Base Editing for Therapeutics: John Evans on The Long Run

John Evans is today’s guest on The Long Run.

John Evans, CEO, Beam Therapeutics

John is the CEO of Cambridge, Mass.-based Beam Therapeutics. The company was founded a little over three years ago to develop several types of DNA base editing developed in David Liu’s lab at Harvard University, along with an RNA base editor platform developed by Feng Zhang, at the Broad Institute of MIT and Harvard.

The gist of the idea, which John describes well, is that it’s possible to make precise gene edits with an adapted form of CRISPR technology that doesn’t need to cut out a whole disease-related gene. It can achieve a therapeutic goal by acting in an even more precise way – by finding an exact spot in the 3-billion base pair genome, and modifying a single chemical base of DNA.

Beam is seeking to put different pieces of the technology puzzle together, with different types of editing, different modes of delivery, and thinking through how these combinations make the most sense for different therapeutic indications. When does it make sense to do edits outside the body (ex vivo), and when it’s better to do the edit inside the body (in vivo)?

The company’s first two programs aimed for the clinic, BEAM 101 and BEAM 102, are for sickle cell disease and beta-thalassemia.

It’s heady stuff. As it matures and becomes closer to becoming a real thing that might become an FDA approved product, it’s likely to generate a lot of fear and controversy in the public. I asked John a bit about that toward the end of the conversation.

Before we get started, here’s a word from the sponsors of the show.


After almost half a decade of being graced by your presence, my sense of wonder and admiration for you has not waned one bit. In fact, it has only grown.”

This is an excerpt from a love letter written by Leonardo to his cells. One of several incredible love letters written by amazing research scientists to give us a glimpse into the wonderment, the beauty, and the challenges of cell research.

Join us in this exploration of a connection like no other, part of the Love Your Cells campaign.

Watch Leonardo read his amazing love letters at thermofisher.com/GibcoLoveYourCells

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Now, please join me and John Evans on The Long Run.


Meet the Climb to Fight Cancer Postdoctoral Fellow: Aleena Arakaki

I’m excited to announce that the first Climb to Fight Cancer postdoctoral fellow has been selected. This is a position designed to advance the careers of young scientists from traditionally underrepresented minority groups.

Aleena Arakaki is the first recipient of this postdoctoral award. She is a Kanaka Maoli (Native Hawaiian) woman.

Aleena Arakaki, postdoctoral fellow, Fred Hutch

Before describing Arakaki’s background and research, here’s what the program is about. This fellowship was created by generous donations in February, by the alumni of the 2019 Kilimanjaro Climb to Fight Cancer expedition that I organized as a volunteer for Fred Hutch.

That campaign raised $1.6 million for cancer research. That awesome group of 27 biotech professionals formed close bonds on a trip to Africa’s highest mountain. They stayed in touch.

When the racial justice protests swept the country last year, they wanted to do more to uplift people from underrepresented minority groups in science.

Together, we raised more than $135,000 to create this program with Fred Hutch.

This program provides funding to support a postdoc position, with an added bonus. The recipient can join one of the future Climb to Fight Cancer expeditions that I organize for the biotech community.

It’s designed to be a great way for a young scientist to advance his or her research, while also building an exceptional industry network.

Arakaki received her bachelor’s in science in Cellular and Molecular Biology, with honors, from Seattle University in 2014. She went on to get her PhD at UCSD, working in the lab of Dr. Joann Trejo. Aleena’s graduate work focused on the regulation and molecular mechanisms of GPCR activation of the Hippo pathway in metastatic breast cancer.

You can read her June 2018 publication in the International Journal of Molecular Sciences, titled “GPCRs in Cancer: Protease-Activated Receptors, Endocytic Adaptors and Signaling.” And this April 2021 paper in The Journal of Cell Sciences on “α-Arrestin ARRDC3 tumor suppressor function is linked to GPCR-induced TAZ activation and breast cancer metastasis.”

Arakaki received a prestigious HHMI Gilliam Fellowship as a grad student, and is now working as a postdoc in the Gujral Lab at Fred Hutch. She was selected by the Office of Diversity, Equity and Inclusion as a Presidential Postdoc Fellow at Fred Hutch, and her research is partially supported by the Translational Adult Glioma Grant Award from The Ben and Catherine Ivy Foundation.

Her research proposal is focused on ependymomas — cancers of the central nervous system. She’s specifically looking at YAP1 gene fusions, and whether they can be targeted with existing kinase inhibitors, including verteporfin and sorafenib combination treatment.

I’m excited to see where the research leads, and whether it will light the way for her to discover a useful new treatment for patients.


Giving Back and Experiencing Nature

Sometimes we need to get away from work, and the news, to recharge our batteries. August is traditionally that time of year for me.

