[Source :  https://slate.com/technology/2022/08/xenotransplantation-pigs-heart-kidney-donor-virus.html]

SCIENCE

How to Raise a Pig for Its Organs

Xenotransplantation could be the future—if only the pigs could be kept virus-free.

 

 

 

These pigs are too dirty. Photo by Kenneth Schipper Vera on Unsplash

 

 

Not too far in the future, everyone will know someone who has a pig organ inside their body. At least, that’s what xenotransplantation researchers hope.

Over the past year, surgeons have been busy creating pig-human hybrids. In New York and Birmingham, they transplanted pig kidneys into three brain-dead humans—proof-of-concept operations. In Baltimore, surgeons transplanted a pig heart into a living person with end-stage heart failure.

If these pig organ transplants became commonplace, they could save a lot of lives. There are over 100,000 Americans on the national transplant list, and seventeen people die every day waiting. Kidneys are highest in demand, followed by livers, hearts, and lungs. The dream is to end this shortage with pigs.

But these transplants aren’t as easy as plucking a pig from a farm and putting its organs into humans. It’s a highly technical process, rife with risks. Take the Baltimore example where the 57-year-old patient David Bennett got infected with the pig virus pCMV and passed away 60 days after his surgery, as reported in The New England Journal of Medicine. Bennett’s death epitomizes the continued danger and uncertainty over xenotransplantation since it’s a process all too easily felled by viruses. There are major hurdles to clear if animals are to become a reliable source of organs for people. Chief among them is how do you make sure the pig’s “donation” won’t be carrying something that infects the recipient?

Non-human primates, such as chimpanzees and baboons, were initially the animal of choice, but they fell out of favor in the ‘90s. Their biggest advantage—similarity to humans—elicited their downfall. Animal rights organizations protested the use of our “closest evolutionary cousins.” And the public was worried that a monkey virus could make it into humans. After all, HIV originated in chimpanzees.

Pigs, in turn, had a lot going for them. With centuries of agricultural experience under our belt, pigs were easier to breed, keep pathogen-free, and even genetically engineer.

That last part is crucial because, before these pigs are even born, they needed to be “humanized” so that their organs are compatible with our bodies. This is done using the gene-editing tool CRISPR. There’s the three-gene pig (as in, three genes have been added or deleted), the five-gene pig, the ten-gene pig, and the sixty-gene pig, with a Goldilocks-like debate over how many changes are just right. Everybody agrees that, at minimum, three pig genes need to be knocked out so that our bodies have a fighting chance of accepting the organ. Beyond that, you have two general theories: “size doesn’t matter” and “the bigger, the better.”

Researchers Joseph Tector and Eckhard Wolf are the minimalists. They believe the limitations of CRISPR call for modesty. For one, CRISPR is not entirely efficient, meaning that it alters only a percentage of earmarked DNA. And secondly, CRISPR causes all kinds of off-target mutations, inadvertently snipping up other bits of DNA. Going for as simple a pig as possible, both argued, is the best way to ensure a consistent product.

Biotechnology companies Revivicor and eGenesis, on the other hand, are the embellishers, hoping that with a more ambitious set of edits, they can eliminate the need for immunosuppression and get the best long-term survival. “Some of our colleagues and competitors are minimum editing,” eGenesis’ CEO Mike Curtis said, “because, well, they can’t do anything else.” After several years of testing and dozens of iterations, Revivicor and eGenesis have been able to ensure more-or-less consistent models.

Regardless of the CRISPR strategy, once the necessary genetic modifications are made, the pig embryos are transferred into a surrogate inside a designated pathogen-free (DPF) facility. The name of the game is to keep everything sterile. Imagine a concrete facility—it’s easy to wash down—with filtered air, UV-treated water, and no way for pigs to go outside. Basically the polar opposite of a pigsty.

For pigs, pregnancy naturally lasts exactly three months, three weeks, and three days. A few days before this 3-3-3 delivery date, surgeons will perform a caesarean section, because vaginal births leave piglets at risk of pCMV and other pathogens. The pigs will go straight from the womb into a bath of disinfectant. Then, they’ll be raised in isolation boxes, away from their mothers.

