At the Lab Season 1 Research Rewind: Genetics

Transcript

Sam Diamond: You’re now At the Lab with Cold Spring Harbor Laboratory. My name is Sam Diamond.

Sara Giarnieri: I’m Sara Giarnieri.

Caroline Cosgrove: My name is Caroline Cosgrove.

Nick Wurm: I’m Nick Wurm.

Nick Fiore: My name is Nick Fiore.

SD: And this week At the Lab we’re revisiting all of our episodes from Season 1 that focus on genetics.

{Music}

SD: CSHL is synonymous with cutting-edge genetics research. Today, we’re not only making new breakthroughs here At the Lab. We’re putting the power of DNA sequencing in the hands of high schoolers across the globe. You’ll hear all about that and much more, but first, a special guest appearance.

{Music}

SD: “Life moves pretty fast. If you don’t stop and look around once in a while, you could miss it.”

SD: In case you’re unfamiliar, that’s the famous 20th-century philosopher—slash fictional high school student—Ferris Bueller.

Economics Teacher: “Bueller? Bueller?”

SD: Ferris is an expert in stopping to look around at life in action. Here at Cold Spring Harbor Laboratory, developmental biologists are interested in looking at life at its earliest and most fundamental stages. Here’s CSHL Professor Christopher Hammell.

Chris Hammell: Genes are controlled by sets of machinery, and you turn genes on and off. And for developmental biologists, we’re interested in figuring out basically how that sets up the body plan of the organism. One of the things that’s been underappreciated in developmental biology is how timing becomes important for that. So, it really is an intuitive problem. You wouldn’t start making fingernails on an arm until you had started to make the arm.

SD: To get to the bottom of this problem, Hammell is looking closely at a kind of worm known as C. elegans. These worms are the perfect test subjects to study the timing of development, because 1) they only live for about 20 days, and 2) they’re see-through.

SD: Hammell and his collaborators came up with a new imaging technique to capture gene expression as it occurs inside C. elegans. They identified a quartet of molecules that time the animal’s growth stages with a concerto-like precision.

CH: This clock we’ve discovered sets up the cadence of that song of development. It’s a coordinator of the orchestra. It controls when the trombone goes, how loud it gets, and how long the note lasts.

SD: This is the first time that gene expression has ever been captured in real time throughout an animal. But perhaps even more incredible, the mechanism that times C. elegans’ development works a little bit like circadian clocks. You know—the thing we plan our days around.

SD: There’s still a lot of work to be done before we can figure out how our developmental clocks enable us to become complex characters like Ferris Bueller or his best friend Cameron Frye. But you can rest assured our scientists aren’t letting the mysteries of life pass us by. We’re looking at them up close every day.

{Musical excerpt from Ferris Bueller’s Day Off}

{Music}

SG: For over two decades, Cold Spring Harbor Laboratory researchers have been working to decipher the genetic origins of autism. Their work has already helped increase autism awareness worldwide.

SG: Today we understand that autism spectrum disorders cover a range of neurological and developmental conditions. Autism often manifests as restricted interests and repetitive behaviors. Here’s CSHL Professor Ivan Iossofiv:

Ivan Iossofiv: There are children diagnosed with autism who are high functioning. They have a completely productive life, although they have some minor troubles in social interactions, as most of us do. But also, there are children diagnosed with autism who never learn to speak, and they have definitely a difficult life.

SG: According to the CDC, 1 in 36 children are diagnosed with autism, and the numbers continue to rise each year.

SG: CSHL researchers like Iossifov have reached several milestones toward our understanding of autism.

SG: In 2007, researchers found a link between spontaneous genetic mutations and autism.

SG: In 2011, they found another genetic clue: the deletion of a 27-gene cluster on chromosome 16 causes autism-like features.

SG: Now, Iossofiv and his colleagues have discovered that siblings with autism share more than 50% of their father’s genome. They’re not sure why, but Iossifov has a couple of ideas.

II: Our future research is also fairly exciting. If one of those theories or two of them prove to be true, then it opens different treatment strategies, which can, in the future, affect quite a lot of families.

SG: Iossifov’s research may also offer helpful tools for educators and therapists. It may lead to earlier diagnoses and continue to deepen our understanding of autism. And that’s what Awareness awareness is all about!

{Music}

Caroline Cosgrove: For decades, scientists have studied DNA, the foundation of life, using a technique called sequencing. This process analyzes the genetic code of an organism by determining the order of its DNA bases: G, A, T, and C.

CC: Now, imagine being able to sequence DNA yourself right in the palm of your hand. Thanks to new, portable sequencing technology, anyone can learn about DNA!

CC: That includes the folks at Cocktails & Chromosomes, our monthly science talk hosted at Industry bar in Huntington, New York. This January, we had a full house of locals eager to witness the sequencing of brewer’s yeast live on stage.

