# E=MC2: Einstein’s equation that gave birth to the atom bomb

Albert Einstein’s famous equation E=mc2 for the first time connected the mass of an object with its energy and heralded a new world of physics

This is the most famous equation in the history of equations. It has been printed on countless T-shirts and posters, starred in films and, even if you’ve never appreciated the beauty or utility of equations, you’ll know this one. And you probably also know who came up with it – physicist and Nobel laureate Albert Einstein.

The ideas that led to the equation were set down by Einstein in 1905, in a paper submitted to the Annalen der Physik called “Does the Inertia of a Body Depend Upon Its Energy Content?”. The relationship between energy and mass came out of another of Einstein’s ideas, special relativity, which was a radical new way to relate the motions of objects in the universe.

At one level, the equation is devastatingly simple. It says that the energy (E) in a system (an atom, a person, the solar system) is equal to its total mass (m) multiplied by the square of the speed of light (c, equal to 186,000 miles per second). Like all good equations, though, its simplicity is a rabbit-hole into something profound about nature: energy and mass are not just mathematically related, they are different ways to measure the same thing. Before Einstein, scientists defined energy as the stuff that allows objects and fields to interact or move in some way – kinetic energy is associated with movement, thermal energy involves heating and electromagnetic fields contain energy that is transmitted as waves. All these types of energy can be transformed from one to another, but nothing can ever be created or destroyed.

In relativity theory, Einstein introduced mass as a new type of energy to the mix. Beforehand, the mass of something in kilograms was just a measure of how much stuff was present and how resistant it was to being moved around. In Einstein’s new world, mass became a way to measure the total energy present in an object, even when it was not being heated, moved or irradiated or whatever else. Mass is just a super-concentrated form of energy and, moreover, these things can turn from one form to the other and back again. Nuclear power stations exploit this idea inside their reactors where subatomic particles, called neutrons, are fired at the nuclei of uranium atoms, which causes the uranium to split into smaller atoms. The process of fission releases energy and further neutrons that can go on to split more uranium atoms. If you made very precise measurements of all the particles before and after the process, you would find that the total mass of the latter was very slightly smaller than the former, a difference known as the “mass defect”. That missing matter has been converted to energy and you can calculate how much using Einstein’s equation.

Despite the tiny discrepancy in mass between the uranium atom and its products, the amount of energy released is big and the reason why is obvious when you look at the c² term in the equation – the speed of light is a huge number by itself and its square is therefore enormous. There is a lot of energy condensed into matter — 1kg of “stuff” contains around 9 x 10^16 joules, if you could somehow transform all of it into energy. That is the equivalent of more than 40 megatons of TNT. More practically, it is the amount of energy that would come out of a 1 gigawatt power plant, big enough to run 10 million homes for at least three years. A 100kg person, therefore, has enough energy locked up inside them to run that many homes for 300 years.

Unlocking that energy is no easy task, however. Nuclear fission is one of several ways to release a tiny bit of an atom’s mass, but most of the stuff remains in the form of familiar protons, neutrons and electrons. One way to turn an entire block of material into pure energy would be to bring it together with antimatter. Particles of matter and antimatter are the same, except for an opposite electrical charge. Bring them together, though, and they will annihilate each other into pure energy. Unfortunately, given that we don’t know any natural sources of antimatter, the only way to produce it is in particle accelerators and it would take 10 million years to produce a kilogram of it.

Particle accelerators studying fundamental physics are another place where Einstein’s equation becomes useful. Special relativity says that the faster something moves, the more massive it becomes. In a particle accelerator, protons are accelerated to almost the speed of light and smashed into each other. The high energy of these collisions allows the formation of new, more massive particles than protons – such as theHiggs boson – that physicists might want to study. Which particles might be formed and how much mass they have can all be calculated using Einstein’s equation.

