Category: Aging

Medical Researchers Have Incentive to Exclude Older Patients from Clinical Trials

As human beings, medical researchers would like to offer experimental therapies to whoever needs them and is willing to take the risks and uncertainty of new frontiers. But as practical medical researchers medical researchers know their careers depend on the success of their clinical trials, and the success of their clinical trials depends on the number of patients who thrive on the new therapy. So their personal incentive is to cherry-pick clinical trial enrollees, picking only the most robust who are most likely to thrive. The solution? Allow medical researchers to be both human beings and medical researchers. Allow them to give the therapy to those at high risk, based on their cumulative experience and judgement. Not all sound actionable knowledge arises from randomized double-blind clinical trials.

(p. A5) Many cancer trials cap enrollment at age 65. Even when trials for older people are available, oncologists are reluctant to enroll elderly patients because frailties might make them less resilient against side effects from toxic treatments, according to a 2020 study in an American Cancer Society journal. People over 70 represent a growing share of the cancer-patient population but are vastly underrepresented in clinical trials, the study said.

“How can we make decisions for people over 70 if people over 70 are not included in the trials that we use to base our decision making?” said Dr. Mina Sedrak, deputy director of the Center for Cancer and Aging at City of Hope, a cancer center near Los Angeles and an author of the paper.

. . .

The Food and Drug Administration guidelines recommend “adequate representation” of the elderly in cancer trials, including people over age 75. The Journal of the National Cancer Institute in December 2022 published a series of papers presented at a workshop focused on how to improve trial enrollment of older people.

Researchers have developed geriatric assessment tools that try to predict patients’ survival chances based on more than age alone. Professional groups are also working to try to address gaps. Despite these efforts, enrollment of older patients still lags behind, cancer doctors said.

. . .

To participate in many trials involving transplants, patients would have to undergo the more intense chemotherapy whether randomly assigned to receive an experimental treatment or the standard of care. That makes it harder to incorporate older patients into randomized trials, cancer doctors said.

For the full story see:

Amy Dockser Marcus. “Cancer Patient Contests Age Limit for Clinical Trials.” The Wall Street Journal (Monday, Jan. 9, 2023 [sic]): A5.

(Note: ellipses added.)

(Note: the online version of the story has the date Jan. 8, 2023 [sic], and has the title “71-Year-Old Cancer Patient Broke Trial Age Limits for a Chance at a Cure.”)

A preface to the “series of papers” about how to improve trial enrollment of older people,” mentioned above, is:

St. Germain, Diane, and Supriya G Mohile. “Preface: Engaging Older Adults in Cancer Clinical Trials Conducted in the National Cancer Institute Clinical Trials Network: Opportunities to Enhance Accrual.” JNCI Monographs 2022, no. 60 (Dec. 2022): 107-10.

If Immortality Does Not Violate the Laws of Physics, Entrepreneurs Can Achieve It

The late Nobel-Prize-winning physicist and idiosyncratic Richard Feynman also said something similar to the quote attributed to Arram Sabeti below.

I do not believe that Feynman was explicitly named, or had any lines, in the movie “Opennheimer,” but you can see his character in the background of one scene playing the bongo drums. Perhaps he was eccentric, but I liked his views on methodology and his unpretentious, optimistic, and straightforward spirit.

(p. 9) As the longevity entrepreneur Arram Sabeti told The New Yorker: “The proposition that we can live forever is obvious. It doesn’t violate the laws of physics, so we can achieve it.”

For the full commentary see:

Dara Horn. “The Men Who Want to Live Forever.” The New York Times, SundayReview Section (Sunday, January 28, 2018 [sic]): 9.

(Note: the online version of the commentary has the date Jan. 25, 2018 [sic], and has the same title as the print version.)

Gene Mutation Doubles Lifespan of Worms

(p. D2) Once there was a mutant worm in an experiment. It lived for 46 days. This was much longer than the oldest normal worm, which lived just 22.

Researchers identified the mutated gene that had lengthened the worm’s life, which led to a breakthrough in the study of aging — it seemed to be controlled by metabolic processes. Later, as researchers studied these processes, all signs seemed to point to the nucleolus.

. . .

“We think the nucleolus plays an important role in regulating the life span of animals,” said Adam Antebi, a cellular biologist at the Max Planck Institute for Biology of Ageing in Germany. He’s an author of a new review published last week in Trends in Cell Biology that examines all the new ways that researchers have fallen in love with the nucleolus — especially its role in aging.

