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Interviewer: Shamini Bundell
Welcome back to the Nature Podcast. This week, creating unnatural proteins.
Interviewer: Adam Levy
Plus, how young worm mothers may hold the answer to a wriggly riddle. This is the Nature Podcastfor November the 30th 2017. I’m Adam Levy.
Interviewer: Shamini Bundell
And I’m Shamini Bundell.
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Interviewer: Adam Levy
There's a species of worm that has an almost celebrity status in biology. That worm is Caenorhabditis elegans, or C. elegans to its friends. C. elegans is the go-to model for understanding basic properties of animals, in part because it's pretty basic itself. But in spite of the reams of research that have been carried out on this tiny worm, there are still some pretty big unanswered questions. Worms with seemingly identical nature and nurture can have markedly different traits. Marcos Perez has been tracking down the cause of this mysterious variation for his PhD. I gave him a call to find out more.
Interviewee: Marcos Perez
C. Elegans is actually one of the best understood animals on the planet and there’s probably in the order of five to ten thousand people working on C. Elegans worldwide so there’s a huge number of papers and a really broad knowledge base and really the idea I think was using C. Elegans as a model organism in the first place was to have a very simple animal, to try and have a complete understanding of an animal – of an animal’s development, of how an animal works on a molecular level.
Interviewer: Adam Levy
And just how complete is our understanding? What kind of things do we already know about C. Elegans?
Interviewee: Marcos Perez
We know a tremendous amount about its development so every single worm develops exactly the same way. So we know all 959 somatic cells in the body of the adult worm. We know exactly where each cell comes from in the embryo. All of that has been painstakingly mapped out.
Interviewer: Adam Levy
Even with all this knowledge there are still some unanswered questions, I suppose. So what unanswered question were you looking at in this paper?
Interviewee: Marcos Perez
One of the unanswered questions was why individuals are different from each other. So this is a question that has concerned our lab for many years. It’s very easy to get vast populations of organisms, of individuals which are genetically identical. And they’re all raised in the same environment, the same petri dish in fact and yet we still see variation in how the animals look. Some seem to grow faster than others. Some are larger, some are slower, some behave a bit differently. Some live longer. Some have more offspring themselves and some fewer. And so the basic question we are really trying to address is where is this variation coming from?
Interviewer: Adam Levy
How do you begin to hunt for that variation because, as you’ve said, you know so much about this worm, so what are we missing?
Interviewee: Marcos Perez
So what we stumbled on in this case is the age of an individual’s mother made quite a difference to how big it was when it was born, to how fast it developed, to how many offspring it produced in itself. Really in this case it was a matter of thinking, how can these worms be different because there’s not really many ways in which they can differ from each other given that we have genetics and environment so tightly controlled.
Interviewer: Adam Levy
So how is the age of the mother affecting these characteristics of their offspring?
Interviewee: Marcos Perez
Actually, it’s quite surprising because it is known in C. Elegans, for instance, that as worms get older, as they age, there’s a decline in their offspring quality. That’s been known for many years. And that’s somewhat more intuitive. But what we found in this paper is actually the opposite – that the youngest mothers, the progeny of the youngest mothers that were seemingly worst off in many respects. So the progeny of the youngest mother, the very first progeny which were produced were shorter at hatching, they grew slower, they had fewer progeny themselves.
Interviewer: Adam Levy
What is it about being a younger mother that is influencing all these characteristics of the offspring?
Interviewee: Marcos Perez
Not all of them are explained by this but many seem to be explained by the fact that younger mothers seem to put less yolk into their eggs and this kind of makes sense in that the younger mothers are quite a lot smaller than the older mothers at the point when they’re producing these first eggs so we think that’s what’s going on.
Interviewer: Adam Levy
So if having young a bit early in life gives them a disadvantage, gives the young a disadvantage, why have young at that stage of life?
Interviewee: Marcos Perez
So we suspect that one of the advantages of producing sub-standard progeny early is that you produce some progeny early and this outweighs some of those fitness impairments. Although that really remains to be proven; this is just our suspicion at this stage.
Interviewer: Adam Levy
So does this now explain all the variation that we see in C. Elegans. Do we now know where it comes from?
Interviewee: Marcos Perez
It doesn’t explain all the variation. It’s an additional source of variation but actually we’re still working on what’s left of the variation that’s not explained by this in the lab. Somewhat mysterious but it seems like there’s still definitely sources.
Interviewer: Adam Levy
Is this result just interesting because it helps us understand theoretically what underpins this variation? Or is it useful in some way to people who use C. Elegans in their experiments?
Interviewee: Marcos Perez
I would say that both are true. For sure it’s important to people who use C. Elegans in their experiments because this is an extra experimental variable that needs to be controlled and often won’t be. So this is going to be very important I think for people working with C. Elegans and especially phenotypic variation within C. Elegans. On a more general sense, I think it’s illustrative of the kinds of ways in which ancestral experience can impact on an individual.
