‘Pacemaker’ for the Brain Can Help Memory, Study Finds

The right hemisphere of a study participant’s brain. The electrodes are overlaid in blue and the one researchers targeted for stimulation is toward the right, highlighted in yellow. CreditYoussef Ezzyat

 

Well-timed pulses from electrodes implanted in the brain can enhance memory in some people, scientists reported on Thursday, in the most rigorous demonstration to date of how a pacemaker-like approach might help reduce symptoms of dementia, head injuries and other conditions.

The report is the result of decades of work decoding brain signals, helped along in recent years by large Department of Defense grants intended to develop novel treatments for people with traumatic brain injuries, a signature wound of the Iraq and Afghanistan wars.

The research, led by a team at the University of Pennsylvania, is published in the journal Current Biology.

Previous attempts to stimulate human memory with implanted electrodes had produced mixed results:

Some experiments seemed to sharpen memory, but others muddled it. The new paper resolves this confusion by demonstrating that the timing of the stimulation is crucial.

Zapping memory areas when they are functioning poorly improves the brain’s encoding of new information. But doing so when those areas are operating well — as they do for stretches of the day in most everyone, including those with deficits — impairs the process.

“We all have good days and bad days, times when we’re foggy, or when we’re sharp,” said Michael Kahana, who with Youssef Ezzyat led the research team. “We found that jostling the system when it’s in a low-functioning state can jump it to a high-functioning one.”

Researchers cautioned that implantation is a delicate procedure and that the reported improvements may not apply broadly.

The study was of epilepsy patients; scientists still have much work to do to determine whether this approach has the same potential in people with other conditions, and if so how best to apply it.

But in establishing the importance of timing, the field seems to have turned a corner, experts said.

Experts said the new report gives scientists a needed blueprint for so-called closed-loop cognitive stimulation: implanted electrodes that both monitor the functional state of memory areas, moment to moment, and deliver pulses only in the very microseconds when they’re helpful.

The hope is that such sensitive, timed implants could bolster thinking and memory in a range of conditions, including Alzheimer’s and other dementias, as well as deficits from brain injury.

“The cool thing about this paper is that they showed why stimulation works in some conditions, and why it doesn’t in others,” said Bradley Voytek, an assistant professor of cognitive science and neuroscience at the University of California, San Diego, who was not involved in the work. “It gives us a blueprint for moving forward.”

Justin Sanchez, director of the biotechnologies office at the Pentagon’s Defense Advanced Research Projects Agency, which has doled out some $77 million to advance cognitive stimulation, said: “To me, this paper is one of the breakthrough moments on this problem, to find locations in the brain to stimulate in this particular way to boost performance.”

The new study is the latest chapter in an extraordinary, decades-long collaboration among cognitive scientists, brain surgeons and people with severe epilepsy being evaluated for an operation.

The preoperative “evaluation” is a fishing expedition of sorts, in which doctors sink an array of electrodes through the top of the skull and wait for a seizure to occur, to see whether it’s operable.

Many of the electrodes sit in or near memory areas, and the wait can take weeks in the hospital.

Cognitive scientists use this opportunity, with patients’ consent, to present memory tests and take recordings.

This approach — called direct neural recording, and piggybacking entirely on the clinical placement of the electrodes — has become the leading edge of research into the biology of human memory.

This study used data from 150 patients, and had 20 collaborators from institutions around the country, including Emory University, the University of Washington, the Mayo Clinic and the University of California, San Francisco.

In a series of experiments, the researchers had patients memorize lists of words and later, after a distraction, asked them to freely recall as many of the words as they could.

All the while, the scientists monitored a handful of “hot spots” in the brain which, previous work had shown, were strongly related to memory encoding.

Before the stimulation tests, the team determined the precise settings for each patient’s high- and low-functioning states.

Each participant carried out the word-memorization tests repeatedly, with different words every time; some lists were memorized with brain stimulation, and other lists with no stimulation, which served as a control.

The authors then examined memory performance based on whether stimulation arrived during low- compared with high-functioning brain states.

The team then statistically analyzed the results and found that people scored slightly higher than usual on words when stimulation arrived during a low or foggy state — and worse, when the pulse arrived in a high state. “The average enhancement effect was about 12 to 13 percent,” Dr. Kahana said. “And when stimulation arrived in a good state, the average was about 15 to 20 percent worse than usual.”

Dr. Doris Greenblatt, a psychiatrist who participated in the trial at Emory, said she sought the surgery because her epilepsy had long caused memory problems. “Each seizure I had tore at the fabric of memory, and it was as if my memories weren’t attached to anything,” Dr. Greenblatt said.