For the full story see:

JoAnna Klein. “Slithering Sleuths: Finding a Methuselah Of Worms, and a Key To the Aging Process.” The New York Times (Tuesday, May 22, 2018 [sic]): D2.

(Note: ellipsis added.)

(Note: the online version of the story has the date May 20, 2018 [sic], and has the title “The Thing Inside Your Cells That Might Determine How Long You Live.”)

The academic study of the role of the nucleolus in extending lifespans, mentioned above, is:

Tiku, Varnesh, and Adam Antebi. “Nucleolar Function in Lifespan Regulation.” Trends in Cell Biology 28, no. 8 (Aug. 2018): 662-72.

Loners Live Longer (At Least if You Are a Marmot)

(p. D2) For many mammals, a busy social life can be an important contributor to a long life. But some animals need more alone time than others, and failure to get it could be lethal, according to new research.

Consider the marmot. After spending 13 years tracking their interactions and life spans in Colorado, Daniel T. Blumstein, a biologist at the University of California, Los Angeles, and his colleagues found in a study published Wednesday [Jan. 17, 2018] in Proceedings of the Royal Society B that yellow-bellied marmots with more active social lives tended to die younger than those that avoided interactions.

For the full story see:

Douglas Quenqua. “Being Antisocial Leads to a Longer Life. For Marmots at Least.” The New York Times (Tuesday, Jan. 23, 2018 [sic]): D2.

(Note: bracketed date added.)

(Note: the online version of the story has the date Jan. 17, 2018 [sic], and has the title “Being Antisocial Leads to a Longer Life. For Marmots.” The Latin words in the first quoted sentence appear in italics in the original version.)

The academic study of Marmots discussed in the passages above is:

Blumstein, Daniel T., Dana M. Williams, Alexandra N. Lim, Svenja Kroeger, and Julien G. A. Martin. “Strong Social Relationships Are Associated with Decreased Longevity in a Facultatively Social Mammal.” Proceedings of the Royal Society B: Biological Sciences 285, no. 1871 (Jan. 2018): 20171934.

Formal and Tacit Knowledge Are Located in Different Parts of the Brain

Brenda Milner turned 106 on July 15, 2024.

(p. D5) At 98, Dr. Milner is not letting up in a nearly 70-year career to clarify the function of many brain regions — frontal lobes, and temporal; vision centers and tactile; the left hemisphere and the right — usually by painstakingly testing people with brain lesions, often from surgery. Her prominence long ago transcended gender, and she is impatient with those who expect her to be a social activist. It’s science first with Dr. Milner, say close colleagues, in her lab and her life.

Perched recently on a chair in her small office, resplendent in a black satin dress and gold floral pin and banked by moldering towers of old files, she volleyed questions rather than answering them. “People think because I’m 98 years old I must be emerita,” she said. “Well, not at all. I’m still nosy, you know, curious.”

. . .

Dr. Milner changed the course of brain science for good as a newly minted Ph.D. in the 1950s by identifying the specific brain organ that is crucial to memory formation.

She did so by observing the behavior of a 29-year-old Connecticut man who had recently undergone an operation to relieve severe epileptic seizures. The operation was an experiment: On a hunch, the surgeon suctioned out two trenches of tissue from the man’s brain, one from each of his medial temporal lobes, located deep below the skull about level with the ears. The seizures subsided.

But the patient, an assembly line worker named Henry Molaison, was forever altered. He could no longer form new memories.

. . .

In a landmark 1957 paper Dr. Milner wrote with Mr. Molaison’s surgeon, she concluded that the medial temporal areas — including, importantly, an organ called the hippocampus — must be critical to memory formation. That finding, though slow to sink in, would upend the accepted teaching at the time, which held that no single area was critical to supporting memory.

Dr. Milner continued to work with Mr. Molaison and later showed that his motor memory was intact: He remembered how to perform certain physical drawing tests, even if he had no memory of learning them.

The finding, reported in 1962, demonstrated that there are at least two systems in the brain for processing memory: one that is explicit and handles names, faces and experiences; and another that is implicit and incorporates skills, like riding a bike or playing a guitar.

