Category: Entrepreneurship

Crispr Gene-Editing Tried Against Cancer

(p. D4) Doctors have for the first time in the United States tested a powerful gene-editing technique in people with cancer.

The test, meant to assess only safety, was a step toward the ultimate goal of editing genes to help a patient’s own immune system to attack cancer. The editing was done by the DNA-snipping tool Crispr.

The procedure was feasible and safe, early results indicate, but whether it is fighting the disease is unclear. Only three patients have been treated so far, and the longest follow-up is nine months. All three patients are in their 60s, with very advanced cancers that had progressed despite standard treatments like surgery, radiation and chemotherapy.

“The good news is that all of them are alive,” said Dr. Edward A. Stadtmauer, the section chief of hematologic malignancies at the University of Pennsylvania Abramson Cancer Center. He added, “The best response we’ve seen so far is stabilization of their disease.”

For the full story, see:

Denise Grady. “Editing Genes in Bid to Fight Cancer.” The New York Times (Tuesday, November 12, 2019): D4.

(Note: the online version of the story was updated Oct. 7, 2020 [sic], and has the title “Crispr Takes Its First Steps in Editing Genes to Fight Cancer.”)

Bennet Chose Pig’s Heart Since “It Was Either Die or Do This Transplant”

(p. A3) A man who had the first transplant to replace his human heart with a genetically-modified pig’s heart without immediate rejection died Tuesday afternoon at the University of Maryland Medical Center in Baltimore, two months after the groundbreaking surgery.

. . .

While Mr. Bennett only lived with the pig heart for a couple of months, Dr. Parsia Vagefi, UT Southwestern Medical Center’s chief of the division of surgical transplantation, said people shouldn’t view the transplant as a failure and that he hopes it serves as a “new beginning” for xenotransplantation.

“I think what this shows is just the enormous amount of progress that’s been made and hopefully it’s just the beginning that we continue to grow on,” he said.

Mr. Bennett wasn’t eligible for a more typical heart transplant because he didn’t comply with doctors’ orders or attend follow-up visits. Several transplant centers—including the Maryland one—declined to list him for the chance to get a human heart, according to David Bennett Jr. , Mr. Bennett’s son. He also didn’t regularly take his medication, the younger Mr. Bennett previously said.

The U.S. Food and Drug Administration had granted Mr. Bennett’s operation emergency authorization on New Year’s Eve. “It was either die or do this transplant,” he said the day before his surgery, according to the University of Maryland Medicine. The handyman and father of two called the transplant his “last choice.”

For the full story, see:

Allison Prang. “Pig-Heart Recipient Dies 2 Months Later.” The Wall Street Journal (Thursday, March 10, 2022): A3.

(Note: ellipsis added.)

(Note: the online version of the story was updated March 9, 2022, and has the title “The Patient Who Received a Pig Heart Dies Two Months After Transplant.” The first two sentences after the ellipsis appear in the online, but not the print, version.)

Stewart Brand Read Rand and Koestler, and Inspired Steve Jobs

At the end of Steve Jobs’s famous commencement address at Stanford, he quoted Stewart Brand’s famous advice at the end of his Last Whole Earth Catalog: “Stay hungry. Stay foolish.”

(p. A15) When I first met Stewart Brand at an upscale ideas festival, I expected to engage with an aging beatnik or hippie, the tree-hugging, whale-saving environmentalist I associated with the “Whole Earth Catalog”—that ’60s-era collectanea of books, resources, tools, technologies and assorted products that became the bible of a techno-utopia DIY movement focused on self-sufficiency, education and ecology. But I found Mr. Brand more like Elon Musk than Timothy Leary, and was astonished to witness him make the best argument I’d ever heard for including nuclear power in plans to replace fossil fuels.

. . .

Although many contemporaries dropped acid for the pure experience, Mr. Brand said he took LSD (and other psychedelics) because he hoped they would accentuate his appreciation of beauty, especially that found in the photographic skills he was developing. For him psychedelics were a tool of creativity: “When you design a tool,” he wrote in 1971, “the best you can do is fashion a prototype and hand it over to the local evolutionary system: ‘Here, try this.’ ”

His model was Arthur Koestler’s “bisociation,” the blending of unrelated concepts into something new. Mr. Brand’s ability to discern unlikely complements, along with the organizational skills he’d honed in the military, helped bring numerous projects to fruition: His imagination had him bounce from one to the next; his pragmatic propensities put them into effect. Decades after the “Whole Earth Catalog” project, for example, Mr. Brand published “Whole Earth Discipline,” which proposed integrating nuclear power, geoengineering, genetic engineering, wildlife restoration, species protection and other environmental technologies aimed at creating a sustainable future for life on Earth. He’s a solutions guy, not a New Age guru—his ability to convene like-minded innovators has resulted in the WELL (Whole Earth ’Lectronic Link), the Global Business Network for futurists and business leaders, the Long Now Foundation, and Revive & Restore, a project to bring back extinct species like passenger pigeons and woolly mammoths.