It would be nice to think that Einstein’s equation became famous simply because of its fundamental importance in making us understand how different the world really is to how we perceived it a century ago. But its fame is mostly because of its association with one of the most devastating weapons produced by humans – the atomic bomb. The equation appeared in the report, prepared for the US government by physicist Henry DeWolf Smyth in 1945, on the Allied efforts to make an atomic bomb during the Manhattan project. The result of that project led to the death of hundreds of thousands of Japanese citizens in Hiroshima and Nagasaki.

Einstein himself had encouraged the US government to fund research into atomic energy during the second world war but his own involvement in the Manhattan project was limited because of his lack of security clearances. It is unlikely that Einstein’s equation was much use in designing the bomb, beyond making scientists and military leaders realise that such a thing would be theoretically possible, but the association has stuck.

# Robot mannequin to test army kit.

The Porton Man has been made for use in the Defence Science and Technology Laboratory

A robotic mannequin that can run, sit and even mimic the movement of a soldier has been unveiled by the Ministry of Defence.

The £1.1m robot – developed using Formula 1 technology – will test protective suits and equipment.

The “Porton Man” has more than 100 sensors over its body to record data during tests.

Developers said it would help them create the next generation of protective equipment.

Unique

The Ministry of Defence said the new animatronic mannequin was unique to the UK.

It has been made for the Defence Science and Technology Laboratory (DSTL) – where clothing systems for soldiers are tested against chemical warfare agents.

The robot can raise its arms to imitate signals given by soldiers and can also march and kneel.

Previous mannequins were brought into use in the late 1990s and helped to influence the design of the chemical, biological and radiological suits currently used by the armed forces.

But the latest has a better movement range than previous models, including of its head.

The Porton Man can walk, march and run

It is hoped tests involving the latest mannequins will help produce a new, lighter protective suit for the miltary.

Dr Colin Willis, principal for the Chemical Biological Protection Group at the DSTL, said testers would be able to put “more realistic stresses” on the robot to achieve better results.

“It’s really the materials and the fact he will be exposed to chemical warfare agents, so the material design has been very important obviously,” Dr Willis told the BBC’s Today programme.

“It sounds simple, but when you see the mannequin and the computer controls, it really is a complex piece of machinery.”

Dr Willis said the goal with the robot, which he described as “much more realistic” than a 10-year-old mannequin that had been in use, was to create suits that strike a balance between protection and physiological burden.

F1 technology

The Porton Man – named after the location of the DSTL in Porton Down, Wiltshire – was made by i-bodi, a technology firm based in Buckingham.

The company also makes animatronics and robotics for film and television.

Its chief executive Jez Gibson-Harris said the mannequin was based on data collected from 2,500 soldiers and that the company had used similar techniques to those seen in Formula 1 cars.

## “Start Quote

This technology, designed by a British company, is enabling the UK to lead the way in this important testing”

Philip DunneDefence minister

He said: “Our brief was to produce a lightweight robotic mannequin that had a wide range of movement and was easy to handle.

“Of course there were a number of challenges associated with this and one way we looked to tackle these challenges was through the use of Formula 1 technology.

“Using the same concepts as those used in racing cars, we were able to produce very light but highly durable carbon composite body parts for the mannequin.”

More realistic

Jaime Cummins, from DSTL’s chemical and biological physical protection group, said the new Porton Man is much lighter than its predecessor at 14kg (30lb), rather than 80kg (176lb).

That will make it easier to move the model in and out of its test chamber.

He said: “It’s a better, more realistic test system, and we are now in a better position to design and develop the next generation of CB (chemical and biological) protective suit equipment.”

Philip Dunne, minister for defence equipment, support and technology, said: “This technology, designed by a British company is enabling the UK to lead the way in this important testing.

“Increased investment in science and technology by the MoD (Ministry of Defence) is not only enabling battle-winning and life-saving equipment to be developed but also helping innovative companies like i-bodi Technology to develop cutting edge capability.”

# Dieting monkeys offer long life hope

Can extreme calorie counting lead to a long, healthy life?

## Related Stories

Extreme calorie counting boosts lifespan in monkeys, according to new research.