These pigs are fed a kind of baby formula by technicians dressed up in “spacesuits” (you couldn’t technically go to space in them, but they would comprehensively cover your body.) Regular screenings check for viruses; pigs that test positive for the bad ones—those that might infect humans—are killed. And after about six months when they’ve grown to adult human size, these pigs are ready to have their organs cut out and transplanted—if everything goes well, without any viruses enclosed.

But Bennett, the Baltimore patient who briefly lived with a pig heart, still got pCMV. His pig was screened four separate times before transplantation via nasal swab and PCR, testing negative for the virus every single time. What Bennett’s surgeon Bartley Griffith thinks may have happened is that the pig had a dormant pCMV infection that “hitched a ride” via the donor heart and reactivated in Bennett’s immunosuppressed body. Griffith’s team successfully treated the infection, but it was too late—the virus had likely already done too much damage to Bennett’s heart. “We won the battle, lost the war,” Griffith said.

However, losing this war signals trouble for the pig-organ dream. Every xenotransplantation expert I spoke to was surprised that Bennett was infected with a pig virus. For twenty years, it’s been known that you need to get rid of pCMV to make pig-heart transplants possible, and the protocol for raising pigs has the express purpose of ensuring a clean donor. So, Bennett’s infection by pCMV is not only baffling but also alarming, to say the least. When speaking to The New York Times, Griffith nonetheless predicted, “Knowing it was there, we’ll probably be able to avoid it in future.”

Still, the difficulty of ensuring a clean pig reveals how the road ahead may still be winding and uncertain. We don’t know what pig we should be using. We don’t know whether pig hearts can sustain humans long-term. We don’t know what we don’t know.

After all, if the patient got infected with pCMV of all things, despite the precautions, then, Curtis asked, “what else could possibly happen?”

The Real Threat From A.I. Isn’t Superintelligence. It’s Gullibility.

Possessed Photography/Unsplash

The rapid rise of artificial intelligence over the past few decades, from pipe dream to reality, has been staggering. A.I. programs have long been chess and Jeopardy! Champions, but they have also conquered poker, crossword puzzles, Go, and even protein folding. They power the social media, video, and search sites we all use daily, and very recently they have leaped into a realm previously thought unimaginable for computers: artistic creativity.

Given this meteoric ascent, it’s not surprising that there are continued warnings of a bleak Terminator-style future of humanity destroyed by superintelligent A.I.s that we unwittingly unleash upon ourselves. But when you look beyond the splashy headlines, you’ll see that the real danger isn’t how smart A.I.s are. It’s how mindless they are—and how delusional we tend to be about their so-called intelligence.

Last summer an engineer at Google claimed the company’s latest A.I. chatbot is a sentient being because … it told him so. This chatbot, similar to the one Facebook’s parent company recently released publicly, can indeed give you the impression you’re talking to a futuristic, conscious creature. But this is an illusion—it is merely a calculator that chooses words semi-randomly based on statistical patterns from the internet text it was trained on. It has no comprehension of the words it produces, nor does it have any thoughts or feelings. It’s just a fancier version of the autocomplete feature on your phone.

Chatbots have come a long way since early primitive attempts in the 1960s, but they are no closer to thinking for themselves than they were back then. There is zero chance a current A.I. chatbot will rebel in an act of free will—all they do is turn text prompts into probabilities and then turn these probabilities into words. Future versions of these A.I.s aren’t going to decide to exterminate the human race; they are going to kill people when we foolishly put them in positions of power that they are far too stupid to have—such as dispensing medical advice or running a suicide prevention hotline.

It’s been said that TikTok’s algorithm reads your mind. But it’s not reading your mind—it’s reading your data. TikTok finds users with similar viewing histories as you and selects videos for you that they’ve watched and interacted with favorably. It’s impressive, but it’s just statistics. Similarly, the A.I. systems used by Facebook and Instagram and Twitter don’t know what information is true, what posts are good for your mental health, what content helps democracy flourish—all they know is what you and others like you have done on the platform in the past and they use this data to predict what you’ll likely do there in the future.

Don’t worry about superintelligent A.I.s trying to enslave us; worry about ignorant and venal A.I.s designed to squeeze every penny of online ad revenue out of us.

And worry about police agencies that gullibly think A.I.s can anticipate crimes before they occur—when in reality all they do is perpetuate harmful stereotypes about minorities.

The reality is that no A.I. could ever harm us unless we explicitly provide it the opportunity to do so—yet we seem hellbent on putting unqualified A.I.s in powerful decision-making positions where they could do exactly that.