I just got back from the summit of Mt. Baker (elevation 10,781 ft) in the North Cascades of Washington. It was another successful mountain trip with terrific biotech people – entrepreneur Julia Owens, investor Dan Bradbury, venture capitalist Nancy Hong, and Ardem Patapoutian (Nancy’s husband and a researcher at The Scripps Research Institute).

We were guided by Lakpa Rita Sherpa, Jangbu Sherpa and Dawa Yangzum Sherpa. They are some of the most accomplished Sherpa mountain guides in the world. Lakpa and Jangbu are good friends of mine, and were part of the guiding team on my Mt. Everest summit expedition in 2018. Dawa Yangzum is famous for being the first Nepali woman to summit K2, and the only woman of color on the all-star team of mountain athletes sponsored by The North Face.

This climb was a fundraiser for the Alpine Ascents Foundation, which supports education for 55 Sherpa schoolchildren in Nepal. Together, we raised $20,000 for the cause.

There were some challenges. We ran into 50 mph winds. We had to avoid some massive crevasses. It was a long, low-visibility day on the icy glaciers of the North Cascades. But everyone made it up and down safely, and had a wonderful time. See a couple photos (that’s me and Julia Owens on the very windy summit).

This isn’t my only outdoor adventure which mobilizes the biotech community for a good cause in 2021.

Next month, I’m taking a team of 20 biotech executives and investors on the Presidential Traverse hike in New Hampshire. We’ll cover more than 20 miles, and gain more than 8,000 feet of elevation as we cross over the summits of Mt. Washington, Mt. Jefferson, Mt. Madison and more.

This Timmerman Traverse is a fundraiser for Life Science Cares. It’s an organization that supports an array of outstanding nonprofits in the Boston area who do critical work on homelessness, hunger, job training, education and more. LSC is now expanding its model to other biotech hubs — the San Francisco Bay Area, San Diego, and Philadelphia.

Life Science Cares provides a way for the biotech community to support the most vulnerable people in our communities, and help them get back on their feet.

The Timmerman Traverse team has raised more than $479,000 so far – well on our way to smashing the $500,000 team goal. I’m proud of this group of dedicated biotech leaders, and grateful for the generous support of so many people.

If you’d like to learn more about this trip and this team, watch this 3-minute video created by SVB, the lead sponsor of the Timmerman Traverse for Life Science Cares.

Doug Fambrough of Dicerna, Katherine Andersen of SVB, Alice Pomponio of the American Cancer Society, Samantha Truex of Atlas Venture, Dave Melville of The Bowdoin Group all have powerful messages about why they’re doing what they do. Art Krieg of Checkmate Pharmaceuticals and Jeb Keiper of Nimbus Therapeutics also have potent video testimonials at the end.

You can click here to see who’s on the team, and make a contribution directly to their fundraising campaign through the JustGiving.org platform.

There is tremendous capacity for good in the biopharmaceutical industry. Let’s show it.


Vaccination and the Delta Variant: Four Steps Forward, Two Steps Back

Larry Corey, MD

The news is all about Delta, Delta, Delta, for good reason.

The variants are forcing us to ask and answer, again, a whole set of uncomfortable questions.

Sobering findings of the past few weeks have shaken both the American and scientific psyche. People have had to re-assess their perceptions about the COVID-19 vaccines, and the re-emergence of an epidemic many thought was over. Many of us have had to come to terms with how life can sometimes just be complicated.

It’s been a scientific and emotional roller coaster. In the spring, we saw the Alpha variant, which was two times more infectious than the ancestral strain. That was followed by Beta, which was eight times more resistant to laboratory assays and to neutralization with therapeutic antibodies in the petri dish. That variant was worrisome, because it was more capable at resisting vaccines. We were lucky because it was outcompeted by Alpha – a variant that the vaccines could handle.

Now Delta is here and just ripping through both of them, like a hot knife through butter. It’s replacing Beta with the same rapidity that it replaced Alpha and all the in-between variants. It’s now the dominant variant in the US, showing up in more than 90 percent of positive cases.

So, what is it about this Delta, or what I should say, many Deltas?

What we’re seeing is this scientifically fascinating, but epidemiologically disconcerting change in the virus that’s happened at an incredibly rapid pace. Delta has some new characteristics which make it a formidable foe. It’s much more infectious to others; initial viral loads in the nose seem to be somewhat higher than previous strains with more rapid spread into the lungs and other organs within the body.

It is clear that the amount of virus required to infect others is lower, making transmissibility to household and casual contacts more efficient than the other variants. The average person who contracts a Delta infection transmits the virus to between 5 and 9 other people – making this variant far more infectious than the original ancestral strain from a year ago.

Case numbers, predictably, are quickly increasing. Younger adults are being hospitalized. ICUs are filling up. Most disconcertingly, we are seeing more children being admitted in our pediatric hospitals. When we look at who’s in the hospital among adults, we see about 95 to 98% are unvaccinated. The same pattern is seen with children. COVID-19 Delta strain is a hospital epidemic of the unvaccinated.

