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Researchers observe human like brain waves in lab grown mini brains

Researchers observe human-like brain waves in lab-grown mini-brains

One method by which researchers can non-invasively analyze the human brain is by developing pea-sized clusters of brain cells called “mini-brains” in the research lab. This week, the team announced that they found human-like brainwaves from these organoids in a magnificent advancement of this field of research.

The movement and nerve tract development of mini-brains has been shown by the previous studies. Biologist Alysson Muotri along with the researchers at the University of California San Diego are the first to study and record human-like neural activity. The researchers wrote that they observed brain wave patterns similar to those of a developing human in their paper published in Cell Stem Cell. Muotri said that sophistication in the in vitro model is a step to help researchers to use mini-brains to study brain development, model diseases, and study about the evolution of the brain. Researchers are good at studying cancer and the heart but the brain has been behind the curve.

Researchers introduced pluripotent human stem cells to a nutrient-rich petri-dish intended to imitate the environment in which our own brains develop to create the technical “mini-brains” called organoids. These cells could be stimulated into building a 3D structure similar to the much smaller human brain because of the multipotential (potential to become any number of different cells) nature of the stem cells. The researchers started to observe the peak of neural activity from the network at around two months of development.

Co-author and Ph.D. student Richard Gao stated that at the beginning, they weren’t checking for parallels between their model and human infant when they began to observe these intermittent bursts of electrical activity. Gao said that they observed a notable feature in organoid oscillations that the network is inactive most of the time and explode spontaneously in every 10-20 seconds. This also occurs in preterm infants called trace discontinu where strong oscillatory transients emphasize the infant’s inactive ECG. He also said that we are very lucky to find a dataset reporting these features in the preterm infant EEG at a point where oscillations vary.

Muotri said that a machine learning algorithm has been prepared by the team to identify important features in the preterm infant EEGs and had it evaluate the cerebral organoids for similarities. It was able to calculate how many weeks the organoids had developed in the culture and could no more distinguish between the organoids and the infant EEGs between 25 and 40 weeks of the organoid’s development.

Muotri and the team clarified that the comparison between the two is not necessarily one-to-one and preterm infant EEGs have some limitations including the impact the thickness of a developing human skull has on readings which differ from the lab-produced organoids.

Arnold Kriegstein, a neurologist from the University of California, San Francisco, who did not contribute to the new study, said that it is difficult to state similarity between organoid activity and preterm EEG. The researchers have clearly shown the development of spontaneous activity in organoids to be reliable on the neuronal activity but organoids are very different from the actual developing cortex and we still need better evidence that the underlying mechanisms are the same even if the phenomenology is similar.

Muotri said that he can’t be sure whether the organoids were developed enough to be considered conscious and questions related to ethical dilemmas might be raised in the future. He intends to hold a meeting at UC San Diego with scientists, philosophers, and ethicists to talk about the ethical future of such technologies. He said that his tendency is always to say that technologies like blood transfusions or organ transplants, or even cars can be used for good as well as bad so brain organoids might also point in a similar direction in the future.

Journal Reference: Cell Stem Cell

human embryo

Japanese Government approves experiments to be conducted for human-animal embryos

Japan has approved the first human-animal embryo that could lead to new sources of organ transplant. Though there are still technical and ethical hurdles. Government of Japan is supporting a stem cell scientist Hiromitsu Nakauchi who leads teams at the University of Tokyo and Stanford University in California for creating animal embryos that contain human cells and transplant them into surrogate creatures as the restriction to practice was overturned this year.

Human cells are planned to be grown in mouse and rat embryos and then it could be transplanted into surrogate animals. Nakauchi said that he wants to produce animals with organs made from human cells which can be eventually transplanted into individuals. He also said that he is planning to grow a hybrid mouse for 14.5 days when the organs are mostly formed, almost to be termed and 15.5 days for the same experiment on rats. He is awaiting government approval for up to 70 days, for growing hybrid embryos in pigs. The study has been published in Nature journal.

Bioethicists are concerned that the human cells might stray beyond the development of the specific organ and travel to the animal’s brain and affect the cognition. He also added that these concerns were taken into consideration during experiments and that he made sure that cells go only to the pancreas and not the entire body.