Interviewer: Adam Levy
Is this a pattern that we notice in more complex organisms as well, that for younger mothers it has a detrimental effect on the offspring?
Interviewee: Marcos Perez
This particular study pertains, I would say, exclusively to C. Elegans’ biology. It’s interesting as an illustration of the kinds of things that can produce phenotypic variation in an organism but in terms of the mechanism there’s not much reason to suspect that this particular mechanism will be in operation in higher organisms.
Interviewer: Adam Levy
That was Marcos Perez who's at the Centre for Genomic Regulation in Barcelona. Read his paper at nature.com/nature.
Interviewer: Shamini Bundell
The News Chat is still to come where we’ll be learning about two very different treatments: AI-controlled brain implants; and traditional Chinese medicine. First though, Benjamin’s here and he’s brought some Research Highlights…
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Interviewer: Benjamin Thompson
Einstein’s Theory of General Relativity is still relevant, that is, according to new papers from two international teams of researchers. The first group dived into data from lasers bounced off mirrors on the moon, hunting for anomalies in its orbit that would point to irregularities in General Relativity’s rules. Turns out, none were found. Team number two used super-conducting gravimeters to measure the earth’s gravitational pull. Again, the results matched the theory so General Relativity can rest easy for now. Gravitate towards the two papers over at Physical Review Letters.
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Interviewer: Benjamin Thompson
Slightly further away than the moon, 12.7 billion light-years to be exact, a team led by researchers at Cornell University, USA, have spied the beginnings of an Intergalactic embrace. Two star crossed galaxies have been seen merging, jointly forming an object known as ADFS-27 the light from which took billions of years to reach earth. The celestial consolidation is the first of its kind to have been seen and should give us an idea of how larger galaxies form. Shoot over to the Astrophysical Journalto read more.
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Interviewer: Shamini Bundell
Next up this week, Benjamin’s back, giving us an update on a synthetic biology story we last covered back in 2014…
Interviewer: Benjamin Thompson
Today I want to talk about DNA and its four bases: adenine, thymine, cytosine and guanine, or A, T, C and G. DNA serves as the instruction manual for all living things with the exception of some RNA based viruses and I’m not sure that today’s the day to get into a debate about whether viruses are alive or not. But why only these four bases? After all there are other similar molecules that exist in nature that could have been used instead. According to Floyd Romesberg from the Scripps Research Institute in California, there are a few schools of thought as to why this is. One is that eons of evolutionary time have led to the best DNA system that there can be. After all, billions of years of survival of the fittest can’t be wrong, right?
Interviewee: Floyd Romesberg
There’s been a lot of thought, a little bit more recently that that’s actually not true and that we’re not actually the best solution, we’re just a solution. Basically we wandered into a set of molecules that are good enough and it allowed for evolution to happen and there might have been lots of other solutions but once you start on a specific pathway it’s virtually impossible to switch to a different pathway.
Interviewer: Benjamin Thompson
But what if we switch the pathway manually? Floyd and his colleagues have been looking to do just that for some time now. They’ve done it by introducing two new DNA bases called X and Y that form what is known as an unnatural base pair. X and Y are designed to be chemically quite different to the existing bases. Normally, an A on one side of a DNA molecule binds with a corresponding T using hydrogen bonds. It’s the same with C and G. by design X and Y pair in a different way to the other bases, as Floyd explains.
Interviewee: Floyd Romesberg
We simply took the hydrogen bonding groups away and left it as a very oily-like molecule with the idea that they would pack with each other in the same way that oil packs with oil when it forms a separate phase away from water. It’s like when you mix water and oil you get two phases, they separate. And so we thought if we go with a very orthogonal force, meaning a force that’s very unrelated to the force that nature uses, that might buy us right at the beginning some specificity against mis-pairing with G, C, A and T because like I said, oil and water don’t mix.
Interviewer: Benjamin Thompson
Back in 2014, Floyd and his colleagues published a paper where they introduced DNA containing unnatural base pairs into E. coli bacteria. These microbes were able to copy and store this DNA as they divided and grew. In a paper published this week, the team have taken this work a step further and added the ability to use the DNA as well.
Interviewee: Ffloyd Romesberg
We didn’t just want to store the information, we wanted to retrieve it. What we’ve done now is take simply a system that can store information and show that we can fully retrieve it in the form of unnatural proteins.