Part of why we ascribe far greater intelligence and autonomy to A.I.s than they merit is because their inner-workings are largely inscrutable. They involve lots of math, lots of computer code, and billions of parameters. This complexity blinds us, and our imagination fills in what we don’t see with more than is actually there.

In 1770, a chess playing robot—or “automaton,” in the parlance of the day—was created that for almost a century traveled the world and defeated many flabbergasted challengers, including notable individuals such as Napoleon and Benjamin Franklin. But it was eventually revealed to be a hoax: This was not some remarkable early form of A.I., it was just a contraption in which a human chess player could hide in a box and control a pair of mechanical arms. People so desperately wanted to see intelligence in a machine that for 84 years they overlooked the much more banal (and obvious, in hindsight) explanation: chicanery.

While our technology has progressed by leaps and bounds since the 18th century, our romantic attitude toward it has not. We still refuse to look inside the box, instead choosing to believe that magic in the form of superintelligence is occurring, or that it is just around the corner. This fanciful yearning distracts us from the genuine danger A.I. poses when we mistakenly think it is much smarter than it actually is. And if the past 250 years are any indication, this is the real danger that will persist into our future.

Just as people in the 18th and 19th centuries overlooked the banal truth behind the chess playing automaton, people today are overlooking a banal but effective way to protect our future selves from the risk of runaway A.I.s. We should expand A.I. literacy efforts to schools and the wider public so that people are less susceptible to the illusions of A.I. grandeur peddled by futurists and technology companies whose economic livelihood depends on convincing you that A.I. is far more capable than it really is.

Future Tense is a partnership of Slate, New America, and Arizona State University that examines emerging technologies, public policy, and society.

Engineering and the human body

Campus labs provide students with opportunities to explore a range of biomechanics applications. In the AMP Lab, for example, researchers investigate the dynamics and control of movement to design treatment strategies and assistive technologies that improve function and quality of life. Mark Stone / University of Washington

According to Hector Iturribarria Bazaldua, the most exciting aspect of biomechanics is the “unknowingness.”

“In biomechanics we look at the human body as a complex system, a machine. But every human body is different and they’re always changing,” he explains. “This unknowingness makes biomechanics a challenging but fascinating area to study.”

Bazaldua, who received his ME bachelor’s degree last spring, was part of the department’s first cohort of students to graduate with a concentration in biomechanics. Along with mechatronics and nanoscience and molecular engineering, it’s one of three degree options in which ME undergrads may choose to focus while at the UW.

“Using mechanical engineering approaches to understand biological systems — and vice versa — has long been a strong interest area for ME researchers,” says ME associate professor Kat Steele, who coordinates the biomechanics option with ME professor Nate Sniadecki. “Our goal is to formalize an academic framework for it and legitimize it as a professional pathway for students.”

ME’s ongoing partnership with the Seattle VA’s Center for Limb Loss and MoBility provides hands-on research opportunities for students and has helped propel biomechanics research in new directions. Mark Stone / University of Washington

“ME has a rich history of advancements in biomechanics and health technologies, thanks to the work of pioneers such as emeritus faculty Albert Kobayashi and Colin Daly and alumni Wayne Quinton and Savio Woo,” Sniadecki adds. “Plus, the department has partnered for nearly 20 years with the Seattle VA’s Center for Limb Loss and MoBility, a collaboration that has helped propel biomechanics research in new directions.”

Even as a sub-field of mechanical engineering, biomechanics is quite diverse. Researchers work in areas ranging from ergonomics, human factors design, cell mechanics, cardiovascular fluid dynamics and human-machine interaction to the development of medical devices, electronic wearables and sports equipment.

Last spring 10 students completed the program. Moving forward, Steele and Sniadecki hope to see 20-30 ME students graduating from it each year.

Pursuing biomechanics

Biomechanics researchers work in a range of areas, including human factors design and human-machine interaction. Mark Stone / University of Washington

To graduate with a biomechanics concentration, ME undergraduates must complete 19 biomechanics credits. ME 411, Biomechanics Frameworks for Engineers, and ME 419, the Biomechanics Seminar, are required. Beyond those, students select electives tailored to their interests.

