A Blog by Erika Engelhaupt

Surgeon Reveals Head Transplant Plan, But Patient Steals the Show

ANNAPOLIS, Md.—Valery Spiridonov looks impossibly small. He is dressed in all white, from his white button-down shirt to the white socks on his feet, which dangle at the ends of white pants and a white blanket. Breaking up the look is a black strap, which holds him to a motorized wheelchair.

He uses his left hand, which he can still move, a little bit, to steer the wheelchair into a hotel meeting room. There, he confirms that he would like to be the first person ever to have his head transplanted onto a new body.

Spiridonov flew from Russia to be at this conference, the American Academy of Neurological and Orthopaedic Surgeons (AANOS). He joined the surgeon proposing to do the transplant, Sergio Canavero of Turin, Italy. Canavero had built up his talk, a keynote address, for months, promising a big reveal of his plans to transplant Spiridonov’s head onto a donor body. (For background, see my earlier blog post and a good overview at New Scientist.)

The meeting is small, maybe 100 or fewer surgeons, and held in a very normal-looking Westin hotel in Annapolis, Md. Conference organizer Maggie Kearney spent much of the day turning away reporters in anticipation of a packed room. She says that in 15 years, she can’t remember a reporter ever attending the surgical conference before.

By the end of Canavero’s three-hour-long presentation (it was supposed to be an hour and a half, Maggie tells me), most of the reporters in the room seem worn out, and a bit confused about what the fuss was all about.

Sergio Canaveros
Sergio Canaveros, right.
Erika Engelhaupt

Canavero reviewed, at length, the scientific literature on spinal cord injury and recovery, regrowth of various parts of the central nervous system, and why some of the basic assumptions of neurosurgery are wrong. Throughout the lecture, he would occasionally point to Valery Spiridonov, his wheelchair parked near the stage, and make a declaration (“Propriospinal tract neurons are the key that will make him walk again!”).

Answering detractors’ comments that the transplant could be “worse than death” or could drive Spiridonov insane, Canavero asked Spiridonov directly, “Don’t you agree that your [current] condition could drive you to madness?”

Spiridonov answered quietly in the affirmative.

His condition is grave: a degenerative motor neuron disease that is slowly killing him. “I am sure that one day gene therapy and stem cells will fulfill their future,” Canavero said, “but for this man it will come too late.”

Finally, near the end of the talk, Canavero roughly outlined the surgery. He plans to sever the spinal cord very cleanly, using a special scalpel honed nano-sharp. (I could not see Spiridonov’s reaction to the special scalpel, but wondered.)

To minimize any die-off of cells at the severed ends during the transfer, Canavero says he will cut Spiridonov’s spinal cord a bit lower on the spine than needed, and the body’s a bit higher, and then at the last minute slice them again for a fresh cut. Then, add some polyethylene glycol (shown to stimulate nerve regrowth in animals), join the two ends together with a special connector, and voila. Electrical stimulation would then be applied to further encourage regrowth.

Of course, there’s a bit more to it, like reconnecting all the blood vessels and so forth, but Canavero is a neurosurgeon and the spinal cord was his focus.

Other neurosurgeons at the meeting responded cautiously to the proposal. The surgery might be possible “someday, but it is really a delicate situation,” said Kazem Fathie, a former chair of the board of AANOS.

Craig Clark, a general neurosurgeon in Greenwood, Mississippi, calls Canavero’s idea “very provocative.”

“There have been many papers over the years that have shown regeneration, but for one reason or another they didn’t pan out when applied clinically,” he said.

“There’s a lot of ethical questions about it,” said neurosurgeon Quirico Torres of Abilene, Texas. But Torres thinks it could be ethical to allow volunteers to do the surgery, and one day we might consider it normal. “Remember, years ago people were questioning Bill Gates: why do you need a computer? And now we can’t live without it.”

What’s Next?

Apart from the rundown of previous work on spinal cord injury, much of what Canavero said about the surgery was pretty much what he has said before. He supported his arguments for individual elements of a head transplant (or body transplant, if you prefer) but did not reveal any new demonstration of the entire procedure working in a person or an animal.

But Canavero has no shortage of confidence. He says he wants to do the surgery in America (implying Italy doesn’t have its act together enough to host a cutting-edge project like this).

“I have a detailed plan to do it,” he said, adding that he is asking Bill Gates and other billionaires to donate. He invited surgeons at the meeting to join his team, which could be enormous—more than 100 surgeons, he has said—and he wants team leaders in orthopedics, vascular surgery, and so on. These surgeons should work on the project full time for the next two years, he said, “and you will be paid through the nose, because I think doctors involved in this should be paid more than football players.”

chair
Valery Spiridonov entering the conference room. Photo: Erika Engelhaupt

After the talk, Spiridonov disappeared into a room to rest. When he came back out, he answered questions for the TV crews that had descended, sounding a bit weary of answering the same questions he’s been asked before. “What will happen to you if you don’t get this surgery?” a reporter called out. “My life will be pretty dark,” he said. “My muscles are growing weaker. It’s pretty scary.”

He looked tired.

During his interviews, I stepped aside to talk with his hosts in Annapolis, who are friends of a friend of the Spiridonov family. “He’s brilliant, he’s happy, he’s funny,” said Briana Alessi. “If this surgery were to go through and if it works, it’s going to give him a life. It’s life-changing. He’ll be able to do the things he could only dream of.”

And if not? “He’s taking a chance either way,” she said.

The final question he takes from the press: What do you say to people who say this surgery should not be done?

Spiridonov’s reply: “Maybe they should imagine themselves in my place.”

A Blog by Erika Engelhaupt

Injecting Electronics Into Brain Not as Freaky as it Sounds

No need to wait for the cyborg future—it’s already here. Adding to a growing list of electronics that can be implanted in the body, scientists are working to perfect the ultimate merger of mind and machine: devices fused directly to the brain.

A new type of flexible electronics can be injected through a syringe to unfurl and implant directly into the brains of mice, shows a study published Monday in Nature Nanotechnology. Researchers injected a fine electronic mesh and were able to monitor brain activity in the mice.

“You’re blurring the living and the nonliving,” says Charles Lieber, a nanoscientist at Harvard and co-author of the study. One day, he says, electronics might not only monitor brain activity but also deliver therapeutic treatments for Parkinson’s disease, or even act as a bridge over damaged areas of the brain. Deep brain stimulation is already used for Parkinson’s, but uses relatively large probes, which can cause formation of scar tissue around the probe.

The tiny size (just a couple of millimeters unfurled) of the new devices allow them to be placed precisely in the brain while minimizing damage, a separate team of Korean researchers note in an accompanying article. Ultimately, the goal is to interweave the electronics so finely with brain cells that communication between the two becomes seamless.