Interviewer: Benjamin Thompson
Translating this unnatural DNA required the team to also add the machinery to let these E. Coli use non-standard amino acids. In this paper they’ve added two of these non-standard amino acids into a fluorescent protein. Having a DNA alphabet with six bases rather than four could greatly increase the options available when it comes to protein production. Individual amino acids are encoded by a sequence of three bases known as a codon. Each of these can be A, T, C or G which gives a maximum of four times four, times four combinations, although it’s a bit more complicated than that and not all codons are used for different amino acids. Adding X and Y in gives the opportunity for six times six times six combinations, in other words, the potential to code for a lot more amino acids.
Interviewee: Ffloyd Romesberg
We now have the ability in principle to encode the synthesis of proteins with many new unnatural amino acids and so the question is, well what are you going t do with that? So there are really two areas of things that we’re interested in. It’s very common to use E. coli simply as a little factory to produce proteins that you’re interested in. So you let the bacteria grow, they produce some protein of interest, you then bust them open and you recover the protein of interest to do with it whatever you want. The other thing, what if we got the cell to make novel proteins that it can’t normally make, but then don’t bust the cell open, don’t throw the cell away. Get the cell to use that protein in a novel way.
Interviewer: Benjamin Thompson
One example that Floyd gave me of using adapted microbes is that they could be introduced to an environment to clean up a specific pollutant. However, this example begs the obvious question about containment but according to Floyd, X and Y don’t exist in nature and because bacteria can’t make them themselves, they’re reliant on the bases being supplied by the researchers.
Interviewee: Ffloyd Romesberg
You know, synthetic biology is doing a lot these days and a lot of this has the potential to be scary and I think that it’s nice to be able to say that look, these bugs, these organisms, these semi-synthetic organisms will grow in the lab as long as you’re providing them X and Y but they can’t get X and Y anywhere else. If they escape out of the soil in front of the Scripps Research Institute or in front of my home, they’re going to simply die.
Interviewer: Benjamin Thompson
Floyd and his team aren’t the only researchers working on non-standard DNA bases. But showing the feasibility of integrating non-standard amino acids into a protein, is another step forward towards expanding the genetic code which has existed unchanged as far as we’re aware for millions if not billions of years.
Interviewer: Shamini Bundell
That was a report from Benjamin Thompson. Floyd Romesberg’s paper can be found at Nature.com/Nature, plus there’s a news story over at Nature.com/News.
Interviewer: Adam Levy
And speaking of news, it’s time now for this week’s News Chat, and we’re joined in the studio by Features editor Richard Van Noorden. Hi Richard.
Interviewee: Richard Van Noorden
Hi Adam.
Interviewer: Adam Levy
Now, first up there’s some news on brain implants for mood disorders but brain implants themselves for mood disorders… that’s not an entirely new thing.
Interviewee: Richard Van Noorden
No. Brain implants have been used to treat movement disorders like Parkinson’s Disease and they’ve been a bit less successful when tested against mood disorders like depression but the new thing that we’re reporting on this week is brain implants that work by themselves. Two teams funded by the research arm of the US military, DARPA, have begun trials of so called closed-loop brain implants and they use algorithms to detect patterns associated with mood disorders and they can shock the brain back to a healthy state without a physician pressing any buttons.
Interviewer: Adam Levy
So what was happening before? Was it a much more manual process?
Interviewee: Richard Van Noorden
Yeah, essentially, delivering electric pulses to alter the activity of your neurons... That’s known as deep brain stimulation. Attempts to treat depression – well, one study with 90 people suggested that after a year of treatment with these implants there was no improvement. Now, the scientists behind these new projects say their work might succeed because they’ve designed their implants specifically to treat mental illness and to switch on only when needed. Previously, the implants were essentially on constantly.
Interviewer: Adam Levy
What are you actually watching for? You say they’re only switching on when needed; how is that evaluated?
Interviewee: Richard Van Noorden
Well, at the society for neuroscience meeting in Washington DC where we heard about this work an electrical engineer, Omid Sani, at the University of Southern California in Los Angeles showed how they’re working out what to do with these implants. Essentially they’re working with people with epilepsy who have electrodes implanted. They are tracking their brain activity and also they’re asking them about their moods in detail over about one to three weeks and you can compare that information and essentially come up with an algorithm to decode that person’s changing moods from their brain activity so you end up with broad patterns of brain areas associated with moods and an algorithm that can essentially deliver pulses that change that pattern back to what’s been associated with a better mood. There’s another team that also reported at this meeting – they, rather than detecting a mood or a mental illness, they want to map brain activity associated with behaviors like distraction or difficulties with empathy so that’s even harder to perhaps figure out than mood and again the idea is to come up with algorithms that automatically simulate the brain when they see these neuronal patterns emerging.
Interviewer: Adam Levy
It seems like there must be some ethical issues connected with actually putting implants in people’s brains and feeding back in this way.
