- Life and death were inseparable for family and surgeons
- Harvard panelists consider worst-case scenarios for climate
- Senior Matthew DeShaw looks back as he moves forward
- As Europe’s economic picture brightens, Harvard summit sees work ahead
- Researchers create new type of quantum computer
- New clues to Alzheimer’s disease
- Harvard visiting professor E.J. Dionne on the art of persuasion
Posted: 01 Dec 2017 09:00 AM PST
Doctors knew from the start that the procedure wasn't going to be easy, but when images showed the patients' tangled insides, they realized that more than a surgical challenge lay ahead.
It was 2016 and a team at MassGeneral Hospital for Children was examining 22-month-old twin girls conjoined at the abdomen and pelvis whose parents had brought them from East Africa to Boston in search of physicians willing and able to take on the profound complexities of separation surgery.
The girls' care over the following weeks involved some 200 people — physicians, nurses, social workers, technicians, and religious leaders — and a single, searing question: When — if ever — is it OK to sacrifice one life to save another?
The parents, who have requested anonymity, had the final say. But doctors and other hospital personnel, no strangers to illness and death, were plunged into a wrenching examination of both their personal values and the responsibilities of their profession: the obligation to do no harm, the duty to act to save a life, and what happens when those concepts conflict.
"My 14-year-old daughter just asked me … 'Did you violate the Hippocratic oath?'" said Allan Goldstein, who directed the procedure as the hospital's surgeon in chief. "I said, 'First, thank God you're not a reporter. And second, it's a great question and I don't know the answer.'"
Goldstein, also professor of surgery at Harvard Medical School (HMS), got involved in the case when he was contacted by a nonprofit on behalf of the parents, who had struggled to find physicians with the expertise to separate the twins.
The search had come up empty in their home country, where stigma attached to the girls' condition had made it difficult to take them out of the house, according to a recent report in the New England Journal of Medicine. After the parents shifted their focus to the U.S., some 20 institutions turned them down before Goldstein answered the phone.
Surgery on conjoined twins is rare, and such a procedure hadn't been performed at MGH for more than 15 years. Still, Goldstein had been involved in complex surgeries before, and, after reviewing the available diagnostic imaging, he invited the family to fly to Boston.
"They were desperate — certainly eager — to do something to help their children," he said.
When the family first arrived at the hospital, doctors examined the twins, completed new imaging scans, and then began to think through whether and how the separation could be accomplished.
The girls had faced each other since birth, heads and shoulders separate but lower trunks fused. They shared a liver, bladder, and intestinal tract, their pelvises were intertwined, and they had three legs between them. Their conjoined circulatory systems were most worrisome of all.
Imaging showed that the larger and stronger twin, whose heart, lungs, and circulatory system were relatively normal, was supporting her weaker sister. The weaker twin's heart had just three chambers instead of the normal four, and irregular blood vessels between the heart and lungs, a critical loop in which blood takes up oxygen and delivers it to the rest of the body.
The most crucial connection was between the stronger twin's oversized superior mesenteric artery, which normally supplies blood to the intestine and pancreas, and the weaker twin's abdominal aorta, the main pipeline that brings blood to the lower body.
Tests of the weaker twin's blood-oxygen levels showed values near normal in her leg and lower body — likely due to her sister's support — and reduced levels in her upper extremities, where she was more reliant on her own malformed heart and lungs. Doctors realized that if the connection between the girls was cut, the weaker twin's circulatory system might give out.
They also realized that, given the conjoined circulatory systems, if the weaker twin were to die, her sister would also perish.
In this harrowing ethical territory, with surgery to save one girl almost certain to mean death for the other, Goldstein sought guidance from Brian Cummings, chair of MassGeneral Hospital for Children's pediatric ethics committee, a physician in the hospital's pediatric intensive care unit, and an assistant professor of pediatrics at HMS.
Cummings turned to medical literature, looking for guidance from past decisions, including accounts of a 1977 surgery by C. Everett Koop on twins who shared a heart, and a U.K. case in which courts determined that a separation surgery should proceed if it allowed at least one twin to live.
After review, Cummings and his fellow committee members advised that the surgery should move forward, with the parents' consent. They also recommended that hospital personnel who objected to the procedure be allowed to step away, an option that several physicians exercised, asserting that doctors should not take actions leading to a child's death, Goldstein said.
Separation, and goodbye
Within a few days of the initial meeting with doctors, the weaker twin had developed a respiratory infection that worsened into pneumonia. The illness reduced oxygen to her upper extremities enough that the beds of her fingernails turned blue. Admitted with her sister to intensive care, she received supplemental oxygen, antibiotics, intravenous fluids, and a nasogastric tube for food.
It took a week for the pneumonia-stricken twin to improve and 10 days before the girls could be discharged. Six days later, however, the infection recurred. The weaker twin arrived at the hospital with a temperature nearing 100 and blood-oxygen levels of just 32 percent.
"There was definitely a realization, from the ICU's perspective … they actually might both die before we could get to an operation," Cummings said.