And that’s just the latest in the merging of electronics into the human body. While Lieber envisions using the implants in science and medicine—for example, to monitor brain activity and improve deep-brain stimulation treatment for Parkinson’s disease—others are already using non-medical electronic implants to become the first generation of cyborgs. These do-it-yourselfers call themselves biohackers, and they aren’t waiting for clinical trials or FDA approval to launch the cybernetic future.

At the website Dangerous Things, you can buy a kit—complete with syringe, surgical gloves and Band-Aid—to inject a small electronic device into your own body. The kits use a radio-frequency ID tag, or RFID, similar to the chips implanted to identify lost dogs and cats. These can be scanned to communicate with other devices. The site warns that implanting the chips should be done with medical supervision and “is strictly at your own risk.”

X-Ray Amal Graafstra
An X-ray image of Amal Graafstra’s hands shows the two electronic tags he had implanted. Image: Dangerous Things

The website’s charismatic founder, Amal Graafstra, has  RFID implants in each hand, and can use them to unlock doors and phones, log into computers, and start his car by waving a hand.

“One of the holy grails of biohacking is the brain-computer interface,” Graafstra says. He likens brain-wiring efforts so far to eavesdropping on neural activity with a glass to our ears and then shouting back with a bullhorn; electronics simply overwhelm the subtle communication between brain cells. “The ultimate goal, I think, would be a synthetic synapse,” he says, in which nanomaterials would function much like living brain cells, allowing far more nuanced communication between mind and machine.

An article in the Telegraph in October 2014 sums up today’s state of the art in brain-hacking:

“Quietly, almost without anyone really noticing, we have entered the age of the cyborg, or cybernetic organism: a living thing both natural and artificial. Artificial retinas and cochlear implants (which connect directly to the brain through the auditory nerve system) restore sight to the blind and hearing to the deaf. Deep-brain implants, known as “brain pacemakers,” alleviate the symptoms of 30,000 Parkinson’s sufferers worldwide. The Wellcome Trust is now trialling a silicon chip that sits directly on the brains of Alzheimer’s patients, stimulating them and warning of dangerous episodes.”

The goal of a complete merger of biology and technology is exciting to champions of transhumanism, which aims to enhance human intelligence, abilities, and longevity through technology.

But not everyone is thrilled about a future filled with genetic engineering, artificial intelligence, and cyborg technology. Implanting electronics in the brain, more so than in the hands or even the eye, goes directly to one of the biggest fear about cyborgs: a threat to free will. Could someone hijack an implant to control its user’s thoughts or actions? Or to read their minds?

That’s unrealistic, at least with current technology. The kinds of electronics that Lieber and others are working on have inherently limited use—such as delivering a small electric pulse to a particular spot—and would be useful only to people with a serious medical condition.

“Some people think we’re going to implant a microprocessor in people’s heads,” Lieber says, “but that has to interface to something.” And a tiny electronic device attached to one part of the brain simply cannot take over a person’s thoughts. “There’s always going to be someone interested in doing something bad,” he adds, so it’s important to monitor the technology as it becomes more sophisticated.

Graafstra says biohacking has “some maturing to do,” and studies like Lieber’s are a good step in bringing scientific rigor to what has at times been a Wild West.

“I think the biohacker understands that we are our brains,” he says. “You are your mind, and the body is the life support system for the mind. And like an SUV, it’s upgradeable now.”

 

A Blog by Carl Zimmer

Talking About Editing Human Embryos on the Radio

This morning I went on the NPR show “On Point” to talk about using CRISPR to edit embryos. I’ve embedded it below, and you can also listen to it at this link.

It was fascinating to listen to my fellow guests. Nobel-prize winner Craig Mello basically said that if we can make it safe, then let’s go for it.  Marcy Danovsky of the Center for Genetics and Society argued that the world needed to put rules in place to ban human germline engineering.

Towards the end of the show, I went on a bit of an anti-GATTACA rant. GATTACA, in case you haven’t seen it, is a movie that puts a biotech twist on Brave New World. Danovsky and other critics frequently warn that embryo editing could lead to a world like the movie–in other words, rich people would create a genetically altered population of super-smart, super-healthy people, leaving the have-nots in the dust.

If we’re going to talk about international bans, I’d like an international ban on invoking GATTACA in these discussions. It’s like saying, “We shouldn’t genetically engineer people because we will end up with an army of flying monkeys who will enslave the rest of us.” I mean, we can imagine an army of flying monkey overlords, and we can all agree that an army of flying monkey overlords would be a bad thing. But is that the most useful way to talk about the real social and medical impacts of a new technology?

Here are a few reasons for my view:

1. Good luck genetically engineering intelligence. We could clearly cure hemophilia with CRISPR, because it’s caused by a single mutation to a single gene. But the genetic basis of intelligence involves hundreds of genes, as far as scientists can tell, and their effects are very dependent on the environment in which a child grows up.

2. Genes get around. The only way to keep the GATTACA flying monkeys as a distinct population would be to stop them from having children with unengineered people. That would require social engineering that would make the genetic engineering look like a grade school science fair project.

3. You don’t need CRISPR to create health inequity. We already live in a world with big inequities in well-being. We didn’t have to wait for genetic engineering to make that happen. And the fact that CRISPR could create inherited changes is also not so special. Socially based inequities get passed down through the generations too. This kind of argument would disappear if the world agreed to provide free CRISPR engineering to all prospective parents if they wanted it.

So let’s have a debate without the flying monkeys, shall we?

A Blog by Ed Yong

A Personalised Mini-Stomach, Grown in a Dish

In a lab at Cincinnati Children’s Hospital Medical Center, a series of small blobs sit in a Petri dish. They’re white, hollow, and the size of small peas.

They are stomachs.

More precisely, they are lab-grown model stomachs. Graduate student Kyle McCracken worked out how to make them by coaxing stem cells into producing stomach tissue—a feat that no one had yet managed. The results look like simple baubles, but the growing cells somehow organise themselves into the classic architecture of an actual stomach. They make the right layers, folds, and pockets, and they switch on the usual genes. “They’re not mixed bags of cells,” says Jim Wells, who led the study. “They look shockingly like mini-stomachs.”

These creations, known as gastric organoids, are more representative of our actual organs than cultured stomach cells, which lack any three-dimensional structure, or lab mice, which don’t suffer from stomach diseases in the same way as us. They’re not going to help you digest your meals, but they do open the door to experiments that couldn’t be done before.

For example, we know that diseases like ulcers and stomach cancer are mostly caused by a bacterium called Helicobacter pylori. This spiralling microbe has been humanity’s companion since our origins in Africa, and used to infect the majority of people. It colonises us during childhood and stays with us for decades, and even helps us to regulate the acids in our stomachs. But it can also cause disease, typically later in life.