Yes, we are now seeing outbreaks of Delta in which vaccinated people are infected, such as the one from early July in Provincetown, Massachusetts. These outbreaks involve two behaviors we’ve seen that result in super-spreader events—crowding and indoor revelry with drinking and eating and no masks. Eating, drinking, shouting, singing—spraying forth, shall we say, produce a density of unseen viral particles in the air that people inhale over and over again.

These behaviors are the food of the virus—a heavy smorgasbord of food: all advantageous to the virus. The result is that we are seeing humans get infected. For the vaccinated, this means just mild infection. But for the unvaccinated, we are seeing rapid spread of the virus to the lungs and other parts of the body.

With more than 100,000 cases a day being tallied nationwide, it’s clear we need to take some new countermeasures to slow the spread.

We’ve seen a necessary reintroduction of masking. Just when many people were ready to celebrate, or breathe a sigh of relief, many of us are now back in an anxious position. Questions that we might have thought were settled a month ago are suddenly back in play.

Will our children be able to safely go back to school? Can we safely go back to work? Will we ever be able to relax and enjoy dinner indoors again with friends, extended family, or in professional settings?

Delta is disconcerting to all of us.

Last week, I cancelled a CoVPN (COVID-19 Prevention Network) scientific meeting in October—one that I’d been eagerly planning and anticipating for months. We wanted to meet and celebrate/review the work the network has done in developing effective COVID-19 vaccines at unprecedented, record-setting pace.

The success of the program and the hard work and toil have shaped the careers of many scientists on this team. In some ways, it has shaped entire worldviews. We wanted to revel in the camaraderie of the team’s success and do so in person. But it was clear—even though the event required vaccination to attend, no one wanted to come to Seattle to celebrate with the possible risk it would carry if anyone contracted Delta and had to be quarantined away from home.

Let’s look at vaccination and Delta as it relates to the US:

  • The mRNA and Janssen vaccines both are highly effective against death and hospitalization (greater than 90 to 98%).
  • The protection from getting symptomatic COVID-19 appears to be a bit less with the Delta variant—studies show a range from 85% to 40%–and this may differ by time post vaccination. But in all studies the severity of illness is markedly less—the immune system of vaccinated persons can rapidly clear Delta. As noted above, severe disease among the vaccinated in the US with the mRNA or Janssen vaccines is rare.
  • Transmission to others from vaccinated persons can occur, but it is less than from the unvaccinated population, although we have not yet demonstrated how much less.

So, yes, one can still get infected with Delta despite being vaccinated if one doesn’t use precautions. That’s a fact. But a bigger fact is that you won’t get very sick, and you can reduce the risk of acquiring COVID-19 and spreading it if you wear a mask.

Perhaps we shouldn’t have been surprised. We understood that reducing acquisition of COVID-19 was a harder goal than ameliorating disease. But we do know the vaccines work and countless lives have been saved by them. So, the vaccines have markedly changed the dynamic of our thought process, but maybe what we need is to change our expectations.

What do I mean by that?

Well, the virus is teaching us another important lesson—its amazing speed to adapt. It’s hard to understand how a virus like this is rolling through the world. But rolling through, it is. Recent data out of Israel estimates that every six to nine days the Delta infection among its population doubles. As Israel has the highest percent vaccination rate (with Pfizer/BioNTech mRNA) of any adult population in the world, this is at first glance surprising. However, not when one recognizes that younger people are not yet vaccinated, and it’s the unvaccinated who are the main fuel for that kind of rapid spread.

Why is it so transmissible? What selective pressure is it under? Delta doesn’t have the obvious neutralization-resistant mutations. What part of the human immune response that you get from vaccination is being delayed by the Delta variant? Will boosters actually slow it down or is it really more important to focus our efforts on reaching the unvaccinated?

These are all scientific questions needing answers. As Israel has made the decision to boost its elderly population, some data about the role that boosting can play in reducing spread will be obtained.

But the boosting issue is a bit of a diversion from the main issue in our country, which is, how do we reduce the spread of this highly infectious variant? 

Do we need a national mandate for vaccination? Is it a personal choice to vaccinate or not? Or do we all have a societal obligation to not be the fuel to this ongoing forest fire? The unvaccinated in some respects are an unsuspecting accomplice to the arsonist at large—they serve as bone-dry tinder for the lighted match.

Should we rethink this?

Our body politic is focused on extreme individualism, and isn’t allowing a universal approach to public health. In such an environment where political leadership is limited, do our corporate leaders who can mandate vaccination step up to the plate?

There are some who are pointing to government action, namely through a full approval of the vaccines by the FDA. But does anyone really believe that the Emergency Use Authorization is that much different than the FDA licensing it under a full Biologics License Application? Yes, there are important steps to licensing the medication so that there is consistency from lot to lot in manufacturing. But at 400 million vaccinated and growing daily, we have ample safety and efficacy data.