The illness heightened the urgency of the situation. One sister was failing. The challenge of assembling and coordinating specialists — including nine surgeons and two anesthesiology teams — still remained. Having spoken to the parents, who made their decision after consulting with a religious leader, Cummings and Goldstein accelerated their plan.
The doctors opted to keep the girls in the hospital after the infection cleared, moving them from intensive care to a regular room, where they could be monitored to ensure they were healthy enough for surgery. The girls connected with their caretakers, Cummings said, singing songs and shaking maracas. They were affectionate with each other, the weaker twin draping her arm over her sister. They were also protective, one protesting and flailing her arms when staff tried to stick the other with needles.
The 14-hour operation involved roughly 50 people, including physicians, nurses, and technicians. It had been carefully choreographed, with one team of specialists taking over, doing its part, and giving way to the next.
Anesthesiologists calibrated the proper dose to sedate two children who shared a circulatory system. Plastic surgeons made the first incisions, heedful of how the bodies would be closed after the procedure. General surgeons separated organs, leaving intact the key artery the girls shared. Orthopedic surgeons worked to untangle the pelvis bones.
Then, stepping forward again, the general surgeons cut the mesenteric artery. The lifeline between the twins was gone.
"I thought about this over and over," Goldstein said. "We probably knew there was no hope and yet I just maintained hope the whole time. We had another operating room ready. We hoped she would live at least a little while — hours, days — so her parents would have a chance to say goodbye. Maybe if you asked me, purely on an intellectual level, I would have admitted there was no hope, but I didn't want to think about it that way."
But Goldstein and the other doctors had been right. With the girls finally separated, the weaker twin's heart wasn't up to the task and her blood pressure began to drop. She did not survive the operation.
"When she died, it was very, very difficult," Goldstein said. "It's definitely the only time I've cried in the operating room."
After plastic surgeons closed openings in their bodies, the sisters were moved back to intensive care, one to start weeks of recovery, and the other so that her parents could say goodbye.
A hopeful reunion
Grand rounds have long been a tradition at Mass General. Unlike everyday rounds, in which a physician visits patients with medical students in tow, offering a firsthand look at treatment and care, grand rounds are less frequent and more lecture-like, a way for doctors to present unusual or important cases — details, outcomes, implications, and lessons — to students and colleagues.
In the spring of this year, Goldstein led grand rounds at a hospital amphitheater, enlisting the help of the ethicists, cardiologists, anesthesiologists, plastic surgeons, and others who had played key roles in separating the twins. It had been 13 months since the surgery and the family was in attendance.
The girl was doing well, Goldstein told his audience. Her bodily functions were relatively normal, and she was crawling on her own and standing with assistance. Several surgeries still lay ahead: to repair a malformed leg and foot so she could walk normally, to correct remaining abnormalities in her pelvis and abdominal organs. She nonetheless clapped, waved, and charmed the crowd packing the room.
"It was surgical grand rounds, which has probably been happening since the 1800s, and multiple people — some who have been there nearly that long — told me it was the best grand rounds they have ever been at," Goldstein said. "Every time the crowd would clap, she would clap. We'd stop, she'd stop, and then we'd clap again."
The parents are happy with the health and progress of their surviving daughter, Goldstein said. He still thinks often about the loss of her sister — in sadness, not agony. He doesn't doubt the right decision was made.
"Step one was a willingness to hear a story," Goldstein said. "This family had gone through so much. … It is what we do every day. Our primary goal is still to help people."
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Posted: 01 Dec 2017 08:43 AM PST
In July, New York magazine published its most-read article ever, surpassing a photo spread of Lindsay Lohan. The topic? Doom.
While defying the belief among author David Wallace-Wells' editors that climate change would be "traffic kryptonite," the story, titled "The Uninhabitable Earth," presented an apocalyptic vision in which rising seas flood Miami and Bangladesh, heat and drought cut grain yields in half, diseases spread, and wars rage.
Unfortunately, that vision isn't fiction, but rather Wallace-Wells' summation of climate change's little-discussed worst-case scenario for the year 2100.
"I think there's real value in scaring people," the journalist said Wednesday during a panel at the Geological Museum, sponsored by the Harvard University Center for the Environment.
The event, "Hope and Despair: Communicating an Uncertain Future," explored whether doom and gloom are more effective than hope in spurring climate action. Panelists agreed that fear is a potentially powerful lever, but also insisted on the importance of covering success stories. Progress is an important motivator, keeping people from succumbing to despair in the face of bad news.
Wallace-Wells said he wrote the article because climate change discussion has centered on limiting global temperature rise to 2 degrees Celsius by 2100. While changes due to that level of warming would be bad enough, the projection, he said, is too often treated as a certainty rather than the middle value in a range that, at its high end, would unleash calamitous effects.
"It just seems so obvious to me that — when you think about the relatively well-off Western world — complacency about climate is just a much bigger problem than fatalism about climate," Wallace-Wells said. "A majority of Americans … are concerned about climate change, but very few Americans are very concerned about climate change."
The discussion, moderated by Assistant Professor of Organismic and Evolutionary Biology Elizabeth Wolkovich, also featured Campbell Webb of the University of Alaska, who penned a 2005 article calling for hope in conservation biology despite discouraging developments. That hope, he wrote, was needed for the benefit of the biologists themselves even as it faded for the environments and organisms of their research.
