Ethics debate as pig brains kept alive without a body

Researchers at Yale University have restored circulation to the brains of decapitated pigs, and kept the organs alive for several hours.

Their aim is to develop a way of studying intact human brains in the lab for medical research.

Although there is no evidence that the animals were aware, there is concern that some degree of consciousness might have remained.

Details of the study were presented at a brain science ethics meeting held at the National Institutes of Health (NIH) in Bethesda in Maryland on 28 March.

The research has also been reported on this week in the MIT Technology Review.

The work, by Prof Nenad Sestan of Yale University, was discussed as part of an NIH investigation of ethical issues arising from neuroscience research in the US.

Prof Sestan explained that he and his team experimented on more than 100 pig brains.

They discovered that he could restore their circulation using a system of pumps, heaters, and bags of artificial blood.

As a result the researchers were reportedly able to keep the cells in the brain alive and capable of normal activity for as long as 36 hours.

Prof Sestan is said to have described the result as “mind-boggling”. If this could be repeated with human brains, researchers would be able to use them to test out new treatments for neurological disorders.

But Prof Sestan is among the first to raise potential ethical concerns. These include whether such brains have any consciousness and if so deserve special protection, or whether their technique could or should be used by individuals to extend their lifespans – by transplanting their brains when their bodies wear out.

In a commentary published in the Journal Nature this week, Prof Sestan and 15 other leading US neuroscientists called for clear regulation to guide them in their work.

“If researchers could create brain tissue in the laboratory that might appear to have conscious experiences or subjective phenomenal states, would that tissue deserve any of the protections routinely given to human or animal research subjects?”, the researchers ask in the commentary.

“This question might seem outlandish. Certainly, today’s experimental models are far from having such capabilities. But various models are now being developed to better understand the human brain, including miniaturised, simplified versions of brain tissue grown in a dish from stem cells. And advances keep being made.”

The researchers say that ways of measuring consciousness need to be developed and strict limits set for them to be able to continue their work with the public’s support.

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    Prof Colin Blakemore, of the School of Advance Study at the University of London, backs the research team’s call for a public debate on the issue.

    “The techniques, even to a researcher, sound pretty ghoulish – so it is very, very important that there should be a public discussion about this, and not least because the researchers who have some investment can tell the public why it would be so important to develop such techniques,” he told BBC News.

    “There is a paradox here, and that is – the better such methods are at maintaining a whole brain, fully functional but without connection to a body, the more useful that would be for research purposes. But the more likely it would also be for the brain to have some sentience and consciousness, which would be deeply worrying”.

    Prof Blakemore said that he was “very uneasy about the quest for immortality” by those considering preserving their brains until surgery advances, in order to place them in a new body.

    “Our planet is already overpopulated. You need space for young people and new ideas, and the notion of desperately clinging on to any mechanism possible for human beings living forever, I find very unsavoury.”

How bacteria are changing your mood

If anything makes us human it’s our minds, thoughts and emotions.

And yet a controversial new concept is emerging that claims gut bacteria are an invisible hand altering our brains.

Science is piecing together how the trillions of microbes that live on and in all of us – our microbiome – affect our physical health.

But even conditions including depression, autism and neurodegenerative disease are now being linked to these tiny creatures.

We’ve known for centuries that how we feel affects our gut – just think what happens before an exam or a job interview – but now it is being seen as a two-way street.

Groups of researchers believe they are on the cusp of a revolution that uses “mood microbes” or “psychobiotics” to improve mental health.

The study that ignited the whole concept took place at Kyushu University in Japan.

The researchers showed that “germ-free” mice – those that never came into contact with microbes – pumped out twice the amount of stress hormone when distressed than normal mice.

The animals were identical except for their microbes. It was a strong hint that the difference was a result of their micro-organisms.

“We all go back to that first paper for the first wave of neuroscientists considering microbes,” says Dr Jane Foster, a neuropsychiatrist at McMaster University in Canada.

“That really was very powerful for those of us who were studying depression and anxiety.”

It was the first hint of microbial medicine in mental health.