So, yes, official product licensure is, to this author, not an appropriate reason to hold back mandated vaccination. We already know the vaccines are extraordinarily effective, and powerful tools for fighting back against the pandemic. Each day the documentation of the positive effect of the vaccines grows, and we understand that the virus is continuing to mutate. Cutting off the fuel to the fire is really the only way to slow down the rate of mutational alterations.

It is true that the Delta variant has swept in like a cold, damp morning shrouded by fog. And it’s left us with a bit of a shiver. But like all days, morning turns to afternoon and the sun gets higher in the horizon and some of the fog lifts. Although Delta has taken us two steps back, a much more important step forward is to continue to vaccinate as many of our citizens as we can – here in the US and around the world.

Once we do, Delta may move itself two steps back, putting us once again two steps forward toward pre-COVID-19 normalcy.

Dr. Larry Corey is the leader of the COVID-19 Prevention Network (CoVPN) Operations Center, which was formed by the National Institute of Allergy and Infectious Diseases at the U.S. National Institutes of Health to respond to the global pandemic and the Chair of the ACTIV COVID-19 Vaccine Clinical Trials Working Group. He is a Professor of Medicine and Virology at University of Washington and a Professor in the Vaccine and Infectious Disease Division and past President and Director of Fred Hutchinson Cancer Research Center.


Better Cancer Drugs for Kids: Julie Grant and Sam Blackman on The Long Run

Today we have a pair of guests on The Long Run — Julie Grant and Sam Blackman.

Julie Grant, co-founder, Day One Biopharmaceuticals; general partner, Canaan Partners

Julie is a venture capitalist – a general partner at Canaan Partners. Sam is a pediatric oncologist and drug developer. After a routine business meeting, they realized they had something in common. They both believed that the pharmaceutical industry can — and should – find a way to do a better job of developing cancer drugs for kids.

So they did what scientific entrepreneurs do. They took a gamble, and tried to figure out how to do something that hadn’t been done before. They poured a lot of time and energy into fleshing out a concept of a purpose-built precision oncology company that puts the needs of children first. That concept became San Francisco-based Day One Biopharmaceuticals. Julie is the board chair, and Sam serves as chief medical officer.

Sam Blackman, MD, PhD; co-founder and chief medical officer, Day One Biopharmaceuticals

I wrote about the company a couple times for Timmerman Report a couple times before it went public, and subscribers can go back and read those articles from May 2020 and February 2021. The company now has a market valuation of more than $1.5 billion on the day of this recording. Side note here–if Day One is successful, its work could spill over and benefit adult cancer populations as well – but I digress.

Julie and Sam are creative, tireless people committed to helping kids with cancer. I think you’ll enjoy hearing them talk about this new journey in applying science for the betterment of human health.

Before we get started, here’s a word from the sponsor of The Long Run.

After almost half a decade of being graced by your presence, my sense of wonder and admiration for you has not waned one bit. In fact, it has only grown.”

This is an excerpt from a love letter written by Leonardo to his cells. One of several
incredible love letters written by amazing research scientists to give us a glimpse into the wonderment, the beauty, and the challenges of cell research.

Join us in this exploration of a connection like no other, part of the Love Your Cells

Watch Leonardo read his amazing love letters at thermofisher.com/GibcoLoveYourCells.

Now please join me and Julie Grant and Sam Blackman on The Long Run.


Tachi Yamada, Physician-Scientist-Biopharma Industry Leader, Dies at 76

Tadataka “Tachi” Yamada, a distinguished physician-scientist who became a biopharmaceutical industry leader and a deeply respected advisor to biotech entrepreneurs, died the morning of Aug. 4. He was 76.

Tachi Yamada

Yamada died from a heart attack while exercising at home in Seattle, said his son, Takao.

“He was a special person who did things to help people. That was his North Star,” his son said.

Yamada was a rare leader with experience in several dimensions of the scientific enterprise – academia, industry, and philanthropy. He was best known for high-profile roles later in his career as the chairman of R&D at GSK, the president of the $9 billion global health program at the Bill & Melinda Gates Foundation, and then as chief medical and scientific officer at Takeda Pharmaceuticals.

Those jobs came after Yamada made an early mark as a physician-scientist, specializing as a professor of gastroenterology at UCLA and then at the University of Michigan. He was elected by peers to National Academy of Medicine in 1994, around the time he made the move to the pharmaceutical industry.

Over the past 25 years, Yamada accomplished a series of things that will last. He built up GSK’s vaccine business to combat rotavirus and shingles and other infectious diseases. He further invested in vaccines at Takeda, including vaccines for dengue and norovirus. He helped transform Takeda from a regional pharmaceutical company into a top-tier global pharma R&D enterprise, serving as an important champion of vedolizumab (Entyvio) for Crohn’s and ulcerative colitis — a blockbuster product.