As for Mr. Brand’s politics, he’s off the spectrum, mostly identifying as a small-l libertarian (he read Ayn Rand at Stanford), committed to bottom-up democracy, with an aversion to orthodoxy of any sort, which means he must adapt when the marginal becomes the mainstream, as in his shift from environmentalism to conservationism, from organic foods to GMOs, and from anti- to pro-nuclear power.

For the full review, see:

Michael Shermer’. “BOOKSHELF; A Man In Whole.” The Wall Street Journal Tuesday, March 29, 2022): A15.

(Note: ellipsis added.)

(Note: the online version of the review has the date March 28, 2022, and has the title “BOOKSHELF; ‘Whole Earth’ Review: A Man in Whole.”)

The book under review is:

Markoff, John. Whole Earth: The Many Lives of Stewart Brand. New York: Penguin Press, 2022.

“Seems Ethernet Does Not Work in Theory, Only in Practice”

(p. A21) David Boggs, an electrical engineer and computer scientist who helped create Ethernet, the computer networking technology that connects PCs to printers, other devices and the internet in offices and homes, died on Feb. 19 [2022] in Palo Alto, Calif.

. . .

In the spring of 1973, just after enrolling as a graduate student at Stanford University, Mr. Boggs began an internship at Xerox PARC, a Silicon Valley research lab that was developing a new kind of personal computer. One afternoon, in the basement of the lab, he noticed another researcher tinkering with a long strand of cable.

The researcher, another new hire named Bob Metcalfe, was exploring ways of sending information to and from the lab’s new computer, the Alto. Mr. Metcalfe was trying to send electrical pulses down the cable, and he was struggling to make it work. So Mr. Boggs offered to help.

Over the next two years, they designed the first version of Ethernet.

“He was the perfect partner for me,” Mr. Metcalfe said in an interview. “I was more of a concept artist, and he was a build-the-hardware-in-the-back-room engineer.”

. . .

Before becoming the dominant networking protocol, Ethernet was challenged by several other technologies. In the early 1980s, Mr. Metcalfe said, when Mr. Boggs took the stage at a California computing conference, at the San Jose Convention Center, to discuss the future of networking, a rival technologist questioned the mathematical theory behind Ethernet, telling Mr. Boggs that it would never work with large numbers of machines.

His response was unequivocal. “Seems Ethernet does not work in theory,” he said, “only in practice.”

For the full obituary, see:

Cade Metz. “David Boggs, Co-Inventor of Ethernet, Dies at 71.” The New York Times (Tuesday, March 1, 2022): A21.

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

(Note: the online version of the obituary has the date Feb. 28, 2022, and has the same title as the print version.)

John List Shows Limitations of Randomized Controlled Trials (RCTs)

(p. A15) John List’s “The Voltage Effect” is marketed as a generic business title on how and whether to scale up an idea or product. Mr. List, an economics professor at the University of Chicago, explores why some ideas attain “voltage” and catch fire while others die out. This angle suggests that it will be another book about how to turn that great invention in your garage into the next Hewlett-Packard. But Mr. List is far too thoughtful to write something gimmicky or simple.

. . .

“The Voltage Effect” is a fine business book, though in many ways it works better as a meditation on the shortcomings of our increasingly data-driven world. The business community and academia have been taken over by data science. Mr. List seemingly argues that good and helpful data analysis may not scale well. It takes tremendous skill and talent to distinguish a scalable idea from one that is doomed to flop when you are working with a limited set of data and have an incentive to overhype your results. Data is the new currency; companies are presumed to have an unfair advantage if they have access to more of it. What gets less attention is the shortage of people who know how to make sense of statistical experiments and generalize them to a larger population.

The fields of business, policy and economics have all become enthralled with Randomized Control Trials. These are statistical experiments in which researchers take two populations: a “treatment” group that may be given cash or some other incentive and a “control” group that is not given anything. Researchers then observe any difference in outcomes from the experiment to make policy recommendations. RCTs can be a useful tool. But taking Mr. List’s lessons to heart, you see how limited they are.