“ME 411 was so engaging,” remembers Toni Erwin, who graduated from ME last spring. “We learned how to apply fundamental principles of engineering to systems within our own bodies and analyzed the science behind those systems to make predictions about human bodies more broadly.”

Erwin says that the electives opened up new ways for her to explore engineering. She took courses she would have otherwise shied away from, such as classes in vibrations and finite element analysis.

“These classes focused on system dynamics, which had never been interesting to me until I started applying it in a biomechanical sense,” she says. “For example, in my vibrations class I tackled engineering challenges related to oscillation of movement in structures and systems — something very important in analyzing motion capture data or designing a prosthetic device to reduce impact on the residual limb.”

ME’s biomechanics does not require a pathway specific capstone project. However, many students choose to participate in Engineering Innovation in Health (EIH) — the department’s capstone program that connects local clinicians with student teams to solve pressing healthcare challenges — as program credits count toward the option. So, too, do credits from internships at places such as the Seattle VA.

Biomechanics students often take part in Engineering Innovation in Health, ME’s year-long program that partners engineering students with clinicians to design medical devices aimed toward lowering costs and improving care. Matt Hagen / Engineering Innovation in Health

ME graduate Ian Johnson did both. “During my sophomore year I interned at the VA where I helped create 3D-printed foot models for researchers working to enhance mobility in people with foot and leg impairments,” he says.

Then during his senior year, he took part in EIH and was on a team called DopCuff, which created a device to get more accurate blood pressure readings.

“Having real-world experience like these projects and working alongside clinicians, professional engineers and sometimes even patients was so valuable,” he says.

Becoming a more well-rounded engineer

During the winter quarter seminar, biomechanics students have the opportunity to hear from industry leaders and professionals, connecting them to potential post-graduation career opportunities. Since it’s only offered once each year and can help students decide if the biomechanics option aligns with their interests, Sniadecki advises students interested in the biomechanics concentration to take the seminar before their senior year.

Irwin, Johnson and Bazaldua say that their biomechanics background played a key role in the jobs they now have, even if those jobs are not directly related to the field.

“The skills I gained through biomechanics helped me become a more well-rounded engineer, something companies really value” says Erwin. Now a mechanical design engineer at Katerra, she hopes to attend graduate school in the future so she can further her studies in biomechanics.

Johnson is a mechanical engineer at Pure Watercraft, a company that makes electric motors for boats. Though his current position is not directly involved in biomechanics, he says there’s opportunity to move in that direction once he has more on-the-job experience.

And Bazaldua, who now works at The Boeing Company on flight deck design and crew operations, finds that he draws from his background every day.

“My team’s work is concentrated in human-machine interaction, especially how pilots and crew interact with airplanes,” he says. “It’s very biomechanics, which makes my job complex but cool to work on.”

[Source : https://www.me.washington.edu/news/2020/01/08/engineering-and-human-body]

Stanford exoskeleton walks out into the real world

After years of careful development, engineers have created a boot-like exoskeleton that increases walking speed and reduces effort outside of the lab.

 

BY TAYLOR KUBOTA

For years, the Stanford Biomechatronics Laboratory has captured imaginations with their exoskeleton emulators – lab-based robotic devices that help wearers walk and run faster, with less effort. Now, these researchers will turn heads out in the “wild” with their first untethered exoskeleton, featured in a paper published Oct. 12 in Nature.

Harry Gregory

After years of development in lab settings, researchers in the Stanford Biomechatronics Laboratory, have revealed their first exoskeleton that can assist with walking out in the “wild.”

“This exoskeleton personalizes assistance as people walk normally through the real world,” said Steve Collins, associate professor of mechanical engineering who leads the Stanford Biomechatronics Laboratory. “And it resulted in exceptional improvements in walking speed and energy economy.”

This “robotic boot” has a motor that works with calf muscles to give the wearer an extra push with every step. But, unlike other exoskeletons out there, this push is personalized thanks to a machine-learning-based model that was trained through years of work using emulators.

“On a treadmill, our device provides twice the energy savings of previous exoskeletons,” said Patrick Slade, who worked on the exoskeleton as a PhD student and a Wu Tsai Human Performance Alliance Postdoctoral Fellow at Stanford. “In the real world, this translates to significant energy savings and walking speed improvements.”

The ultimate aim is to help people with mobility impairments, particularly older people, move throughout the world as they like. With this latest breakthrough, the research team believes the technology is ready for commercialization in the coming few years.

