黑料吃瓜资源

AA: Welcome to the first episode of Base Pairs, a new podcast from 黑料吃瓜资源. I鈥檓 Andrea Alfano, and my co-host Brian Stallard and I鈥攚e aren鈥檛 scientists. But we do get to spend quite a bit of time talking to scientists around the Lab.

BS: When you sit down and talk with a scientist, you get to hear about all of the stuff that academic journals usually leave out: stories of the remarkable lengths scientists go to make discoveries, the way they felt when they first saw an important result, the relationships they formed through their scientific endeavors, the sparks that ignited their curiosity鈥�

AA: This podcast is a way for us to share these stories with you. Some of them will be about recent discoveries, some will be historical鈥�

BS: 鈥�some will reveal insights about the brain or the body while others will delve into ideas for protecting our planet.

AA: But they will all be rooted in one magical family of molecules: nucleic acids, the molecules that make life possible.

鈥�

BS: Nucleic acid is what the N-A in DNA stands for.

AA: And DNA鈥� well that鈥檚 the blueprint for life! It鈥檚 how cells know what proteins to make, what structures to form, which cells go where.

BS: All of this is dictated by that essential little molecule. But curiously enough, even a year before James Watson and Francis Crick announced their discovery of the double helix, scientists were still arguing about whether DNA was in-fact the incredible blueprint we now know it is.

AA: In the early 1950s, there was a clear divide among experts. On one side were the scientists who saw DNA for what it was: this seemingly modest molecule that somehow wields the power to pass information from one generation to next.

BS: Then there was the other camp: experts who looked at DNA- this large yet simple molecule that鈥檚 essentially just the same four 鈥榣etters,鈥� or bases, strung together, and thought, 鈥渢here鈥檚 no way! it鈥檚 too simple!鈥�

AA: This latter group even went as far as to call DNA the 鈥渟tupid molecule.鈥� They argued that proteins, which have incredibly complex structures, were the master molecules behind genetics.

BS: 鈥淪tupid molecule!鈥� That鈥檚 pretty harsh. You鈥檇 expect such polar groups to be at each other鈥檚 throats鈥�

AA: But apparently most academics at the time were just thrilled to be part of a new and exciting field.

FS: The idea that you could understand Gregor Mendel鈥檚 wonderful data at the level of a molecule was鈥攅ntrancing.

AA: That鈥檚 Frank Stahl,

FS: Professor of biology emeritus at the University of Oregon.

AA: He鈥檚 the Stahl in the famous Meselson-Stahl experiment you may remember from your high school biology textbook 鈥� which was a major contribution to understanding how DNA replicates.

BS: and he鈥檚 talking about Mendel鈥� the 鈥渇ather of Genetics,鈥� Mendel 鈥� the guy who used peas to show the world that heredity followed strict rules.

BS: In 1952, Frank was just a wide-eyed graduate student newly arrived at 黑料吃瓜资源.

FS: I said, 鈥淲ell, my boss wanted to get rid of me for the summer so he shipped me down here!鈥�

AA: That鈥檚 what Frank told people anyway. His thesis advisor had actually sent him to work in the kitchen at the Lab, but he was quickly enamored with the science that was going on鈥� (music cut in) not to mention the party life.

FS: Hey, I don鈥檛 remember an awful lot about that summer, I鈥檒l have to tell you, because it was a pretty wild summer. But I do remember that I was convinced that I had to work in that field.

BS: [Laughs] This is kind of hard to believe, really. Scientific greats gallivanting around the harbor by night, making world-changing discoveries by day 鈥� even while still nursing their hangovers.

FS: Uhhh, let鈥檚 not go any further with that.

AA: (in phone call recording) That鈥檚 fair!

AA: Still, Frank does remember that there was cause for celebration that summer. Remember that big debate we mentioned earlier? Protein vs. DNA? Someone had all but settled it.

FS: People there were talking about the experiment. People were pleased, impressed, and considered it real progress.