Until now, the rationale for following an ultra-low calorie diet to ward off ageing has been based on experiments in worms and mice.

Studies reported in Nature Communications found primates also benefited from the regime.

A nutritionist urged caution over severe calorie restriction in humans, saying more research was needed.

## “Start Quote

Perhaps Benjamin Franklin was right when he said, ‘To lengthen thy life lessen thy meals’”

Dr Emma WilliamsBritish Nutrition Foundation

Advocates of the Calorie Restriction (CR) diet claim that by severely restricting the number of calories they consume they will live longer, perhaps into their hundreds.

They cite a wealth of scientific evidence dating back more than 75 years.

Much of the research is based on experiments in animals such as mice and worms, with primate studies giving conflicting results.

Now, a US team has published new evidence showing CR also shows benefits in primates.

Less is more

“CR works to delay ageing in primate species,” Dr Rozalyn Anderson of the department of medicine at the University of Wisconsin-Madison, told BBC News. “Our study data is consistent with that.”

The study found CR boosted survival in a group of rhesus monkeys studied over the course of decades.

Monkeys lived longer when their daily food intake was reduced by a quarter

And she said conflicting findings, from a previous study at a different institute, might be due to flaws in the control group.

But she said CR was a research tool not a lifestyle recommendation.

“The concept is to delve into the biology of ageing and try to understand what’s the basis for increased risk for diseases as you get older and with advanced age,” she said.

“It would be very difficult to implement CR in a long term way in humans.”

A US study is currently looking at whether healthy humans live longer on less food.

The participants restrict calories by 25% over several years, existing mainly on a diet of vegetables, fruits (especially apples), and soups.

Dr Emma Williams, a nutrition scientist at the British Nutrition Foundation, said caution was advised until results from human trials were available.

“Perhaps Benjamin Franklin was right when he said, ‘To lengthen thy life lessen thy meals,'” she said.

“However, as this research was based on studies in primates more research is needed regarding the precise role of calorie restriction in human life expectancy before any definitive conclusions can be made.”

# Good teeth may help sporting success

Mo Farah enjoying Olympic gold

Dentists say elite athletes could stand a better chance of winning gold medals if they look after their teeth.

The Oral Health and Performance in Sport conference in London heard that athletes’ oral health was often bad and could impair training and performance.

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I’ve become aware over the years that dental problems have been interfering with training. It stops [boxers] getting that little bit fitter and may have a consequence when they get into the ring and box”

Dr Mike Loosemore GB boxing team doctor

At the pinnacle of elite sport, the difference between winning and losing is tiny, so even marginal improvements can make a crucial difference.

Doctors for Team GB’s boxing squad are already trying to improve oral health.

Disruptive

A study, published in the British Journal of Sports Medicine, showed a fifth of athletes said their oral health damaged their training and performance for the Games.

At the conference, dentists said tooth pain could disrupt sleep and training and that inflammation of the gums could affect the rest of the body, impairing performance.

It is not unusual for poor oral health to have wider effects. The NHS says it is linked to type 2 diabetes and heart problems.

A regular floss, a bottle of mouthwash and good brushing technique are not going to transform a weekend jogger into an Olympian.

Marginal gains can make all the difference between defeat and victory for elite athletes

However, Prof Ian Needleman, director of the International Centre for Evidence-Based Oral Health at University College London, says there could be an impact in elite sport.

He told the BBC: “It’s the accumulation of marginal gains, where the difference between elite athletes at the very top is small. Then oral health, amongst other aspects, could make a difference.

“The research we did at London 2012 found a large proportion of young athletes, fantastically well tuned physically, had really poor oral health.

“Quite a high proportion reported an impact on their training and performance so it’s clearly an issue for them.”

Regular checks

Doctors with GB Boxing are already trying to improve dental hygiene after noticing poor oral health had affected training.

Dr Mike Loosemore, who has worked with the GB boxing team for 17 years and is a consultant at the English Institute of Sport, told the BBC: “I’ve become aware over the years that dental problems have been interfering with training. It stops them getting that little bit fitter and may have a consequence when they get into the ring and box.”

