservation and breeding these species back to health.

Dynamic evolution of the alpha (α) and beta (β) keratins has accompanied integument diversification and the adaptation of birds into novel lifestyles. Matthew J. Greenwold, et al. BMC Evolutionary Biology.  Keratin, the structural protein that makes hair, fingernails and skin in mammals, also makes feathers. Beta-keratin genes have undergone widespread evolution to account for the many forms of feathers and claws among birds.

Comparative genomics reveals molecular features unique to the songbird lineage. Morgan Wirthlin, et al. BMC Genomics. Analysis of 48 complete bird genomes and 4 non-bird genomes identified 10 genes unique to the songbirds, which account for almost half of bird species today. Two of the genes are more active in the vocal learning centers of the songbird brain.

Reconstruction of gross avian genome structure, organization and evolution suggests that the chicken lineage most closely resembles the dinosaur avian ancestor. Michael N. Romanov, et al. BMC Biology. Of 21 bird species analyzed, the chicken lineage appears to have undergone the fewest changes compared to the dinosaur ancestor.

Two Antarctic penguin genomes reveal insights into their evolutionary history and molecular changes related to the cold aquatic environment. Cai Li, et al. Gigascience. The first penguins appeared 60 million years ago during a period of global warming. Comparisons of two Antarctic species show differences and commonalities in gene adaptations for extreme cold and underwater swimming.

Evolutionary genomics and adaptive evolution of the hedgehog gene family (SHH, IHH, and DHH) in vertebrates. Joana Pereira, et al. PLoS ONE. Whole-genome sequences for 45 bird species and 3 non-bird species allow a more detailed tracing of the evolutionary history of three genes important to embryo development.

A Duke lab led the effort to isolate bird DNA for sequencing at BGI: (L-R) Erich Jarvis, associate professor of neurobiology and Howard Hughes Medical Institute investigator, lab research analyst Carole Parent, undergraduate research assistant Nisarg Dabhi, and research scientist Jason Howard. (Duke Photo, Les Todd)

A Duke lab led the effort to isolate bird DNA for sequencing at BGI: (L-R) Erich Jarvis, associate professor of neurobiology and Howard Hughes Medical Institute investigator, lab research analyst Carole Parent, undergraduate research assistant Nisarg Dabhi, and research scientist Jason Howard. (Duke Photo, Les Todd)