AA: He鈥檚 talking about the famous experiment conducted by Al Hershey and Martha Chase 鈥� one of the final nails in the coffin for the theory that protein carried genetic information.

BS: So what was this experiment? Put simply, the researchers put a bunch of bacteria in a blender鈥� and what came out was strong evidence that DNA carried the blueprints for life.

AA: Isn鈥檛 that a bit TOO simple?

BS: Sure, but that was kind of the beauty of this experiment. Modern scientists have come to call it Hershey Heaven if you have an experiment that not only works, but you can do every day.

AA: Let鈥檚 maybe break it down a little more.

BS: Alright, let鈥檚!

AA: Alright, listeners, meet the bacteriophage 鈥� a type of virus that turns bacteria into its own personal factories.

BS: Today, we know that these little critters physically inject DNA into their victims, hijacking the bacteria鈥檚 machinery to produce more phages.

AA: Phages are what scientists call bacteriophages for short 鈥� viruses that make a living by infecting bacteria. Anyway, phages have to take over bacteria because, like other viruses, they aren鈥檛 exactly living. They鈥檙e just a protein shell with DNA inside, and that鈥檚 it. They don鈥檛 have the rest of the stuff they need to reproduce, so they sneak into bacteria and steal theirs.

BS: It鈥檚 like if Skynet had to enslave humans to make more terminators. Like that.

AA: Uh鈥� Sure? But back in the 1950s, it wasn鈥檛 clear how exactly phages hijacked their victims. All experts knew was that this little virus 鈥�

BS: It looks a lot like a turkey baster with robotic legs 鈥�

AA: Ok, they knew this turkey baster would latch onto the outside of a bacteria cell and a little later, dozens of new phages could be found within.

BS: Frank鈥攍ike Jim Watson before him鈥攚ound up taking a course on phages during his summer at the Lab, and he quickly learned why they were ideal for study.

FS: Phages could multiply, mutate, segregate their genes, genetically recombine鈥攖hey could do everything, it seemed, that higher organisms could do when it came to the transmission of hereditary material.

BS: And, as we mentioned before, they are also made of just protein and DNA. No other organism yet discovered was so perfectly designed to settle the genetic molecule debate.

AA: Hershey and Chase were also well aware of this, and that鈥檚 why they chose to work with these simple phage viruses. They designed two tags鈥攐ne to mark the phages鈥� protein and the other for their DNA.

AA: They theorized that if one of those molecular tags also wound up inside the bacteria鈥� that would indicate which molecule was providing the blueprint for the new phage babies.

BS: Still, there was one hitch to this plan: parent phages latch securely onto outside of their bacterial victims, which means some tags were present outside of the bacteria. But Hershey and Chase were only interested in what wound up INSIDE. So the scientists designed an elegant solution. They used a blender.

(blender sounds)

AA: Normally when I think of lab equipment, I envision fancy microscopes, test tubes, super-specialized machines that I have know idea what they could even possibly do. But that鈥檚 not what this was.

BS: That鈥檚 right. Hershey and Chase dumped all their hard work into a metal Waring blender鈥攈ardly different that your standard kitchen blender鈥攁nd hit the power button.

BS: But they weren鈥檛 making a smoothie. The blending dislodged and separated the phage shells from the infected bacteria. When they then looked inside these bacteria, they saw a whole lot of DNA tag and hardly any protein tag. It was really compelling evidence that DNA was the blueprint a phage factory needs.

AA: Hershey and Chase published their work in April of 1952, just before the start of the summer phage course. Perfect opportunity to party, you鈥檇 think. But unlike the rest of the Lab, that just wasn鈥檛 their style.

(ocean sounds)

FS: He spent his summers sailing on Lake Superior, I think.

BS: that鈥檚 Frank again, remembering Hershey.