Many scientists have studied H.pylori and how it affects the stomach for decades. Some have even won Nobel prizes for their efforts. But the moments when the microbe colonises a young stomach—those very first handshakes between host and bacterium—are still a mystery, and one that Wells hopes the organoids can solve. “Now we can say: Bacteria, meet stomach,” says Wells. “Then, what happens?”

The gastric organoids are the latest in a growing line of ‘organs-in-a-dish’. Other scientists have used stem cells to grow versions of many other organs, including eyes, guts, kidneys, and even brains. But growing stomachs proved to be exceptionally challenging, because the team didn’t have a clear map to follow.

Through decades of work, researchers have thoroughly charted the genes and molecules that turn stem cells into different organs, and followed these steps to direct the development of the equivalent organoids. But the stomach is the Ringo of viscera—it doesn’t get a lot of attention compared to starrier neighbours like the liver or pancreas. “We just didn’t have a good blueprint for how the stomach forms,” says Wells. They had to work that out for themselves.

For example, McCracken showed that two genes, WNT3A and FGF4, work together to convince a ball of stem cells to create a gut tube—a primitive tube that eventually becomes the entire digestive system. The gut tube divides into three sections and the stomach develops from the first of these—the foregut. To make that, the team had to block a gene called BMP that defines the later sections. In similar ways, McCracken had to identify genes and chemicals that tell the developing organoids to make a complex lining, full of glands that secrete digestive juices and cells that release appetite-controlling hormones.

For the moment, the organoids are still immature. They’re like the stomach of a third-trimester foetus, so they lack some of the features that adult organs have. They also represent just one part of the stomach—the antrum, which connects it to the intestine. The team are now working on developing the other part—the acid-secreting fundus.

But as they stand, the organoids can already be used for experiments. Team member Yana Zavros found that they react to H.pylori much like actual stomachs would. The bacteria stick to their linings and trigger the growth of more cells, but only if they carried a gene called CagA. This gene makes a protein that H.pylori can injects into its host’s cells to exert its influence over them. It’s an interaction gene, and strains with CagA are more likely to cause stomach cancer and to protect against oesophageal cancer. The organoids could help scientists to study both of these effects.

They can also be personalised. Wells’ team can take your cells, revert them to stem cells, and create a miniature version of your stomach in a dish.

There’s a lot of potential there. You could see how different strains of H.pylori affect people from different parts of the world, for example. We know this match between host and microbes is important. In some regions, people have much higher rates of stomach cancer because they carry H.pylori strains that don’t share their ancestry. With organoids, perhaps scientists can work out why that is, or whether your particular strains are going to cause trouble in your particular stomach.

Reference: McCracken, Cata, Crawford, Sinagoga, Schumacher, Rockich, Tsai, Mayhew, Spence, Zavros & Wells. 2014. Modelling human development and disease in pluripotent stem-cell-derived gastric organoids. Nature http://dx.doi.org/10.1038/nature13863

More on organoids:The Cerebral Organoid, a Lab-Grown Model Brain

A Blog by Ed Yong

An Electric Sock For the Heart

The titles of scientific papers can be a bit intimidating. For example, I’m currently reading “3D multifunctional integumentary membranes for spatiotemporal cardiac measurements and stimulation across the entire epicardium”.

In other words: electric heart socks.

A team of scientists led by John Rogers at the University of Illinois at Urbana-Champaign has created a web of electronics that wraps around a living heart and measures everything from temperature to electrical activity. It’s an ultra-thin and skin-like sheath, which looks like a grid of tiny black squares connected by S-shaped wires. Its embrace is snug and form-fitting, but gentle and elastic. It measures the heart’s beats, without ever impeding them.

Electronic cardiac sock

Its goal is to monitor the heart in unprecedented detail, and to spot the unusual patterns of electrical activity that precede a heart attack. Eventually, it might even be able to intervene by delivering its own electrical bursts.

Cardiac socks have been around since the 1980s but the earliest ones were literal socks—fabric wraps that resembled the shape of the heart, with large electrodes sewn into place. They were crude devices, and the electrodes had a tough time making close and unchanging contact with the heart. After all, this is an organ known for constantly and vigorously moving.

The new socks solve these problems. To make one, graduate students Lizhi Xu and Sarah Gutbrod scan a target heart and print out a three-dimensional model of it. They mould the electronics to the contours of the model, before peeling them off, and applying them to the actual heart. They engineer the sock to be ever so slightly smaller than the real organ, so its fit is snug but never constraining.

This is all part of Rogers’ incredible line of flexible, stretchable electronics. His devices are made of mostly made of the usual brittle and rigid materials like silicon, but they eschew right angles and flat planes of traditional electronics for the curves and flexibility of living tissues. I’ve written about his tattoo-like “electronic-skin”, curved cameras inspired by an insect’s eye, and even electronics that dissolve over time.

The heart sock is typical of these devices. The tiny black squares contain a number of different sensors, which detect temperature, pressure, pH, electrical activity and LEDs. (The LEDs shine onto voltage-sensitive dyes, which emit different colours of light depending on the electrical activity of the heart.) Meanwhile, the flexible, S-shaped wires that connect them allow the grid to stretch and flex without breaking. As the heart expands and contracts, the web does too.

So far, the team have tested their device on isolated rabbit hearts and one from a deceased organ donor. Since these organs are hooked up to artificial pumps, the team could wilfully change their temperature or pH to see if the sensors could detect the changes. They could. They could sense when the hearts switched from steady beats to uncoordinated quivers.

Rogers thinks that tests in live patients are close. If anything, the doctors he is working with are more eager to push ahead. “We’re scientists of a very conservative mindset. They have patients who are dying,” he says. “They have a great appetite for trying out good stuff.”

The main challenge is to find a way of powering the device independently, and communicating with it wirelessly, so that it can be implanted for a long time. Eventually, Rogers also wants to add components that can stimulate the heart as well as recording from it, and fix any aberrant problems rather than just divining them.

It’s a “remarkable accomplishment” and a “great advance in materials science”, says Ronald Berger at Johns Hopkins Medicine, although he is less sure that the device will be useful is diagnosing or treating heart disease. “I don’t quite see the clinical application of these sensors.  There might be some therapy that is best implemented with careful titration using advanced sensors, but I’m not sure what that therapy is.”

But Berger adds that the sock has great promise as a research tool, and a couple of other scientists I contacted agree. After all, scientists can use the device to do what other technologies cannot: measure and match the heart’s electrical activity and physical changes, over its entire surface and in real-time.

For more on John Rogers’ flexible electronics, check out this feature from Discover that I co-wrote with Valerie Ross.

