Category: Biotechnology

Why porcupine quills slide in with ease but come out with difficulty

By Ed Yong | December 11, 2012 8:00 am

A shorter version of this story appears at Nature News.

In August of this year, Allison Noles rushed her bulldog Bella Mae to the vet. The dog’s face looked like a pincushion, with some 500 spines protruding from her face, paws and body. The internet is littered with such pictures, of Bella Mae and other unfortunate dogs. To find them, just search for “porcupine quills”.

North American porcupines have around 30,000 quills on their backs. While it’s a myth that the quills can be shot out, they can certainly be rammed into the face of a would-be predator. Each one is tipped with microscopic backwards-facing barbs, which supposedly make it harder to pull the quills out once they’re stuck in. That explains why punctured pooches need trips to the vet to denude their faces.

But that’s not all the barbs do. Woo Kyung Cho from Harvard Medical School and Massachusetts Institute of Technology has found that the barbs also make it easier for the quills to impale flesh in the first place. “This is the only system with this dual functionality, where a single feature—the barbs—both reduces penetration force and increases pull-out force,” says Jeffrey Karp, who led the study.

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“We took a rat apart and rebuilt it as a jellyfish.”

By Ed Yong | July 22, 2012 1:12 pm

Kit Parker has built an artificial jellyfish out of silicone and muscle cells from a rat heart. When it’s immersed in an electric field, it pulses and swims exactly like a real jellyfish. The unusual creature is part of Parker’s efforts to understand the ways in which muscles work, so that he can better engineer heart tissue. And it has a bizarre intended purpose: Parker wants to use it to test heart drugs. I wrote about his work for Nature, so head over there for the main story. Meanwhile, here’s my full interview with Parker about the jellyfish. He’s a fantastic interviewee – you’ve got to imagine him almost shouting this stuff.

Building a jellyfish using rat tissue isn’t exactly a typical everyday idea. Where did it come from?

My group does cardiovascular research and I spend a lot of time thinking about building tools for early-stage drug discovery. We’re known for making actuators and things you can measure contractility with, and using micro-scale tissue engineering to build tissues on chips. Several years ago, I got really frustrated with the field. Drug companies are screaming because their drug pipelines are running dry. We don’t have good ways of treating a lot of these heart diseases in the clinic. It dawned on me that probably the reason why is that we’re failing to understand the fundamental laws of muscular pumps.

I started looking around for inspiration in a simpler system. This was late 2007, and I was visiting the New England aquarium. I saw the jellyfish display and it hit me like a thunderbolt I thought: I know I can build that.

That spring, we had a visitor: John Dabiri from CalTech, a famous fluid mechanician. He does a variety of propulsion studies on various species. He was walking down the hall and I grabbed him and said: John, I think I can build a jellyfish. He didn’t know who I was. He looked at me like I had a horn growing out of my head but I was pretty excited and waving my arms, and I think he was afraid to say no. So, he said yeah. He sent a graduate student Janna Nawroth to my lab for four years. Three of my postdocs who are on that paper are now professors – this is the best of the best that we put on that project.

And what did you actually do?

We took a jellyfish, and did a bunch of studies to understand how it activates its muscles. We studied its propulsion and we made a map of where every single cell was. We used a software programme that we had developed a few years ago, borrowed from law enforcement agencies for doing quantitative analysis of fingerprints, and we used it to analyse the protein networks inside the cells.

We found something very interesting right away: the electrical signals that the jellyfish uses to coordinate its pumping are exactly like that of the heart. In the heart, the action potential [electrical signal that travels along nerves – Ed] propagates as a wave through cardiac muscle. That’s how you get this nice, smooth contraction. The activation has to spread like when you drop a pebble in water. The same thing happens in the jellyfish, and I don’t think that’s by accident. My bet is that to get a muscular pump, the electrical activity has got to spread as a wavefront

After we had the map of where every cell was, we took a rat apart and rebuilt it as a jellyfish.

Why study jellyfish?

The one that we used is a juvenile – it’s like a thin monolayer of cells. It’s a very simple structure to build.