How could bacteria be altering the brain?

The brain is the most complex object in the known universe so how could it be reacting to bacteria in the gut?

  • One route is the vagus nerve, it’s an information superhighway connecting the brain and the gut.
  • Bacteria break down fibre in the diet into chemicals called short-chain fatty acids, which can have effects throughout the body.
  • The microbiome influences the immune system, which has also been implicated in brain disorders.
  • There is even emerging evidence that gut bugs could be using tiny strips of genetic code called microRNAs to alter how DNA works in nerve cells.

    There is now a rich vein of research linking germ-free mice with changes in behaviour and even the structure of the brain.

    But their completely sterile upbringing is nothing like the real world. We’re constantly coming into contact with microbes in our environment, none of us are germ-free.

    At Cork University Hospital, Prof Ted Dinan is trying to uncover what happens to the microbiome in his depressed patients.

    A good rule of thumb is a healthy microbiome is a diverse microbiome, containing a wide variety of different species living all over our bodies.

    Prof Dinan says: “If you compare somebody who is clinically depressed with someone who is healthy, there is a narrowing in the diversity of the microbiota.

    “I’m not suggesting it is the sole cause of depression, but I do believe for many individuals it does play a role in the genesis of depression.”

    And he argues some lifestyles that weaken our gut bacteria, such as a diet low in fibre, can make us more vulnerable.

    The microbiome

    • You’re more microbe than human – if you count all the cells in your body, only 43% are human
    • The rest is our microbiome and includes bacteria, viruses, fungi and single-celled archaea
    • The human genome – the full set of genetic instructions for a human being – is made up of 20,000 instructions called genes
    • But add all the genes in our microbiome together and the figure comes out at between two million and 20 million microbial genes
    • It’s known as the second genome and is linked to diseases including allergy, obesity, inflammatory bowel disease, Parkinson’s, whether cancer drugs work and even depression and autism

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      It’s an intriguing concept – that an imbalance in the gut microbiome could be involved in depression.

      So scientists at the APC Microbiome centre, at University College Cork, started transplanting the microbiome from depressed patients to animals. It’s known in the biz as a trans-poo-sion.

      It showed that if you transfer the bacteria, you transfer the behaviour too.

      Prof John Cryan told the BBC: “We were very surprised that you could, by just taking microbiome samples, reproduce many of the features of a depressed individual in a rat.”

      This included anhedonia – the way depression can lead to people losing interest in what they normally find pleasurable.

      For the rats, that was sugary water they could not get enough of, yet “when they were given the microbiome from a depressed individual, they no longer cared”, says Prof Cryan.

      Listen to The Second Genome on BBC Radio 4.

      The next episode airs at 11:00 BST on Tuesday April 24, repeated 21:00 BST Monday April 30 and on the BBC iPlayer

      Similar evidence – linking the microbiome, the gut and the brain – is emerging in Parkinson’s disease.

      It is clearly a brain disorder. Patients lose control over their muscles as brain cells die and it leads to a characteristic tremor.

      But Prof Sarkis Mazmanian, a medical microbiologist from Caltech, is building the case that gut bacteria are involved.

      “Classical neuroscientists would find this as heresy to think you can understand events in the brain by researching the gut,” he says.

      He has found “very powerful” differences between the microbiomes of people with Parkinson’s and those without the disease.

      Studies in animals, genetically hardwired to develop Parkinson’s, show gut bacteria were necessary for the disease to emerge.

      And when stool was transplanted from Parkinson’s patients to those mice, they developed “much worse” symptoms than using faeces sourced from a healthy individual.

      Prof Mazmanian told the BBC: “The changes in the microbiome appear to be driving the motor symptoms, appear to be causal to the motor symptoms.

      “We’re very excited about this because it allows us to target the microbiome as an avenue for new therapies.”

      The evidence linking the microbiome and the brain is as fascinating as it is early.

      But the pioneers of this field see an exciting prospect on the horizon – a whole new way of influencing our health and wellbeing.

      If microbes do influence our brains then maybe we can change our microbes for the better.