Even the best-designed experiment may not give you insights that scale. For example, studies have found that it is more effective to give people cash in Kenya than to distribute aid through arcane development programs. The mantra in the development community has become “just give people money.” But just because cash is better than aid in Kenya, it doesn’t necessarily mean that a Universal Basic Income will work well in California.

For the full review, see:

Allison Schrager. “BOOKSHELF; Do We Have a Winner?” The Wall Street Journal (Monday, March 28, 2022): A15.

(Note: ellipsis added.)

(Note: the online version of the review has the date March 27, 2022, and has the title “BOOKSHELF; ‘The Voltage Effect’ Review: Do We Have a Winner?”)

The book under review is:

List, John A. The Voltage Effect: How to Make Good Ideas Great and Great Ideas Scale. New York: Currency, 2022.

Executive Chose “Exciting” Entrepreneurship, and Failed

We read the stories of those who choose entrepreneurship and succeed. The stories of those who choose entrepreneurship and fail, are less often told. Those who fail do not always regret their choice, nor should they.

(p. A21) Alex Mandl was a leading contender for the chief executive job at AT&T Corp. in 1996 when he defected to head a wireless-telecommunications startup that became Teligent Inc.

. . .

Heading a startup, he said, was “the most exciting thing to do.”

Teligent had ambitious plans to undercut prices of traditional phone companies by setting up a microwave network that would beam voice and data to business users via rooftop antennas. But Teligent had technical problems, losses piled up and investors fled. Mr. Mandl resigned as chief executive in April 2001, shortly before the company filed for Chapter 11 bankruptcy.

For the full obituary, see:

James R. Hagerty. “Executive Risked Career on a Startup.” The Wall Street Journal (Saturday, April 2, 2022): A21.

(Note: ellipsis added.)

(Note: the online version of the obituary has the date April 1, 2022, and has the title “Alex Mandl, Who Gave Up a Top AT&T Job to Lead a Startup, Has Died at Age 78.”)

Discoverer of Catalyst Role of mRNA Had Trouble “Getting His Work Published”

(p. B12) Sidney Altman, a molecular biologist who was awarded the Nobel Prize for Chemistry for sharing in the discovery that ribonucleic acid, or RNA, was not just a carrier of genetic information but could also be a catalyst for chemical reactions in cells — a breakthrough that paved the way for new gene therapies and treatments for viral infections — died on April 5 [2022] in Rockleigh, N.J.

. . .

HAs seems to happen so often in science, Dr. Altman stumbled upon his discovery. “I wasn’t looking for what I found,” he said in a 2010 interview with Harry Kreisler at the Institute for International Studies at the University of California, Berkeley.

He had studied how a small RNA molecule, called transfer RNA, carries genetic code to make new proteins. Some of the code is not necessary, so an enzyme cuts it out before it is used.

Then, in 1978, Dr. Altman began studying an RNA-cutting enzyme from E. coli bacteria that was composed of an RNA molecule and a protein. He managed to separate the two pieces and test them to see how they reacted in the enzyme process. Much to his surprise, he discovered that the protein did not perform as an enzyme without the RNA molecule. He later discovered that the RNA molecule could be the catalyst, even without the protein.

The finding ran completely contrary to what at the time was established theory, which held that it was the proteins that were the catalysts in enzymes.

The discovery of what are now known as ribozymes was so radical that Dr. Altman had trouble getting it accepted.

Joel Rosenbaum, a professor of cell biology at Yale and a colleague of Dr. Altman’s, told Chemistry World magazine that when Dr. Altman first tried to get other scientists to accept his research, “the community of molecular biologists, including several at Yale working on RNA, did not want to believe the work.”

“He had a hard time obtaining invitations to speak at scientific meetings and, indeed, getting his work published,” Dr. Rosenbaum said.

For the full obituary, see:

Dylan Loeb McClain. “Sidney Altman, Who Stumbled on a Breakthrough in Genetics, Dies at 82.” The New York Times (Saturday, April 16, 2022): B12.

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

(Note: the online version of the obituary was updated April 18, 2022, and has the same title as the print version.)

CAR T Therapy Is a Durable “Cure” for Some Leukemia Cancers

(p. A17) Doug Olson was feeling kind of tired in 1996. When a doctor examined him she frowned. “I don’t like the feel of those lymph nodes,” she said, poking his neck. She ordered a biopsy. The result was terrifying. He had chronic lymphocytic leukemia, a blood cancer that mostly strikes older people and accounts for about a quarter of new cases of leukemia.

