UK artificial intelligence company Exscientia has added another big pharma company to its partner roster, with Bayer seeking to use its platform to find new cardiovascular and cancer drugs.
Bayer is pledging up to €240 million ($266 million) in upfront fees, ongoing research funding and clinical milestone payments under the terms of the three-year deal.
The collaboration will use AI to accelerate discovery of small molecule drug candidates against targets in oncology and cardiovascular disease, with Bayer claiming rights to the compounds and Dundee-based Exscientia eligible for royalties on sales if they reach the market.
Cancer and heart disease are at the forefront of Bayer’s R&D focus along with women’s health, haematology and ophthalmology.
For eight-year-old Exscientia, Bayer joins a growing list of drugmakers who see its AI platform as a way to accelerate drug discovery and improve drug development productivity, potentially trimming years off the current 12 to 15 year cycle from early research to marketed product.
It has similar pharma partnerships with Bristol-Myers Squibb’s Celgene unit, Sanofi, GlaxoSmithKline, Roche and Sumitomo Pharma, as well as co-development alliances with smaller biotech players including Evotec, Apeiron and Rallybio.
Some of those partnerships are already generating candidates for further development and potentially entry into clinical testing, and the total value of the deals has climbed well in excess of $1 billion.
Last year, Sanofi took up an option on a bispecific small molecule coming out of an alliance focusing on inflammatory and fibrotic disease, and the UK biotech also delivered a lead molecule for GlaxoSmithKline targeting a novel pathway for the treatment of chronic obstructive pulmonary disease (COPD). Both projects started up just two years earlier.
Bayer’s head of R&D Dr Joerg Moeller said the deal was part of a drive towards digital transformation of R&D, “as we believe that digital technologies such as AI can simplify and speed up the discovery and development of new drugs for patients.”
Deploying an AI approach can speed up projects but also provide “more precise identification of suitable drug targets and lead structures,” he added.
Deloitte’s Centre for Health Solutions estimated at the end of 2018 that the projected returns on investment in pharma R&D have fallen to 1.9%, the lowest level since 2010.
The 38th annual JPMorgan Healthcare Conference, which is tipped off as the biggest health care investment symposium, kicks off Monday in San Francisco, California.
From the high and mighty to the smallest of nanocaps, biopharma and health care companies have scheduled presentations at the four-day event. It’s a no-brainer that the presentations will move stocks and serve as key catalysts for respective companies.
BofA Securities analyst Geoff Meacham expects investors to be acutely focused on 2020 expectations and the potential to maintain the positive momentum of 2019’s year-end rally. The analyst is bracing for a conservative tone from larger-cap names, given the moderate but improving growth expectations that would offer scope for multiple guidance revisions throughout the year.
Meacham expects discussions at the conference to be focused on value creating themes such as expanding indications, new product cycles, especially with oncology, inflammation & immunology and orphan diseases and advancing innovation in gene/cell therapy.
“Combined with the unlikelihood of near-term major structural reform and P/E ratios that now lag improving expectations, we remain positive on the sector and the outlook for multiple expansion, with greater generalist participation,” Meacham wrote in a note this week.
Here’s what BofA expects from some key presenters in its coverage universe.
Bristol-Myers Squibb, which completed the acquisition of Celgene late last year, is likely to give at least partial guidance. Meacham believes 2020 guidance could be an early positive driver of shares.
The analyst expects Vertex to provide fourth-quarter update on its cystic fibrosis agent Trikafta, with the analyst expecting sales of $223 million, well above the consensus estimate of $64 million.
BioMarin could delve on the commercial opportunity of valrox and vosoritide following the filing for the former and positive Phase 3 data for the latter.
Regeneron is likely to release fourth-quarter sales of Eylea. Given Eylea’s declining growth, Meacham said the focus could shift to Dupixent, which remains a key P&L driver.
BofA expects Biogen to specify the timing of its aducanumab regulatory filing, if it hasn’t been already submitted. The company could also announce a settlement with Mylan NV MYL 0.38% over the Tecfidera intellectual property right.
Meacham expects Alexion to focus on its portfolio diversification strategy, especially due to pressure from activists and competitors. Updates on ALXN1830 and anti-Factor D ACH-5228 is likely.
Meachem expects Amgen to discuss the integration of Otezla into its I&I franchise, update the status of assets in its oncology pipeline and give its expectations for the launch of its biosimilars.
Biotech is celebrating a platinum anniversary next week: 20 years since J.P. Morgan took over the industry’s biggest conference, an annual ritual of brokered mergers, broken promises, and breakthrough science.
The J.P. Morgan Healthcare Conference is more than a venue for deals. It’s a place where fierce arguments break out, where industry memes get made, and where biotech examines its warts and wrinkles.