Scientists are investigating a strategy to make an animal embryo that lacks a gene vital for the generation of a specific organ, like the pancreas and then infuse human induced pluripotent stem (iPS) into the animal fetus. iPS cells have been programmed to an embryonic-like state which can offer ascent to all cell types. As the animal starts to develop, it will make use of the human iPS cells to make an organ which it cannot make on its own.

At the American Association for the Advancement of Science meeting in Austin, Texas in 2018 scientists reported they had put human iPS cells into the sheep embryos and had been engineered not to produce a pancreas but even after growth for 28 days, it contained very less human cells and nothing resembling organs. Nakauchi thinks that is due to the genetic distance between humans and sheep.

Jun Wu who is a researcher at the University of Texas Southwestern Medical Center in Dallas said that it is not useful to bring human-animal hybrid embryos in evolutionarily distant species like pigs and sheep as human cells will be eliminated by the host early on. There is a need to understand the molecular basics and then develop strategies to overcome problems. The approval in Japan will be helpful in experimenting with iPS cells at different stages to find out the limit of growth of human cells in animal embryos.

 

Red reporter cells showing the change in edited cells on the right.

Scientists demonstrate genetic editing of stem cells inside the body of mice

Researchers have been successful in genetic modification of stem cells inside the body of mice for the first time ever. This feat can unlock various avenues in stem cell therapy, which have not been explored so far. The study has been published in Cell Reports.

Stem cells can grow into all other types of body cells and the body uses this ability for its growth and repair in several parts. Because of the potential in stem cells, researchers are always looking to incorporate stem cells in the medical treatments but it has not been easy so far. For example in the case of a bone marrow transplant, the stem cells which produce blood have to be first removed from the human body, genetically modified and only then be transfused back into the human body.

From the results of this experiment on mice, it is likely that the complicated extraction step can be bypassed. The genetic edits which are needed can be performed in vivo, which is estimated to be much faster and effective than the techniques which are currently used.

Amy Wagers from Harvard University who is the principal researcher behind the study commented that when stem cells are taken out of the body, they are being removed from the circumstances which provide nourishment and helps to sustain them. As a result of this change, they go into shock. The researchers wanted to make the genetic changes in the cells without isolating or transplanting them as it changes them altogether.

Researchers did this by using adeno-associated virus(AAV). This virus is able to enter the body for infecting and altering the cells without generating any sort of disease. In the tests which were conducted on mice, AAVs packed with CRISPR gene editing technology were released in various types of skin, blood, muscle stem cells, progenitor cells.

With the help of activated reporter genes which turn to fluorescent red inside cells, researchers could observe the genetic changes, upto 60 percent of stem cells in skeletal muscles, 38 percent in bone marrow and 27 percent of progenitor cells.

Sharif Tabebordbar from Broad Institute, Massachusetts who is a member of the team said that till now delivering genes to stem cells using AAV was not possible as the cells get divided very fast in living bodies. But the team was successful in modifying the genome of the stem cells within the body itself.

However, the job is not yet done as this has to be successfully demonstrated in the human bodies but the combination of AAV and CRISPR has turned out to be quite promising for tackling various problems.

Porcine EPSC colony

HKU Discovers Stem Cell Breakthrough Offers New Avenue for Advancing Research

A new approach to deriving stem cells that was led and developed by scholars from LKS Faculty of Medicine of The University of Hong Kong (HKUMed), in collaboration with scientists from the Wellcome Sanger Institute in Cambridge, UK and the Friedrich-Loeffler-Institut in Germany, offers groundbreaking potential for studying embryonic development and producing translational research in genomics and regenerative medicine, biotechnology and agriculture. The findings were published in Nature Cell Biology.

The Expanded Potential Stem Cells (EPSCs) of both porcine (pig) and human have been established. The porcine EPSCs are particularly important because this is the first time scientists have been able to derive stem cells from early pig embryos. Domestic pigs have great potential for biomedical research because of their similarity to human genetics, anatomy and physiology (such as organ size). Being able to genetically-modify pig stem cells will also be beneficial for animal health and food production. Human EPSCs are expected to provide a new cell source for studying human development and regenerative medicine.