CC: Our on-stage sequencer was Jason Williams. He’s the Assistant Director of Diversity and Research Readiness at CSHL’s Dolan DNA Learning Center—the world’s first science center dedicated to genetics education. Williams used a palm-sized sequencing device from Oxford Nanopore Technologies.

Jason Williams: Using the techniques of molecular biology, we can put DNA onto this surface, a little enzyme guides the DNA to the pore, and the pore sucks it down. And as it’s going through the little hole, it’s creating minute disturbances in the electric charge that’s being measured.

CC: The device then translates these electric charges into DNA sequences.

CC: Today, DNA sequencing technology is cheaper, simpler, and more accessible than ever. That means more people can learn about DNA, whether they’re high school students here in America or in remote locations across the globe.

JW: You could imagine somebody in a rural area whether it’s in the U.S., whether it’s in Africa, whether it’s somewhere else. The ability for people who might have questions, which they need to know something about DNA to answer, for that to be portable to almost any location is really, really important.

{Music}

Nick Wurm: Sickle cell disease is a group of inherited blood disorders that cause red blood cells to be misshapen. Twenty million people across the globe, most of them Black or of African origin, live with intense pain and fatigue as a result of this debilitating disease. However, there is hope.

NW: In 2019, a Mississippi woman became the first person to receive treatment for sickle cell disease with CRISPR gene-editing technology. Today, she is thriving and symptom-free. Meet Victoria Gray.

Victoria Gray: When my life changed for the better through science and my faith, I knew I needed to share this with other people.

NW: Now, Gray is a public speaker and patient advocate who aims to educate the broader community about sickle cell disease and the potential of CRISPR gene editing. She’s especially concerned with reaching those who have historically been excluded from conversations around science and medicine.

VG: I get to speak. Having a voice is important. I felt as though I didn’t have a voice before. That’s something that CRISPR has given me. I get to travel and be at places like this and even speak internationally.

NW: In July, Cold Spring Harbor Laboratory welcomed a diverse group of students, families, and community members to hear Gray share her personal experience. During this Students Talk Science event, Gray was interviewed by alumni from the DNA Learning Center’s STARS Program. This was followed by a panel discussion with professionals in science, medicine, and public health. Representing CSHL was Associate Professor Tobias Janowitz, a cancer researcher and practicing oncologist.

Tobias Janowitz: I think this dialogue between the patients and the scientists and the clinicians, but also between the generations—what you are trying to do—is really important in the pursuit of truth.

NW: Widespread education opens up discussions across communities, bringing in more voices and perspectives. That’s inspiring for clinical scientists like Janowitz.

TJ: I think some of the best science was inspired by patients in that they ask very insightful questions.

NW: As important as biomedical breakthroughs are, making sure everyone has access to and awareness of these advances is just as vital. And that’s part of our ongoing mission here, At the Lab.

{Music followed by ‘space-age’ sound effect}

SD: “The tomato of tomorrow.”

SD: We’ll hear from MacArthur Award-winning plant biologist Zach Lippman. He’s designed a new tomato to grow indoors, in a city, with artificial light, no pesticides, and minimal water.

SD: To find out more, we popped into his office at Cold Spring Harbor. We found it filled with plant seeds, farm tools, and . . . a large dog.

Zach Lippman: This is Charlie, Charlie Lippman. Most of the day he spends here sleeping until people come in that smell good and he wants to lick them.

SD: Lippman can’t keep his dog from licking people. But he did manage to trick tomato plants into flowering faster. His lab changed a gene in tomatoes so that they’d fruit as quickly as possible. What does that mean for tomato growers?

ZL: You can get your yield really fast, and then you immediately turn around and you go in again. Right? So you’re basically getting multiple seasons of growth.

SD: Altering two more genes converted the tomato vines into bushes. This way, Lippman’s plants can stack in vertical hydroponic systems. As climate change makes more land less usable, Lippman says indoor farms that can run 365 days a year should be set for big-time growth.

ZL: You just can imagine, maybe a little bit in the distant future, that you have all of these quote-unquote “farms” laid out in this area that are all under climate control, computer operated. And now you’re able to produce on that land, whereas the more traditional way of producing would no longer be possible.

SD: NASA is also interested in Lippman’s tomatoes for long-distance space travel.

ZL: You know what? We’re going to be eating our own space-grown lettuce and tomatoes for dinner tonight—right before our freeze-dried beef.

{Music}

Nick Fiore: Corn starch, corn syrup, cornmeal, cornbread, cornflakes, and good old-fashioned corn on the cob. Nowadays, corn is everywhere you look. But how did it get here?

NF: I don’t mean “here” as in the kitchen table. This question is much bigger. It goes back millennia. Here’s CSHL Professor Rob Martienssen.