FS: In that way, he escaped the summer crowds, got genuine rest away from the laboratory, because when he was at the Cold Spring Harbor, he was a compulsive worker. He worked two sessions each day: he worked from early morning 鈥榯il lunch, then he went home and took a nap, then he came back and worked on into the night, day after day.

BS: This is not to say that you can鈥檛 be fun-loving to do great research. Plenty of other scientific greats have been known as the life of the party.

AA: Still, many will argue that it was Hershey鈥檚 reserved nature and penchant for detail that helped him craft such an elegant experiment. And as for Martha Chase, she shared this understated nature.

FS: She was a rather shy person, reticent, not easy to converse with [BS: Kind of like Hershey in that regard?] Indeed, but a nice person.

BS: And I know what you鈥檙e all wondering: 鈥渨hat about that third celebrity? The blender that changed the field of genetics as we know it!鈥� Well according to biologist Gerry Rubin, somehow even it eschewed the limelight.

GR: When I was in Ray Gesteland鈥檚 lab I needed a blender. And he said to go to the shed and look if there are any blenders there. And I actually came back with this little metal blender. And he said, oh, my god. This is the blender from the Hershey-Chase experiment! For the next four years this blender sat on Ray Gesteland鈥檚 desk with his pencils in it as his pencil holder, and then finally I guess it went to the museum.

AA: The blender is indeed in CSHL鈥檚 Archives now. Hershey and Chase may not have been the type to boast about their work, but CSHL is certainly proud to have them in its history.

BS: It鈥檚 been about 65 years since the Hershey-Chase experiment鈥�65 years since the big question in biology was 鈥渉ow in the world is genetic information passed from generation to generation?鈥� And now, scientists are able to take basic scientific insights about genetic inheritance and answer really specific questions like, 鈥榟ow did these two boys from Utah inherit a severely disabling disorder that no one else in the family has?鈥�

AA: As you might suspect, we didn鈥檛 pull that last question completely out of nowhere. We know someone who asked it鈥攁nd amazingly, was able to answer it.

GL: My name is Gholson Lyon, I work here at the Lab, 黑料吃瓜资源, I鈥檓 on faculty here in genetics鈥攁nd yes, I am a child and adolescent and adult psychiatrist.

AA: That鈥檚 our friend Gholson, and he鈥檚 spent the last decade not only investigating harmful mutations, but also getting to know the people who are affected by them.

GL: Many people that are doing genetics research鈥� they鈥檝e never really interacted longitudinally鈥� with patients鈥攜ou know, people that have real disease.

BS: Real patients, like a pair of disabled brothers鈥�

AA: Ryker and Daxton, 15 and 13 respectively

BS: 鈥攚ho Gholson had the pleasure of meeting back in 2006.

(cut to recording of Gholson with patients)

GL: All right Heyyyy Ryker how are you?

(Dax makes noise)

GL: Can I see your palm like that for me?

JL: Flip your hand over鈥� oh! Look at that!

(JL/Daxton/Ryker: Wooooow!)

AA: And something about them 鈥� well a lot of things, actually 卢鈥� caught Gholson鈥檚 attention right away.

GL: These boys have very severe intellectual disabilities, trouble walking, their gait is a little bit off, cramping in their muscles, very odd facial features, problems with their ears, hyperactive鈥�

BS: All tell-tale signs of one or many genetic disorders. Just鈥� no one was sure which.

JL: Can you pick that up for mom? Hand it to mom?

(Child succeeds this time with a pleased sound)

JL: That鈥檚 better than he normally does it.

AA: That鈥檚 Jalene Lee, Ryker and Daxton鈥檚 mother, and she鈥檚 a pretty incredible person.

JL: I was introduced to Dr Lyon through Alan Rope, he works at the University of Utah through their genetic department and felt like we would be good candidates to sort of push forward with genetics testing.

GL: Do they ever lock their legs when they walk at all? Or is this about how they always walk?

JL: It鈥檚 pretty average.