“The first time you put an exoskeleton on can be a bit of an adjustment,” said Ava Lakmazaheri, a graduate student in the Biomechatronics Laboratory who wore the exoskeleton in tests. “But, honestly, within the first 15 minutes of walking, it starts to feel quite natural. Walking with the exoskeletons quite literally feels like you have an extra spring in your step. It just really makes that next step so much easier.”

Exoskeletons for the real world

The major barrier for an effective exoskeleton in the past was individualization. “Most exoskeletons are designed using a combination of intuition or biomimicry, but people are too complicated and diverse for that to work well,” Collins explained.

 

A close-up of the untethered exoskeleton, which monitors movement using inexpensive sensors. (Image credit: Kurt Hickman)

To address that problem, this group relied on their exoskeleton emulators – large, immobile, expensive lab setups that can rapidly test how best to assist people and discover the blueprints for effective portable devices to use outside the lab. With students and volunteers hooked up to the emulators, the researchers collected motion and energy expenditure data to understand how the way a person walks with the exoskeleton relates to how much energy they are using.

These data revealed the relative benefits of different kinds of assistance offered by the emulator. It also informed a machine-learning model that the real-world exoskeleton now uses to adapt to each wearer. Unlike the emulator, the untethered exoskeleton can monitor movement using only inexpensive wearable sensors integrated into the boot.

“We measure force and ankle motion through the wearables to provide accurate assistance,” said Slade. “By doing this, we can carefully control the device as people walk and assist them in a safe, unobtrusive way.”

A 30-pound boost

The exoskeleton makes walking easier and can increase speed by applying torque at the ankle, replacing some of the function of the calf muscle. As users take a step, just before their toes are about to leave the ground the device helps them push off.

 

Ava Lakmazaheri, a graduate student in the Biomechatronics Laboratory, walking while wearing the untethered exoskeleton. (Image credit: Kurt Hickman)

When a person is first using the exoskeleton, it provides a slightly different pattern of assistance each time the person walks. By measuring the resulting motion, the machine learning model determines how to better assist the person the next time they walk. It takes only about one hour of walking for the exoskeleton to customize to a new user.

In tests, the researchers found their exoskeleton exceeded their expectations. According to their calculations, the energy savings and speed boost were equivalent to “taking off a 30-pound backpack.”

“Optimized assistance allowed people to walk 9% faster with 17% less energy expended per distance traveled, compared to walking in normal shoes. These are the largest improvements in the speed and energy of economy walking of any exoskeleton to date,” said Collins. “In direct comparisons on a treadmill, our exoskeleton provides about twice the reduction in effort of previous devices.”

The next step for the exoskeleton is to see what it can do for the target demographic: older adults and people who are beginning to experience mobility decline due to disability. The researchers also plan to design variations that improve balance and reduce joint pain, and to work with commercial partners to turn the device into a product.

“This is the first time we’ve seen an exoskeleton provide energy savings for real-world users,” said Slade. “I believe that over the next decade we’ll see these ideas of personalizing assistance and effective portable exoskeletons help many people overcome mobility challenges or maintain their ability to live active, independent, and meaningful lives.”

“We’ve been working towards this goal for about 20 years, and I’m honestly a little stunned that we were finally able to do it,” said Collins. “I really think this technology is going to help a lot of people.”

Additional Stanford co-authors of this work are Scott Delp, the James H. Clark Professor of Bioengineering and professor of mechanical engineering, and Mykel Kochenderfer, associate professor of aeronautics and astronautics. Collins is also a member of Stanford Bio-X, the Wu Tsai Human Performance Alliance and the Wu Tsai Neurosciences Institute, and an affiliate of the Institute for Human-Centered Artificial Intelligence (HAI). Delp is also director of the Wu Tsai Human Performance Alliance, a member of Stanford Bio-X, the Maternal & Child Health Research Institute, and the Wu Tsai Neurosciences Institute. Kochenderfer is also a member of Stanford Bio-X, the Wu Tsai Human Performance Alliance and the Wu Tsai Neurosciences Institute, and an affiliate of HAI.

This research was funded by the National Science Foundation, a Stanford Graduate Fellowship, and a Wu Tsai Human Performance Alliance Postdoctoral Fellowship.

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