The great thing about this is that most tissue engineering is just arts and crafts. We throw cells together and we say, ‘It looks like a liver; there’s a bunch of cells’. Or we throw heart cells together and hope that we build bits of heart. But if I’m building an aircraft or bridge, we don’t just throw concrete and aluminium and alloys together. We do mechanical testing on the substrates. We have mathematical models and computer simulations to understand the flight of the aircraft. We know how the bridge is going to work. Some engineers build out of copper or concrete or steel. I build things out of cells. If I’m going to be an engineer rather than an artist, I’m going to need to build quality control methods into what I’m doing.

Nobody is going to get into an airplane unless they’ve done computer simulations and assumed that they’ve manufactured this within allowable tolerance. It’s not just guesswork. No one’s going to want a tissue-engineered heart or other organ put into their body unless they’ve got some manufacturers’ specification. The great thing about the jellyfish is that you can do all these highly quantitative propulsion studies. That’s why I had to have John Dabiri’s team with this – they’re the best in the world at biological propulsion. And we were able to match quantitatively match the exact same propulsion characteristics in our medusoid – our engineered jellyfish – as the real one.

The most interesting thing is that the mouth of the jellyfish is inside the bell. In order to feed itself, it creates a vortex on the power stroke that throws particulate matter up towards its mouth. We thought if we’re good, if we’re really good at this, we’re going to recreate that vortex, and we did. We found that it depended on some very precise organisation of the protein networks inside the cells.

The whole idea was to bring engineering design methodology with tissue engineering, with a very rigorous set of parameters to show that our tissue-engineered jellyfish is very much a jellyfish. Morphologically, we’ve built a jellyfish. Functionally, we’ve built a jellyfish. Genetically, this thing is a rat.

So, the jellyfish isn’t the endpoint. The point of building it, and getting it to behave exactly like a normal jellyfish, is to show how much you understand about how the cells work. Is that it?

That’s right, but it depends on the lens through which you do this. For the marine biologist who’s interested in how jellyfish swim, we’ve demonstrated how important the muscular structure is and the protein alignment inside these cells for the jellyfish to survive and feed itself. The jellyfish scientist looks at this different rather than someone who’s trying to mimic biological propulsion. They look at this as how do you build something that can propel itself with this peristaltic pumping. The tissue engineer looks at this as applying the tissue engineering methodology to the highest possible standard to tissue engineering, which hadn’t been done before.

If you’re a cardiovascular physiologist or a company doing discovery, you look at this and say: wow, for years, all we’ve measure in a dish is contractility. But there’s a big difference between that and pumping. Now we’ve shown that we can build a muscular pump in a dish. You’ve got a heart drug? You let me put it on my jellyfish, and I’ll tell you if it can improve the pumping.

The first two or three years of any drug’s lifetime is always spent in a dish. We filed a patent on this to use this and variations on it as a drug discovery assay. The next stage is to see if we can build this out of human cells. And we’ll probably build a variation on the jellyfish for actual drug-testing.

In your paper, you describe the jellyfish as a synthetic organism.

Usually when we talk about synthetic life forms, somebody will take an existing living cell and put new genes into the cell so that it behaves in a different manner. That’s synthetic biology but I think it’s overstating what you did. We built an animal. I think we’re taking synthetic biology to a new level. It’s not just about genes. It’s about morphology and function.

So has this study got you further towards understanding the “fundamental laws of muscular pumps”?

Yeah it has. The heart and your guts both have action potential wavefronts that propagate through the tissue. We’re going to try this in an octopus and squid, but my bet is that to get a muscular pump, you have to organise the electrical activity in the same way. You have this clean wavefront, not a single pulse down a one-dimensional nerve fibre. It’s got to spread as a wavefront.

We also found that the muscle cells in a jellyfish are shaped freakishly differently to a cardiac muscle cell. But if you strip away the outer part of the cells, the protein networks within that cell are universally built in the same way and aligned among cellular aggregates in the same way. We think structure begets function. What I’m really pleased about is that everything that my group has learned about the heart in terms of structure and function equally applies to the jellyfish. I feel like we’re learning some fundamental biology here. Some people do basic biology by deconstructing stuff. Engineers do basic science in a different way. What we’ve done is learned something about the basic science by building it de novo.