“I clearly remember to this day my excitement, sitting there with H. M. and watching this beautiful learning curve develop right there in front of me,” Dr. Milner said. “I knew very well I was witnessing something important.”

. . .

For Dr. Milner, after a lifetime exploring the brain, the motive for the work is personal as well as professional. “I live very close; it’s a 10-minute walk up the hill,” she said. “So it gives me a good reason to come in regularly.”

For the full story see:

Benedict Carey. “At 98, ‘Still Nosy’ About the Brain.” The New York Times (Tuesday, May 16, 2017 [sic]): D5.

(Note: ellipses added.)

(Note: the online version of the story has the date May 15, 2017 [sic], and has the title “Brenda Milner, Eminent Brain Scientist, Is ‘Still Nosy’ at 98.”)

The “landmark 1957 paper” mentioned above is:

Scoville, William Beecher, and Brenda Milner. “Loss of Recent Memory after Bilateral Hippocampal Lesions.” Journal of Neurology, Neurosurgery & Psychiatry 20, no. 1 (Feb. 1957): 11-21.

Hayflick Said Lifespans Are Limited by Maximum Times Cells Can Divide (the “Hayflick Limit”)

Hayflick thought the “Hayflick limit” was a permanently binding constraint on the maximum lifespans that humans could achieve. But cancer cells provide a proof-of-concept that some cells are able to escape the limit. The challenge is to engineer cells that escape the limit without otherwise killing us. (Hayflick himself died of cancer.)

(p. A20) Leonard Hayflick, a biomedical researcher who discovered that normal cells can divide only a certain number of times — setting a limit on the human life span and frustrating would-be-immortalists everywhere — died on Aug. 1 [2024] at his home in Sea Ranch, Calif. He was 96.

His son, Joel Hayflick, said the cause was pancreatic cancer.

Like many great scientific findings, Dr. Hayflick’s came somewhat by accident. As a young scientist in the early 1960s at the Wistar Institute, a research organization at the University of Pennsylvania, he was trying to develop healthy embryonic cell lines in order to study whether viruses can cause certain types of cancer.

He and a colleague, Paul Moorhead, soon noticed that somatic — that is, nonreproductive — cells went through a phase of division, splitting between 40 and 60 times, before lapsing into what he called senescence.

. . .

This finding, which the Nobel-winning virologist Macfarlane Burnet later called the Hayflick limit, ran counter to everything scientists believed about cells and aging — especially the thesis that cells themselves are immortal, and that aging is a result of external causes, like disease, diet and solar radiation.

. . .

Dr. Hayflick made other important contributions to science. He developed a particularly vibrant cell line, WI-38, which has been used for decades to make vaccines.

. . .

The National Institutes of Health had funded the research on his WI-38 cell line but declined to fund its distribution, even as other researchers clamored for samples. Dr. Hayflick established a company to process orders, charged a minimal fee for shipping and set the proceeds aside until ownership was clarified.

But in a private report that was released to the news media, the N.I.H. accused Dr. Hayflick of theft. He sued the institute, charging invasion of privacy and reputational damage, including a forced resignation from his position at Stanford. The litigation took six years and ended in a settlement that allowed him to keep some of the money and cell samples.

During those six years, Congress passed the Bayh-Dole Act, which allows scientists to profit off government-funded research. The law, which would have made Dr. Hayflick’s earlier actions unquestionably legal, helped catalyze the biotech industry.

For the full obituary see:

Clay Risen. “Leonard Hayflick, 96, Explorer of Cells Who Showed Why No One Lives Forever.” The New York Times (Tuesday, August 20, 2024): A20.

(Note: ellipses, and bracketed year, added.)

(Note: the online version of the obituary was updated Aug. 19, 2024, and has the title “Leonard Hayflick, Who Discovered Why No One Lives Forever, Dies at 96.”)

Is Longevity Constrained by Nature or by Government Regulations?

I am a longevity optimist. If regulatory constraints are loosened, I believe entrepreneurs will bring us quicker progress.

(p. A12) S. Jay Olshansky, who studies the upper bounds of human longevity at the University of Illinois Chicago, believes people shouldn’t expect to live to 100.

. . .

Kaare Christensen, co-author of a paper predicting most newborns born in the 2000s would live to 100 if medical progress continued, said it is too soon to know who is right. Future advances could make up for stalled life expectancy gains.