With that in mind, STAT decided to look back at the record. What emerged was not just a series of recollections about a conference, but the history of an industry, chock-full of lessons about management, leadership, and communication. Over the past two decades, many of the biggest heroes and villains in the pharmaceutical industry have graced the stages of the Westin St. Francis Hotel in San Francisco, where the conference has been held since it began 38 years ago under the auspices of Hambrecht & Quist, a now largely forgotten investment bank.
J.P. Morgan’s tenure started when the current crop of pharmaceutical giants were only just being created in a consolidation wave. The conference witnessed the 2000s crisis around drug safety, the era’s big biotech boom, and the birth of a thriving sector. And today, for better or worse, it is still where the action happens.
Here, then, are some specters from JPMs past.
2000-2001: The beginning and end of the genome boom
Genetics at the turn of the century felt like an insurgence. At H&Q in 2000, Roy Whitfield, the CEO of a tiny startup called Incyte, bragged that his company had “revolutionized drug target discovery,” adding: “We have sequenced, patented, and broadly licensed more genes than anyone else in this first critical phase of the genomics revolution.”
Incyte’s stock price quadrupled in the first few months of 2000, giving it a market capitalization approaching $8 billion. Other gene database companies similarly saw enormous appreciation. Mark Levin, the CEO of Millennium, boasted the company’s genomic platform would deliver an approvable drug every year. In May 2001, Celera, Incyte’s highest-profile rival, was feted on the White House lawn for its role in sequencing the first draft of the human genome.
And, then, Wall Street soured on genomics stocks, as the whole market plummeted. Investors realized that the business of selling genetic data was far less lucrative than they had thought. In 2001, Incyte hired former DuPont Pharmaceuticals CEO Paul Friedman to turn it toward drug discovery, shifting the company into its current form.
2002: ‘We screwed up’
It was the start of one of the most sensational scandals in biotech history — and the chain of events that would send domestic doyenne Martha Stewart to jail. A haggard-looking Sam Waksal, the chief executive of ImClone Systems, entered the meeting room at the Westin St. Francis hotel to face an overflow crowd of seething investors.
Two weeks earlier, the Food and Drug Administration had rejected ImClone’s groundbreaking colon cancer drug Erbitux. For years, a cocksure Waksal had promised Wall Street that Erbitux would be approved quickly and deliver billions of dollars in sales.
”How did we get in a situation where I’m standing here trying to explain how we got a [refusal-to-file] letter in an indication where nothing else worked?” Waksal asked, according to press reports at the time. ”We screwed up.”
J.P. Morgan had opened two overflow rooms for investors and others to hear Waksal and piped in audio. What they learned was that ImClone had ignored repeated FDA warnings about certain Erbitux data.
From that first, damaging disclosure, the scandal only got worse. Waksal was ousted as CEO. He was arrested and charged with tipping off friends — including Stewart — and family in the days before the Erbitux news was made public. He pleaded guilty to insider trading and bank fraud, and spent five years in federal prison.
2003: Bulls, bears, and wire fraud
In 2003, JPM attendees gathered for a standing-room-only breakout session to hear from InterMune.
The company was engaged in a brazen off-label marketing push, trying to get an old drug called Actimmune used as a treatment for idiopathic pulmonary fibrosis, a serious and deadly lung disease. InterMune CEO Scott Harkonen claimed the drug helped IPF patients live longer — based on selectively parsed data. Critics, including short sellers, argued that Actimmune was nothing more than a toxic placebo.
Six months later, Harkonen had resigned. Years later, he was arrested and convicted by federal prosecutors for wire fraud related to the dissemination of false and misleading statements from the Actimmune clinical trial.
2004: Genentech’s big hit
Genentech was red hot at the start of the J.P. Morgan Healthcare Conference in January 2004. Months before, the biotech had presented Phase 3 clinical trial data showing for the first time that Avastin — an entirely new type of targeted therapy — helped colon cancer patients live longer by preventing new blood vessels from feeding tumors.
Investors packed into Genentech’s J.P. Morgan presentation, eager to hear the company’s plans for Avastin’s imminent approval, commercial launch, and expansion into other types of cancer. Avastin would go on to become one of the most significant and important cancer treatments ever developed and a blockbuster commercial product for Genentech.
2005: Merck staggers after Vioxx withdrawal
In September 2004, Merck announced that it would pull its arthritis pain drug, Vioxx, from the market because a study that linked the widely prescribed medicine to heart attacks and strokes. The company’s CEO, Raymond Gilmartin, took the stage to try and reassure investors that Merck was still on strong footing.