Reference: Xu, Gutbrod, Bonifas, Su, Sulkin, Lu, Chung, Jang, Liu, Lu, Webb, Kim, Laughner, Cheng, Liu, Ameen, Jeong, Kim, Huang, Efimov & Rogers. 2014.  3D multifunctional integumentary membranes for spatiotemporal cardiac measurements and stimulation across the entire epicardium. Nature Communications. http://dx.doi.org/ 10.1038/ncomms4329

A Blog by Ed Yong

Insect-Eye Digital Camera Sees What You Just Did

Almost all of our cameras form images by using a single lens to focus light onto a light-sensitive sheet. That’s how our own eyes actually work, but there are many other ways of seeing the world. Arthropods—insects, spiders and their kin—have compound eyes, which consist of hundreds or thousands of individual units or ommatidia. Each one has its own lens and light detectors. They form separate images, which are then united in the brain. And since arthropods greatly outnumber all other animals, the vast majority of eyes are compound ones.

Now, John Rogers from the University of Illinois at Urbana-Champaign has developed a camera that mimics compound eyes. It might not have the same resolution as a state-of-the-art digital camera, but it compensates with many advantages that make it ideal for surveillance. Perhaps in the future, we’ll be watched by man-made flies on the walls.

Rogers chose to mimic apposition eyes—a type of compound eye where each ommatidium sees a narrow part of the insect’s visual field, effectively capturing just one pixel of a full image.

First, his team makes a grid of tiny light-sensitive diodes out of silicon. They’re connected by flexible S-shaped wires that allow the grid to flex without breaking. On top of that, they lay a sheet of silicone (PDMS) that’s moulded into small bubble-shaped lenses, one sitting over each diode. The two layers are fused together and deformed into a dome. Each diode-and-lens combo acts as an ommatidium and the full camera has 180 of them, each pointing in a slightly different direction.

Fly-Eye-cameraThe camera builds on decades of Rogers’ work on flexible electronics—devices that are largely made of brittle, rigid materials like silicon, but can flex and curve like living tissues. He has created “electronic-skin” that can be applied like tattoos and used to measure muscle and nerve activity, sensors that can mould to the shape of the brain or heart, and even electronics that dissolve over time.

Rogers’ inventions include a flexible camera that’s based on our own eyes. Like other cameras, this one has a lens and a sheet of light detectors that acts as a retina. But while modern cameras have flat ‘retinas’, Rogers’ machine has a curved one, just like our actual eyes. This makes it more compact. Much of the weight of modern cameras comes from bulky secondary lenses that correct the incoming light so it can project onto a flat surface without distortions. With a curved retina, you don’t need these lenses, and the camera can shrink.

With one eyeball camera in the works, it might seem strange that the team decided to build a compound one too. After all, compound eyes—especially apposition ones—aren’t that sensitive to light and have fairly low resolution. Dan-E. Nilsson, who studies insect vision at Lund University, says, “The type of compound eye they have mimicked has long been known to be a poor solution to vision. And to have one private lens for every pixel in the image is the most inefficient use possible of the space available for an eye.”

But, wait! Compound eyes have some advantages. Since their ommatidia point in all directions, they give their owners a panoramic 180-degree view of the world that’s clear over the entire field of view. By contrast, our eyes can only see a narrow angle ahead of us, and the images they form are only sharp at the very centre of our visual field.

Compound eyes also have an almost infinite depth of field—that is, objects stay in focus regardless of how far they are from the eye. So, flies can clearly see something far and near objects at the same time, without having to adjust any lenses. And compound eyes are also exquisitely sensitive to movement, since their owners can compare the passage of shapes across different ommatidia.

Wide angles. Sharp focus at all distances. Sensitivity to movement. If you were building a surveillance camera, these are exactly the properties you’d want. Indeed, Rogers thinks that surveillance is an obvious application for his fly-eye design.

In a related editorial, Alexander Borst and Johannes Plett from the Max-Planck-Institute of Neurobiology suggest that the cameras might be useful for controlling tiny drones. At the moment, these use normal cameras with fish-eye lenses to give them a wide field of view. An insect-eye camera could do the same, while possibly making the robot more sensitive to movements.

“It’s great work, and a nice example of biomimetics,” says Nicholas Roberts from the University of Bristol, who studies animal eyes. Although it doesn’t tell us anything that “crosses back to biology”, the camera’s huge depth of field is a “nice benefit over single lens designs”.

And though Rogers admits that while the fly-eye camera will never match the resolution of a normal one, he thinks that’s not a deal-breaker. “If you can combine multiple images over time, you can effectively get a high resolution,” he says. “Surveillance cameras use this trick to spot speeding cars – the resolution from a single frame can’t identify the letters on a licence plate.”

There’s obviously room for improvement but with 180 ommatidia, the digital camera is already more sophisticated than the eyes of some insects—some worker ants, for example, only have 100 in each eye. But it’s a long way off from the best insect eyes, like those of the green darner dragonfly (28,000 ommatidia) or the praying mantis (15,000). For the moment, nature still wins.

Reference: Song, Xie, Malyarchuk, Xiao, Jung, Choi, Liu, Park, Lu, Kim, Crozier, Huang & Rogers. 2013. Digital cameras with designs inspired by the arthropod eye. Nature http://dx.doi.org/10.1038/nature12083

A Blog by Ed Yong

Can We Save the World by Remixing Life?

In 2011, a team of undergraduate students from Imperial College London devised a fresh way of halting the spread of deserts: Make bacteria that will persuade plants to grow more roots.

Drylands—areas that get little rain—cover around 40 percent of the Earth’s surface. They are already fragile places and a combination of drought, climate change, overgrazing, and unsustainable farming can finish off any plants precariously clinging to life there. Without roots to hold the soil together, wind and water erode the top layers, leaving only the infertile lower ones. In this way, more and more land transforms into barren desert with each passing year.

There are many possible ways of countering or preventing desertification but the Imperial team wanted to try something new. They added a set of genes to the gut microbe Escherichia coli that allow it to detect malate—a chemical released by plant roots. When placed in soil, the bacteria swim towards roots and gets taken up by the plant. Once inside, they use another second set of added genes to produce auxin, a hormone that stimulates the growth of roots. Longer roots mean more stable soil, which means less desertification.

Individually, the bacteria, genes and hormones are all found in nature. But it was the combination of these components that yielded a synthetic organism unlike anything seen before—a plant-tracking, root-making, soil-stabilising gut bug.

Remixing life

This project is just one example of synthetic biology, a growing field that brings engineering principles to the world of cells, genes and living things. It’s telling that the team described their creations in the lingo of engineers. They took genetic “parts” from a standardised registry, packaged them into different “modules” and shoved them into a bacterial “chassis”. Other scientists should be able to assemble the same parts in new combinations to do different jobs, just like Lego bricks.

Living things have been doing this for millions of years, borrowing “parts” from each other to survive in the world’s worst environmentsharness sunlight, snatch bodies, and destroy coffee. Synthetic biologists pull off similar tricks but with a dash of deliberate design. As in engineering, each part should have a specific purpose and its role in the whole should be predictable.