He says things are now improving after regular dental checks were introduced, even if they are not always popular with the boxers.

“They don’t like going to the dentist. They’d much rather be training. However, it has made a difference to their teeth and they are spending less time away from their training, and that will make them a better boxer.

“They may not appreciate it now, but hopefully they’ll appreciate when they’ve got a gold medal round their neck in Rio [at the 2016 Olympics].”

# Cancer virus discovery helped by delayed flight.

Electron micrograph of the Epstein Barr virus, DR GOPAL MURTI/SCIENCE PHOTO LIBRARY

Bad weather and a delayed flight might be a recipe for misery – but in one instance 50 years ago it led to a discovery that has saved countless thousands of lives.

The discovery of the Epstein Barr virus – named after British doctor Anthony Epstein – resulted from his specialist knowledge of viruses which caused tumours in chickens plus his skills gained using one of the first commercially-available electron microscopes.

## “Start Quote

I had the feeling that this was something special”

Sir Anthony Epstein

His hunch was assisted by a longer than expected journey of some tumour cells from Uganda, which were nearly thrown in the bin.

But it would never have happened if Epstein’s curiosity hadn’t been fired up by a lecture by the Irish doctor turned “bush surgeon”, Denis Burkitt.

In the lecture, billed as a staff meeting on “The Commonest Children’s Cancer in Tropical Africa”, Burkitt described how he had noticed a number of cases of debilitating tumours which grew around the jawbone of children in specific regions – particularly those with high temperatures and high rainfall.

We now know this as Burkitt lymphoma.

British doctor Sir Anthony Epstein

Sir Anthony Epstein, now 93, speaking to the BBC’s Health Check programme, recalls: “I thought there must be some biological agent involved. I was working on chicken viruses which cause cancer. I had virus-inducing tumours at the front of my head. I thought… [it] was being carried by some insect vector, or some tic. That’s why it was temperature-related.”

The Epstein Barr virus belongs to the family of herpes viruses – and is linked to a number of different conditions, depending on where you live.

Most people are infected with the Epstein Barr virus. It’s best known in high-income countries for causing glandular fever which causes a sore throat, extreme fatigue and swollen glands in the neck.

According to Dorothy Crawford, emeritus professor of microbiology at Edinburgh University, up to 95% of all adults are infected with the virus.

“The virus is spread in childhood at different rates – in the saliva, so through close contact. In African countries most children have it by the age of two because they share cups in their household.

“The rate is lower in middle-class areas of England, so if you haven’t already been exposed by your early teens it can cause glandular fever.”

This has given it the nickname the kissing disease because, she explained: “People kissing in the back row of the cinema exchange more saliva than young children sharing toys.”

Epstein asked for samples of the tumours from Burkitt and they were sent back on overnight flights from Uganda.

Sir Anthony Epstein and Dr Yvonne Barr, courtesy of Anthony Epstein

For almost three years Epstein’s efforts to retrieve virus from the tumour cells failed, despite trying several culture methods used successfully for other viruses like influenza and measles.

In the end bad weather came to the rescue.

Fog delayed one flight which was diverted to Manchester, 200 miles from London. So the sample taken from the upper jaw of a nine-year-old girl with Burkitt lymphoma didn’t get to Epstein until late one Friday afternoon on 5 December 1963.

At that point it looked past its sell-by date.

“The fluid was cloudy. This suggested it had been contaminated on the way,” Epstein said.

“Was it full of multiplying bacteria? Before we threw it away I looked at it under a wet preparation microscope and saw huge numbers of free-floating, healthy looking tumour cells which had been shed from the edge of the tumour.”

Traditionally, growing cells successfully in culture had involved sticking them to a glass surface for support, but the lymphoma cells seemed to favour growing in a suspension.

Once all other conventional tests for identifying the virus from the cultured cells had failed, Epstein tried electron microscopy. The very first grid square he viewed included a cell filled with herpes virus.