“We were financially strong before the voluntary withdrawal of Vioxx,” Gilmartin said, according to a transcript. “We’re finally financially strong post the withdrawal of Vioxx.” But the scandal became a public firestorm, creating new scrutiny of the way the FDA regulated drugs. Why, critics wanted to know, had concerns that Vioxx might be riskier than other painkillers lingered until Merck took such a big, dramatic step?
Gilmartin resigned that May, and was replaced by Richard Clark, a Merck lifer. It would be years before Merck recovered from the hit to its reputation.
2006: Vertex’s would-be game-changer
Vertex Pharmaceuticals CEO Josh Boger was brilliant and boastful. During his J.P. Morgan presentation in 2006, he argued Vertex’s still-nascent hepatitis C drug, VX-950, was the biotech equivalent to Apple’s iPod. “Every so often, there’s a game-changing product — one that transforms a product category, one that transforms a company and one that transforms an industry,” he said.
Boger was partially right. VX-950, renamed Incivek, was approved in 2011 and significantly improved hepatitis C cure rates. It quickly became Vertex’s first billion-dollar product. But just as fast, Incivek sales disappeared as more potent and better tolerated hepatitis C drugs reached the market. Incivek might have transformed Vertex, but it also almost killed the company.
2007: The dawn of Big PBM
Whether they knew it or not, conference attendees were getting a peek at the future of the drug industry in January 2007, as CVS and Express Scripts battled over the pharmacy benefits manager Caremark Rx. At the time, Caremark and Express Scripts were the second- and third-biggest PBMs, trailing Medco in a competitive market.
Caremark had entered into a $21 billion deal to merge with CVS, then merely a drugstore chain. Express Scripts wasn’t having it, and announced its own hostile bid.
At the Westin, Caremark CEO Mac Crawford decried “unsolicited proposal” Express Scripts had made in December. “There is no strategic benefit to this transaction, nothing new that is brought to the table. The financial benefits we believe are illusory,” Crawford said. “The risk of antitrust delay is high.”
Crawford’s comments helped fend off Express Scripts, and the CVS/Caremark deal closed in March.
The reason for the battle would become clear later: The PBM business was fundamentally changing from simple prescription processing to negotiating drug prices and excluding medicines from formularies.
A decade later, Express Scripts has merged with Medco and been acquired by the provider Cigna, while Optum, UnitedHealth’s PBM, has spent billions on smaller acquisitions. The resulting arms race has left three companies presiding over about 80% of the market, giving PBMs unprecedented power over how drugs get paid for in the U.S.
2008: The Vytorin shuffle
Sometimes what a CEO doesn’t mention is as interesting as what he does. On Jan. 8, 2008, Merck’s Richard Clark didn’t say anything about the controversy around the two blockbuster cholesterol drugs, Vytorin and Zetia, that Merck sold with Schering-Plough.
But Schering’s chief executive, Fred Hassan, had spent most of a 40-minute session talking about the drugs the week before. Pressreports had accused scientists at Schering of dragging its heels in analyzing a study using artery imaging technology to study the medicines. A week after J.P. Morgan, the companies released the results: Vytorin, a combination pill that combined Zetia and the older Merck drug Zocor, appeared no better than Zocor alone.
Shares in both companies fell. In 2009, Merck bought Schering-Plough for $41 billion, in part to capture all the economics of the medicines. In 2014, a huge study comparing Vytorin to Zocor showed it had a small additional benefit in reducing the rate of heart attacks and strokes.
2009: The financial crisis doesn’t spare biotech
The global market downturn that spelled the end for Lehman Brothers and Bear Stearns had crushing effect on biotech, palpable at the industry’s annual get-together. Stock prices fell, liquidity dried up, and a few venture capital firms went into hibernation, if not out of business entirely. In meetings and presentations at the conference, questions focused less on growth than on survival. J.P. Morgan even canceled the conference’s traditional opening-night gala, held at San Francisco’s City Hall, perhaps because a lavish party bearing the name of a bailed-out bank would have been optically problematic.
2009: The case of the backward DNA molecule
By 2009, Genentech CEO Art Levinson had become an industry legend. He was known for his scientific acumen, his skill as a manager, and his sharp tongue.
When he took the stage at the Westin that year, he was presiding over a room in which the mood was already grim thanks to the financial crisis. He directed his attention to the conference organizer, noting that ever since J.P. Morgan had taken over the conference, its pictures of DNA were “backwards.” That is, instead of being a right-handed helix, the molecules turned in the wrong direction. “This is a left-handed helix, and this does not exist in nature,” Levinson said.