It’s grander in scope than most genetic modification, which involves modestly changing a few genes. By contrast, synthetic biologists work with large networks of genes to produce yeast that can brew antimalarial drugs instead of beer or cells that self-destruct if they turn cancerous. In his new book Creation, Adam Rutherford compares the field to the hip-hop scene of the 1970s, where DJs would start to create new music by mixing existing beats, riffs and lyrics. “Synthetic biology is remixing,” he wrote. “The ethos of this emergent scene is one of unprecedented and unbridled creativity.”

Take the root-making bacteria. It was the second-place winner of the 2011 iGEM (International Genetically Engineered Machine)—a vibrant talent competition where teams of undergrads design and build new genetic machines to solve a problem, using an inventory of standard “parts”. They have 10 weeks—it’s basically a summer project. While many college students spend similar projects on achingly dull menial tasks, the iGEM competitors tinker with biology before they even enter a PhD programme.

Two households, both alike in dignity

Chris Schoene, now at Oxford University, was part of the Imperial iGEM team and described their work at a conference at Cambridge, UK, entitled “How will synthetic biology and conservation shape the future of nature?” The meeting aimed to bridge these fields, which rarely talk but definitely should. Many of the mooted applications for synthetic biology have the potential to affect the planet for good or ill, from yeast engineered to make fuels, to plants modified to use resources more efficiently, to sensors that detect and break down pollutants.

But while both camps are often looking at the same problems, their outlooks are so different that tensions inevitably emerge. As conference organiser Kent Redford  from the Wildlife Conservation Society said, “Conservationists get more pessimistic when they drink, but synthetic biologists only get more optimistic.”

Synthetic biologists combine the brash hopefulness of people in a hot, growing field with the can-do attitudes of engineers. Like the iGEM competitors, they look for solutions and work backwards. But conservationists are facing huge and depressing challenges, and they’ve been burned by the unintended consequences of well-meaning solutions. Many hear “synthetic biology” and their minds race to creatures like cane toads and mongooses that were introduced to islands to deal with pests and ended up killing local wildlife instead. Or, as someone inevitably mentioned, Jurassic Park.

“It’s not like engineering a machine. If you make a really bad car, it won’t make itself,” said Steve Palumbi , an ecologist from Stanford University. If you make a mistake with a living thing, “you may be stuck with your ‘solution’ forever.”

Many of these concerns are longstanding ones, imported from debates over genetically modified organisms. Synthetic biology stands out if only for the complexity of its manipulations. Also, cheapening technology and the field’s free-spirited ethos mean that amateur “biohackers” now have the tools to run experiments in their garages or kitchens. As one delegate said, “There could be thousands of people making millions of invasive species.”

Adding known genes to well-studied microbes like E.coli, as the Imperial iGEM team did, is unlikely to have such dire consequences. But even then Paul Falkowski from Rutgers University noted that we have sequenced scores of microbial genomes, but still don’t know what 40 percent of the identified genes are doing. “We are monkeying with stuff we don’t really understand,” he says. “We say we’re going to invent a bug that will make a fuel and solve problems? It’s naive.”

Jim Haseloff, a synthetic biologist from the University of Cambridge who works on plants, understands the risks of introducing species into new environments (“I’m Australian!”). But he noted that possible harms are a given for any new technology. Focusing upon that ignores the fact that conservationists already face a dire uphill battle and need new solutions. “We’re living in an environment where we’re progressively eroding the natural environment—that’s the default,” he said. “Can we divert or deflect that harm?”

Peter Kareiva, chief scientist at the Nature Conservancy, adds that ecologists have learned from the lessons of the past. “Mongooses and Jurassic Park are old stories. Ecologists know not to release predators,” he says. By contrast, most modern invasive species are escapees from the pet and aquarium trade. Those are existing challenges that worry Kareiva more than any synthetic organisms might.

Still, risks exist, and Palumbi would be reassured if the synthetic biology community devoted as much creativity and cleverness into avoiding unintended consequences as it does into cool engineering fixes. “We want a culture where containment is as well-researched as creation,” he said.

Lego tigers. Credit: Stefan, via Flickr.
Lego tigers. Credit: Stefan, via Flickr.

Doing it right

Amid all the hype and hubris, the doom and gloom, Schoene’s root-making bacteria stood out as a tangible, grounded nexus for discussion. For starters, their goal seemed sensible. Jon Hoekstra from the World Wildlife Fund noted that the world has around 2 billion hectares of degraded land—an area the size of South America. Rehabilitating that land, either to create spaces where life can thrive or to grow crops that then don’t have to encroach on pristine spaces, is a goal that synthetic biology could realistically help with.

They were also wary of risks from the start and consulted extensively with biotech companies like Syngenta and environmental organisations like Greenpeace. Again and again, the same concern came up: Genes from the synthetic bugs might move into naturally occurring ones. Microbes, after all, can swap genes with tremendous ease, especially by exchanging mobile rings of DNA called plasmids.

So Schoene and his crew created a containment system called GeneGuard. They loaded their microbes with plasmids containing a toxin gene that kill the bacteria by making them literally split their sides. The only thing saving them is an antitoxin gene in the bacteria’s main genome. If the engineered bug passes its plasmid into a wild one, the recipient would make the toxin but not the anti-toxin, and self-destruct.

The team took steps to mitigate other risks. They chose to modify a gut bacterium rather than a more obvious soil-dweller like Bacillus subtilis because they didn’t want the engineered microbe to outcompete others in its environment. They consulted with ecologists who confirmed that the extra auxin wouldn’t cause problems if it leached into the soil, because it breaks down quickly outside a plant. They talked to the Berkeley Reafforestation Trust about how they might eventually piggyback off existing reforestation initiatives. And through panel discussions, they discussed whether the engineered bacteria could ever harm human health or hurt their plant partners.

“It’s a really nice example of not just solving a problem, but talking to people and finding out the issues that they’re concerned about,” said Keith Crandall, a geneticist from Brigham Young University. “That’s really the key— putting in safeguards that will satisfy the community.” The iGEM judges felt similarly, and specifically commended the team for being inclusive.

Plasters, panaceas and open doors

But the root-making bacteria also became a symbol for a different debate: Should synthetic biology play a role in conservation at all? Does it merely provide “sticking-plaster solutions” that seductively tackle some aspects of conservation problems, while distracting from more important issues. Desertification, for example, is largely caused by overgrazing. What will root-making bacteria do about that?

“The starting point of taking a tool and asking how it will solve a set of problems is putting the cart before the horse,” said Jim Thomas from The ETC group, a watchdog organisation looking at ecological aspects of new technologies. “Farmers already have other techniques to deal with desertification. The danger is that these inventive technological fixes might develop a halo as a way of dealing with the problem.”