“The setback could be temporary,” he said.

Christensen, who runs studies on very old people at the Danish Aging Research Center in Denmark, said people in their 90s have better cognitive function and healthier teeth over their lifetimes than counterparts of the same age born just 10 years earlier.

“I would say prepare for your 90s instead,” Christensen said.

Old-age debate

Olshansky’s foray into the limits of lifespan began in 1990 when he published a paper in Science stating that life expectancy wouldn’t rise dramatically even if diseases including cancer and heart disease are eliminated. He has been fighting about it ever since.

James Vaupel, a demographer, pushed back. In a 2021 paper, Vaupel pointed to statistics showing that since around 1840 life expectancy at birth has increased almost 2.5 years per decade in some countries.

Vaupel and Olshansky published dueling papers over the decades until Vaupel’s death at age 76 in 2022.

Steven Austad, a professor of biology at the University of Alabama at Birmingham, was asked at a 2001 scientific meeting when he thought the first person to live to 150 would be born. “I think that person is already alive,” Austad replied. Austad said he based his answer on optimism that scientists will figure out how to change the biology of aging.

When Olshansky heard about the exchange, he bet Austad that wasn’t true. In 150 years, he argued, there still wouldn’t be a person alive at 150. The men wagered $150 each, which they put in a fund to pay out in 150 years, with the winner’s heirs to reap the profit. A decade ago, they each added another $150 to the account.

Austad said he agreed with Olshansky that most newborns born now won’t live to 100. But he thinks his optimism that someone will live to 150 is justified. He pointed to a study showing the compound rapamycin extended the lifespan of mice, even if they start getting it later in life. Some longevity enthusiasts are taking rapamycin themselves. Studies on other potentially antiaging compounds are under way.

“If any turn out to work,” Austad said, “they will win my bet for me.”

For the full story see:

Amy Dockser Marcus. “Live Until 100? Our Chances Are Slim.” The Wall Street Journal (Wednesday, July 17, 2024): A12.

(Note: ellipsis added.)

(Note: the online version of the story has the date July 11, 2024, and has the title “Think You Will Live to 100? These Scientists Think You’re Wrong.”)

The paper co-authored by Christensen and mentioned above, is:

Christensen, Kaare, Gabriele Doblhammer, Roland Rau, and James W. Vaupel. “Ageing Populations: The Challenges Ahead.” Lancet 374, no. 9696 (Oct. 3, 2009): 1196-208.

The 2021 paper co-authored by Vaupel and mentioned above, is:

Vaupel, James W., Francisco Villavicencio, and Marie-Pier Bergeron-Boucher. “Demographic Perspectives on the Rise of Longevity.” Proceedings of the National Academy of Sciences 118, no. 9 (2021): e2019536118.

Diet Low in Fat and Sugar May Have Helped Morera Become Oldest Person in World

But at least it appears that she was able to keep drinking coffee. She also apparently embraced new technology and stayed intellectually sharp (maybe the coffee helped ;).

(p. A1) Maria Branyas Morera, an American-born Spanish woman believed to be the oldest person in the world, died on Monday [Aug. 19, 2024] in Olot, Spain. She was 117.

Her family wrote in a post on her X account that she had died in her sleep. She had been living in a nursing home.

“A few days ago she told us: ‘One day I will leave here. I will not try coffee again, nor eat yogurt, nor pet my dog,’” her family wrote in Catalan in the post. “‘I will also leave my memories, my reflections, and I will cease to exist in this body. One day I don’t know, but it’s very close, this long journey will be over.’”

. . .

Having been born before the emergence of the telephone, Ms. Branyas came to embrace the digital revolution, fashioning herself on social media as “Super Àvia Catalana,” or “Super Catalan Grandma.” She posted bite-size pieces of life advice, observations and jokes to thousands of followers.

In her biography on X, she wrote, “I’m old, very old, but not an idiot.”

. . .

Like many supercentenarians, Ms. Branyas became the subject of scientific fascination. Dr. Esteller, the researcher who studied her genetics and lifestyle, found that her genes were protective against DNA damage, and that she had low levels of fat and sugar in her blood — all of which he said was helpful for living a long life. His research also found that her cells aged much slower than she did, meaning that she had a lower “biological age” than her actual age.