Rob Martienssen: What we think of now as maize was domesticated from teosinte parviglumis, a wild grass in the lowlands of Mexico, about 9,000 years ago. However, domesticated maize was confined to that area for climatic reasons for the next 5,000 years until it hybridized with another wild teosinte called teosinte mexicana, which could grow in much colder and dryer climates. And that hybridization is thought to have been responsible for the remarkably rapid dispersal of maize throughout the Americas.

NF: Plant biologists like Martienssen have known this much for decades. The real question was how did maize adopt the traits needed to spread so widely so quickly? Now, with the help of Jerry Kermicle, a corn whiz from the University of Wisconsin, and Ben Berube, a CSHL grad student, Martienssen may have an answer.

RM: Something called selfish inheritance or gene drive, where a gene becomes preferentially inherited because it kills the other, in this case, pollen grains that don’t carry that gene. Gene drive is one way in which you can get an awful lot of genes into a hybrid in such a way that it’s forced into the next generations. And if you’re lucky, that will carry along with it traits that are very useful.

NF: What’s remarkable about this instance of gene drive is that it involves a particular group of molecules known as small RNAs.

RM: Even more remarkable, animal genomes have something similar going on in fruit flies. And there’s even an example in mouse.

NF: Small RNAs are also quite common in human sperm cells. So, one question now is could similarly selfish inheritance help explain the sudden jump from Neanderthals to homo sapiens? In other words, could a gene drive be the missing link? It might sound crazy, but when it comes to maize and corn, we now think the answer is yes.

{Music}

SG: Cold Spring Harbor Laboratory has been home to many brilliant women in science. Today, we are examining the life of one researcher under the microscope: Martha Cowles Chase.

SG: Chase was born on November 30th, 1927, in Cleveland, Ohio. After completing her bachelor’s degree in 1950, she became a research assistant at CSHL for Alfred Hershey. This led to one of the most famous experiments in history.

SG: The Hershey-Chase experiment was game-changing for the field of genetics. Using a mere kitchen blender, the pair confirmed that genes are made of DNA, not protein. This same blender is housed in the CSHL archives.

SG: Chase stayed with CSHL until 1953 and went on to conduct research at other institutions. Yet, she came back yearly to work with the “Phage Group,” which consisted of Alfred Hershey, Salvador Luria, and Max Delbrück.

SG: Meanwhile, Chase continued her education at the University of Southern California, receiving a Ph.D. in microbiology in 1964.

SG: In 1969, Alfred Hershey won the Nobel Prize for his team’s groundbreaking genetic discovery. Even though Chase was not acknowledged by the Nobel committee, she has been recognized for her work in other ways. A family of bacterial viruses called Chaseviridae was named in her honor.

SG: Chase passed in 2003 at the age of 75 from pneumonia, but she still lives on through the work of modern-day geneticists. Indeed, much of the research happening today at Cold Spring Harbor would be impossible were it not for women in science like Martha Chase.

{Music}

SD: The human reference genome is one of the greatest achievements of the modern scientific era. It pushed biology into the 21st century and revolutionized our understanding of genetics.

SD: But, at the end of the day, it’s just a reference—one genomic profile standing in for all of us. In reality, each of our genomes contains about 4.5 million genetic variants. Today, thanks in part to scientists who were involved in the Human Genome Project, it’s no longer cost-prohibitive to sequence any given individual’s genome.

SD: One such scientist is CSHL Professor Thomas Gingeras. After the Human Genome Project wrapped up, Gingeras became involved in a follow-up project called ENCODE. Short for the Encyclopedia of DNA Elements, this genomic database opened a world of possibility. Gingeras was quick to dive in, with EN-TEx.

Thomas Gingeras: This project started at the end of phase 3 of ENCODE. It was clear that more and more, individual genome sequences were going to be used in place of the reference human genome sequence. And the question then becomes what are the differences that you would see using the reference genome versus taking individual genome sequences, and then doing the same kind of analysis?

SD: If ENCODE was the sequel to the Human Genome Project, EN-TEx is the third installment in the trilogy. Gingeras launched EN-TEx alongside Yale Professor Mark Gerstein. Together, they led a team in profiling 30 tissues from four donors with 24 different genomic tests per tissue. As a result, they were able to compile a catalog of more than one million genomic variants—making it the most comprehensive per-genome resource of its kind.

SD: But they didn’t stop there. They also developed computational prediction models for evaluating each individual genetic variant in cases where collecting a tissue sample would be overly invasive, like if you’re looking into heart or brain conditions. How does Gingeras feel about all this?

TG: I think it’s quite exciting. I mean this [path leads us to a] golden grail that [scientists and physicians] have been wanting to do for a long time. And this is really the first attempt to provide a paradigm for getting to that goal.

SD: And it started right here At the Lab.

{Music}

SD: Thanks again for listening. If you like what you heard, be sure to subscribe wherever you get your podcasts and tune in next week as we rewind more cool science stories from this past season. You can also find us online at CSHL.edu. For Cold Spring Harbor Laboratory, I’m Sam Diamond, and I’ll see you next time At the Lab.