More recently, as an advisor to small companies, Yamada helped launch the Philadelphia-based gene therapy company Passage Bio with longtime friend and colleague Jim Wilson of the University of Pennsylvania, as well as Florham Park, NJ-based Phathom Pharmaceuticals, a developer of gastrointestinal drugs.

Many colleagues were shocked and in mourning over the death of such a healthy and vibrant man.

Andy Plump, president of R&D, Takeda Pharmaceutical

“He was the embodiment of life,” said Andy Plump, the president of R&D at Takeda who took over when Yamada left in 2015. “He took care of himself. Ate well. Exercised, literally every day.”

As a business leader, Yamada “was really, really smart. Very sharp. Extremely experienced,” Plump said. “He was tough. He had a vision and was not shy around that vision and really driving something he believed in.”

“I’m heartbroken,” said Thong Le, the CEO of Accelerator Life Science Partners in Seattle, who recruited Yamada to join his board of directors seven years ago. “It wasn’t his time. He was still doing so many great things…no matter how complicated the situation, he got to the nub and knew what needed to be done. He’s one of those few guys with a unique mix of understanding the medical need and all the business and technology challenges that go with developing a new treatment.”

Thong Le, CEO, Accelerator Life Science Partners

Bruce Goldsmith, the CEO of Philadelphia-based Passage Bio, a gene therapy company where Yamada was chairman of the board, was in grief.

“He put a lot of faith in me as a first-time CEO. He always gave me the support I needed to work independently, to build the company independently, but that wouldn’t mean he wouldn’t give me critical comments to think about…once he decided to invest in a person…I saw a massive amount of commitment from him. When there was uncertainty, questions as there always are, he’d set aside time constantly to make sure we’d figure it out.”

Yamada’s life journey started in Japan. He was born in Tokyo on June 5, 1945, just before the end of World War II. He moved to the United States as a boy and attended Phillips Academy in Andover, Mass. before going to Stanford University, where he majored in history.

After getting his medical degree at New York University, he did his internship and residency in Richmond, Virginia, followed by a three-year stint as a major specializing in infectious diseases at the US Army Medical Research Institute of Infectious Diseases. He spent the next 20 years as an academic gastroenterologist, starting at UCLA and then building one of the nation’s leading departments at the University of Michigan.

He sought new opportunity to help patients through industry at SmithKline Beecham in 1994, starting in a non-executive director position. He quickly worked his way up, ultimately overseeing one of the industry’s major R&D engines at GSK in the early 2000s, following a megamerger with Glaxo Wellcome.

Yamada saw a new opportunity in 2006 to take over the global health program at the Bill & Melinda Gates Foundation. The world’s largest private philanthropy was ascendant on the global stage, flush with cash from Warren Buffett, and in position influence global health priorities around fighting tuberculosis, malaria and HIV. He stayed five years before moving back to industry.

At Takeda, Yamada was able to use his accumulated experience to help position the company to make a bigger global impact.

At the time, Takeda was fragmented across four organizations – Takeda Japan, the TAP Pharmaceuticals joint venture between Takeda and Abbott, the Millennium Pharmaceuticals team in Cambridge, Mass., and Nycomed in Europe. “He started a process, a fairly challenging process, of consolidating activities,” Plump said.

Yamada worked closely with then-Takeda CEO Yasuo Hasegawa to bring the far-flung operations together, implement more disciplined decision-making processes, and step up its game in science, Plump said.

When Hasegawa stepped aside and Christophe Weber came in as the first non-Japanese CEO of the 200-year-old company, Yamada, about 70 at the time, played an important role in keeping the transition on track until it was time for Weber to bring in a new R&D chief he could work with for the next decade. “Tachi bridged between them [Hasegawa and Weber] and lit the flames of cultural change in R&D,” Plump said.

“Few people can lead in so many different capacities as he did — in academia, in the NGO world at the highest level, and two times in pharma at the highest level in R&D,” Plump said.

The last chapter of Yamada’s career was a whirlwind. He served as chairman of the board at Phathom Pharmaceuticals, Passage Bio, and Athira Pharma. He served on the boards of a number of other small companies, partly through his relationship with Frazier Healthcare Partners.

The Frazier relationship provided an avenue for him to help a number of entrepreneurs across disciplines. The work there dated back to his time at the Gates Foundation. He stepped away from Frazier during his time at Takeda to avoid conflicts, and then returned as a venture partner in 2015.

It was an opportunity to paint on a broader canvas across the startup community, and to pick the people and projects he felt passionate about.

A day after the announcement that he was leaving Takeda, Le happened to have a pre-scheduled meeting. He walked in and got straight to the point. “Hey, I saw the announcement, and I’m sure 100 people will ask you the same thing. But I need your help,” Le said.