What’s next?

Bait. Tissue-engineered bait. I want to go fishing and have a much better form of bait. That’s the only thing that’s going to impress my family. They could care less about this high-order science. They want to know if they can win a bass tournament.

Seriously, there are lots of different things. We’re going to develop this into assays for drug discovery. That’s pretty important to use. We’re working on that. We’re looking to reverse-engineer other marine life-forms too; we’ve got a whole tank of stuff in there, and an octopus on order. We’re trying to build larger and smaller versions of the jellyfish so we can look at drug effects.

Engineering mosquito gut bacteria to fight malaria

By Ed Yong | July 16, 2012 3:00 pm

A malarial mosquito is a flying factory for Plasmodium – a parasite that fills its guts, and storms the blood of every person it bites. By hosting and spreading these parasites, mosquitoes kill 1.2 million people every year.

But Plasmodium isn’t the only thing living inside a mosquito’s guts. Just as our bowels are home to trillions of bacteria, mosquitoes also carry their own microscopic menageries. Now, Sibao Wang from Johns Hopkins Bloomberg School of Public Health has transformed one of these bacterial associates into the latest recruit in our war against malaria. By loading it with genes that destroy malarial parasites, Wang has turned the friend of our enemy into our friend.

Many groups of scientists have tried to beat malaria by genetically modifying the species of mosquito that carries it – Anopheles gambiae. Marcelo Jacobs-Lorena, who led Wang’s new study, has been at the forefront of these efforts. In 2002, his team loaded mosquitoes with a modified gene so that their guts produce a substance that kills off Plasmodium.

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Will we ever grow organs?

By Ed Yong | February 28, 2012 9:00 am

Here’s the second piece for my new BBC column. From now on, they’ll be every two weeks.

In June 2011, an Eritrean man entered an operating theatre with a cancer-ridden windpipe, but left with a brand new one. People had received windpipe transplants before, but Andemariam Teklesenbet Beyene’s was different. His was the first organ of its kind to be completely grown in a lab using the patient’s own cells.

Beyene’s windpipe is one of the latest successes in the ongoing quest to grow artificial organs in a lab. The goal is deceptively simple: build bespoke organs for individual patients by sculpting them from living flesh on demand. No-one will have to wait on lengthy transplant lists for donor organs and no-one will have to take powerful and debilitating drugs to prevent their immune systems from rejecting new body parts.

The practicalities are, as you can imagine, less straightforward. Take the example I have already described. The process began with researchers taking 3D scans of Beyene’s windpipe, and from these scans Alexander Seifalian at University College London built an exact replica from a special polymer and a glass mould. This was flown to Sweden, where surgeon Paolo Macchiarini seeded this scaffold with stem cells taken from Beyene’s bone marrow. These stem cells, which can develop into every type of cell in the body, soaked into the structure and slowly recreated the man’s own tissues. The team at Stockholm’s Karolinska University Hospital incubated the growing windpipe in a bioreactor – a vat designed to mimic the conditions inside the human body.

Two days later, Macchiarini transplanted the windpipe during a 12-hour operation, and after a month, Beyene was discharged from the hospital, cancer-free. A few months later, the team repeated the trick with another cancer patient, an American man called Christopher Lyles.

Macchiarini’s success shows how far we have advanced towards the goal of bespoke organs. But even researchers at the cutting edge of this area admit that decades of research lie ahead to overcome all obstacles.

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CATEGORIZED UNDER: Biotechnology, Medicine & health

Genetically engineered silkworms with spider genes spin super-strong silk

By Ed Yong | January 3, 2012 9:00 am

In a lab at the University of Wyoming, some silkworms are spinning cocoons of silk, just as every silkworm has done for millions of years. But these insects are special. They have been genetically engineered to spin a hybrid material that’s partly their own silk, and partly that of a spider. With spider DNA at their disposal, they can weave fibres that are unusually strong and tough. It’s the latest step in a decades-long quest to produce artificial spider silk.