      Can altering the bacteria in Parkinson’s patients’ guts change the course of their disease?

      There is talk of psychiatrists prescribing mood microbes or psychobiotics – effectively a probiotic cocktail of healthy bacteria – to boost our mental health.

      Dr Kirsten Tillisch, at University of California, Los Angeles, told me: “If we change the bacteria can we change the way we respond?

      But she says we need far bigger studies that really probe what species, and even sub-species, of bacteria may be exerting an effect on the brain and what products they are making in the gut.

      Dr Tillisch said: “There’s clearly connections here, I think our enthusiasm and our excitement is there because we haven’t had great treatments.

      “It’s very exciting to think there’s a whole new pathway that we can study and we can look and we can help people, maybe even prevent disease.”

      And that’s the powerful idea here.

      The microbiome – our second genome – is opening up an entirely new way of doing medicine and its role is being investigated in nearly every disease you can imagine including allergies, cancer and obesity.

      I’ve been struck by how malleable the second genome is and how that is in such stark contrast to our own DNA.

      The food we eat, the pets we have, the drugs we take, how we’re born… all alter our microbial inhabitants.

      And if we’re doing that unwittingly, imagine the potential of being able to change our microbiome for the better.

      Prof Cryan said: “I predict in the next five years when you go to your doctor for your cholesterol testing etc, you’ll also get your microbiome assessed.

      “The microbiome is the fundamental future of personalised medicine.”

      Follow James on Twitter.

      Illustrations: Katie Horwich

More than half your body is not human

More than half of your body is not human, say scientists.

Human cells make up only 43% of the body’s total cell count. The rest are microscopic colonists.

Understanding this hidden half of ourselves – our microbiome – is rapidly transforming understanding of diseases from allergy to Parkinson’s.

The field is even asking questions of what it means to be “human” and is leading to new innovative treatments as a result.

“They are essential to your health,” says Prof Ruth Ley, the director of the department of microbiome science at the Max Planck Institute, “your body isn’t just you”.

No matter how well you wash, nearly every nook and cranny of your body is covered in microscopic creatures.

This includes bacteria, viruses, fungi and archaea (organisms originally misclassified as bacteria). The greatest concentration of this microscopic life is in the dark murky depths of our oxygen-deprived bowels.

Prof Rob Knight, from University of California San Diego, told the BBC: “You’re more microbe than you are human.”

Originally it was thought our cells were outnumbered 10 to one.

“That’s been refined much closer to one-to-one, so the current estimate is you’re about 43% human if you’re counting up all the cells,” he says.

But genetically we’re even more outgunned.

The human genome – the full set of genetic instructions for a human being – is made up of 20,000 instructions called genes.

But add all the genes in our microbiome together and the figure comes out between two and 20 million microbial genes.

Prof Sarkis Mazmanian, a microbiologist from Caltech, argues: “We don’t have just one genome, the genes of our microbiome present essentially a second genome which augment the activity of our own.

“What makes us human is, in my opinion, the combination of our own DNA, plus the DNA of our gut microbes.”

Listen to The Second Genome on BBC Radio 4.

Airs 11:00 BST Tuesday April 10, repeated 21:00 BST Monday April 16 and on the BBC iPlayer

It would be naive to think we carry around so much microbial material without it interacting or having any effect on our bodies at all.

Science is rapidly uncovering the role the microbiome plays in digestion, regulating the immune system, protecting against disease and manufacturing vital vitamins.

Prof Knight said: “We’re finding ways that these tiny creatures totally transform our health in ways we never imagined until recently.”

It is a new way of thinking about the microbial world. To date, our relationship with microbes has largely been one of warfare.

Microbial battleground

Antibiotics and vaccines have been the weapons unleashed against the likes of smallpox, Mycobacterium tuberculosis or MRSA.

That’s been a good thing and has saved large numbers of lives.

But some researchers are concerned that our assault on the bad guys has done untold damage to our “good bacteria”.

Prof Ley told me: “We have over the past 50 years done a terrific job of eliminating infectious disease.

“But we have seen an enormous and terrifying increase in autoimmune disease and in allergy.