He asked Yamada to join his board.

“He chuckled, like he always does,” Le recalled.

Then came an unequivocal answer.

I haven’t figured out what to do with my time, Yamada told Le, “but I believe in you. Of course, I’m going to help you.”

Le was a bit choked up re-telling the story, knowing how many doors Yamada opened, and how much his committed counsel helped keep things moving forward for Accelerator. “I feel like I’ve lost a mentor, and almost like I’ve lost a father,” Le said.

Yamada, for instance, played a key behind-the-scenes role in Accelerator’s successful sale of Rodeo Therapeutics to Amgen earlier this year. (TR coverage, Mar. 2021).

Jamie Topper, managing partner, Frazier Healthcare Partners

Jamie Topper, managing partner at Frazier, said the firm was eager to have Yamada re-engage the last six years. Phathom and Passage are a couple of the portfolio companies that he helped ignite.

“Tachi is a polymath. As far as I can tell, he worked 22 hours a day, 7 days a week,” Topper said. “When he was looking at an area, he read widely in that area. He would know everything from the basic science to the clinical relevance. He lived and breathed medicine his entire career. He was a man of breadth and depth. He brought a compassion for patients and the families of the patients.”

Stylistically, Yamada was poised. He could come across as mild-mannered and soft-spoken. A man who would choose his words carefully, and speak succinctly.

“One of my favorite things about Tachi is that he was always very direct. He would do it in a polite and respectful way. If he disagreed with you about something, he could disagree and it would remain civil,” Topper said.

Le, of Accelerator, spoke of that same directness. Yamada would listen carefully and absorb information. He would also suffer no fools. “He could cut the BS and get right to whatever was most important,” Le said. “It’s such an important skill in today’s world with so much information. Knowing what to focus on can mean the difference between success and failure.”

Goldsmith of Passage Bio said he was struck by a certain agility of mind.

“You can have these big strategic overarching vision conversations with him, and then these really detailed operational conversations. He could back and forth, and it was his experience that enabled him to go back and forth. We could talk about where we should go and how to get there,” Goldsmith said.

Bruce Goldsmith, CEO, Passage Bio

Not every polymath is known for personal warmth, but those who know Yamada said he radiated that, too.

Le said that when having a meeting, Yamada would often invite him to come sit down on a couch beside him, instead of from an imposing chair behind a desk.

Goldsmith said Yamada once told him, as the senior person in the company, it’s good to always show up 1-2 minutes purposely late for a meeting so that no one on the team would feel bad for showing up late and potentially irritating the boss. It was a subtlety, but it worked, Goldsmith said.

Plump recalls traveling to Japan and waking up at the hotel, jet-lagged, and heading down to the gym at some odd hour like 3 am or 4 am or 5 am. Always, he’d see Yamada already there doing his workout. Over 30 years, Yamada told him, he’d taken two days off from his physical fitness routine.

Yamada’s favorite drink was always an ice-cold green tea. It helped him stay fresh and energized for the work. He avoided alcohol. Those consistent, disciplined habits — of body and mind — were part of what made Yamada successful. Among the many bits of advice he gave his successor, Plump remembers the part about not getting worn out. “Take care of yourself,” Yamada said. “Because the things you’re going to have to do will be stressful at times.”

Another key piece of advice from Yamada: “Everyone you work with will have something positive to offer. You need to find out what that is, and position them best so they can provide that.”

The two men had many dinner meetings during the transition at Takeda, and Yamada enjoyed discussing his family and introducing them. Goldsmith noticed the same thing – no matter how focused or intense a meeting might have been, Yamada had time at the end to talk about life, family, what was new and interesting.

Plump shared one last story. Once, when he was stuck in traffic and running 30 minutes late for a meeting with Yamada, he felt terrible and apologized profusely upon arrival.

Yamada, the picture of discipline and poise, shrugged it off, and told him not to worry. Yamada had spent the time with four different newspapers open in front of him, absorbing information from different sources and perspectives.

Plump took note. There was a scientific executive always seeking to learn, always seeking to understand, always synthesizing different perspectives. A man on a quest to get to the heart of the matter, and to advance human health.


An Industry that Depends on Diversity Should Defend It

Paul Hastings, CEO, Nkarta Therapeutics

[Editor’s Note: I asked Paul to write in response to a biotech executive who’s marketing a new book that claims diversity and inclusion in business is “the defining scam of our time.”]

As CEO of a cell therapy company, I know that the human immune system is a pointillist masterpiece, containing trillions of B and T cells with unique antigen receptors that allow them to latch on to and neutralize endless permutations of potential threats.

Within the human body, our diversity is – quite literally – our greatest strength.

The COVID-19 pandemic, for all the tragedy it has wrought, helped ignite two long-overdue conversations in America: one about health equity and another about the value of diversity and inclusion in a time of heightened attacks against those who identify, look or love differently.