Exhilarated by what he’d seen, Epstein went for a walk in the winter snow and came back feeling calmer.

“I was extremely frightened in case the electron beam [of the microscope] burned up the sample. I recognised at once the herpes virus – there were five then, now nine. Any of the then-known ones would have wiped the culture out when they were replicating but this wasn’t happening. I had the feeling that this was something special.”

Virus particles in the nucleus of a cancerous white blood cell

Our understanding of this pervasive virus, named after Epstein and one of his PhD students Yvonne Barr who helped to prepare the samples, has increased over the years since Epstein confirmed his findings with American virologist colleagues.

Burkitt’s data helped to identify that the tumour named after him was seen in children with chronic malaria, which reduced their resistance to the Epstein Barr virus, allowing it to thrive.

But most of us live quite happily with the virus.

“If you disturb the host-virus balance in any way then changes take place which lead to very unpleasant consequences,” says Epstein.

“Once the link between Epstein Barr virus and Burkitt lymphoma was established, other seemingly unrelated conditions followed. These include a cancer at the back of the nose which is the commonest cancer seen in men in southern China and the second commonest in women in the same region.

There is also a link to Hodgkins lymphoma, a cancer of the white blood cells.

“Each one came out of the blue,” according to Epstein, “and we’ve just heard about another. About 20% of Japanese cancers of the stomach are associated with the virus.”

Yet another connection was made by Professor Dorothy Crawford, while waiting for the lift at the Royal Free hospital in London.

“It’s such a tall building everyone meets outside the lifts. I was standing next to a renal [kidney] transplant surgeon and overheard him say they’d just had their first case of post-transplant lymphoma. So I went with him to the pathology department and asked for some sections of the tissue to look at under the microscope.”

Burkitt lymphoma can now often be treated successfully with chemotherapy.

At a recent meeting in Oxford of the Epstein Barr Virus Associationfuture directions for research were explored.

Attention is now focusing on a vaccine for the Epstein Barr virus – and some efficacy has already been demonstrated.

Epstein hopes that a vaccine will lead to the kind of success seen in other cancers caused by viruses – such as Hepatitis B and the human papillomavirus, which cause liver and cervical cancer respectively.

# First look at reversible USB cable.

The new designs will put an end to inserting a USB cable the wrong way round

## Related Stories

A new design for USB – a standardised connection for data transfers between electronic devices – has been shown off for the first time.

The new connector will be reversible, bringing an end to the everyday irritant of trying to force a USB cable in the wrong way.

The USB Implementers Forum anticipates the new designs will be finalised in July.

But rollout of new ports will take some time as manufacturers gradually incorporate them into their products.

The smaller port resembles Apple’s Lightning port

The new Type-C standard will be similar in size to the current MicroUSB connector, typically used for charging mobile phones and cameras.

The first USB cables were released in the mid-1990s and, until now, could only be plugged into a computer or other device one way round to ensure a data connection.

Other improvements to the new cable include:

• Support for scalable power charging, allowing the cable to offer up to 100 watts
• Data speed transfers of up to 10 gigabits per second, double what is possible at the moment
• A promise that the new design will accommodate further upgrades

# Management of portal vein thrombosis in liver cirrhosis

Portal vein thrombosis (PVT) is a fairly common complication of liver cirrhosis. Importantly, occlusive PVT might influence the prognosis of patients with cirrhosis. Evidence from a randomized controlled trial has shown that anticoagulation can prevent the occurrence of PVT in patients with cirrhosis without prior PVT. Evidence from several case series has also demonstrated that anticoagulation can achieve portal vein recanalization in patients with cirrhosis and PVT. Early initiation of anticoagulation therapy and absence of previous portal hypertensive bleeding might be positively associated with a high rate of portal vein recanalization after anticoagulation. However, the possibility of spontaneous resolution of partial PVT questions the necessity of anticoagulation for the treatment of partial PVT. In addition, a relatively low recanalization rate of complete PVT after anticoagulation therapy suggests its limited usefulness in patients with complete PVT. Successful insertion of a transjugular intrahepatic portosystemic shunt (TIPS) not only recanalizes the thrombosed portal vein, but also relieves the symptomatic portal hypertension. However, the technical difficulty of TIPS potentially limits its widespread application, and the risk and benefits should be fully balanced. Notably, current recommendations regarding the management of PVT in liver cirrhosis are insufficient owing to low-quality evidence.