“Perhaps in a parallel universe, but nowhere on this planet.” He turned to the J.P. representative and said: “We’re representatives of an industry that as of last night had a market cap of $301 billion. It’s almost a third of $1 trillion, we should get the structure of DNA right.”
Roche had always owned a large stake in Genentech; later that year, it bought the rest. Levinson fought the deal, and left after it was concluded. He is currently the chairman of Apple and the CEO of Calico, a drug research arm of Alphabet.
2010: Genzyme vs. Icahn
Genzyme in the early days of 2010 was a biotech company in crisis. A year’s worth of manufacturing problems had caused drug shortages, a drop in earnings, and a plunging stock price. Meantime, billionaire investor Carl Icahn was buying a stake in Genzyme and started a proxy fight to wrest control of the company’s board.
Genzyme CEO Henri Termeer used his podium time at the conference to accept responsibility for the company’s problems, but also insisted that he was the best man to lead its recovery. “I accept with great humility that these manufacturing interruptions have happened under my watch,” Termeer told investors during a breakout session.
Genzyme and Icahn settled their differences later in 2010. And then in early 2011, Sanofi acquired Genzyme for $20 billion.
2011: The future through a straw
It felt a bit like a publicity stunt. Vertex asked investors attending its 2011 presentation to breathe through narrow plastic straws so they could feel what it was like to live with the respiratory impairment caused by cystic fibrosis.
At that time, Vertex was still very much focused on the approval and launch of its first hepatitis C drug, but cystic fibrosis was becoming an increasingly important part of the biotech’s R&D plans. From those straws, a dominant cystic fibrosis drug franchise was born. The company’s first CF drug, Kalydeco, was approved the next year, and could help just 4% of CF patients. Last year, Trikafta, a new Vertex treatment, was approved to help 90% of them.
2011: Shkreli vs. a billionaire
Before Martin Shkreli was getting in trouble with the general public, he was taunting billionaires. In 2011, he picked a fight with MannKind founder and CEO Al Mann during the latter’s breakout session with investors. Shkreli was shorting MannKind stock at the time. Tempers flared. Insults were exchanged.
2012: An eye-catching surprise
When Regeneron’s Eylea, a treatment for a cause of blindness, was approved in late 2011, expectations were not high. Analysts figured the drug could generate a few million dollars in its first quarter.
So it was with characteristic glee that Regeneron CEO and founder Leonard Schleifer took the stage in 2012. “The expectations I’m told out there for the launch were somewhere between $2 million to $5 million in the initial launch, period,” he said. “So, how did we do? OK. So we did very well. We did $24 million to $25 million of unaudited net sales to distributors in 2011 since the launch on Nov. 21.” He noted that this was “an order of magnitude” better than expected.
Schleifer said Regeneron expected annual sales of about $150 million in Eylea’s first year, but warned that it was early and that the company couldn’t be entirely confident in those numbers. A month later, he added another $100 million to that forecast. Not surprisingly, Regeneron’s share price spiked. In 2018, Eylea generated $4.1 billion in annual sales. Regeneron now sports a $41 billion market capitalization.
2013: Twitter takes off
The very first tweet was sent in 2006, but it would take another seven years or so before Twitter became a major force at J.P. Morgan.
The conference hashtag started being used slowly — you’d be forgiven for blaming the bad Wi-Fi in the Westin St. Francis — with about 300 #jpm10 tweets in 2010, about 1,000 #jpm11 tweets in 2011, and close to 4,000 #jpm12 tweets in 2012, according to a contemporaneouscount by public relations professional Brian Reid. But it’s safe to say that 2013 was around the time the hashtag really exploded: #jpm13 was used about 7,000 times that conference, setting the stage for the next year’s gathering to break into the five digits.
In the years since, Twitter has democratized the conference. It’s given the folks at home a way to follow along, in real time, with what’s happening in presentations, during breakout sessions, and out in Union Square.
2014: A young dealmaker strikes
Anyone who goes to J.P. Morgan knows the most important conversations happen over dinner or drinks.
Such was the case for Brent Saunders, then 44, in 2014. The previous year, he’d been CEO of eye care maker Bausch & Lomb. Then it was sold to Valeant Pharmaceuticals for $8.7 billion. As soon as the deal closed, he had been put in charge of Forest Labs, a company known for its antidepressants and antibiotics. At J.P. Morgan, he had a steak dinner with Paul Bisaro, the CEO of the generic drugs company Actavis, formerly known as Watson Pharmaceuticals.
Over dinner, they hatched a plan for Actavis to buy Forest for $28 billion. Saunders had been CEO for just five months. Later, Saunders engineered Actavis’ $67 billion purchase of Allergan, the maker of Botox. Investors chilled to the new drug giant, but Saunders is still good at deals. Last year AbbVie agreed to buy the new Allergan for $63 billion.