“Where work on the microbiome comes in is seeing how changes in the microbiome, that happened as a result of the success we’ve had fighting pathogens, have now contributed to a whole new set of diseases that we have to deal with.”

The microbiome is also being linked to diseases including inflammatory bowel disease, Parkinson’s, whether cancer drugs work and even depression and autism.

Obesity is another example. Family history and lifestyle choices clearly play a role, but what about your gut microbes?

This is where it might get confusing.

A diet of burgers and chocolate will affect both your risk of obesity and the type of microbes that grow in your digestive tract.

So how do you know if it is a bad mix of bacteria metabolising your food in such a way, that contributes to obesity?

Prof Knight has performed experiments on mice that were born in the most sanitised world imaginable.

Their entire existence is completely free of microbes.

He says: “We were able to show that if you take lean and obese humans and take their faeces and transplant the bacteria into mice you can make the mouse thinner or fatter depending on whose microbiome it got.”

Topping up obese with lean bacteria also helped the mice lose weight.

“This is pretty amazing right, but the question now is will this be translatable to humans”

This is the big hope for the field, that microbes could be a new form of medicine. It is known as using “bugs as drugs”.

Goldmine of information

I met Dr Trevor Lawley at the Wellcome Trust Sanger Institute, where he is trying to grow the whole microbiome from healthy patients and those who are ill.

“In a diseased state there could be bugs missing, for example, the concept is to reintroduce those.”

Dr Lawley says there’s growing evidence that repairing someone’s microbiome “can actually lead to remission” in diseases such as ulcerative colitis, a type of inflammatory bowel disease.

And he added: “I think for a lot of diseases we study it’s going to be defined mixtures of bugs, maybe 10 or 15 that are going into a patient.”

Microbial medicine is in its early stages, but some researchers think that monitoring our microbiome will soon become a daily event that provides a brown goldmine of information about our health.

Prof Knight said: “It’s incredible to think each teaspoon of your stool contains more data in the DNA of those microbes than it would take literally a tonne of DVDs to store.

“At the moment every time you’re taking one of those data dumps as it were, you’re just flushing that information away.

“Part of our vision is, in the not too distant future, where as soon as you flush it’ll do some kind of instant read-out and tells you are you going in a good direction or a bad direction.

“That I think is going to be really transformative.”

Follow James on Twitter.

Illustrations: Katie Horwich

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Why some cancers are ‘born to be bad’

A groundbreaking study has uncovered why some patients’ cancers are more deadly than others, despite appearing identical.

Francis Crick Institute scientists developed a way of analysing a cancer’s history to predict its future.

The study on kidney cancer patients showed some tumours were “born to be bad” while others never became aggressive and may not need treating.

Cancer Research UK says the study could help patients get the best care.

“We don’t really have tools to differentiate between those that need treatment and those that can be observed,” said researcher and cancer doctor Samra Turajlic.

One cancer could kill quickly while a patient with a seemingly identical cancer could live for decades after treatment.

It means uncertainty for both the patient and the doctor.

Kidney cancer

It is most common in people in their 60s and 70s. Symptoms include:

  • Blood in your pee
  • Persistent pain in the lower back or side
  • Sometimes a lump or swelling in your side

    The work, published in three papers in the journal Cell, analysed kidney cancers in 100 patients.

    The team at the Crick performed a sophisticated feat of genetics to work out the cancer’s history.

    It works like a paternity or ancestry test on steroids.

    As cancers grow and evolve, they become more mutated and, eventually, different parts of the tumour start to mutate in different ways.

    Researchers take dozens of samples from different parts of the same tumour and then work out how closely related they are.

    It allows scientists to piece together the evolutionary history of the whole tumour.

    “That also tells us where the tumour might be heading as well,” said Dr Turajlic.

    Chance to change care

    The researchers were able to classify kidney cancer into one of three broad categories:

    • Born to be bad
    • Benign
    • Intermediate

      The “born to be bad” tumours had rapid and extensive mutations and would grow so quickly they are likely to have spread round the body before they are even detected.