# Bright light – early and often – linked to lower BMI, study finds

To maximize your chances of fighting flab, new research offers some simple advice: Wake up early and go outside.

People who loaded up on light exposure at the beginning of the day were most likely to have a lower body mass index, according to a study published Wednesday in the journal PLOS ONE. That relationship between morning light and BMI was independent of how many calories the study participants consumed.

It may sound crazy, but there is sound scientific evidence to back up the link. Circadian rhythm plays an important role in regulating metabolism, and studies have shown that exposure to morning light can influence body fat and the hormones that regulate appetite.

In one study, for instance, sleep-deprived subjects whose levels of the hormones leptin and ghrelin were out of whack saw those levels improve after being exposed to light for two hours after waking up. In another study, obese women who were exposed to bright light for at least 45 minutes between the hours of 6 a.m. and 9 a.m. dropped some of their body fat after three weeks. And studies in animals have found that altering light exposure changed their metabolism, resulting in weight gain even when the animals consumed the same amount of calories as before.

With all this in mind, researchers at Northwestern University’s Feinberg School of Medicine in Chicago persuaded 54 volunteers to wear a wrist monitor that measured their light exposure (including its timing and intensity) as well as their sleep patterns. The volunteers were also asked to keep a detailed log of everything they ate and drank during a seven-day period.

The volunteers (whose average age was 30) tended to be night owls – on average, they went to sleep at 1:26 a.m. and woke up at 8:49 a.m. Compared to Americans as a whole, they were thin, with 58% reporting a body mass index of 24 or lower.

When the researchers analyzed the data, they found only one variable that correlated to BMI: MLiT. That stands for “mean light  timing above threshold,” and it’s a measurement that takes into account the timing, length and brightness of each volunteer’s light exposure.

Translating that into practical terms, the researchers said the key was to bask in light of at least 500 lux, and that such basking was most valuable when the exposure came early in the day. For every hour that light exposure was delayed, BMI rose by 1.28 points.

The complete mathematical model took into account demographic factors like age and gender; the amount of sleep and exercise volunteers got; and the season of the year. But of all these variables, MLiT did the best job of predicting a person’s BMI.

When the researchers limited their analysis to BMI and light exposure between the hours of 8 a.m. and noon, they found no significant correlation. This suggested that light exposure throughout the day helps regulate body weight, the researchers wrote.

But there’s clearly something special about morning light. They’re not sure what it is, but one possibility is the fact that morning light contains more wavelengths in the blue portion of the spectrum. “Blue light has been shown to have the strongest effect on the circadian system,” the study authors wrote.

It shouldn’t be too hard to get yourself exposed to 500 lux. A typical office is about that bright. If you go outside, you’ll get more than 10,000 lux in full daylight, and if it’s overcast you’ll still get more than 1,000 lux.

Though more study is needed, of course, the researchers concluded that “light is a powerful biological signal and appropriate timing, intensity and duration of exposure may represent a potentially modifiable risk factor for the prevention and management of obesity in modern societies.”

# The Liquid Biopsy: A Noninvasive Tumor Tracker.

To date, the “liquid biopsy,” a blood test that detects evidence of cancer in the circulation, has generated a lot of excitement in the lab but little in the clinic.

The only liquid biopsy currently approved by the US Food and Drug Administration (FDA) for clinical use is a prognostic survival tool with no potential to guide treatment decisions (CellSearch, Janssen Diagnostics).