Spider silk is a remarkable material, wonderfully adapted for trapping, crushing, climbing and more. It is extraordinarily strong and tough, while still being elastic enough to stretch several times its original length. Indeed, the toughest biological material ever found is the record-breaking silk of the Darwin’s bark spider. It’s 10 times tougher than Kevlar, and the basis of webs that can span rivers.

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Without some basic science, GM mosquitoes won't bite

By Ed Yong | November 14, 2011 4:49 pm

There have been several stories recently about genetically modified mosquitoes, bred for the purpose of fighting diseases like malaria and dengue fever. These are exciting, sophisticated techniques, but in a new piece for Slate, I argue that they’re being let down by the fact that we still don’t know a lot about basic mosquito biology, like thier mating behaviour. Ecology may not be as sexy as tinkering with genes, but history teaches us that it’s vital if these approaches are to work.

Here’s a taster; head to Slate for more.

But all of these recent attempts to turn mosquitoes into malaria- and dengue-killing machines have something in common: The modified mosquitoes need to have lots of sex to spread their altered genes through the wild population. They must live long enough to become sexually active, and they have to compete successfully for mates with their wild peers. And that is a problem, because we still know surprisingly little about the behavior and ecology of mosquitoes, especially the males. How far do they travel? What separates the Casanovas from the sexual failures. What affects their odds of survival in the wild? How should you breed the growing mosquitoes to make them sexier? Big question marks hang over these seemingly straightforward questions.

Heather Ferguson from the University of Glasgow studies mosquito ecology. She views the knowledge gap in this field as a significant obstacle that stands in the way of the GM-mosquito initiatives. History tells us how dismally such initiatives can fare if they are not constructed on solid ecological foundations. In the 1970s and 1980s, several groups tried to control the mosquito population by releasing sterile males that would engage females in fruitless sex. The vast majority of the experiments failed.

Their poor performance is often blamed on the fact that the males were sterilized with damaging doses of radiation. But they had many other disadvantages. Lab-bred mosquitoes are frequently reared in large, dense groups, which produces smaller, less competitive individuals. The artificial lights of a lab could also entrain their body clocks to the wrong daily rhythms, driving them to search for mates at the wrong time of the day. And in several cases, the modified males ignored the wild mosquitoes and preferred to mate with their lab-reared kin instead. These problems went unnoticed in lab tests, where the modified mosquitoes were compared with unaltered ones that had been raised in the same conditions. They seemed to be perfectly competitive, but they proved to be feeble challengers to their wild peers.

Picture by James Gathany

Living invisible ink

By Ed Yong | September 27, 2011 9:00 am

I’ve got a new piece in Nature News about a cool new technique that uses glowing bacteria to send encrypted messages. There’s lots to like about this: they call the technique SPAM, they reference Mission Impossible in the paper, and the whole thing is actually funded by DARPA (the US Defense Advanced Research Projects Agency).

But most importantly of all, it allowed me to get Godwin’s Law into Nature (3rd paragraph from bottom). Thanks Meredith L Patterson!

From the piece (do read the full one):

For millennia, people have written secret messages in invisible ink, which could only be read under certain lights or after developing with certain chemicals. Now, scientists have come up with a way of encoding messages in the colours of glowing bacteria.

The technique, dubbed steganography by printed arrays of microbes (SPAM), creates messages that can be sent through the post, unlocked with antibiotics and deciphered using simple equipment.

Manuel Palacios, a chemist at Tufts University in Medford Massachusetts, [encrypted] messages using seven strains of Escherichia coli bacteria. Each one was engineered to produce a different fluorescent protein, which glows in a different colour under the right light.

Colonies of bacteria are grown in rows of paired spots, every combination of two colours corresponding to a different letter, digit or symbol. For example, two yellow spots signify a ‘t’, whereas an orange and a green spot denote a ‘d’. Once grown, the pattern of colonies is imprinted onto a nitrocellulose sheet, which is posted in an envelope. The recipient can use the sheet to regrow the bacteria in the same pattern and decipher the message.