Webb said during the panel that the article was a reflection of the grief he felt at the loss of Indonesian rainforests where he had worked. Today, he said, whether he feels optimistic or pessimistic depends on the day.
Panelist Nancy Knowlton, Sant Chair for Marine Science at the Smithsonian Institution, began an "ocean optimism" Twitter account over negative predictions for coral reefs. The feed, according to the account page, is aimed at "sharing solutions and creating a new narrative of hope for our ocean." That optimism, she said, is fueled by success stories that are too often ignored.
Knowlton recalled a conference in Tampa Bay, Florida, where she asked how many in the audience of 200 knew about the restoration of nearby seagrass beds that had been wiped out by the 1960s. Four people raised their hands.
Panelist Nikhil Advani, who works with rural communities on behalf of the World Wildlife Fund, agreed with Knowlton on the importance of promoting successes, especially in the case of small-scale entrepreneurs who make a regional impact.
Wallace-Wells sees cause for optimism in the potential scale of disruption. That humans can drive negative effects, he said, also suggests their potential to be agents of positive change. The question is how to stoke that potential.
Knowlton said that different audiences demand different approaches. While some people can be motivated by fear of a dark future and others by hope, still others, like the Republican mayor of Georgetown, Texas, which is powered entirely by renewables, are moved by economic arguments.
It's crucial to get young people involved in climate action, said Knowlton and Advani.
While students have the energy and ideas to make a difference, they can also be discouraged by feelings of hopelessness. This group needs to be told not only of the problems we face, but also of strong foundations where they can build, Knowlton said.
"I've had many, many students come up to me after talks about optimism or the Earth optimism summit that we ran in Washington, saying, 'You know, this was incredibly empowering. I now want to go out and work on solving this problem. I almost left the field of conservation because I thought there was nothing we could do.'"
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Posted: 01 Dec 2017 08:06 AM PST
Walking across the Yard, there is special meaning to the crunch of the brown leaves beneath my feet. The perennial sound brings to mind the Harvard student's "cycle."
On the brink of the next phase of this cycle, the words of Socrates come to mind: ὅτι ἃ μὴ οἶδα οὐδὲ οἴομαι εἰδέναι — "That what I do not know, I do not think that I know." While senior year is when I will be completing my College education, I cannot use "complete" and "education" in the same phrase. With three-plus years here flashing before me, I am in the process of making life-changing decisions.
Still wrapped in my Harvard cocoon, I am preparing to enter the final stage in the cycle, yet I am filled with more questions and a desire for further understanding. I have become acutely aware of the significance of my College years. This has been a time of excitement, a time of regret, a time of uncertainty, and most of all, a time of gratitude.
Between my classes and experiences as a Radcliffe research partner, I learn more every day and, as I start to imagine my post-graduate pass through Johnston Gate, I know it is just the beginning of my education.
When I started this journey, I was living my dream, determined to take advantage of all Harvard had to offer. That feeling has never waned. Not only have I seized each opportunity with gusto, I have done so with a grateful spirit and an inquisitive mind. Part of this process has been the preparation of my senior thesis, what I hope to be my College magnum opus, original research on a topic about which I am passionate and curious: memory and identity in Roman Morgantina. Honing my topic taught me how many topics are still left to investigate, and after my first library run, I finally understood why seniors are always lugging around stacks of books — and it's not just to burn off that freshman 15 or build a replica of the Parthenon in their suite.
As seniors, we are told that fellowships, graduate school admissions, and job offers are not a measure of intelligence or worth. Yet I am not sure anyone truly accepts it as true. The pressure builds as the talk of applications, interviews, and superdays fills the air. I am frequently asked about my humanities joint concentration, and its place in my life and goals.
Through studying Ancient History (Greek and Roman), I have honed the skills necessary not only to succeed within the concentration, but also to prepare for post-College life. Professor Kathleen Coleman, my idol and the reason I chose my concentration, encouraged me to question history and focus on detail. While her guidance has inspired me to work harder and think critically, she undoubtedly regrets telling me to ask more questions! My thesis adviser, Emma Dench, McLean Professor of Ancient and Modern History, introduced me to field study in Classics 112, which took our class to Sicily to study the ancient sites.
Finally, becoming a Radcliffe research partner under Professor Paul Kosmin has greatly expanded my research experience and historical knowledge, as well as shown me how I continue to learn in every way. Through his patience and instruction, I have grown both as a researcher and as a student.
With my lifelong obsession with history, what I have learned as a humanities concentrator seems to be a natural match for graduate school, fellowship, or firm. With the ability to think creatively, read quickly, and synthesize ideas, many doors will be open — I just need to get my foot into one of them!
So here I stand, in my final fall as a Harvard undergraduate. I know how much more there is to experience in the months ahead. But as I struggle with the decisions that will outline my next chapter, I can reflect on that Friday four years ago when I opened the email titled "Harvard Early Action Application." I had never wanted something so much.
In this, I am reminded of my mother's message to me on my family's high school yearbook tribute page: "Every once in a while, life exceeds your expectations."