(walking sounds in the park)

AA: They would plan meetings 鈥� sometimes in an office, sometimes at a park, and Gholson would just鈥� get to know them鈥� all the time taking notes and video.

GL: And neither one of them has ever said a word, right?

JL: Ummm, Daxton does some voice inflection 鈥� kind of imitates words. And Ryker, about the only thing he can say is 鈥渕om.鈥�

(cuts back to interview)

JL: I mean, their personalities are different because they are two different children, but their disabilities themselves鈥攊t was kind ok one of those things where we said, 鈥渙k, so there is definitely some sort of genetic basis.鈥� And we just sort of proceeded from there.

BS: Ok sooo everybody鈥檚 got 46 chromosomes… that鈥檚 23 pairs?

AA: 23 for us humans, anyway.

BS: Right. But there鈥檚 one pair in particular that really separates us guys and gals. They鈥檙e often called the 鈥渟ex chromosomes鈥�

GL: In males, you have both an X chromosome and a Y chromosome and in females you have two X chromosomes.

And in boys of course, of course they only have one X chromosome so there鈥檚 only one X chromosome being expressed. In women, they have this thing called dosage compensation where one of the X chromosomes is randomly inactivated.

BS: Basically, the genome is protecting itself. You know, 鈥渃ompensating鈥� because too much X chromosome can kill a cell.

AA: And Gholson knew that when one X is carrying a harmful mutation, that X is more likely to be turned off.

BS: It鈥檚 a lot like a second line of defense that guys just don鈥檛 have, since instead of having two X chromosomes, we have an X and a Y.

GL: In this family, with the mother, we鈥攚e speculated that because this was in the two boys that it might be on the X chromosome

AA: Gholson ended up doing something called an GL: X chromosome skewing analysis AA: which is essentially a blood test of the mother that shows which copy of the X got shut off.

BS: In a typical woman, you鈥檇 expect to see a 50:50 ratio. And yet, when Gholson tested the Lee family, a rare 99:1 ratio turned up in Jalene.

AA: It seemed that for some reason, her cells were strongly favoring one X over the other.

GL: We still don鈥檛 know which of the genes, which of the chromosomes was being expressed, um, but we kind of assume that because it鈥檚 99 percent that probably the skewing was favoring the copy that does not have the mutation on it. So we ended up conjecturing that maybe that this was an X chromosome linked disorder between the two boys

BS: And that鈥檚 it, right? He looked at the X and found what was wrong?

AA: Well, not exactly.

GL: So, we ended up doing whole genome sequencing in that family because I wanted to make sure that we didn鈥檛 miss something that was not on the X chromosome.

AA: Basically, the odds were that there was something wrong on the X. But that didn鈥檛 rule out the possibility of troublesome mutations on the other 22 chromosomes.

BS: What did they find?

AA: TAF1.

BS: That鈥檚 T-A-F and the number 1?

AA: Exactly. Ryker and Daxton both had the same mutation in this gene called TAF1 which was right where Gholson expected it to be.

BS: On the X.

AA: And, it was the only meaningful mutation shared between these two brothers.

BS: But wait鈥� you鈥檙e saying that a mutation in this one gene hinders development in the brain, the body鈥� everything?

AA: Yeah, TAF1 influences how cells read information in the rest of the genome, and so any trouble with it can cause a cascade of problems. Think about it like a traffic accident.

BS: So, a mutation of a less important gene would sort of be like a fender bender on a side street. It could slow some things down, but you鈥檙e probably getting to work on time.

AA: Right. But a mutation in TAF1 could be like a major collision on a highway.

BS: Everyone鈥檚 going to be late.

AA: Or, in Ryker and Daxton鈥檚 case, that means global developmental delay.

BS: And that鈥檚 it, isn鈥檛 it? Now we can say for sure what鈥檚 causing this disease.

AA: Not quite. The problem was that Gholson only had the case of the Lee brothers to work with.