      Surgery to remove the original tumour may delay the use of drugs that can slow the disease.

      The benign tumours are at the complete opposite and are likely to grow so slowly they may never be a problem to patients and could just be monitored.

      The intermediate tumours were likely to initially spread to just one other location in the body and could be treated with surgery.

      Michael Malley, 72, from London, took part in the trial at the Royal Marsden Hospital after being diagnosed with kidney cancer.

      He said: “Clearly studies like these are really important for understanding how kidney cancer evolves over time, and I hope this one day leads to better treatments for patients like me.”

      There is still the challenge of figuring out how best to tailor treatments to each tumour type, and even how to perform such tests in a hospital rather than a research lab.

      The tools used in this study are being investigated in other cancers, including lung cancer.

      Dr Turajlic says: “We’ve no doubt they will be applicable to other types of cancer.”

      The studies also revealed that the earliest mutations that lead to kidney cancer were happening up to half a century before the cancer was detected.

      Sir Harpal Kumar, the chief executive of Cancer Research UK, said the study was “groundbreaking”.

      He added: “For years we’ve grappled with the fact that patients with seemingly very similar diagnoses nevertheless have very different outcomes.

      “We’re learning from the history of these tumours to better predict the future.

      “This is profoundly important because hopefully we can predict the path a cancer will take for each individual patient and that will drive us towards more personalised treatment.”

      Follow James on Twitter.

Macular degeneration: ‘I’ve been given my sight back’

Doctors have taken a major step towards curing the most common form of blindness in the UK – age-related macular degeneration.

Douglas Waters, 86, could not see out of his right eye, but “I can now read the newspaper” with it, he says.

He was one of two patients given pioneering stem cell therapy at Moorfields Eye Hospital in London.

Cells from a human embryo were grown into a patch that was delicately inserted into the back of the eye.

‘Couldn’t see anything’

Douglas, who is from London, developed severe age-related macular degeneration in his right eye three years ago.

The macula is the part of the eye that allows you to see straight ahead – whether to recognise faces, watch TV or read a book.

He says: “In the months before the operation my sight was really poor and I couldn’t see anything out of my right eye.

“It’s brilliant what the team have done and I feel so lucky to have been given my sight back.”

The macula is made up of rods and cones that sense light and behind those are a layer of nourishing cells called the retinal pigment epithelium.

When this support layer fails, it causes macular degeneration and blindness.

Doctors have devised a way of building a new retinal pigment epithelium and surgically implanting it into the eye.

The technique, published in Nature Biotechnology, starts with embryonic stem cells. These are a special type of cell that can become any other in the human body.

They are converted into the type of cell that makes up the retinal pigment epithelium and embedded into a scaffold to hold them in place.

The living patch is only one layer of cells thick – about 40 microns – and 6mm long and 4mm wide.

It is then placed underneath the rods and cones in the back of the eye. The operation takes up to two hours.

‘Incredibly exciting’

Prof Lyndon da Cruz, consultant retinal surgeon at Moorfields, told the BBC: “We’ve restored vision where there was none.

“It’s incredibly exciting. As you get older, parts of you stop working and for the first time we’ve been able to take a cell and make it into a specific part of the eye that’s failing and put it back in the eye and get vision back.”

However, he does not call this a “cure” as completely normal vision is not restored.

Only one diseased eye was operated on in each patient.

So far the patients, the other is a woman in her early sixties, have maintained improved vision in the treated eye for a year.

They went from not being able to read with their affected eye at all, to reading 60 to 80 words per minute.

Eight more patients will take part in this clinical trial.

Doctors need to be sure it is safe. One concern is the transplanted cells could become cancerous, although there have been no such signs so far.

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    Prof Pete Coffey, from the UCL Institute of Ophthalmology, said: “This study represents real progress in regenerative medicine.

    “We hope this will lead to an affordable ‘off-the-shelf’ therapy that could be made available to NHS patients within the next five years.”

    More than 600,000 people have age-related macular degeneration in the UK. It’s the leading cause of blindness and the third globally.