Harvard has done that, and much more.
Matthew DeShaw writes an occasional column about his experiences as a member of Harvard's Class of 2018.
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Posted: 30 Nov 2017 02:00 PM PST
A slow but robust economic recovery is well underway in Europe, but the European Union now faces serious new threats from both within and without, foreign policy experts warned at the daylong 2017 Summit on the Future of Europe at the Minda de Gunzburg Center for European Studies in early November.
Daniel Gros, director of the Center for European Policy Studies think tank, said that sustained growth in domestic demand is a crucial element to economic recovery, and in Europe that has been increasing at a rate of about 2 percent a year since 2012. In addition, he said, while unemployment in much of Europe remains high, the labor force participation rate (the percentage of the working-age population either employed or actively looking for work) has grown steadily for many years — in contrast with the situation in the U.S., where the participation rate, initially higher than that of Europe, has fallen since the economic crisis began and shows no sign of bouncing back. The absence of a "discouraged worker" effect in Europe signals that a robust recovery is likely, Gros said.
Gros added that worries about decreased investments in Europe are misplaced, because the drop occurred mainly in the construction sector, which bloated during the boom years. Non-construction investment has held steady. The danger of deflation has also been exaggerated, he said, because the growth rate of nominal gross domestic product is higher than the nominal interest rate, making a classical debt deflation scenario unlikely.
Agnès Bénassy-Quéré, who chairs the French Council of Economic Analysis, was less sanguine, however. She said the crisis upended assumptions on which the Euro was based, no new consensus has emerged, and there has been no effective policy response to the crisis. In particular, she said fiscal tightening began too early and overshot its mark, especially in Germany, contributing to a double-dip recession.
Germany's persistently large current account surplus calls for demand stimulus there, while France needs structural reforms, which President Emmanuel Macron has initiated. Bénassy-Quéré said that in addition to coordinating these disparate policies, Europe may need to move toward true policy integration, such as Macron's proposed tax harmonization.
Kyriakos Pierrakakis, research director of the diaNEOsis Research and Policy Institute in Athens and a graduate of the Master in Public Policy program at Harvard Kennedy School (HKS), put the focus on Greece, where persistent severe economic difficulties have resulted in significantly increased anti-EU sentiment since the 2015 referendum. Pierrakakis reported that despite media stories about the effects of the crisis on Greek pensioners, a diaNEOsis survey found the rate of extreme poverty among Greeks over 65 is considerably lower than in other age cohorts. However, Greece has lost population since the onset of the crisis, as better-educated young people emigrate for better jobs, he said. This brain drain indicates a deep structural problem not reflected in improving economic measures such as the government's primary surplus. In a lunchtime conversation with Joseph Nye, former Spanish foreign minister Ana Palacio considered the threat of Catalonian secession from Spain and potential challenges to European integration stemming from separatist movements elsewhere.
Even where economic anxieties have waned in Europe, security threats loom increasingly large, Harvard experts said. Joseph S. Nye, Harvard University Distinguished Service Professor Emeritus, at HKS, and Ash Carter, director of the Belfer Center for Science and International Affairs and former U.S. Secretary of Defense, discussed the degradation of U.S.-Russian relations. Carter argued that bridges are harder to build and that the U.S. needs to stay "strong and balanced" and hold "the doors open" even though this may be conditional. Karen Donfried, president of the German Marshall Fund of the United States, said that America's shifting international commitment puts Europe to the test, and the jury is out on whether Macron and Germany's Angela Merkel can carve out a strong role for Europe at the global level.
Angela Stent, director of Georgetown's Center for Eurasian, Russian, and East European Studies, addressed Russia's wariness of the European Union. She noted Vladimir Putin's belief that the EU is paralyzed by its divided sovereignty, and his preference for bilateral to multilateral negotiations in his dealings with Europe. Merkel, who came of age in a Communist regime and speaks fluent Russian, understands Russia better than other European leaders, Stent added.
Lilia Shevtsova, an associate fellow of the Russia and Eurasia Program at Chatham House, an NGO based in London that analyzes and promotes understanding of major international issues and current affairs, agreed that Russia would much prefer to deal with Berlin and to a lesser extent Paris and London than with Brussels, which it views as a "retirement house" for end-of-career politicians. Nevertheless, she said, Russia recognizes that Europe is "an important engine" for its own economic development, indeed more essential than the U.S. She described as a "Putinesque" effort to reconcile tradition with globalization that would have Russia recognized as the center of a "greater Eurasian" pole as the U.S. retrenches.
Finally, Rawi Abdelal, Joseph C. Wilson Professor of Business Administration at Harvard Business School, focused on energy policy, drawing a distinction between interfirm and intergovernmental relations. Even in times of severe tension between Russia and western governments, energy sector firms have continued to cooperate to keep the gas flowing. He said that although Europeans have been "infuriated" by "extraterritorial" U.S. sanctions imposed on their firms for political reasons, the existence of "overlapping" firm-to-firm and government-to-government relations remains "incredibly valuable" for Europe and Russia.
The conference was co-sponsored by the Berlin Social Science Center and the diaNEOsis Research and Policy Institute.