She agreed to the memory testing for the study. “It was a little humiliating, to be honest,” she said of the testing. “I would remember one or two items from a list of objects in a kitchen, for instance, then think, ‘Oh no, what else was there?’ ”

She said she had no idea whether the electrodes in her brain were stimulating or not. “All I can say is that it was exhausting, and I worried about how I was doing.” She had the surgery for her epilepsy a year ago, with Dr. Robert Gross, and has not had a seizure since; her memory is also improved, she said.

The timed component in this study represented a clear break from previous approaches. In 2014 the Defense Department had funded another group testing stimulation in epilepsy patients — directly to a brain area near the hippocampus, which is crucial to memory formation.

That approach did not take into account brain states, the high and low function, and it was not successful.

“To me,” said Dr. Voytek, the new approach “is a clear demarcation that the era of dumb stimulators is over.”

Source:     NY Times

Scientists Create Part Pig Part Human Embryo!!!!

Scientists create a part-human, part-pig embryo — raising the possibility of interspecies organ transplants

For the first time, scientists have grown an embryo that is part-pig, part-human.

The experiment, described Thursday in the journal Cell, involves injecting human stem cells into the embryo of a pig, then implanting the embryo in the uterus of a sow and allowing it to grow. After four weeks, the stem cells had developed into the precursors of various tissue types, including heart, liver and neurons, and a small fraction of the developing pig was made up of human cells.

The human-pig hybrid — dubbed a “chimera” for the mythical creature with a lion's head, a goat's body and a serpent's tail — was “highly inefficient,” the researchers cautioned. But it's the most successful human-animal chimera and a significant step toward the development of animal embryos with functioning human organs.

In a study published a day earlier, an international team of researchers demonstrated that organs for transplant can be grown in chimera embryos that are part-mouse, part-rat. 

Writing in Nature, the researchers reported Wednesday that they were able to grow a mouse pancreas inside a rat embryo, then transfer insulin-secreting tissue from that organ into diabetic mice, alleviating their illness without triggering an immune response.

It was the first demonstration that such an interspecies organ transplant is possible. Researchers hope that one day doctors may be able to grow human tissue using chimera embryos in farm animals, making organs available for sick humans who might otherwise wait years for a transplant.

[Human embryo experiment shows progress toward 'three-parent' babies]

The technique is already the subject of a vigorous debate about the ethics of introducing human material into animals; since 2015, the National Institutes of Health has had a moratorium on funding for certain human-animal chimera research.

(The new study was performed in California at the Salk Institute without federal funds.)

Some argue that, since stem cells can become any kind of tissue, including parts of the nervous system, chimeras raise the specter of an animal with a human brain or reproductive organs.

Others think there's a symbolic or sacred line between human and animal genetic material that should not be crossed.

But Vardit Ravitsky, a bioethicist at the University of Montreal's School of Public Health, said that the two studies published this week could help make a case for further human-animal chimera research by demonstrating the field's potential benefits. 

“I think the point of these papers is sort of a proof of principle, showing that what researchers intend to achieve with human-non-human chimeras might be possible,” she said. “The more you can show that it stands to produce something that will actually save lives … the more we can demonstrate that the benefit is real, tangible and probable — overall it shifts the scale of risk-benefit assessment, potentially in favor of pursuing research and away from those concerns that are more philosophical and conceptual.”

[NIH may allow funding for human-animal stem cell research]

In an effort to address the world's growing organ shortage — an estimated 22 people a day die waiting for transplants, according to the U.S. Department of Health and Human Services  — scientists have been trying to grow organs outside the human body. But organs developed in petri dishes are not identical to the ones that grow inside a living thing.

“That's where the rationale of this kind of experiment comes in,” said Juan Carlos Izpisua Belmonte, a developmental biologist at the Salk Institute and the senior author on the study of the human-pig chimera.

“What if we let nature do the work for us? What if we just put human cells inside the embryo and the embryo knows what do to?”

 

The model for using chimeras for organ transplant would probably look something like the technique reported in Nature. In that experiment, researchers took induced pluripotent stem cells (ordinary cells that have been reverted to an early embryonic state, so that they have the potential to develop into any tissue type) from mice. These cells were then injected into rat embryos that had been genetically modified so that they were unable to grow their own pancreas — “emptying a niche” for the mouse stem cells to fill.

The embryonic rats developed normally and were born healthy. Each had a rat-sized pancreas made of mouse cells. The whole pancreases were too big to transplant into tiny mice, so the researchers extracted just the islets — the region of the pancreas that produces hormones like insulin — and planted them in mice that had been induced to have diabetes.

Because the transplanted cells were grown from stem cells taken from mice, the animals required just five days of immunosuppressive drugs to keep their bodies from rejecting the new tissue. After that, they were able to live normally with healthy blood glucose levels for over a year — half a lifetime in human terms.