But research published in the February 19 issue of Science Translational Medicine shows how liquid biopsies can provide a noninvasive, ongoing picture of a patient’s cancer, offering valuable insight into how best to fight it.

Work from 2 different groups shows how liquid biopsies are being used in the lab to identify tumors at a very early stage, monitor them for metastasis, and even pick up signs of early treatment resistance.

In the future, instead of extensive imaging and invasive tissue biopsies, liquid biopsies could be used to guide cancer treatment decisions and perhaps even screen for tumors that are not yet visible on imaging.

“I think early detection is the Holy Grail of cancer research,” said Luis Diaz Jr., MD, from Johns Hopkins University School of Medicine in Baltimore. Liquid biopsies will likely offer a screening method for most cancers one day, he told Medscape Medical News.

However, this exciting potential is probably furthest from being ready for the clinic, he acknowledged; other potential applications include genotyping, detection of minimal residual disease, and detection of treatment resistance.

In their research, Dr. Diaz and colleagues show that a liquid biopsy measuring the serum level of circulating tumor (ct)DNA could one day be a very useful tool in cancer decision-making, giving clues about what type of cancer a patient has and whether it has spread.

“Mutant DNA fragments are found at relatively high concentrations in the circulation of most patients with metastatic cancer and at lower but detectable concentrations in a substantial fraction of patients with localized cancers,” they write.

The team found this to be particularly true in cases of breast, colon, pancreas, and gastroesophageal tumors, where “detectable levels of ctDNA were present in 49% to 78% of patients with localized tumors and 86% to 100% of patients with metastatic tumors.”

They evaluated 136 metastatic tumors in 14 different tumor types, and found that “most patients with stage III ovarian and liver cancers and metastatic cancers of the pancreas, bladder, colon, stomach, breast, liver, esophagus, and head and neck, as well as neuroblastoma and melanoma, harbored detectable levels of ctDNA. In contrast, less than 50% of patients with medulloblastomas or metastatic cancers of the kidney, prostate, or thyroid, and less than 10% of patients with gliomas, harbored detectable ctDNA.”

In addition to offering clues about stage and spread, liquid biopsies can be used to monitor the effects of cancer treatment, give an early warning about possible recurrence, and offer clues to the reasons for treatment resistance.

A second team of researchers used liquid biopsies in colorectal cancer patients to show that early resistance to treatment with epidermal growth-factor receptor (EGFR) inhibitors could be identified by the presence of certain mutations in the blood.

In their research, Sandra Misale, a PhD student from the Department of Oncology at the University of Torino in Italy, and colleagues showed that this resistance can be overcome by concomitant treatment with mitogen-activated protein kinase (MEK) inhibitors.

“We reasoned that tissue biopsies would only offer a snapshot of the overall tumor mass and might therefore be ill suited to capture the multiclonal feature of the resistant disease,” the researchers note, explaining that liquid biopsies are “more likely to capture the overall genetic complexity of tumors in patients with advanced disease.”

In fact, Dr. Diaz’s team found the same mutations in treatment-resistant colorectal cancer patients, suggesting a future clinical application for liquid biopsies. “These data therefore strongly suggest that patients being considered for treatment with EGFR blockading agents should be tested for these additional mutations,” they advise. Patients harboring such mutations “are unlikely to benefit from these agents and would be better served by other therapeutic approaches.”

Tissue Biopsy Can Be Challenging

There is good reason to want to learn about cancer through the blood, said Terence Friedlander, MD, from the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco. “For most tumors, a tissue biopsy is quite challenging, in that it’s costly, painful, and potentially risky for the patient,” he explained.

The research by both teams illustrates that there is “a lot of reason to be excited” about liquid biopsies, he told Medscape Medical News. “Together, both of these papers show that you can detect resistance as it’s happening in real time.”

Although the current FDA-approved liquid biopsy measures intact circulating tumor cells (CTC) to give a prognosis of overall survival, the potential predictive value of ctDNA is much more exciting, he said.