The Catalan diet, which is similar to the Mediterranean diet and includes a lot of olive oil, has also been linked to longer survival, he said. He added that Ms. Branyas liked to eat yogurt.

“What do you expect from life?” a doctor once asked Ms. Branyas while retrieving blood samples for study, according to El País.

Ms. Branyas, unmoved, answered simply: “Death.”

For the full obituary see:

Ali Watkins. “Maria Branyas Morera, 117; Was Oldest Person in the World.” The New York Times (Friday, August 23, 2024): B11.

(Note: ellipses, and bracketed date, added.)

(Note: the online version of the obituary was updated Aug. 22, 2024, and has the title “Maria Branyas Morera, World’s Oldest Person, Dies at 117.”)

The “Innovative Approach” of the Dog Aging Project May Have Hurt Its Odds for Renewed Funding

Veterinary medicine is less regulated than human medicine, and so trial and error experiments may allow faster innovation that would benefit both dogs and humans.

(p. D3) In late 2019, scientists began searching for 10,000 Americans willing to enroll their pets in an ambitious new study of health and longevity in dogs. The researchers planned to track the dogs over the course of their lives, collecting detailed information about their bodies, lifestyles and home environments. Over time, the scientists hoped to identify the biological and environmental factors that kept some dogs healthy in their golden years — and uncover insights about aging that could help both dogs and humans lead longer, healthier lives.

Today, the Dog Aging Project has enrolled 47,000 canines and counting, and the data are starting to stream in. The scientists say that they are just getting started.

“We think of the Dog Aging Project as a forever project, so recruitment is ongoing,” said Daniel Promislow, a biogerontologist at the University of Washington and a co-director of the project. “There will always be new questions to ask. We want to always have dogs of all ages participating.”

But Dr. Promislow and his colleagues are now facing the prospect that the Dog Aging Project might have its own life cut short. About 90 percent of the study’s funding comes from the National Institute on Aging, a part of the National Institutes of Health, which has provided more than $28 million since 2018. But that money will run out in June, and the institute does not seem likely to approve the researchers’ recent application for a five-year grant renewal, the scientists say.

“We have been told informally that the grant is not going to be funded,” said Matt Kaeberlein, the other director of the Dog Aging Project and a former biogerontology researcher at the University of Washington. (Dr. Kaeberlein is now the chief executive of Optispan, a health technology company.)

. . .

Steven Austad, a biogerontologist at the University of Alabama at Birmingham who is not part of the research team, said he was surprised that the researchers’ grant might not be renewed. “The importance of the things they publish and the depth of detail will increase over time, but I thought they got off to a really good start,” he said. “A large study like this really deserves a chance to mature.”

Dr. Austad’s miniature dachshund, Emmylou, is enrolled in the Dog Aging Project. But at 2 years old, he noted, Emmylou is “not going to teach them a lot about aging for a long time yet.”

The project’s innovative approach might have worked against it, Dr. Austad added. Reviewers accustomed to evaluating short-term research on lab mice and long-term studies of humans may not have known what to make of an enormous epidemiological study of pet dogs.

Whatever the reason, the refusal to commit to more funding is “wrong,” Dr. Kaeberlein said. “It’s just really, really difficult to justify this decision, if you look at the productivity and the impact of the project.”

That impact extends beyond the findings themselves, he added. “This project has engaged almost 50,000 Americans in biomedical scientific research.”

Over the last few years, Shelley Carpenter, of Gulfport, Miss., has provided the researchers with regular updates on and medical records for her Pembroke Welsh corgi, Murfee. (She also collected a cheek swab for genomic sequencing.) Ms. Carpenter, whose previous corgi died from a neurodegenerative disease similar to A.L.S., hoped that the project might produce new medical knowledge that could help both dogs and people.

For the full story see:

Emily Anthes. “Scientists Scramble to Keep Dog Aging Project Alive.” The New York Times (Tuesday, January 16, 2024): D3.

(Note: ellipses added.)

(Note: the online version of the story has the date Jan. 11, 2024, and has the same title as the print version.)

Techno-Optimist Claims AI Tools “Will Help Scientists Design Therapies Faster and Better”

(p. A13) It is said that triumphant Roman generals, to ensure that the rapture of victory didn’t go to their heads, would require a companion to whisper in their ear: “Remember, you are only a man.” Jamie Metzl worries that we may have learned all too well such lessons in humility. Given remarkable recent advances in technology—and the promise of more to come—we need to lean into our emerging godlike powers, he believes, and embrace the opportunity to shape the world into a better place. In “Superconvergence,” he sets out to show us how, after first helping us overcome our hesitations.