Professor Pengtao Liu of the School of Biomedical Sciences and Stem Cell and Regenerative Medicine Consortium, HKUMed, who leads the research, said: “Scientists have been attempting to derive porcine embryonic stem cells for decades without much success. With our EPSC technology, we have now successfully derived and characterised stem cells from porcine preimplantation embryos. We have also established similar human stem cells. Our study represents a major advance in stem cell research.”

The key characteristic of EPSCs is that they are derived from pre-implantation embryos of very early developmental stages. Until now, embryonic stem cells, in general, are established from pre-implantation embryos made up of at least dozens of cells that are called blastocysts. In the embryos earlier than the blastocysts stage, cells are less differentiated and have potential to develop into more kinds of cells. EPSCs have the potential to produce all types of cell and thus have totipotency features.

Professor Liu’s group has so far established EPSCs from mouse, pig and human. These new stem cells across species are molecularly similar and amenable to multiple rounds of genome-editing. Besides their capacity to produce all types of cell found in our body and are useful for studying human disease and regenerative medicine, human EPSCs can produce large numbers of placenta cells, called trophoblasts, which offer new opportunities to investigate pregnancy complications such as pre-eclampsia and miscarriages.

“These EPSC stem cells possess developmental potency that is not generally seen in conventional or standard embryonic or induced pluripotent stem cells. They have the potential to produce all embryonic and extra-embryonic cell lines – including those in the placenta and yolk sac, turning back the development clock to the very earliest cell type. These cells will enable researchers to study early embryonic development, miscarriage and developmental disorders,” said Dr Xuefui Gao, who was the first author of the Nature Cell Biology paper.

Professor Liu provided the inspiration for this approach after noticing the difficulties scientists faced in developing stem cell lines for mammals beyond some rodents and primates. The practice of using blastocysts for deriving stem cells dates back to the 1970s and 1980s when the first study to derive stem cells was carried out and the technology and understanding of molecular events were much more limited than today. Blastocysts have been the norm ever since, but the HKU scientists thought that earlier intervention might offer a greater chance of success.

“The earlier embryonic developmental stages that we get embryonic stem cells, the less diversity there might be among mammalian species, the higher chance that the EPSC technology works for more mammalian species. Our idea was to try to investigate conditions that could allow us to capture and derive stem cells from the very early embryos of different species – when they are like a blank sheet of paper – and remarkably it works,” said Professor Pengtao Liu.

The first breakthrough from Professor Liu’s research group came with mice in 2017, when key molecular pathways that drive cell lineage differentiation were targeted. The most recent study on human and porcine EPSCs suggests that this approach might be possible with mammals that hitherto had been elusive to stem cell researchers.

Dr Monika Nowak-Imialek of the Friedrich-Loeffler-Institut (FLI), a co-first author of the paper, said: “Our porcine EPSCs isolated from pig embryos are the first well-characterised porcine cell lines worldwide. EPSC’s great potential to develop into any type of cell provides important implications for developmental biology, regenerative medicine, organ transplantation, disease modeling, animal health, agriculture and biotechnology.”

Building on this work, the HKUMed researchers are continuing to push the EPSC technology and are collaborating with other research groups. “We are excited that these new stem cells are expected to have broad applications in basic and translational research in the near future,” said Professor Pengtao Liu.

About the research team

The research was led and conducted by Professor Pengtao Liu’s laboratory at HKUMed, in collaboration with Professor William Yeung of the Department of Obstetrics and Gynaecology, HKUMed; together with Professor Heiner Niemann, Director Emeritus of Friedrich-Loeffler-Institut (FLI) and Dr. Monika Nowak-Imialek of FLI; Professor Sarah Teichmann and Dr Xi Chen of the Wellcome Sanger Institute in Cambridge, UK; Professor Asif Ahmed of Aston University, UK; and several collaborating research laboratories in Mainland China. This study was supported by HKUMed and HKU internal funding and by the Wellcome Sanger Institute.

Materials provided by University of Hong Kong

boy treated with gene therapy

Scientists cure “bubble boy” disease with help of an improved gene therapy

Researchers declared that ten newborn children with a rare genetic disorder, the “bubble boy disease” were cured with the help of gene therapy.