The study showed that interspecies organ transplants are not only possible, but they can be done effectively and safely, said Hiromitsu Nakauchi, a stem cell researcher at Stanford University and the University of Tokyo who is the senior author of the study. 

“This is a form of transplantation we could do in the clinic with human patients someday,” he said. 

[Stem-cell clinics face new scrutiny from federal regulators]

Nakauchi also conducts research on human-chimera embryos, but his efforts to inject human stem cells into sheep embryos have largely been unsuccessful — the evolutionary distance between humans and livestock may be making it difficult to get human stem cells to take hold in those animals. 

Other researchers have achieved human-mouse chimeras that developed to full size and grew to adulthood, but there is debate about how substantially human cells can contribute to mice, which are much more distantly related.

He said he was cheered to read the Cell study, which represents the most significant progress on human-animal chimeras yet, though the technique is still nowhere near ready for an experiment like the one performed in Nakauchi's mice.

“If you read the paper, the contribution of human cells is very limited, is very, very minor, and only in the early embryonic phase, so we’re still not sure if we can make human chimeras,” he cautioned. “But I'm glad that they're doing this research.”

The Cell study was the result of four years of work involving some 1,500 pig embryos. These embryos were not genetically modified, like Nakauchi's rat embryos, but the Salk scientists used a similar technique to inject human stem cells.

Pigs are an ideal animal for chimera research, said co-author Pablo Ross, an associate professor in the department of animal science at the University of California, Davis. Their organs are roughly the same size as those of humans (recall that the pancreases grown in Nakauchi's rats were rat-sized, even though they were grown with mouse cells), but they reach their full size far more quickly than humans and other primates. 

“You go from one cell [at] fertilization to 200 pounds, the average size of an adult [pig], in nine months,” Ross said. “I think that's very reasonable, when you think about the fact that the average wait for a kidney transplant is about three years.”

[Scientists turned mouse skin cells into egg cells — and made babies]

Still, pigs' rapid gestation means that their organs develop much more rapidly than those of humans. If researchers want to create a successful chimera, they have to consider timing.

So Ross and his colleagues used three different types of stem cells for their experiment: “naive” cells that were at the very earliest stages of development, “primed” cells that have developed further (but are still pluripotent), and “intermediate” cells that are somewhere in between.

Dozens of cells of each type were injected into pig embryos, which were then implanted in sows and allowed to develop for three to four weeks (about a quarter of a pig's gestation period). The primed cells never really took hold in the host embryo. The naive cells were initially incorporated into the growing animal, but were indistinguishable in the developing pig four weeks later.

The intermediate cells were most successful; by the time the embryos were removed from the sow and analyzed, about one in every 100,000 cells was human rather than pig, lead author Jun Wu estimated. The human cells were distributed randomly across the chimera: Many wound up in what would become the heart (where they made up about 10 percent of tissue), some in the kidneys and liver (1 percent or less).

A few developed into the precursors of neurons, a fear of bioethicists who worry about creating an animal with human or even humanlike consciousness.

But Izpisua Belmonte said that prospect is still a long way off. The contribution of human cells to the chimera was tiny, and research protocols were in place to prevent the development of any human-animal chimera to maturity.

“We were just trying to answer the yes or no question of, can human cells contribute at all?” he said. “And the answer to that question is yes.”

The Cell study researchers also discussed progress with rat-mouse chimeras. Though they have not performed an interspecies organ transfer, they were able to grow hearts, eyes and pancreases in chimeric embryos.

They also grew a rat gall bladder inside a mouse embryo, even though rats don't grow gall bladders during normal development — suggesting that rats have the genetic coding for gall bladders but those genes are suppressed by their developmental environment.

That's another important aspect of chimera embryo research, Izpisua Belmonte said, one that is sometimes overlooked in the focus on organ transplants. Chimera embryos can be used to understand development, examine genetic diseases and test drugs without risking the health of humans.

In August, NIH released a draft of a policy that would change the guidelines to allow funding of certain human animal chimeras. Under the proposed new rule, the taxpayer funds could be used for experiments that introduced human stem cells to early stage embryos of all animals except other primates. Some nonhuman primate research would also be allowed, but only using embryos at later stages of development and only after an extra layer of review by a special NIH committee. But the policy change is still under review.

Neither Nakauchi's nor Izpisua Belmonte's study was funded by NIH grants. Nakauchi said he hoped that recent progress in the field might garner support for easing the ban.

“Finally we’re able to provide a proof of principle that ... this approach of making organs … is possible and also safe and efficient,” he said. “So I hope people will understand this.”

He continued, “Many people think this is a kind of science fiction story. But this is becoming reality.”

Source:     Washington Post News