. . .

. . . the big advances will be in medicine—and indeed are already in evidence. Mr. Metzl points to the blisteringly fast development of the Covid-19 mRNA vaccine, from digital file to widespread immunization in less than a year; and to gene-editing technologies like Crispr. He cites the experience of Victoria Gray, a young woman from Mississippi who was suffering from sickle-cell disease until, in 2019, researchers in Nashville, Tenn., reinfused her with her own cells, which had been Crispr-edited; the treatment worked, liberating her from the disease’s tormenting pain and crippling fatigue. For Mr. Metzl, these are just the first intimations of a revolution to come. AI tools like DeepMind’s Alphafold, he says, will help scientists design therapies faster and better.

To get smarter about human health, though, AI will need more information, and here Mr. Metzl’s ebullience edges toward the willful suspension of disbelief. His imagined future of healthcare will require “collecting huge amounts of genetic and systems biology data in massive and searchable databases.” The details will include not only medical records and the results of laboratory tests but data from the sensors he anticipates will be everywhere—“bathrooms, bedrooms, and offices”—as information is hoovered up from “toilets, mirrors, computers, phones and other devices without the people even noticing.” While acknowledging that such a scenario sounds like “an authoritarian’s dream and a free person’s nightmare,” he suggests that the chance to catch disease early may offset the risks. This trade-off promises to be a tough sell.

More than many techno-optimists, Mr. Metzl seems to grasp the intricacy of biological systems; he notes that they are beyond our full understanding right now. Even so, a time will come when “the sophistication of our tools and understanding meets and then exceeds the complexity of biology.”

For the full review, see:

David A. Shaywitz. “Getting Better, Faster.” The Wall Street Journal (Thursday, July 11, 2024): A13.

(Note: the online version of the review has the date July 10, 2024, and has the title “‘Superconvergence’ Review: Getting Better, Faster.”)

The book under review is:

Metzl, Jamie. Superconvergence: How the Genetics, Biotech, and AI Revolutions Will Transform Our Lives, Work, and World. New York: Timber Press, 2024.

Some Variants of One Mitochondrial Gene Double Your Odds of Living to 100

(p. D3) . . . what made the great blooming of biodiversity possible? Dr. Lane, building on ideas developed with the evolutionary biologist William Martin, traces its origins to a freak accident billions of years ago, when one microbe took up residence inside another. This event was not a branching of the evolutionary tree but a fusion with, he argues, profound consequences.

The new tenant provided energy for its host, paying chemical rent in exchange for safe dwelling. With this additional income, the host cell could afford investments in more complex biological amenities. The pairing thrived, replicated and evolved.

Today we call these inner microbes mitochondria; nearly every cell in our body has thousands of these energy factories. Dr. Lane and Dr. Martin have argued that because of mitochondria, complex cells have nearly 200,000 times as much energy per gene, setting the stage for larger genomes and unfettered evolution.

. . .

With age, mitochondrial mutations accumulate. Elsewhere, Dr. Lane has pointed to research showing that variants in a single mitochondrial gene halved the prospect of being hospitalized for age-related disease in patients who have them, and doubled the prospect of living to 100. This finding, Dr. Lane believes, could lead to medical advances if we understood how to protect mitochondrial DNA.

“How can we hope to understand disease,” he asks, “if we have no idea why cells work the way they do?”

. . .

Whether research will bear him out remains to be seen, but Dr. Lane’s many predictions, however incredible they seem, are testable and could keep scientists busy for years. As Sherlock Holmes remarked, “When you have eliminated the impossible, then whatever remains, however improbable, must be the truth.”

For the full review see:

Tim Requarth. “Rethinking the Textbook on Life.” The New York Times (Tuesday, July 21, 2015 [sic]): D3.

(Note: ellipses added.)

(Note: the online version of the review was updated July 20, 2015 [sic], and has the title “Book Review: Taking on ‘The Vital Question’ About Life.”)

The book under review is:

Lane, Nick. The Vital Question: Energy, Evolution, and the Origins of Complex Life. New York: W. W. Norton & Company, 2015.