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Posted: 30 Nov 2017 01:30 PM PST
Programming a computer is generally a fairly arduous process, involving hours of coding, not to mention the laborious work of debugging, testing, and documenting to make sure it works properly.
But for a team of physicists from the Harvard-MIT Center for Ultracold Atoms and the California Institute of Technology, things are actually much tougher.
Working in a Harvard Physics Department lab, a team of researchers led by Harvard Professors Mikhail Lukin and Markus Greiner and Massachusetts Institute of Technology Professor Vladan Vuletic developed a special type of quantum computer, known as a quantum simulator, that is programmed by capturing super-cooled rubidium atoms with lasers and arranging them in a specific order, then allowing quantum mechanics to do the necessary calculations.
The system could be used to shed light on a host of complex quantum processes, including the connection between quantum mechanics and material properties, and it could investigate new phases of matter and solve complex real-world optimization problems. The system is described in a Nov. 30 paper published in the journal Nature.
The combination of the system's large size and high degree of quantum coherence make it an important achievement, researchers say. With more than 50 coherent qubits, this is one of the largest quantum systems ever created with individual assembly and measurement.
In the same issue of Nature, a team from the Joint Quantum Institute at the University of Maryland described a similarly sized system of cold charged ions, also controlled with lasers. Taken together, these complimentary advances constitute a major step toward large-scale quantum machines.
"Everything happens in a small vacuum chamber where we have a very dilute vapor of atoms which are cooled close to absolute zero," Lukin said. "When we focus about 100 laser beams through this cloud, each of them acts like a trap. The beams are so tightly focused, they can either grab one atom or zero; they can't grab two. And that's when the fun starts."
Using a microscope, researchers can take images of the captured atoms in real time, and then arrange them in arbitrary patterns for input.
"We assemble them in a way that's very controlled," said Ahmed Omran, a postdoctoral fellow in Lukin's lab and a co-author of the paper. "Starting with a random pattern, we decide which trap needs to go where to arrange them into desired clusters."
As researchers begin feeding energy into the system, the atoms begin to interact with each other. Those interactions, Lukin said, give the system its quantum nature.
"We make the atoms interact, and that's really what's performing the computation," Omran said. "In essence, as we excite the system with laser light, it self-organizes. It's not that we say this atom has to be a one or a zero — we could do that easily just by throwing light on the atoms — but what we do is allow the atoms to perform the computation for us, and then we measure the results."
Those results, Lukin and colleagues said, could shed light on complex quantum mechanical phenomena that are all but impossible to model using conventional computers.
"If you have an abstract model where a certain number of particles are interacting with each other in a certain way, the question is why don't we just sit down at a computer and simulate it that way?" asked Ph.D. student Alexander Keesling, another co-author. "The reason is because these interactions are quantum mechanical in nature. If you try to simulate these systems on a computer, you're restricted to very small system sizes, and the number of parameters are limited.
"If you make systems larger and larger, very quickly you will run out of memory and computing power to simulate it on a classical computer," he added. "The way around that is to actually build the problem with particles that follow the same rules as the system you're simulating. That's why we call this a quantum simulator."
Though it's possible to use classical computers to model small quantum systems, the simulator developed by Lukin and colleagues uses 51 qubits, making it virtually impossible to replicate using conventional computing techniques.
"It is important that we can start by simulating small systems using our machine," he said. "So we are able to show those results are correct … until we get to the larger systems, because there is no simple comparison we can make."
"When we start off, all the atoms are in a classical state. And when we read out at the end, we obtain a string of classical bits, zeros, and ones," said Hannes Bernien, another postdoctoral fellow in Lukin's lab, and also a co-author. "But in order to get from the start to the end, they have to go through the complex quantum mechanical state. If you have a substantial error rate, the quantum mechanical state will collapse."
It's that coherent quantum state, Bernien said, that allows the system to work as a simulator, and also makes the machine a potentially valuable tool for gaining insight into complex quantum phenomena and eventually performing useful calculations. The system already allows researchers to obtain unique insights into transformations between different types of quantum phases, called quantum phase transitions. It may also help shed light on new and exotic forms of matter, Lukin said.
"Normally, when you talk about phases of matter, you talk about matter being in equilibrium," he said. "But some very interesting new states of matter may occur far away from equilibrium … and there are many possibilities for that in the quantum domain. This is a completely new frontier."
Already, Lukin said, the researchers have seen evidence of such states. In one of the first experiments conducted with the new system, the team discovered a coherent non-equilibrium state that remained stable for a surprisingly long time.
"Quantum computers will be used to realize and study such non-equilibrium states of matter in the coming years," he said. "Another intriguing direction involves solving complex optimization problems. It turns out one can encode some very complicated problems by programming atom locations and interactions between them. In such systems, some proposed quantum algorithms could potentially outperform classical machines. It's not yet clear whether they will or not, because we just can't test them classically. But we are on the verge of entering the regime where we can test them on the fully quantum machines containing over 100 controlled qubits. Scientifically, this is really exciting."
Other co-authors of the study were visiting scientist Sylvain Schwartz, Harvard graduate students Harry Levine and Soonwon Choi, research associate Alexander S. Zibrov, and Professor Manuel Endres.