“Predictive markers are better because they help guide treatment decisions. In a sense, the ctDNA liquid biopsy allows us to understand specifically what kind of molecular changes are happening in the tumor in real time, which is a very big step beyond where CTCs are today, clinically.”

# Autism May Begin Before Birth, Autopsy Study Reveals

Disorganized neurons in the prefrontal cortex suggest that brain abnormalities in children with autism may begin before birth, a detailed postmortem study shows.

The analysis revealed the presence of patches of disorganized neurons in areas that mediate functions that are disturbed in autism, including social, emotional, communication, and language function, according to the study authors, led by Rich Stoner, PhD, Autism Center of Excellence and the Department of Neuroscience, University of California at San Diego.

The patches suggest that brain cell activity has been disrupted during pregnancy, which possibly points more to a genetic than an environmental trigger for autism.

“Such abnormalities may represent a common set of developmental neuropathological features that underlie autism and probably result from dysregulation of layer formation and layer-specific neuronal differentiation at prenatal developmental stages,” the authors write.

The study was published March 27 in the New England Journal of Medicine.

New Insight

Researchers obtained 42 fresh-frozen postmortem cortical tissue blocks from the superior or middle frontal gyrus of the dorsolateral prefrontal cortex, posterior superior temporal cortex, or occipital cortex of boys and girls aged 2 to 15 years with and without autism. The tissue blocks were selected for their high RNA integrity, thereby ensuring the quality of the samples.

The investigators used a large panel of highly selective markers for specific cell subtypes and a subset of 25 autism candidate genes. These included biomarkers for brain cell types in different layers of the cortex and genes implicated in autism.

They detected what they described as “pathological patches of abnormal laminar cytoarchitecture and disorganization” in samples of the prefrontal and temporal cortex samples, but not the occipital cortex. The patches were found in 91% (10 of 11) of the children with autism (cases) and 9% (1 of 11) of control individuals.

The patches had fewer cells expressing layer- or cell-type-specific markers than normally present in fully differentiated cortical neurons and decreased expression of certain autism candidate genes.

The focal patches of abnormal gene expression measured 5 to 7 mm in length and were located in areas adjacent to apparently unaffected areas of the cortex. They spanned multiple contiguous neocortical layers; the clearest evidence of abnormal expression was found in layers 4 and 5.

“This defect indicates that the crucial early developmental step of creating 6 distinct layers with specific types of brain cells ― something that begins in prenatal life ― had been disrupted,” study investigator Eric Courchesne, PhD, Autism Center of Excellence and the Department of Neuroscience, University of California at San Diego, said in a release.

“The finding that these defects occur in patches rather than across the entirety of cortex gives hope as well as insight about the nature of autism,” he added.

The fact that the researchers sampled only small portions of cortex but observed focal patches in nearly every case sample suggests that “pathological patches are widespread across prefrontal and temporal cortex in children with autism,” according to investigators.

The patches were present both in boys and girls, in high- and low-functioning children, and regardless of the cause of death or postmortem interval.

Presentation of the patches varied across cases, which, said the authors, was unexpected given the phenotypic heterogeneity of autism.

“However, the features that we describe here may explain some of the heterogeneity of autism: disorganized patches in different locations could disrupt disparate functional systems in the prefrontal and temporal cortexes and potentially influence symptom expression, response to treatment, and clinical outcome,” the researchers write.

Although the data suggest a novel pathologic mechanism in autism, the exact biological process is unknown.

“The identified laminar disorganization could result from migration defects resulting in the failure of cells to reach their targeted destination and the accumulation of such cells in nearby regions,” the authors write.

Or, they added, the patches could reflect de novo changes early in neurodevelopmental processes, which yield regions of affected progenitor cells adjacent to regions of unaffected progenitor cells.

In any case, the data are consistent with an early prenatal origin of autism, or at least prenatal processes, that may confer a predisposition to autism, according to investigators.

Although the sample size was small compared with postmortem studies of adult diseases, it is as large ― or larger ― than most previous such studies of autism, the authors note.