“It would be hubristic to claim that the project was a panacea, but I didn’t hear anyone claim that,” countered Luke Alphey from the University of Oxford, who is developing genetically-modified mosquitoes to control dengue fever. “It would be equally hubristic to claim that these problems are so complex that no new technology could contribute to a solution.”

“It’s nowhere near perfect, and we haven’t been able to test it in a normal field, let alone in arid environments,” said Schoene. “It was a 10-week project.” Indeed, by the end of the competition, the team had tested the bacteria’s root-finding and auxin-making modules, but had not completed the GeneGuard. And since then, they have disbanded and started their own graduate programmes. The root-making bacteria are languishing in development limbo. Their legacy isn’t so much as a barricade for deserts, but as a symbol of tensions between a young hopeful discipline and an older weary one.

But they also show that tentative bridges are starting to form between the two communities. In 10 short weeks, the Imperial team focused on a relevant problem, carried out an incredible amount of engineering, took due heed of potential risks, and engaged with people from all sides. Perhaps, as one delegate suggested, if conservation biologists could take part in the next iGEM alongside synthetic biologists, they could infuse the competition and the discipline with their own values and priorities.

“You’re pushing against a huge open door, and I invite you to walk through,” said Paul Freemont, co-director of a synthetic biology centre at Imperial College London, to the assembled crowd. And with a smile: “And do please cheer up just a little bit.”

A Blog by Ed Yong

Can We Fake Leaves That Stab Bed Bugs in the Feet?

Bed bugs have been sucking human blood for thousands of years and they’re enjoying a new resurgence. They are among the most difficult pests to control, and infestations have risen in the last few decades. Old defences like insecticides are failing us, leaving scientists racing to find new solutions. But in the Balkan countries of southeastern Europe, there’s a old folk remedy that might be the insects’ undoing.

Before nightfall, people would scatter the leaves of bean plants on the floor by their beds. In the morning, the leaves would be full of immobilised bed bugs, which could then be taken outside and burned.

In 1944, a scientist called H. H. Richardson realised that this works because of tiny hooked hairs called trichomes dotting the surface of the bean leaves. Each is just a tenth as wide as a human hair and Richardson thought that they tangle the claws of walking bed bugs. Velcro, which was conceived at roughly the same time, works along similar principles.

But no one followed up on Richardson’s discovery. There was the small matter of a distracting world war, and there was little impetus to research other forms of control when insecticides like DDT were so good at killing bed bugs. But since their post-war nadir, the bugs are on the rise again and many have evolved resistance to the pesticides. The bean leaves are looking pretty tempting again.

Mike Potter from the University of Kentucky heard about Richardson’s work and decided to create a synthetic version of the leaves. After a few failed attempts, he turned to Catherine Loudon from the University of California, Irvine, who specialises in insect movements.

Loudon and former student Megan Szyndler discovered that Richardson got one crucial detail wrong about the bean leaves. By photographing and filming them under a microscope, they saw that the hairs aren’t merely tangling the bugs’ feet—they are actually impaling them, stabbing through at their weakest spots. (Bed bugs, of course, are no stranger to awkward stabbings.)

When a bed bug walks onto a bean leaf, it strides across a lethal minefield. The hooked hairs are so dense, that it takes just a few seconds (and around 50 footsteps) for the insect to become inescapably trapped. Sometimes, the hairs just wrap around their claws as Richardson envisioned, in which case they always managed to pull free. But often, they became irreversibly stuck, unable to break away.

When Szyndler scanned the trapped feet using a powerful electron microscope, she saw that the hairs had actually pierced the bugs’ feet. They typically penetrated the softest parts, like the underside of the claws, or the thin membranes between their segments. They’re less like Velcro, and more like butchers’ hooks. Even if the bugs could pull themselves free—which involved either breaking the trichome or their own shells—they would immediately get recaptured.

The results will be unsurprising to some, since bean trichomes are known to puncture the feet of other insects, including agricultural pests like leafhoppers and aphids, and (unfortunately) guardian insects like ladybirds. In fact, these are probably the victims that the beans’ stabby hairs have evolved to entrap. The fact that they also capture bed bugs is (for us) a happy offshoot of a different evolutionary conflict.

But few people have studied the hairs in detail—how many are needed, how sharp they need to be, whether insects can pull free, and so on. Those details could point the way to new ways of controlling bed bugs. After all, people have tried to trap the insects with glue or double-sided sticky tape with little success.

The team returned to the original goal of creating materials that mimic the penetrating bean hooks. You could just scatter bean leaves, but these dry out fairly rapidly and they can only be applied to horizontal surfaces—they’d do nothing to trap bed bugs that are already living in a mattress.

Szyndler first made a mould of a bean leaf’s surface and then used this to create replicas. They looked indistinguishable. They had the same density of trichomes, which came in the same size and had the same sharp, hooked tips. But there was one big difference—they were rubbish at capturing bed bugs. Disappointingly, the fake leaves completely failed to pierce the bugs’ feet.

It’s not clear why. In some cases, the tips of the real trichomes broke off during the moulding process and became incorporated into the synthetic hairs. But even these hybrid trichomes didn’t pierce bed bugs like their natural cousins. Clearly, the real and fake hairs differ in some subtle physical property.

The team thinks that stiffness might be the key one. The natural trichomes are solid at their tips but hollow down their length, while the synthetic ones are completely solid. That makes them stiffer. When a bed bug walks on a natural trichome, Szyndler suspects that the hair would bend and twist, allowing the tip to skit the surface of the bug’s foot until it ‘finds’ a weak spot. By contrast, an artificial trichome would just bend out of the way. The next step is to create synthetic trichomes that mimic the full properties of the real ones, and that’s exactly what the team is working on.

Reference: Szyndler, Haynes, Potter, Corn & Loudon. 2013. Entrapment of bed bugs by leaf trichomes inspires microfabrication. Interface http://dx.doi.org/10.1098/rsif.2013.0174

 

 

 

A Blog by Ed Yong

3-D Printer Makes Synthetic Tissues from Watery Drops

In the University of Oxford, Gabriel Villar has created a 3-D printer with a difference. While most such printers create three-dimensional objects by laying down metals or plastics in thin layers, this one prints in watery droplets. And rather than making dolls or artworks or replica dinosaur skulls, it fashions the droplets into something a bit like living tissue.

Each of your cells, whether it’s a neuron or muscle cell, is basically a ball of liquid encased by a membrane. The membrane is made from fat-like molecules called lipids, which line up next to one another to create two layers. And that’s exactly what Villar’s 3-D printer makes—balls of liquid encased by a double-layer of lipids.

Other scientists have already created 3-D printers that spit out human cells in the shape of living tissues, and some have even created facsimiles of entire organs. But Hagan Bayley, who led Villar’s study, thinks that there’s value in creating tissues that look and behave like living ones, but that don’t actually contain any cells. They would probably be cheaper and without any genetic material, you don’t have to worry about controlling growth or division.