This research was supported with funding from the National Science Foundation, the Center for Ultracold Atoms, the Army Research Office, and the Vannevar Bush Faculty Fellowship.
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Posted: 30 Nov 2017 11:47 AM PST
Researchers probing the complexities of Alzheimer's disease have detected issues involving cellular energy production, and those problems may be an important contributor to the late-onset form of the illness.
A team at Harvard-affiliated McLean Hospital tested the cells of late-onset Alzheimer's patients and found malfunctions in their energy production, including problems with the health of their mitochondria, the cellular power plants that provide most of their energy.
Bruce Cohen, director of McLean's Program for Neuropsychiatric Research and the Robertson-Steele Professor of Psychiatry at Harvard Medical School (HMS), said disrupted energy production would present particularly severe problems in the brain, because it is the body's most energy-hungry organ, demanding as much as 20 times the energy of other tissues. Such a malfunction, he said, could damage or kill nerve cells and help explain the cognitive decline associated with the disease.
Much of the scientific attention focused on Alzheimer's has centered on what's called the amyloid cascade hypothesis. That suggests that a protein called amyloid-beta forms plaques in the brain, triggering tangles made up of a second protein called tau, which sets off the inflammation that destroys neurons and leads to Alzheimer's signature cognitive decline.
The problem with that hypothesis, according to Kai Sonntag, associate stem cell researcher at McLean and assistant professor of psychiatry at HMS, is that it's not uncommon to examine the brains of cognitively normal older people after they've died and find similar plaques and tangles. In addition, Alzheimer's drugs developed to target amyloid-beta have failed to halt or reverse cognitive decline. That indicates that something else — or something in addition — is likely in play, Sonntag and Cohen said,
"I do think there's a need in the field to look at different angles," Sonntag said.
Lending additional complexity to the Alzheimer's picture are differences between its two forms: early onset — which, though relatively rare, has been intensively studied — and late-onset, which accounts for 95 percent of the cases. Early onset Alzheimer's is a particularly severe form that runs in families whose members develop the disease in their 50s and early 60s. It has been traced to a handful of genetic mutations that produce heavy loads of amyloid plaques in the brain. Insights from early onset Alzheimer's have informed medical understanding of the disease more broadly, while the identified genetic mutations have been used to create mouse models of the ailment so it can be better studied in the lab, Sonntag said.
But it's possible that lessons from those studies may not neatly apply to the late-onset form, called sporadic Alzheimer's, which typically strikes after age 65, Sonntag said. While the two forms of Alzheimer's share many features — including heightened risk if there is a history of Alzheimer's in the family, the development of plaques and tangles in the brain, and the hallmark cognitive decline — Sonntag and Cohen said late-onset Alzheimer's could be an aberration of the normal aging process.
"You could say maybe sporadic disease isn't like early onset disease, but a reflection of abnormal aging," Sonntag said. "Every aspect of Alzheimer's disease you can [also] find in normal aging. Accumulation of [amyloid]-beta occurs in all of us, phosphorylation of tau, all these things. Even when you look at post-mortem brains, there's a high percentage of people with high levels of [amyloid]-beta, but who are not demented. There's no 100 percent correlation between accumulation of plaque and Alzheimer's disease, even when you look at post-mortem brains."
The work grew out of Cohen's prior research, which looked at the role of cellular energy dysfunction in psychiatric diseases. With aging also marked by reduced cellular energy production and Alzheimer's, particularly the late-onset form, tied to aging, it was a short leap to wonder whether dysfunctions similar to those seen in psychiatric disorders might contribute to Alzheimer's, Cohen said.
"Energy production and use seem to be one thing that goes wrong [in cells] as we get older," Cohen said. "We do see changes with aging, and we do see changes that are shared with aging and Alzheimer's, but also some changes that are specific to Alzheimer's."
In work published recently in the journal Scientific Reports, Cohen, Sonntag, and colleagues at McLean took a type of skin cells called fibroblasts from late-onset Alzheimer's patients and compared their energy production with those of age-matched controls without Alzheimer's. Because energy metabolism is largely genetically determined, it's likely that what was occurring in the fibroblasts was replicated throughout the body, including the neurons.
Cells typically produce most of their energy (88 percent) through mitochondrial respiration, which takes place inside a cell's mitochondria. A smaller amount (12 percent) is produced through a process called glycolysis. The researchers showed that skin cells from late-onset Alzheimer's patients had impaired mitochondrial metabolic potential and shifted their energy production toward glycolysis to compensate.
The brain, however, is not only energy-hungry, its neurons are handicapped compared with fibroblasts, according to Sonntag. That's because neurons make energy primarily through mitochondrial respiration, and so don't have the process of glycolysis to fall back on. That means impaired mitochondrial respiration could result in the death of neurons, which could help explain Alzheimer's cognitive decline.
If energy dysfunction is shown to play a role, Cohen said, it's likely just a piece of the Alzheimer's puzzle, one affected by multiple factors interacting in complex ways to provide outcomes that differ in various patients.