2015: The age of Keytruda begins
Again and again, Merck CEO Ken Frazier has come back to the idea that it is his job to protect the company’s legacy. It was something he said when he was Merck’s general counsel, charged with defending the firm from a flood of Vioxx-related lawsuits. It was an idea he returned to at the Westin in 2015.
“I just want to be clear that we have a lot of respect for the other companies in this industry, but we also have a very strong legacy based in research,” Frazier said. “And our goal as a company is to move back towards the kinds of productivity that we saw in R&D historically at Merck, bringing forward first-in-class products that make a huge difference to humanity.”
Not a small goal. But that year, Frazier could crow about a big drug: Keytruda, the first of a new class of immune-targeting medicines. Bristol-Myers Squibb had laid the groundwork for such drugs. But Merck had managed to get approved first, and then, clinical trial by clinical trial, became dominant. “Keytruda is an example of unprecedented execution and focus across the research, manufacturing and commercial divisions of Merck,” Frazier said.
He was right.
2016: Biotech’s infamous afterparty
“There are the models!” yelled an unnamed biotech man in line for a J.P. Morgan party, unwittingly kicking off a still-vibrant conversation about the culture of the conference. As Bloomberg reported, he was heralding the arrival of women hired to mingle with a predominantly male crowd at an event held by LifeSci Advisors, an investor relations firm.
The ensuing weeks brought industry-wide outcry, an apology from LifeSci, and a lot of promises to do better. But the party also shined a light on subtler, still unsolved gender issues at the conference and with biopharma as a whole.
2017: Pharma faces a ‘murder’ charge
As the sun rose on the third day of J.P. Morgan, the leaders of the drug industry found out just what the incoming president thought of them. Donald Trump, weeks away from inauguration, used the occasion of his first post-election press conference to declare that pharma is “getting away with murder” when it comes to drug pricing. That sent scores of conference attendees to the Bloomberg terminals scattered about the Westin St. Francis, watching as biotech stocks plunged on the apparent emergence of an anti-industry president.
It’s worth remembering that, in the early days of 2017, biopharma was still trying to parse the doctrine of “seriously but not literally” when it came to Trump (some were willing to pay seven figures for a clue). Three years later, Trump’s rhetoric hasn’t softened much, but the White House’s efforts to lower the cost of medicine have largely floundered.
2018: The year of the Michaels
On the eve of the conference, STAT published a story that led with a simple, memorable factoid: More men named Michael would be giving company presentations than female CEOs.
Almost immediately, “the Michaels” became a meme. Conference-goers couldn’t stop talking about it. Corporate Twitter accounts promoted their female CEO’s presentation as part of a tiny club. Jonathan Bush, then the CEO of Athenahealth, joked during his presentation that he, as a non-Michael, hoped the crowd would “appreciate my contribution to the diversity of the conference.”
The Michaels went viral near the peak of the #MeToo cultural reckoning about sexual harassment and the hurdles women face in the workplace. And they gave a name to the biotech industry’s male-dominated upper ranks.
2019: J.P. Morgan fatigue sets in
With each passing year come the familiar gripes about cramped spaces, overpriced hotels, and entropic conversations that fade from memory the second they conclude. Despite those complaints, the conference isn’t going anywhere anytime soon thanks to a long-term contract with the Westin St. Francis hotel, which means the smaller meetings that orbit J.P. Morgan are staying put, too.
And thus, in 2019, the annual kvetching turned to action: People started vowing to just stay home in January. The early members of the separatist movement are mostly high-profile investors who, by virtue of having lots of money, can make people come to them. But if frustrated tweets are any indication, more and more biotech types will choose to watch from afar each time the industry descends on San Francisco.
More than eight years after PPD Biotech was taken private in a $3.9 billion deal, the 35-years-old contract research organization is bracing for the public market again with a $100 million ask.
Having served all of the top 50 biopharma companies in the world by R&D spending and over 300 biotech fledglings, PPD’s filings highlighted the entrenched role CROs play in an industry chasing an ever dwindling return on investment by pushing for faster timelines and tackling payer resistance to pricey therapies.