Reference: Palacios, Benito-Pena, Manesse, Mazzeo, LaFratta, Whitesides & Walt. 2011. InfoBiology by printed arrays of microorganism colonies for timed and on-demand release of messages. PNAS http://dx.doi.org/10.1073/pnas.1109554108

CATEGORIZED UNDER: Bacteria, Biotechnology, Technology

Bacteria use electric wires to shock uranium out of groundwater

By Ed Yong | September 5, 2011 3:00 pm

Even today, the legacy of the Cold War leaches into the waters of Colorado. Uranium, freed from the earth and destined for nuclear weapons, now contaminates the groundwater beneath several Colorado mines. But at some of these mines, a most unusual clean-up crew is at work. Lashing about with long electric cables connected to their own bodies, they remove dissolved uranium from the water. Each one of these janitors is just a thousandth of a millimetre across. They’re called Geobacter. They’re bacteria.

The handful of Geobacter species are recent discoveries. The first one, G.metallireducens, was discovered in the Potomac River in 1987. Another, G.sulfurreducens, was later found in oil-soaked Oklahoman soils. The group has the remarkable and useful ability to break down a range of contaminating chemicals, such as petroleum compounds. While humans use oxygen to rend carbon compounds into carbon dioxide and water, Geobacter can use iron oxides and other metals for the same purpose. Roughly speaking, it breathes metal and rock.

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CATEGORIZED UNDER: Bacteria, Biotechnology, Select

Scientists engineer suicide bomber bacteria to kill other bacteria

By Ed Yong | August 16, 2011 9:00 am

In a lab in Singapore, scientists are designing and breeding suicide bombers. If their efforts pan out, they will be applauded rather than jailed, for their targets are neither humans nor buildings. They’re bacteria.

Nazanin Saeidi and Choon Kit Wong have found a new way of killing Pseudomonas aeruginosa, an opportunistic species that thrives wherever humans are weak. It commonly infects hospital patients whose immune systems have taken a hit. It targets any tissue it can get a foothold on – lungs, bladders, guts – and it often causes fatal infections. To seek and destroy this threat, Saiedi and Wong have used the common lab bacterium Escherichia coli as a sacrificial pawn.

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Hacking the genome with a MAGE and a CAGE

By Ed Yong | July 14, 2011 4:00 pm

It couldn’t be easier to make sweeping edits on a computer document. If I were so inclined, I could find every instance of the word “genome” in this article and replace it with the word “cake”. Now, a team of scientists from Harvard Medical School and MIT have found a way to do similar trick with DNA. Geneticists have long been able to edit individual genes, but this group has developed a way of rewriting DNA en masse, turning the entire genome of a bacterium into an “editable and evolvable template”.

Their success was possible because the same genetic code underlies all life. The code is written in the four letters (nucleotides) that chain together to form DNA: A, C, G and T. Every set of three letters (or ‘codon’) corresponds to a different amino acid, the building blocks of proteins. For example, GCA codes for alanine; TGT means cysteine. The chain of letters is translated into a chain of amino acids until you get to a ‘stop codon’. These special triplets act as full stops that indicate when a protein is finished.

This code is virtually the same in every gene on the planet. In every human, tree and bacterium, the same codons correspond to the same amino acids, with only minor variations. The code also includes a lot of redundancy. Four DNA letters can be arranged into 64 possible triplets, which are assigned to only 20 amino acids and one stop codon. So for example, GCT, GCA, GCC and GCG all code for alanine. And these surplus codons provide enough wiggle room for geneticists to play around with.

Farren Isaacs, Peter Carr and Harris Wang have started to replace every instance of TAG with TAA in the genome of the common gut bacterium Escherichia coli. Both are stop codons, so there’s no noticeable difference to the bacterium – it’s like replacing every word in a document with a synonym. But to the team, the genome-wide swap will eventually free up one of the 64 triplets in the genetic code. And that opens up many possible applications.

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