"Although people hope with a lot of these conditions we study — normal or abnormal — that there are going to be simple answers … it's never simple, it's always all kinds of factors interacting to determine whether you get lucky or not, whether you get sick or not," Cohen said.
The next step, Cohen said, will be to do a similar study on the neurons and other brain cells of Alzheimer's patients, to see whether the energy dysfunction detected in skin cells is replicated there. Even if medical understanding of the disease remains imperfect, Cohen said the ultimate hope is to find an intervention that interrupts Alzheimer's most devastating effects.
"You don't have to fix everything to keep somebody from getting sick," Cohen said. "The reason somebody gets sick is you're unlucky five different ways and it all combines to tip you over the edge. Maybe you only need to fix one of them and you don't tip over the edge anymore."
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Posted: 30 Nov 2017 10:46 AM PST
E.J. Dionne's early passion for language grew out of the debates and books that filled his Fall River home. His writing grew out of his love for reading. A 1973 graduate of Harvard, where he wrote for The Crimson, Dionne covered politics for 14 years for The New York Times before moving to The Washington Post in 1990. The column he started three years later gained and maintains a wide following in D.C. and beyond.
Dionne is the author of seven books, including "One Nation After Trump: A Guide for the Perplexed, the Disillusioned, the Desperate, and the Not-Yet Deported," co-written with Norman J. Ornstein and Thomas E. Mann. He taught and lectured this fall as the William H. Bloomberg Visiting Professor at Harvard Divinity School, with a joint appointment at the Faculty of Arts and Sciences and Harvard Kennedy School.
This interview is part of the on-writing series "Decisions and Revisions."
GAZETTE: What do you think your job is as a columnist?
DIONNE: I think a lot about the possibility that someone who holds another view could read my column and at least have second thoughts about what they are thinking, or look at a question from a slightly different angle, even if I don't persuade them. Sometimes as a political columnist you are simply standing up for what you think is right. That sounds very pretentious, but we have the gift of being able to express a view. Mary McGrory, the great Boston-born columnist, once said that sometimes your job is to just make people realize they are not alone, especially at moments when people who broadly share your point of view feel beleaguered. Occasionally your job is to challenge people who think like you and to challenge yourself and to talk about when your side is wrong or when your side is being untrue to its own principles. And sometimes I hope I make people laugh. Just being able to smile while you are reading something can be a useful thing.
GAZETTE: How do you come up with your ideas?
DIONNE: I think David Brooks may have said this once: It's never out of your head that you have to write a column in one, two, three, or four days and so everything you hear, see — every person you talk to — is a potential inspiration. You are always thinking about it. You always have a list in the back of your head of things that you want to get to or things that you think you should get to. There are certain issues I care about that I try to keep on the radar. I have written a lot about health care over the years. I care a lot about national service, and whenever AmeriCorps is threatened I write about that. I care about kids' poverty. I care a lot about political reform and have written a lot about campaign money.
GAZETTE: What is your editing process like?
DIONNE: I am an incessant reviser. I am an echo-phobe. My first reader is my personal assistant and whenever I hire one, I say, "This may sound strange, but I want you to be absolutely mean to everything I write. I want you to take it apart. I want you to point out every terrible sentence. I want you to fact check me relentlessly and I want you to look for echoes."
I fail sometimes. I sometimes use a word more than once, and once in a while it's the right thing to do. But I've found mostly that when you have used a word two or three times, you are being lazy and that a sentence can be better when you try to find another word.
I had an unkind but extremely helpful reader years ago send me a column in which he had circled a bunch of words and scrawled across the top "useless adverbs." I read the column again and he was absolutely right. They were useless adverbs, and for about the next six months I checked every column I sent in for the letters "ly," and I cut out at least half the adverbs. To this day, I go after the adverbs and it's almost always the right thing to cut them. … Adverbs should be used sparingly. I rewrite myself a lot. I don't think I get it right the first time. There are some people who write perfect prose the first time around. I am not one of them. I reread sentences. I cut sentences in half. There are times when you are writing with a passion — when the first draft has an immediacy. If you feel really strongly about something, especially if you are mad, that can be very powerful.
My editors help on all these fronts — facts, style, echoes. One of the most useful things an editor can do is point out to you that a sentence you think says one thing actually says something else. Editors are almost always right when they point this out.
GAZETTE: Were there editors at The Washington Post or The New York Times who made a lasting impact?
DIONNE: There have been a number of them. One of my favorite editors was a man called Shelly Binn, the metropolitan political editor [at The New York Times] who was, in the best sense, an old-fashioned journalist. He had a strong sense about the civic responsibility of newspapers. He was very grandfatherly and he was also more conservative than I was. He asked me skeptical questions, which was good for me as a journalist, but always in the most generous way. You'd talk through stories and he would ask you about the holes in them. Once I had a story on some politician, some scandalous thing. I had a lot of information and I knew another paper was chasing it, too, but something didn't feel right and I told Shelly. He said something that few editors ever would: "Sometimes it's better being second." He meant it's better being second and right than first and wrong. That is just what you want a good editor to do. It turned out the story was wrong, and the other paper went with it.