PPD highlighted five key trends that it believes will drive higher demand for its services: Growth in R&D spending: Between 2008 to 2018, R&D budgets rose around 3.3% annually, PPD reckoned; Increased levels of outsourcing: “Outsourcing penetration as a percentage of total development spending by biopharmaceutical companies increased from approximately 36% in 2007 to approximately 49% in 2018”; Increased complexity in clinical development: New therapeutic modalities, more targeted drug development and new regulatory requirements have made clinical trials harder to design and recruit — highlighting the need for experts; Biotechnology sector growth: With over $150 billion of capital raised for biotech companies in the last three years, there’s plenty of fuel for new players to carry on their R&D projects; Increasing importance to prove value of new therapies: Real-world evidence is becoming more central to every drug program. It is of course not the only player capitalizing on this demand. On the clinical development side, which accounts for roughly 80% of its revenue, it listed IQVIA, ICON, Parexel, PRA Health Sciences, LabCorp (Covance business), Syneos Health and MedPace as its major competitors. As for laboratory services, LabCorp, Syneos, Q2 Solutions, ICON, Eurofins Scientific, WuXi AppTec, BioAgilytix and SGS were cited as chief rivals. Unlike the drug developers PPD serves, its IPO is not designed to fund any expansion in services or capabilities — its revenue, which neared $3 billion by September of 2019, got it covered — but to redeem bonds issued as part of a recapitalization engineered by its biggest private equity backers in 2017.
Hellman & Friedman and the Carlyle Group, the two players responsible for taking PPD off the Nasdaq in 2011, remain the largest stockholders. The former holds the lion’s share at 56.7%, while the latter kept 23.8%. After jumping on board in the 2017 recapitalization, Blue Spectrum and GIC — investing on behalf of Singapore and Abu Dhabi, respectively — each claimed 9.2% of the stock, to be back on the Nasdaq as $PPD
David Simmons, the Pfizer vet who took PPD’s helm in 2012, is in for 1.1%. His compensation package for 2019 totaled $6.2 million, double that of 2018, mostly thanks to option awards. Fellow Pfizer alum and CFO Christopher Scully got $1.2 million while COO William Sharbaugh received $1.7 million.
We all will experience it at some point, unfortunately: The older we get the more our brains will find it difficult to learn and remember new things. What the reasons underlying these impairments are is yet unclear but scientists at the Center for Regenerative Therapies of TU Dresden (CRTD) wanted to investigate if increasing the number of stem cells in the brain would help in recovering cognitive functions, such as learning and memory, that are lost during ageing.
To investigate this, the research group led by Prof. Federico Calegari used a method developed in his lab to stimulate the small pool of neural stem cells that reside in the brain in order to increase their number and, as a result, to also increase the number of neurons generated by those stem cells. Surprisingly, additional neurons could survive and form new contacts with neighbouring cells in the brain of old mice. Next, the scientists examined a key cognitive ability that is lost, similarly in mice and in humans, during ageing: navigation.
It is well known that individuals learn to navigate in a new environment in a different way depending on whether they are young or old. When young, the brain can build and remember a cognitive map of the environment but this ability fades away in older brains. As an alternative solution to the problem, older brains without a cognitive map of the environment need to learn the fixed series of turns and twists that are needed to reach a certain destination. While the two strategies may superficially appear similar, only a cognitive map can allow individuals to navigate efficiently when starting from a new location or when in need of reaching a new destination.
Would boosting the number of neurons be sufficient to counteract the decreasing performance of the brain in navigation and slow down this ageing process? The teams of Prof. Calegari (CRTD) together with Prof. Gerd Kempermann (German Center for Neurodegenerative Diseases DZNE / CRTD) and Dr. Kentaroh Takagaki (Otto von Guericke University Magdeburg) found the answer to this challenging question and published it this week in the scientific journal Nature Communications.
The answer is “Yes”: Old mice with more stem cells and neurons recovered their lost ability to build a map of the environment and remembered it for longer times making them more similar to young mice. Even better, when neural stem cells were stimulated in the brain of young mice, cognitive impairments were delayed and memory was better preserved over the entire course of the animal natural life.
In young individuals, a brain area called the hippocampus is crucial for remembering places and events, and is also responsible for creating maps of new environments. However, old individuals use other structures that are more related to the development of habits. It was very interesting to see that adding more neurons in the hippocampus of old mice allowed them to use strategies typical of young animals. It was not only about how fast they were learning but, rather, how different the learning process itself was ,” explains Gabriel Berdugo-Vega, first author of the study.
“Also humans have a few stem cells in the brain and these stem cells are known to severely reduce in numbers over the course of life. Identifying the causes underlying cognitive deficits in ageing and rescuing them is crucial for our rapidly ageing societies. Our work demonstrates that age-related impairments can be rescued by hijacking the endogenous neurogenic potential of the brain, thus, rejuvenating its function. Being a human myself with my own stem cells and being the senior author of this study, I felt that I had a personal interest in this topic.” says Prof. Federico Calegari, senior author of this study.