    Both patients in the trial had “wet” age-related macular degeneration.

    This form of the disease is caused by abnormal blood vessels growing through the retinal pigment epithelium and damaging the macula.

    Dry age-related macular degeneration is more common and caused by the retinal pigment epithelium breaking down.

    It is hoped the patch will be able to treat both forms of the disease.

    Dr Carmel Toomes, from Leeds Institutes of Molecular Medicine, said: “What’s exciting about this study is that the patients recorded an increase in vision.

    “To see an improvement is a good sign that this therapy may help patients in the future, although further studies are needed before real conclusions can be drawn.”

    Follow James on Twitter.

    View comments

Macular degeneration: ‘I’ve been given my sight back’

Doctors have taken a major step towards curing the most common form of blindness in the UK – age-related macular degeneration.

Douglas Waters, 86, could not see out of his right eye, but “I can now read the newspaper” with it, he says.

He was one of two patients given pioneering stem cell therapy at Moorfields Eye Hospital in London.

Cells from a human embryo were grown into a patch that was delicately inserted into the back of the eye.

‘Couldn’t see anything’

Douglas, who is from London, developed severe age-related macular degeneration in his right eye three years ago.

The macula is the part of the eye that allows you to see straight ahead – whether to recognise faces, watch TV or read a book.

He says: “In the months before the operation my sight was really poor and I couldn’t see anything out of my right eye.

“It’s brilliant what the team have done and I feel so lucky to have been given my sight back.”

The macula is made up of rods and cones that sense light and behind those are a layer of nourishing cells called the retinal pigment epithelium.

When this support layer fails, it causes macular degeneration and blindness.

Doctors have devised a way of building a new retinal pigment epithelium and surgically implanting it into the eye.

The technique, published in Nature Biotechnology, starts with embryonic stem cells. These are a special type of cell that can become any other in the human body.

They are converted into the type of cell that makes up the retinal pigment epithelium and embedded into a scaffold to hold them in place.

The living patch is only one layer of cells thick – about 40 microns – and 6mm long and 4mm wide.

It is then placed underneath the rods and cones in the back of the eye. The operation takes up to two hours.

‘Incredibly exciting’

Prof Lyndon da Cruz, consultant retinal surgeon at Moorfields, told the BBC: “We’ve restored vision where there was none.

“It’s incredibly exciting. As you get older, parts of you stop working and for the first time we’ve been able to take a cell and make it into a specific part of the eye that’s failing and put it back in the eye and get vision back.”

However, he does not call this a “cure” as completely normal vision is not restored.

Only one diseased eye was operated on in each patient.

So far the patients, the other is a woman in her early sixties, have maintained improved vision in the treated eye for a year.

They went from not being able to read with their affected eye at all, to reading 60 to 80 words per minute.

Eight more patients will take part in this clinical trial.

Doctors need to be sure it is safe. One concern is the transplanted cells could become cancerous, although there have been no such signs so far.

You may also be interested in:

  • Mums’ Down’s syndrome video goes viral
  • Essential oils ‘make male breasts develop’
  • UK teacher wins global best teacher prize

    Prof Pete Coffey, from the UCL Institute of Ophthalmology, said: “This study represents real progress in regenerative medicine.

    “We hope this will lead to an affordable ‘off-the-shelf’ therapy that could be made available to NHS patients within the next five years.”

    More than 600,000 people have age-related macular degeneration in the UK. It’s the leading cause of blindness and the third globally.

    Both patients in the trial had “wet” age-related macular degeneration.

    This form of the disease is caused by abnormal blood vessels growing through the retinal pigment epithelium and damaging the macula.

    Dry age-related macular degeneration is more common and caused by the retinal pigment epithelium breaking down.

    It is hoped the patch will be able to treat both forms of the disease.

    Dr Carmel Toomes, from Leeds Institutes of Molecular Medicine, said: “What’s exciting about this study is that the patients recorded an increase in vision.

    “To see an improvement is a good sign that this therapy may help patients in the future, although further studies are needed before real conclusions can be drawn.”

    Follow James on Twitter.

    View comments