Credit: Villar et al. Science/AAAS
Credit: Villar et al. Science/AAAS

The team’s printer has two nozzles that exude incredibly small droplets, each one just 65 picolitres—65 billionths of a millilitre—in volume. The nozzles “print” the drops into oil at the rate of one per second, laying them down with extreme precision. As each drop settles, it picks up a layer of lipids from the surrounding oil, and the layers of neighbouring drops unite to create a double-layered membrane, just like in our cells.

The printer can lay a drop every second, and create shapes made of up to 35,000 of them. In the diagram below, they’re being printed into a drop of oil, sitting on a metal frame and suspended in some water. It all looks precarious but the drops hold their shape, even after the remaining oil is drawn away. They have the consistency of brains, fat or other soft tissues, and they’ll last for weeks. And by colouring them with dyes, Villar could produce pretty, shiny baubles.

Credit: Villar et al. Science/AAAS
Credit: Villar et al. Science/AAAS

But aesthetics are just the start. The tissues can also do things… like carry currents. Villar loaded some of them with ion channels—little pores that sit in membranes and let charged molecules flow through. In the photo below, the channel-loaded droplets are the green ones, cutting a right-angled path across their translucent neighbours. When Villar touched electrodes to either end of the path, ions flowed through the channels and he registered a current. This mimics some of the properties of a neuron, allowing one end of the tissue to communicate with the other side very quickly and along a fixed path.

Villar could also create tissues that can fold and contract, by printing drops with different salt concentrations. Once they are printed, the saltier drops soak up more water and swell to a greater size. And if two sheets of drops are printed next to each other—one heavily salted and one lightly so—they will automatically coil into a tube. Villar even printed a four-petal flower than folded into a hollow sphere.

Credit: Villar et al. Science/AAAS
Credit: Villar et al. Science/AAAS

These tissues are the start of something a bit like muscle—that is, if the team can reverse the process and get them to unfold. They also hint at potential applications. A hollow sphere is very hard to print, but if you can get one to fold on its own, you have something that could be very useful in medicine. A sphere, for example, could hold a drug. Better still, two spheres could hold molecules that react together to form a drug, but are too unstable to put in a pill. Load these molecules into different drops and inject them separately into a patient, and you could brew a drug on the spot, where it’s needed.

These applications are far-off, as is the team’s long-term goal of creating tissues that fuse these droplets with actual living cells. Perhaps, with more development, they could even be used to support or replace failing organs.

Reference: Villar, Graham & Bayley. 2013. A Tissue-Like Printed Material. Science http://dx.doi.org/10.1126/science.1229495

A Blog by Virginia Hughes

Biotech’s Beasts

Fluorescent fish, cloned cats, dolphins with prosthetic tails — these are just a few of the many oddball creatures you’ll read about in Frankenstein’s Cat: Cuddling Up to Biotech’s Brave New Beasts, a new book by science journalist Emily Anthes.

In it, Emily describes her tour through unconventional animal facilities across the country, from a barn of transgenic goats in California to a lab that’s cloning endangered species in a forest outside of New Orleans. Emily somehow manages to tell a fun story without glossing over complex scientific concepts and thorny ethical issues. The book comes out officially on March 12, but you can pre-order a copy now.

Emily and I worked together at SEED Magazine (back when there was a SEED Magazine…), and we both love Brooklyn and dogs. I learned a lot from her book, and she kindly agreed to answer some of my questions about its content and her writing experience.

Milo and Emily. Photo by Nina Subin
Milo and Emily. Photo by Nina Subin

VH: I want to start with the AquAdvantage salmon, the genetically modified fish that grow super fast. When you wrote about them in the book, the FDA was still — after 17 years! — making up its mind about whether it would allow the fish to be sold as food. Finally, at the end of December, the agency issued a draft document declaring AquAdvantage safe, and we’re now nearing the end of the 60-day public comment period.

So, if the approval happens, what would it mean for the U.S. biotech industry? Why is this fish such a big deal?

EA: The short answer is that this fish is much more than just a fish — it’s a test case. If the fish are approved, they’ll be the first transgenic animals approved as consumer products in the U.S. (The FDA has approved a pharmaceutical that is extracted from the milk of genetically modified goats, but the AquAdvantage salmon would be the first whole GE animals cleared for human consumption.)

Many, many researchers and entrepreneurs who are interested in animal biotechnology are watching this case very closely. If the fish, which have been politically controversial, are approved, it means that good science can still triumph over politics. If they’re not approved, it will send the opposite message, discouraging further research and innovation in all sorts of promising biotech applications.

VH: I think you and I have a similar attitude toward the unnecessary fear (and sometimes, excessive regulation) that seems to swirl around new technologies, whether that’s these new salmon and other GMOs or personal genetics. I loved your quote: “It’s easy to oppose biotechnology in the abstract, but when that technology can save your life, grand pronouncements about scientific evils tend to dissolve.”

Your book is full of life-saving, useful, compelling, and delightful applications of biotechnology. But was there anything you came across in your reporting that you think is really, really worrisome? What’s worthy (if anything) of intense regulatory scrutiny, or even an outright ban?

EA: Well, the practice that most unsettled me was the emerging business of cloning pets. It’s not the cloning itself that bothers me — I have no philosophical problem with making genetic copies of animals, and I firmly believe that cloning, like other biotechnologies, is value neutral, that whether it’s good or bad depends on how we’re using it. But the problem is that right now, cloning remains a highly experimental technology. Clones of some species suffer from health problems at elevated rates, and the cloning process itself is extremely inefficient. To make a single cloned dog, you need lots of dog eggs and lots of cloned embryos. That means that you’re putting a lot of female dogs through unnecessary surgeries and surrogate pregnancies all so one pet owner can get a duplicate of a beloved pet. To me, that’s not an acceptable trade-off.

But if scientists can improve cloning’s efficiency — or figure out how to reduce the health problems among clones — my objections would begin to fade away. As they would if the benefits were higher — if the fate of the world somehow rested upon creating a cloned dog. (That’s why I’m less willing to condemn research projects in which scientists are doing seemingly more useful things, such as cloning disease-resistant animals or endangered species.)

VH: Human cloning — ever gonna happen? Yes or no.

EA: Honestly, I doubt it. Not because scientists won’t be able to do it, but because society won’t accept it. I think people will push to ban human cloning before scientists manage to pull it off. Or scientists will do it once and then politicians and the public will immediately push for legislation to prevent anyone from ever doing the same thing again. (But then again, predictions about the future of technology are notoriously easy to botch. Maybe human cloning will one day become as safe and routine as IVF. That’s not what my gut tells me, but who knows?)

VH: On to some fun stuff now, because your book is chock-full of colorful stories and a lot of Anthes wit. Of all of the famous Franken-critters you met — CC the cat, Winter the dolphin, and your very own GloFish, just to name a few — which was your favorite?