The research group of Prof. Federico Calegari focuses on mammalian neural stem cells in the context of development, evolution and cognitive function at the CRTD. The institute is the academic home for scientists from more than 30 nations. Their mission is to discover the principles of cell and tissue regeneration and leveraging this for recognition, treatment and reversal of diseases. The CRTD links the bench to the clinic, scientists to clinicians to pool expertise in stem cells, developmental biology, gene-editing and regeneration towards innovative therapies for neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease, haematological diseases such as leukaemia, metabolic diseases such as diabetes, retina and bone diseases.
This study was funded by TU Dresden / CRTD through the German Excellence Initiative, the German Research Foundation and a European grant from the H2020 programme. In addition, it was supported by the Faculty of Natural Sciences of Otto-von-Guericke University Magdeburg, the Dresden International Graduate School for Biomedicine and Bioengineering (DIGS-BB) and the German Center for Neurodegenerative Diseases (DZNE).
Gastric bypass vastly improves the health of the patients who elect to receive the surgery. Post-bariatric hypoglycemia, however, can be a severe complication experienced by 10 to 30 percent of patients.
Researchers at Joslin Diabetes Center and Harvard John A. Paulson School of Engineering and Applied Sciences have developed a closed-loop system that automatically provides patients with an appropriate, as-needed dose of liquid glucagon to treat this condition. The system, comprised of a continuous glucose monitor (CGM) and a glucagon pump that communicate via an algorithm-controlled application, would allow patients to go about their daily activities without the fear of dipping into dangerous low blood sugar levels. The success of the system was reported on Nov. 13 in The Journal of Clinical Endocrinology & Metabolism.
“Post-bariatric hypoglycemia is a profoundly life-altering condition for patients. Having unpredictable hypoglycemia that people can’t detect is really an unsafe situation,” says Mary Elizabeth Patti, M.D., Associate Professor of Medicine at Harvard Medical School, Investigator at Joslin, and senior author on the paper. “This system provides a way to help individuals keep their glucose in a safe range.”
Over two hundred thousand people in the United States have bariatric surgery each year. Some types of these surgeries not only shrink the size of the stomach, but also change the way food travels through the intestines. As a result, high levels of certain hormones are released from the intestine after eating, and these hormones increase insulin production. These changes, in part, account for the reduction in obesity-associated problems, including type 2 diabetes. But in some patients, the surgery can trigger the body to over-produce insulin, leading to sharp drops in blood glucose levels.
“Hypoglycemia can be very disabling,” says Dr. Patti. “Since it is not predictable, people can’t plan in advance for it. And if it happens repeatedly, people can become unaware that their glucose is low. And if the glucose is severely low, they may have alterations in brain function and may not be able to think clearly. With more severe hypoglycemia, they may have loss of consciousness and may require the assistance of someone else. It becomes quite a dangerous situation.”
Current treatments for post-bariatric hypoglycemia include strictly regulated meal plans, and medications to reduce insulin production after meals. Once a low blood glucose develops, patients have to consume sugar. If the patient has lost consciousness, a family member may have to administer an emergency dose of glucagon, a medication that increases glucose. These treatments, however, are frequently not sufficient on their own and may lead to unhealthy swings in blood sugar.
“This new automated glucagon delivery system is an important development because it helps protect these patients from developing undetected or difficult to treat low blood sugars,” says Christopher Mulla, MD, first author on the study. “Glucagon provides patients with a treatment that doesn’t involve eating, which they’re often afraid of doing, and it does not cause rebound high blood sugars, which can then trigger another low blood sugar.”
The system grew from a collaboration between clinical and computational scientists at Joslin Diabetes Center and Harvard John A. Paulson School of Engineering and Applied Sciences. Work on this system began about four years ago, when Dr. Patti realized that artificial pancreas algorithms which had been developed to treat diabetes by study co-senior author Dr. Eyal Dassau, Director, Biomedical Systems Engineering Research Group at the Harvard John A. Paulson School of Engineering and Applied Sciences and his team, could similarly be developed to detect, treat, and prevent severe hypoglycemia.
The team tested whether a glucagon pump and CGM could communicate to provide an adequate dose of glucagon to treat an impending low. During this first phase, glucagon doses were administered by the study physicians. In this newly published paper, the team closed the loop and allowed Dr. Dassau’s algorithm to sense impending low blood sugar levels and automatically deliver an appropriate glucagon dose under supervision by the medical team.
“The way that we look at it, it is very similar to how in your car, you have an airbag,” says Dr. Dassau. “You don’t use that airbag every time that you stop at a traffic light, but when there is a severe event and there’s a need to prevent catastrophe, the airbag will be deployed. We employing the same idea for the glucagon system: we detect, we analyze and then we deliver automatically a mini dose of glucagon.”