“Oh Lordy,” Mr. Olson said. “I thought I was done for.” He was only 49 and, he said, had always been healthy.

Six years went by without the cancer progressing. Then it started to grow. He had four rounds of chemotherapy but the cancer kept coming back. He had reached pretty much the end of the line when his oncologist, Dr. David Porter at the University of Pennsylvania, offered him a chance to be among the very first patients to try something unprecedented, known as CAR T cell therapy.

In 2010, he became the second of three patients to get the new treatment.

At the time, the idea for this sort of therapy “was way out there,” said Dr. Carl June, the principal investigator for the trial at Penn, and he had tempered his own expectations that the cells he was providing to Mr. Olson as therapy would survive.

“We thought they would be gone in a month or two,” Dr. June said.

Now, a decade later, he reports that his expectations were completely confounded. In a paper published Wednesday in Nature, Dr. June and his colleagues, Dr. J. Joseph Melenhorst and Dr. Porter, report that the CAR T treatment made the cancer vanish in two out of the three patients in that early trial. All had chronic lymphocytic leukemia. The big surprise, though, was that even though the cancer seemed to be long gone, the CAR T cells remained in the patients’ bloodstreams, circulating as sentinels.

“Now we can finally say the word ‘cure’ with CAR T cells,” Dr. June said.

Although most patients will not do as well, the results hold out hope that, for some, their cancer will be vanquished.

For the full story, see:

Gina Kolata. “Potential Leukemia Cure Leads to New Mysteries.” The New York Times (Thursday, February 3, 2022): A17.

(Note: the online version of the story has the date Feb. 2, 2022, and has the title “A Cancer Treatment Makes Leukemia Vanish, but Creates More Mysteries.”)

BioNTech Is Running Clinical Trials for mRNA Cancer Vaccines

(p. C2) Scientists are . . . advancing mRNA vaccines and therapies to treat cancer, which poses a particular challenge because tumor cells arise from the body’s own cells and can easily deceive the immune system into thinking they are normal. Cancer patients today receive varying types of treatments, but they involve therapies manufactured outside the body. The mRNA researchers believe that the body’s own immune system can be used against cancer if it’s given the right tools.

BioNTech, now a household name for its Covid-19 vaccine with Pfizer, was founded in 2008 to pursue mRNA cancer treatments. The German company says that even at a low dose, a strong enough mRNA treatment can be developed to prompt immune cells to make certain proteins and to train the rest of the immune system to recognize and target tumor cells that express these same proteins. “It needs to be louder and more aggressive for cancer because the immune system needs stronger persuasion to attack something that appears to resemble a normal cell which it should respect and not attack,” said Özlem Türeci, BioNTech’s chief medical officer.

The company’s pipeline includes at least 10 cancer vaccines in human clinical trials using mRNA for skin, pancreatic, ovarian and other tumors. Two of its most advanced programs in mid-stage clinical studies, one for melanoma and the other for head and neck cancer, harness mRNA to make specific proteins seen with these cancers that will prompt a vigorous response from the patient’s immune system. Research from BioNTech published in 2020 in the journal Nature showed that the treatment caused the lesions of melanoma patients to shrink.

Some of BioNTech’s other cancer treatments are tailored to individual patients. A tumor is removed surgically and then shipped to the company’s laboratories, where researchers sequence the DNA and search for proteins, using machine learning to decide which ones are needed for that individual’s therapy. To address how quickly cancer can spread in the body, BioNTech designs and develops these clinical-trial treatments in just four to six weeks—a potentially lifesaving turnaround time for more pressing cases.

For the full essay, see:

Jared S. Hopkins and Felicia Schwartz. “Can the Technology Behind Covid Vaccines Cure Other Diseases?” The Wall Street Journal (Saturday, February 5, 2022): C1-C2.

(Note: ellipsis added.)

(Note: the online version of the essay has the date February 4, 2022, and has the same title as the print version.)