EA: Oh man — that’s an unfair question! It doesn’t seem quite right to choose. But meeting CC, the world’s first cloned cat, was probably the most fun. I’m not sure what I expected, but I definitely did not expect to discover that the scientist who helped create her would have built her her very own, two-story, air-conditioned house in his backyard. Or that she’d live there with her cat “husband” and their three kids. CC is a very cute cat, but it was a little surreal to be a guest in her “home.”

VH: Yeah, that was crazy! I laughed out loud. Did visiting all these animals change the way you interact with your dog, Milo? Or vice-versa: Did your experience as a dog owner change the way you approached these visits?

EA: I’m not sure that having a dog changed how I approached the visits, but they definitely gave me perspective on some of the drivers behind these biotechnological interventions. I certainly understand how strong the bond between humans and animals can be, and I also understand the urge to create or acquire a pet that fits a long list of exact specifications. I spent a long time trying to pick out the “perfect” dog for me, and even now, there are tweaks I’d make to Milo if I could. For instance, he’s very sweet but pretty skittish. If it were possible to give him a strong dose of courage with, say, a round of gene therapy, I’d be all for it.

VH: Your book talks a bit about genetic testing for dogs. From the little I had read about it before, I thought most people were interested in these tests in order to figure out the dog’s pedigree. But you describe how they might be used for medical purposes, too. For example, a breeder could avoid mating two dogs that are both carriers of the same genetic disease. So how common is the use of dog genetic tests for medical purposes? Is it pricey? Do you think it will become a more routine thing?

EA: I don’t think canine genetic testing — for either pedigree or medical purposes — is super common yet. But it has huge potential. There are a variety of commercial labs that offer owners the chance to see whether their dogs have certain disease-causing mutations. Many of these tests cost less than $100, and they’re simple to do — just swab the inside of your dog’s cheek and mail the swabs into the company, which will process the samples and deliver the results. I think this kind of testing is bound to become more common, especially as the price drops and researchers uncover more and more disease-linked genetic mutations.

VH: Very tempting!

My last question is about bioethics. Strachan Donnelley, a philosopher, apparently coined this concept of the “troubled middle” to describe people who love animals and care about their welfare, and yet don’t have a moral problem with eating them or having scientists do research on them. I’m probably in that muddled middle somewhere, and you write that you are, too. Are there any guiding principles in that middle that we can turn to in sticky situations? I guess another way to ask this is, what is at the heart of animal welfare?

EA: Well, the first thing to note is that if you’re in the troubled middle — and I really think that the vast majority of us are — then overly broad, blanket ethical statements don’t work very well. Most of us don’t want to ban all use of animals in research, nor do we want to allow scientists to use as many animals as they want for anything they want anytime they want. So we need to think about each proposed use of animals on a case-by-case basis. In doing that, we should be evaluating the cost to animals against the potential gain. So I don’t mind sacrificing some mice in order to study Alzheimer’s, for instance, but I’m not so willing to sanction animal experimentation in the search of, say, a better treatment for wrinkles.

And the second point that I think is important is that even in those instances in which we decide animal use is justified, we should still take welfare seriously. So just because a mouse is destined for Alzheimer’s research doesn’t mean that we can shrug off our ethical obligations to treat that mouse well during its scientific service. (That means providing anesthesia and pain control, when necessary, as well as comfortable living conditions, physical and mental stimulation, etc.) Even experimental animals deserve the best quality of life we can give them.

*

The cover art for Frankenstein’s Cat, featured at the top of this post, was done by Diego Patino. Nina Subin took the photo of Milo and Emily.

A Blog by Carl Zimmer

The Quantum Earthworm

When things get small–like millionths-of-an-inch small–they get very interesting. The ordinary rules of physics we’re used to fade back as the oddness of quantum physics looms large. Engineers have taken advantage of this fact by fashioning tiny bits of matter, known as quantum dots, that behave in all sorts of useful ways. For example, quantum dots made from cadmium telluride will respond to ultraviolet light by giving off a flash of visible light–the color depending on their size. If you attach certain molecules to cadmium telluride quantum dots, they will latch onto certain targets, making it possible to detect trace amounts of substances ranging from pesticides to cancer cells.

As versatile as cadmium telluride quantum dots are, however, they’re not easy to make. It’s especially tedious to fashion them so that they’re not toxic to living cells, since both cadmium and tellurium are nasty metals. In the latest issue of Nature Nanotechnology, a group of scientists at Kings College London offer a remarkably easy way to make them.

In earthworms.

The scientists started with some dirt, into which they mixed cadmium chloride and sodium tellurite. Then they dropped earthworms into this polluted soil. The earthworms did what earthworms do: they sucked the dirt into their mouth and pushed it down the length of their bodies, digesting the nutrients and excreting waste out their back ends.

After eleven days, the worms were still happily grazing through the dirt, despite its Superfund-scale pollution. The scientists cut the animals open and searched for metals inside their bodies. They found that the cadmium and telluride the worms had eaten had broken away from their original molecular partners and had combined into cadmium telluride. In other words, the worms had manufacture quantum dots.

When the scientists flashed the dots with ultraviolet light, they gave off a green glow. The worm-fashioned quantum dots played nicely with living cells, the scientists found. They could use the dots to make cancer cells shine amidst a background of ordinary tissue.

Cancer cells glow green with quantum dots made by earthworms. (The blue is from a dye that stains the nuclei of cells.)

There are many things to marvel at in such a study. We can imagine engineers harvesting quantum dots from giant earthworm farms and not be considered mad. But what I marvel at most of all is the fact that the earthworms were naturally so well prepared for the challenge. They have evolved to be underground alchemists. After all, when you make a living eating dirt, you have to be prepared for all sorts of unexpected nastiness.

Earthworms can sense metals in their meals. They immediately respond by making special enzymes. Exposing a worm to cadmium, for example, causes it to produce enzymes called metallothionein in its gut. The metallothionein grabs hold of the cadmium and stores it away in special cavities inside the cells, where it undergoes chemical reactions to make it less dangerous to the worm. Then immune cells attack the cells and engulf them. The worm eventually excretes them safely out of its body.

When scientists began decipering the chemistry that the worms use, their first idea was to enlist worms to clean up heavy metal pollution. That turned out to be a failure of the imagination. It may be that in the realm of nanotechnology, earthworm may truly shine.

[Worm engraving: Florida Center for Instructional Technology]

A Blog by Ed Yong

Why Porcupine Quills Go In Easily but Are Hard to Pull Out

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.

(more…)

A Blog by Ed Yong

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

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.

A Blog by Ed Yong

Engineering mosquito gut bacteria to fight malaria

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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A Blog by Ed Yong

Will we ever grow organs?

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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