In so many ways, biopharma CEOs sit at the intersection of both this new disease and this new dialogue. I know many CEOs and industry leaders who have been championing diversity and inclusion long before it was as popular to do so, but I celebrate the current focus on addressing systemic barriers. As a an openly LGBTQ CEO and a longtime warrior in the diversity trenches, I’m endlessly proud that a growing majority of my biopharma CEO colleagues are embracing this leadership role.

Some critics don’t believe that advocating for diversity and inclusion is in the job description of biotech CEOs and dismiss our efforts as “woke” and insincere.

Here’s what I believe: To lead a company charged with creating “living” biologic medicines in 2021 is to understand, as a fundamental matter of science, the life-sustaining value of biological diversity. The value of diversity is equally self-evident when we look up from our lab benches and look out at our colleagues around the conference-room table.

To create a culture of innovation, experience as a five-time biotech CEO has taught me to insist on teams full of people with different backgrounds, experiences, perspectives and ideas. CEOs who fail to proactively seek out such synergies aren’t just “unwoke”. In my opinion, they’re asleep at the wheel.

The truth is, some biopharma leaders have hit the snooze button for far too long on diversifying clinical trials, on building inclusive leadership teams, on hiring outside of homogenous comfort zones and on assembling culturally competent teams that can understand and meaningfully connect with underserved patient populations.

Now, from the ashes of the COVID and George Floyd tragedies, progress has a chance. There is no filibuster in the biopharma C-suite. Industry CEOs have great power to effect change and be part of an industrywide effort to invest in health equity to regain public trust and affection.

We are in the midst of a paradigm-shifting global pandemic that preys on the immunocompromised, the underinsured and the unseen. Conversations are changing. Companies are engaging contract research organizations to amplify efforts to reach diverse populations. Health equity and Corporate Social Responsibility (CSR) budgets are becoming more substantial line items. Investors now demand it.

The biotech industry is charting a more compassionate, inclusive, patient-focused course, one Zoom meeting at a time. If dedicating time and resources to achieve that kind of overdue progress is “woke,” I don’t ever want to go back to sleep.

Paul Hastings is the CEO of Nkarta Therapeutics in South San Francisco.


Career Arc of a Biotech Leader: Sue Desmond-Hellmann on The Long Run

Today’s guest on The Long Run is Sue Desmond-Hellmann.

Sue — and I don’t say this about many people — is a biotech industry legend.

Sue Desmond-Hellmann

Sue is an oncologist and a public health professional by training. She made her name in biopharmaceuticals at Genentech from 1995-2009 — the glory days when it became the world’s most important developer of new cancer drugs.

She was part of the leadership team when the company developed the original targeted antibodies for cancer – Rituxan, Herceptin, and Avastin.

After Genentech, Sue served as chancellor of UCSF, and then worked as CEO of the Bill & Melinda Gates Foundation until January 2020.

Currently, among other things, Sue is a board member for Pfizer, and is an advisor to GV, the venture capital firm formerly known as Google Ventures.

In this episode, we talk mostly about Sue’s early career – growing up, becoming a doctor, working on the frontlines of the AIDS epidemic, and finding her way into industry. We talk some toward the end about her time at Genentech.

Before we dive in, a word from the sponsor of The Long Run.

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The SYNTAX System prints DNA, on-demand, right in the lab. Researchers simply import their sequences, and within hours the system synthesizes DNA oligos that can be used immediately in molecular biology and genomics workflows.

DNA Script’s enzymatic DNA synthesis emulates nature to overcome the drawbacks of the chemical-based methods traditionally used until now. Designed for fully automated, walk-away synthesis, the SYNTAX System takes less than 15 minutes to set up with no special training to operate.

With SYNTAX, researchers can accelerate discovery with DNA on-demand.

For more information on DNA Script, please visit www.dnascript.com.


Now please join me and Sue Desmond-Hellmann on The Long Run.


Why We Need mRNA Vaccines in Africa, and For All Who Are Immunocompromised

Larry Corey, MD

The HIV pandemic, and COVID-19 pandemic, are intersecting.

The relationship between the two conditions is creating an epidemiological synergy that is starting to translate into additional misery for humankind.

If we can better understand this phenomenon, we can think more clearly about how to better protect the most vulnerable populations among us – people with HIV, and millions of others who are immunocompromised. We have seen overlapping epidemics before, and can draw from that experience.

Let’s start with HIV. Individuals living with HIV have a degree of immunosuppression which varies based on their therapy and disease course. If the disease course is well controlled and fully virologically suppressed on antiretroviral therapy, there is evidence to believe that these patients are at a normal risk of acquiring and controlling COVID-19, much like others in their families and communities.

This analogy is partially accurate in that those living with HIV can, because of their medicines, have obesity, diabetes, and increased lung disease, which are all predispositions or comorbidities associated with severe COVID-19.