Twelve patients participated in the study, which took place at Joslin’s Clinical Research Center on two separate days. Upon arrival at Joslin, patients were hooked into a CGM and a pump that was filled either with glucagon or a placebo. The study was double-blind, meaning neither the study team nor the patients knew which medication was being delivered which day until the conclusion of the study . The team then induced hypoglycemia in each patient and allowed the algorithm to predict impending or detect current low blood sugar and deliver either glucagon or placebo. The results from each day were analyzed and compared.
“I was very pleased that the system was able to detect hypoglycemia consistently, that the patients were able to tolerate the small dose of glucagon that we used, and that it was effective,” says Dr. Patti. “We used about a third of the usual emergency rescue glucagon dose, and that was sufficient to raise the glucose without causing a high glucose level.”
Too high a dose of glucagon can lead to vomiting and other symptoms of hyperglycemia, which often occurs in patients given emergency-level doses for hypoglycemia. This new, closed-loop system significantly reduced the risk of over-treating. “That’s one of the benefits of automation and running a closed loop. You can start with a very low dose of glucagon as it’s needed, and add an additional small dose if indicated without overdosing,” says Dr. Dassau.
The team has already started to adapt the algorithm from a computer application to a cell phone in preparation for the next phase of a clinical trial, which will send the entire system home with study participants to test in a real-world setting.
“We believe that it will provide a particularly helpful therapeutic option,” says Dr. Patti. “Using the system to detect an upcoming severe low and treat it before it gets unsafe would be so important to improve safety and quality of life of patients with this type of hypoglycemia.”
Christopher M Mulla, Stamatina Zavitsanou, Alejandro Jose Laguna Sanz, David Pober, Lauren Richardson, Pamela Walcott, Ipsa Arora, Brett Newswanger, Martin J Cummins, Steve J Prestrelski, Francis J Doyle, Eyal Dassau, Mary Elizabeth Patti. A Randomized, Placebo-Controlled Double-Blind Trial of a Closed-Loop Glucagon System for Post-Bariatric Hypoglycemia. The Journal of Clinical Endocrinology & Metabolism, 2019; DOI: 10.1210/clinem/dgz197
Cancer patients may one day be able to get their entire course of radiation therapy in less than a second rather than coming in for treatment over the course of several weeks, and researchers in the Abramson Cancer Center of the University of Pennsylvania have taken the first steps toward making it a reality. In a new report published today in the International Journal of Radiation Oncology, Biology, and Physics, researchers detail how they used proton radiation to generate the dosage needed to theoretically give a cancer patient their entire course of radiotherapy in one rapid treatment. It’s known as FLASH radiotherapy, and it’s an experimental paradigm that could represent a sea change for the world of oncology in the future. In this study, researchers also found FLASH demonstrated the same effect on tumors as traditional photon radiation while sparing healthy tissue due to the shorter exposure time.
“This is the first time anyone has published findings that demonstrate the feasibility of using protons — rather than electrons — to generate FLASH doses, with an accelerator currently used for clinical treatments,” said the study’s co-senior author James M. Metz, MD, director of the Roberts Proton Therapy Center and chair of Radiation Oncology. The co-senior authors on the study are Constantinos Koumenis, PhD, the Richard H. Chamberlain Professor of Research Oncology, and Keith A. Cengel, MD, PhD, an associate professor of Radiation Oncology, both in Penn’s Perelman School of Medicine.
Metz noted that other research teams have generated similar doses using electrons, which do not penetrate deep enough into the body to be clinically useful as a cancer treatment for internal tumors. Other groups have tried the approach with conventional photons, but currently available treatment devices do not have the ability to generate the necessary dosage. This study shows, that with technical modifications, the currently available accelerators for protons can achieve FLASH doses with the biologic effects today.
The key for the Penn team was the ability to generate the dose with protons, and even in that setting, researchers had to specially develop the tools needed to effectively and accurately measure radiation doses, since the standard detectors were quickly saturated due to the high levels of radiation. The Roberts Proton Therapy Center includes a dedicated research room to run experiments like these, allowing investigators to use photon and proton radiation side-by-side just feet from the clinic. It’s one of the few facilities in the world with those unique features, and Metz said this infrastructure is what made Penn’s FLASH experiments possible.
“We’ve been able to develop specialized systems in the research room to generate FLASH doses, demonstrate that we can control the proton beam, and perform a large number of experiments to help us understand the implications of FLASH radiation that we simply could not have done with a more traditional research setup,” Metz said.
Researchers said they are already beginning to optimize how they would use this down the road for clinical trials, including taking the necessary steps to translate the ability from the research room to a clinical space, as well as designing a delivery system for FLASH in humans.