I've had many good editors over the years. I was in Lebanon during the war and I was asked to write a piece on massacre claims made by the Druze and the Christians. I wrote the story and Craig Whitney, who was the foreign editor at The Times, wrote me back and in a nice way essentially said it felt like a story of dueling press conferences. I reread it and he was right. It needed more feeling in it; there was something deeply missing. I rewrote it and it was a much better story. I had the same experience with a profile of Pat Buchanan that I wrote for The Post when my editor was Bill Hamilton '72, a great guy who is now at The New York Times. He said, "We need a little more Buchanan here; you need a little more of the man." I disagree with Pat Buchanan on so many things, but he actually is a very charming man, and at the end of a campaign stop I explained that I had this problem and we went drinking at a bar in Derry, N.H. He gave me two hours and it made the piece infinitely better.
GAZETTE: Where did your love of words come from?
DIONNE: My mother was a teacher and a librarian and my dad was a dentist who got four newspapers every Sunday, so there were words around our house all the time. We were a family that loved to talk and argue. It's said you are not supposed to talk about religion or politics at the dinner table. Those were two subjects that we talked about all the time.
I never expected to write for a living. It's just something I started doing and not necessarily even well, but it's something I enjoyed because I loved reading. Two books really influenced me as a teen. One was "Franklin D. Roosevelt and the New Deal" by William E. Leuchtenburg. He was a wonderful stylist and gave you a sense of the excitement of the New Deal. The other was "Strength to Love," a collection of sermons by Martin Luther King Jr. There is something about King's language that has always stayed with me — the combination of biblical language, language from our founding, and the preaching style of the African-American church. I started life as a conservative and started becoming a liberal when I was about 12 or 13 partly because of the influence of those two books.
My dad was a conservative with a very open mind and he liked for me to argue with him, which I always loved. That's something I treasure. When I was 13 I asked him to give me a subscription to the New Republic so I could strengthen my side of the argument. That was an eye-opener for a kid in Fall River. In high school, a friend and I started a political magazine. I was the conservative and he was the liberal, and I think now he is a conservative and I am a liberal, so there you go.
GAZETTE: What's the difference between being a beat reporter and being a columnist?
DIONNE: It took me a while to adjust, to find my voice as a columnist, even though I've always been very opinionated. I took the discipline of old-fashioned reporting — the idea of not being opinionated in your writing — seriously. I had written a book called "Why Americans Hate Politics" before I became a columnist, and it was helpful because it was a kind of coming out in being plain about my own views. But the old journalistic discipline is still very helpful in opinion writing, which should be fact-based and reporting-based. That's not always the case. I'd still insist that if you want to claim to be both a columnist and a journalist, you must remain fact-based.
In every class I teach, I assign my students George Orwell's "Politics and the English Language," his essay that shows how the corruption of language can corrupt politics, and the corruption of politics can corrupt language. He does this wonderful thing with Ecclesiastes 9:11, the great passage "the race is not to the swift." He rewrites it in vulgar, awful, modern, bureaucratic English, and it's the most wonderful lesson in how not to corrupt language. Orwell also has some rules about straightforwardness in writing and not using euphemisms and saying what you actually mean.
GAZETTE: Can you compare your book self to your newsroom self?
DIONNE: The book self doesn't have the word limit so there is a certain freedom there. But there is also the need to organize the material over a long narrative, so there are organizational issues with a book that you don't face with a column. You still have to cut. One of the reasons I get a kick out of our new book — besides the fact that it was three people on two coasts in four months, which is a very interesting exercise — is that I think we came in at the right length. Our publisher did a great job of putting the book together. It's long enough so people will see it as substantive, and short enough that people will not see it as daunting. On a book like this you don't want to write a tome, and yet you want your reader to know this wasn't a slapdash instant Trump book. We really tried to go beyond just an instant reaction to events that happened 20 minutes ago. We wanted to take seriously the reasons Trump happened.
Again, cutting was critical because there were chapters that were too long. My assistant, Adam Waters, and I were the first-round editors. We chopped and rewrote and sent sections back to our colleagues Norm and Tom. It's hard cutting somebody else's work because it's not yours, but they gave us the freedom to cut. They, in turn, commented on and improved the parts I had written.
GAZETTE: Is there one column that struck the biggest chord with your readers?
DIONNE: The political column that probably had the biggest ripple was one I wrote in 2005 saying the Bush era is over. That struck a particular chord. A couple of columns I wrote on humility and uncertainty, those actually reached people. Then the very personal ones. I wrote a column years ago on summer baseball. I got the most wonderful responses from people.
GAZETTE: Do you have a favorite?
DIONNE: I probably like the columns I wrote about my mom, and my mother-in-law, my dad — I always tell people three great Americans died in 1968: King, Bobby Kennedy, and my dad. Those are the columns that in some ways mean the most to me. Then there are certain moments when I feel I may have pushed an issue forward. You never know what effect a column might have, but there were moments when I felt I just might have affected things for what I saw as the better. But with all the columns I have written this year on Trump, my favorite was the column about Helen Boyle, my mother-in-law. I explained why she will always be one of my heroes. It's the best case I ever made, and the easiest case I ever had to make.
Interview was edited and condensed.
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