BS: And in science, a sample size of just two鈥� that doesn鈥檛 cut it.

AA: So, he started searching

GL: Going to mini conferences鈥�putting up posters鈥�giving talks鈥�I would meet with other medical geneticists and I would show them the pictures of the boys and ask them if they had seen anything like this before.

BS: In the end, and we鈥檙e talking about years of searching here, Gholson and his colleagues identified a whopping 14 cases world-wide

AA: It鈥檚 amazing that鈥檚 all they found.

BS: But you鈥檝e got to remember鈥� this is but one mutation in the estimated 20,000 or-so protein-coding genes humans have.

AA: And it鈥檚 important to note: this is a diagnosis, not a cure. It isn鈥檛 going to solve Ryker and Daxton鈥檚 problems, and it鈥檚 not even going to solve all of Jalene鈥檚 problems.

JL: When I say 鈥淭hey have global developmental delay and TAF1 gene mutation鈥� people look at me and go, 鈥渨ell, what the hell does that mean?鈥�

BS: I recently spoke with Jalene, and she made me realize that the fact that her boys鈥� syndrome is undefined鈥� it makes getting help all the more difficult.

JL: You know, Down syndrome families get to discuss certain things and autism families deal with certain things and they鈥檙e able to bounce ideas off of each other and to be honest I feel kind of alone in my situation, because nobody exactly understand what it is that we鈥檙e going through鈥� and it鈥檚 almost as if they鈥檙e not even accepted without some sort of a name.

BS: Jalene even resorted to calling her boys鈥� disease RykDax, a combination of their names, Ryker and Daxton.

JL: We鈥檒l get people that are like, 鈥渃an I ask you what they have?鈥濃�斺�淚 don鈥檛 know.鈥� And they look at me funny almost like I don鈥檛 even care to know, type of scenario鈥�And from there it just kind of stuck that they have 鈥淩ykDax disease.鈥� And, you know, people kind of settle down and are like 鈥渙h, ok!鈥� Like that makes sense. And I don鈥檛 know why it makes sense but鈥� it鈥檚 fine and that鈥檚 just kind of how we鈥檝e dealt.

AA: That鈥檚 how they鈥檝e dealt, but now that impromptu name may become an official part of medical texts across the world.

GL: You know鈥� you and I have talked about trying to name this syndrome after the two boys so, in the current paper we have down that we鈥檙e thinking about calling it RykDax Syndrome — (spells it out)

JL: Absolutely. Yes.

AA: The thing is, while a name might seem pretty arbitrary, it gives people a way to come together and talk about the disease for the first time.

GL: What I鈥檓 hoping is that the families will now start to communicate with each other more through maybe social media like Facebook and maybe they鈥檒l begin to get a better idea of the natural course of the illness.

BS: And that鈥檚 an important point. Gholson and his colleagues kept the Lee family in the loop even as they went on to discover other cases of RykDax. And learning about these patients has given Jalene some peace of mind about Ryker and Daxton鈥檚 futures.

JL: We鈥檙e ready to go. In whatever direction life takes us, whether something to do with this disease that they have affects it or not, you know, our path is there and we just need to move forward and while we still have them maybe we can help someone else.

BS: It鈥檚 a forward-looking perspective, Jalene鈥檚. And it鈥檚 one that Gholson hopes other families will share.

AA: Every test, every grain of knowledge, is just another step towards a better future for those affected by this disease.

GL: This is just a small piece of the puzzle. You know, there鈥檚 so much more that needs to be done in terms of trying to figure out if there鈥檚 anything that we can do to help the children.

JL: The long鈥攕uper long鈥攕tory is that I鈥檓 happy that the boys are here and that we are able to help.

BS: Well, that鈥檚 it! Our first episode, done.

JL: Sorry for my little rant (laughing).

FS: Well I think I鈥檝e told it all. Thanks. Bye bye.

GL: Thank you very much for having me on this podcast.