Interviewee: Richard Van Noorden
First of all there’s the possibility of over-correcting emotions. You might create extreme happiness that overwhelms all other feelings and there’s a bigger question here: might people feel an altered sense of idea or agency? Naturepublished a Comment piece earlier this month from neuro-technologists who are looking at this and other emerging neuro-implant technologies and warning that the loss of agency or identity because some implant is controlling your mood for you is a real concern. They reference a 2016 study with a man who’d used at brain stimulator to treat his depression for seven years and he reported he began to wonder whether the way he was interacting with others was due to the device or his depression or something deeper about himself. He said I’m really not sure who I am. And the other concern perhaps is that these researchers will – they won’t be able to read minds – but in reading these patterns they will have access to activity that encodes a person’s feelings or mood. There’s a lot of ethical discussion around what’s going to come out of this technology five, ten, fifteen years down the line.
Interviewer: Adam Levy
Let’s move from one controversial treatment to another which is rather than very hi-tech, very modern, it’s actually quite a very traditional type of treatment and that’s a Chinese traditional medicine. Now, I imagine many in our audience have heard of Chinese traditional medicine but they might not know just how big a source of treatment it is in China.
Interviewee: Richard Van Noorden
Support for Chinese traditional and herbal medicines goes right to the top of China, all the way to the Chinese government and it’s been forcefully promoting these herbal medicines as an alternative to expensive western drugs. Its ultimate goal is to have all Chinese healthcare institutions provide Chinese traditional medicine by 2020. We’re reporting this week on draught plans that would roll back some of the regulations on these traditional medicines. And that has scientists worrying that it could put people at risk because from early next year these medicines may no longer be required to pass trials of safety and efficacy in humans in China.
Interviewer: Adam Levy
How big actually is the risk? Is the risk only that people might avoid more effective remedies or are there potential harms associated with some Chinese traditional medicines?
Interviewee: Richard Van Noorden
There are of course examples of problems with Chinese traditional medicines and one we sight is with aristolochic acid which is a component of a plant often called birthwort. In September this year, China’s food and drug administration recalled some batches of this injectable medicine after about ten people fell ill with fevers and in October a study was published in Science Translational Medicine, linking liver cancer to this aristolochic acid. This is still in common use. The US Food and Drug Administration has warned that it’s associated with kidney disease but people take remedies containing this every day. The defence given by some Chinese researchers is that well, these herbal formulas have been used for hundreds and thousands of years unlike Western drugs. So it’s okay. But scientists are concerned that if you roll back clinical trials and safety tests in humans, given that these recalls such as the one I quoted are happening, are safety measures adequate? Another concern is that doctors may be unwilling to criticize misuse of Chinese traditional medicines because they are supported at such a high level in China. In late October, for instance, an article on the medical news site that called for closer attention to the risks of aristolochic acid was removed from WeChat, the social media site. It had been viewed more than 700,000 times.
Interviewer: Adam Levy
And we’re not just reporting on that in this week’s Nature. There’s actually an editorial discussing this very topic.
Interviewee: Richard Van Noorden
Yeah so in our editorial we say that this draft rule is a backward step, that only controlled clinical trials can satisfy safety concerns and there’s an interesting parallel with the United States’ traditional and herbal supplements industry because advocates of Chinese traditional medicines often say, just align the system with the US where herbal preparation doesn’t need to pass FDA tests before going on sale. Well, we say the US system isn’t one to emulate and there’s a few differences between the US and China. In the US such supplements are listed as a separate category – neither food nor drug – and the FDA can only try and ban them if it proves them to be dangerous and actually it’s just been playing catch up ever since. It’s only been able to recommend after fatalities that unsafe remedies be removed from the market. And the herbal and supplement business has ballooned in the United States but in the United States companies are not supposed to say that herbal remedies cure disease. In China such remedies are often prescribed for specific diseases. So it’s not quite parallel. The herbal medicines in China are seen as much more therapeutic than they are in the supplements industry in the United States although our editorial criticizes the lax safety regulations applied to both. Now some doctors say, well, you can’t test these remedies in clinical trials because they have to be tailored personally to each patient based on the doctor’s intuitive interpretation of what the patient needs and they usually use in combination. Well, we’re saying that’s not convincing and we’re also saying that just because standardized trials are difficult or expensive, it’s not a reason to say they can’t be done. Fast and cheap, can’t be the goal of drug regulation.
Interviewer: Adam Levy
Thanks for the update Richard. For more on those two news stories, plus the editorial on traditional Chinese medicine, head on over to nature.com/news
Interviewer: Shamini Bundell
That’s it for this week. You can follow the show on Twitter, we’re @NaturePodcast. And don’t forget to have a look at our YouTube channel, there’s loads of great stuff on there, including a new film about axolotl conservation to go with our podcast section from a couple of weeks back. That’s at nature.com/NatureVideoChannel. I’m Shamini Bundell.
Interviewer: Adam Levy
And I’m Adam Levy. Thanks for listening.
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