Importantly, there are subsets of persons living with HIV, including those who are immune deficient with low T cell counts, those with viremia due to drug-resistant HIV viral strains, those not receiving or not taking antiretroviral therapy; and the many millions we know are living with undiagnosed HIV infection, including those recently infected.

These persons are subject to acquire persistent, prolonged COVID-19 infection, akin to organ transplant recipients and severely immunosuppressed cancer patients.  

There are many causes of immune deficiency, but in many countries, HIV infection is among the most common.

A recent case report by Karim et al. from South Africa, the country with the largest percentage of the population living with HIV of any country, described a case of HIV infection in a person who had very low CD4 counts due to resistant virus and a lack of compliance who developed COVID-19. Over a period of 200 days, this patient—who was ambulatory, living in the community, and without serious symptoms—shed COVID-19. The person had mild illness early on, which is why they were observed, and because of HIV, follow-up care ensued. The investigators had samples from the patient, and they shed COVID-19 at high titers, showing the development of multi-mutational changes in the virus over time. Mutational changes that essentially recapitulated the Beta variant, which has 9 to 11 different mutational changes from the original ancestral strain.

This is a single case, but it’s important because it illustrates a broader issue at work in our communities.

Individual patients living with HIV and compromised immune systems who have this prolonged shedding pattern can result in the kind of mutational changes that lead to germination and spread of variants of concern.

This case is illustrative because it’s not rare. Out of the estimated 38 million people living with HIV worldwide, South Africa alone has more than 16 million. In South Africa, that means one out of every four of its 65 million people are living with HIV.

So okay, the two epidemics are intertwined, what’s the concern? The concern is that these people will suffer more serious COVID-19 cases and that they may serve as the potential unwitting source of super-spreading events of new variants through household and community contacts.

As the greatest population of persons living with HIV is in sub-Saharan Africa, where vaccination rates are currently less than 2% of the populace, this continual reservoir of variant generation is and should be of concern to all of us. We need to recognize that we do not have a demonstrably effective vaccine against COVID-19 among persons living with HIV. People with immunocompromised profiles weren’t included in the well-controlled vaccine studies of the past year, when speed of enrollment was of the essence (see June 29 article in Timmerman Report).

While we lack comprehensive data, we have good reason to be concerned about vaccine efficacy in immunocompromised groups. The data that we have from the Novavax study in South Africa showed absolutely no efficacy against COVID-19. In the Ensemble Johnson & Johnson (J&J) study, too few cases were acquired to adequately evaluate the effectiveness of the one-dose J&J vaccine. And in the Moderna trial, no cases of COVID-19 were reported in the 150 HIV+ recipients who received vaccination. The reason for the lack of efficacy of the Novavax vaccine is puzzling and worrisome, as the post-vaccination binding antibody titers were well above natural infection and in the range associated with reasonable efficacy (median 33,000).

So, what’s going on here? The answer is, I don’t know the reason for lack of effectiveness, but I do know that the mRNA vaccines offer the most immediate solution to this major hole in the public health control of COVID-19 variants.

The data suggest that we need to take our most potent vaccines—mRNA or perhaps two doses of the J&J vaccine or a heterologous “mix-and-match” prime-and-boost with one of the vaccines being an mRNA vaccine—into areas of the world where there is HIV.

We need to urgently take steps to evaluate if our best vaccine regimens are able to effectively prevent acquisition of COVID-19 in all persons living with HIV, but especially among those with uncontrolled HIV.

This is the kind of urgent, heavy lifting that only the US government can do in an emergency.

The tale of these two intersecting epidemics needs a better ending than what we—as a global community—are currently creating. The Delta variant epidemic is rapidly illustrating that chasing variants is not a successful strategy. The Delta variant has swept through countries like the UK, Israel, and South Africa in four to eight weeks and is approaching the predominant variant in the United States at a speed that even with RNA technologies, we cannot keep up. Our approach must be to slow down the generation of these rapidly doubling super-spreading micro-epidemics of infection among unvaccinated persons.

The equation today among those unvaccinated individuals is not whether you will get COVID-19 infection but when you will get it. Slowing it down requires our best vaccine strategies. It’s certainly not too late. But we need both studies and implementation of our most potent vaccines and vaccine regimens to be applied to all of our immunosuppressed populations, the largest of which is HIV, for us to have a globally effective strategy.

Dr. Larry Corey is the leader of the COVID-19 Prevention Network (CoVPN ) Operations Center, which was formed by the National Institute of Allergy and Infectious Diseases at the U.S. National Institutes of Health to respond to the global pandemic and the Chair of the ACTIV COVID-19 Vaccine Clinical Trials Working Group. He is a Professor of Medicine and Virology at University of Washington and a Professor in the Vaccine and Infectious Disease Division and past President and Director of Fred Hutchinson Cancer Research Center.