Some Venture Capitalists “Act as Mentors,” Some Install Seasoned Veterans as C.E.O.s, and Some Are “Founder-Friendly,” Allowing Genius “to Do Its Work”

(p. C4) . . . Mallaby never quite settles on the story he wants to tell. He introduces the book by laying out what he intends to do: “to explain the venture-capital mind-set” and “to evaluate venture capital’s social impact.” This mind-set, he says, revolves around the “power law” of his title — the idea that the distribution of phenomena is not “normal” but skewed. Instead of a bell curve, picture a long tail, where “winners advance at an accelerating, exponential rate.” Adapt or die, sink or swim — there’s no middle ground. This is why V.C.s like to talk about “grand slams” and “moon shots”; Peter Thiel says that a fund’s top investment should generate returns so spectacular that it will outperform everything else in the fund put together.

This, clearly, isn’t the kind of logic that has much use for steady, incremental growth, to say nothing of a flourishing middle class. You might therefore wonder about the “social impact” of venture capital, which Mallaby deems to be, on the whole, good. He concedes that “V.C.s as individuals can stumble sideways into lucky fortunes,” or can sometimes do unhelpful things. But he is ultimately bullish on what they have to offer: “Venture capital as a system is a formidable engine of progress — more so than is frequently acknowledged.” That engine, Mallaby reminds us, has funded such ventures as the development of synthetic insulin and, more recently, plant-based alternatives to ecologically damaging meat.

. . .

He gives examples of the different kinds of funds, with their various personalities and philosophies. There are V.C.s who see it as their role to act as mentors and coaches to inexperienced founders. There are V.C.s who insist on installing seasoned outsiders at start-ups to serve as C.E.O.s. There are also “founder-friendly” V.C.s, who promise to be hands-off, allowing genius, no matter how unorthodox or weird, to do its work.

For the full review, see:

Jennifer Szalai. “BOOKS OF THE TIMES; A Funder-Friendly Look at Venture Capital.” The New York Times (Tuesday, February 1, 2022): C4.

(Note: ellipses added.)

(Note: the online version of the review has the date Jan. 31, 2022, and has the title “BOOKS OF THE TIMES; ‘The Power Law’ Is a Funder-Friendly Look at the World of Venture Capital.”)

The book under review is:

Mallaby, Sebastian. The Power Law: Venture Capital and the Making of the New Future. New York: Penguin Press, 2022.

Venture Capital’s “Massive” Role in Funding Innovation

(p. A15) The average venture-capital fund launched in 2011 outperformed the S&P 500 by 7% per year. But that statistic understates the astronomical returns earned by a few top performers—and the mediocre returns earned by the rest. Between 1979 and 2018, the median fund underperformed the S&P 500, while the top 5% of funds nearly tripled the index’s performance.

The investor Bill Gurley, of Benchmark, describes venture capital as a “grand-slam business.” In “The Power Law,” business journalist Sebastian Mallaby argues that venture is defined by its most extravagant successes. A few deals explain the majority of returns, a few funds drive the majority of asset-class performance, a few wild ideas change the world.

Venture’s contribution to innovation and entrepreneurship is massive. Mr. Mallaby notes that between 1995 and 2019 venture-backed companies accounted for nearly half of U.S. nonfinancial IPOs. These firms are orders of magnitude more likely to launch an IPO than startups that don’t receive venture backing. The U.S. economy’s dynamism depends in large part on the Silicon Valley ecosystem.

. . .

Though the book focuses on the winners, Mr. Mallaby doesn’t shy away from criticism, especially in his description of the decline of Kleiner Perkins. The firm was successful in the 1990s, but lead partner John Doerr became more interested in virtue signaling than in profit making. He started a cleantech fund, based on a conversation with his teenage daughter about saving the planet, that put a significant dent in the firm’s long-term track record. And he embarked on a highly publicized gender-equity campaign to hire female partners, only to see some of the most talented women quit and then see the firm be sued by a disgruntled employee for gender discrimination.

. . .

In his closing words in “The Power Law,” Mr. Mallaby warns that it’s “unwise” to bet against venture. But public markets have recently turned against IPOs and other venture-backed companies, sending venture-style portfolios like Cathie Wood’s ETF into steep losses. With the IPO window closing and tech stocks selling off, some venture investors might well be thinking: “There but by the grace of God go I.”

For the full review, see:

Daniel Rasmussen. “BOOKSHELF; Chasing Unicorns.” The Wall Street Journal (Thursday, February 3, 2022): A15.

(Note: ellipses added.)

(Note: the online version of the review has the date February 2, 2022, and has the title “BOOKSHELF; ‘The Power Law’ Review: Chasing Unicorns.”)

The book under review is:

Mallaby, Sebastian. The Power Law: Venture Capital and the Making of the New Future. New York: Penguin Press, 2022.