With the help of this treatment, the babies have been cured of the disorder without any side effects or post-treatment complications. Scientists carrying out research hoped for this result for decades but had always received setbacks until now.

In 2003, researchers tried to use gene therapy for treating Severe Combined Immunodeficiency Disease, but they stopped midway as it was detected that the therapy gave them cancer. The present treatment does not come with any such dangerous side effects and scientists hope that it can be used for other rare diseases too such as sickle cell disease.

Children born with SCID did not have a properly working immune system and without receiving any treatment they did not even make it past their first birthday. Even simple illnesses such as common cold were fatal for these children. These children were kept in very protected environments and it gave rise to the name “bubble boy“. However, a boost in the mortality rate has been observed recently owing to the advanced detection tests and treatments such as bone marrow transplants. Unfortunately, even these treatments have complications and they make the patients dependent on regular dosages of immunoglobulin.

The latest gene therapy has been developed by St. Jude Children’s Research Hospital and UCSF Benioff Children’s Hospital based in San Francisco. The therapy rectifies the genetic defects which are there in the DNA of the babies just after they are born, which helps the body to develop the parts of the immune system that are missing.

After the extraction of blood stem cells from the bone marrow of the infants, researchers used a virus as a means of transport to send the corrected version of the defective gene to the stem cells of the patients. The rectified cells were reinfused into the body of the patients where the proliferation of the cells took place to grow healthy immune cells.

Scientists took special care in not enabling the genes which cause cancer, so they added “insulators” with the virus such that surrounding genes would not get affected when the virus is inserted into DNA. Apart from this, the patients were also given chemotherapy to a small extent for clearing the existing cells from the bone marrow so that proliferation of the corrected cells can occur in a better way.

It was an emotional day for the announcement at the St. Jude Children’s Research Hospital, as the team leader Brian Sorrentino had spent his last days fighting against his cancer to finish the work on the treatment.

Scanning electron micrograph of HIV-1

Another man became free of HIV using the stem cell treatment

A man from London is being said to be free from the AIDS virus. The person, known as the “London patient”, had leukemia and underwent a stem cell transplant to treat cancer. The donor’s cells had a protein which is supposed to combat the HIV virus.

Timothy Ray Brown, from the USA, was the first man who was treated in Germany and is originally known as the “Berlin patient”. He is still free of HIV even after 12 years of the treatment. Until now, Brown was the only person known to have been cured of infection with HIV, the virus that causes AIDS.

Brown is the only person in the history who went through two successful stem cell transplants and when asked about the same, post this second victorious treatment, he said, “I knew I was the only person cured of HIV at that point and I didn’t want to be the only person“.

How does it work?

CCR5 is the most commonly used receptor by HIV to enter the cells. But a very small number of HIV resistant people have two mutated copies of the CCR5 receptor, called delta-32 mutation. This mutation stops the virus to penetrate cells in the body that it normally infects.

The London patient received stem cells from a donor with this specific genetic mutation, which made him resistant to HIV as well. But even after the treatment, cells carrying HIV can still remain in the body, in a resting state, for many years.

The Doctors’ verdicts:

According to the doctors, treatments like stem cell transplant are difficult, dangerous and have failed in other patients. They’re also impractical to try to cure the millions of people worldwide who are infected with HIV.

“The latest successful operation shows that the cure of Timothy Brown was not just a matter of chance or luck and can be repeated”, said Dr.Keith Jerome of Fred Hutchinson Cancer Research Centre in Seattle. He added that it could generate a simpler formula that could be used more widely.

Dr. Rowena Johnston, who oversaw the research at the Foundation for AIDS Research, said that this is a really exciting news.

Dr. Anthony Fauci, the person who is in charge of government HIV research, cautions: “This approach is unsafe, unsuitable and not scalable”, meaning it could not be replicated among many patients. But, he points out that it may have pertinence in future attempts to use gene editing to treat AIDS.

The latest patients are part of a research project which has so far enrolled 45 patients with cancer and HIV, who have received or will receive stem cell transplants.

Read More:

  1. WHAT ARE HIV AND AIDS?
  2. Stem cells: What they are and what they do