Rethinking premedical education

 JOHN A. GLADYSZ Authors Info & Affiliations

The world needs more physicians. Increasing their numbers alone won’t solve the many problems associated with improving health care. But it doesn’t help to have a dearth of doctors, who were generally in short supply before COVID-19 struck. The pandemic has only exacerbated doctor shortages everywhere. This doesn’t bode well for a world that must prepare for future pandemics and for populations that are both growing and aging. Better health outcomes require more physicians. So, where are the bottlenecks?

Physician training takes different tracks in different countries. The United States has the longest and most expensive medical education system in the developed world. Many facets of this system have been criticized, from the financial burden to the requisite 12 years of education and training, not to mention the intense competition to enter this career track. A US medical education requires 4 years of undergraduate studies and 4 years of medical school, whereas in most European countries, students can accomplish this in 6 years. Recently on this page, it was argued that the US pre–medical school (premed) curriculum should be reconsidered by medical schools and medical regulatory bodies. One question addressed the degree to which all undergraduates who pursue science and medicine require science courses of the same breadth and depth. For example, the content in the customary introductory four-semester chemistry sequence is highly relevant for future practicing chemists. But which units are essential for future medical professionals? Of course, some premed students major in chemistry, but does one chemistry track optimally serve all? Reconfiguring the science requirements for premed students might go a long way in attracting—and keeping—students in the physician pipeline.

When analyzing curriculum and policy issues in US academia, there can be a tendency to overlook practices in other countries. I’ve taught organic chemistry at all levels in the United States and Germany (Universität Erlangen–Nürnberg). The German premed students directly matriculate into medical schools on the basis of a post–secondary school exam. Unlike their US counterparts, they do not declare subject “majors.” Rather, they take the same standardized 2-year preclinical curriculum. This culminates with a comprehensive “state exam” that lasts 2 or more days, which must be passed to advance to clinical training. In stark contrast to US practices, the premed students in Germany are only required to take one semester of a combined general and organic chemistry course, a single laboratory course, and (at Erlangen) one final exam that is graded as pass/fail (typically 85 ± 5% passing). Thus, what would take four semesters in the United States is condensed to a single semester in Germany (further biochemistry is required in subsequent preclinical semesters). Other European countries have different practices, but none require the depth and breadth of chemistry that is customary in the United States.

Given the successful operation of streamlined science tracks outside the United States, and an absence of data suggesting that less qualified physicians are produced as a result, what factors anchor the US status quo? The medical school at Texas A&M University, for example, requires two semesters of both general and organic chemistry (all including a laboratory) as well as biochemistry. There have been experiments with shortened versions of the four-semester sequence at several US universities, but this wouldn’t suffice for admission into Texas A&M’s medical school. Compounding this gridlock, the lines of communication to medical schools and examination boards regarding optimal “learning outcomes” for future generations of doctors are broken. To cut this Gordian knot and help increase the number of doctors and much needed clinics and hospitals, a high-profile forum is urgently needed in which all the constituents of the doctor-producing pipeline rethink premedical education. Otherwise, substantive modernization and the rational development of widely accepted alternative tracks will never be possible.

One overarching issue remains: Around the globe, students in premedical curricula face intense pressure both inside and outside the classroom and are often highly stressed. This leads to mental health difficulties and student attrition, consequences that could be ameliorated with renewed attention to program and pedagogy. To disregard this is collective malpractice that further constricts the bottleneck for producing the medical professionals that the world so desperately needs.

https://www.science.org/doi/10.1126/science.adf8727

MIT researchers reveal DNA "Paste" tech behind latest gene editing startup

 MIT scientists have developed a tool that they say can insert large gene sequences where they want in the genome.

In a paper published Thursday in Nature Biotechnology, MIT fellows Omar Abudayyeh, Jonathan Gootenberg and colleagues detail a technology they call PASTE, which they say can potentially be used to insert long strands of DNA and treat genetic diseases caused by many different mutations, such as cystic fibrosis and Leber congenital amaurosis, a rare eye disorder that causes blindness.

The technology has been licensed to Tome Biosciences — a biotech co-founded by the duo back in February of 2021 and backed by ARCH, Google’s venture arm, a16z, Longwood Fund, Polaris Partners and Alexandria Venture, which joined after its Series A, according to a recent pitch deck obtained by Endpoints News.

Sana Biotechnology also has a stake in the company, according to an April SEC filing.

Abudayyeh and Gootenberg declined to comment on Tome. The Watertown, MA-based biotech is led by CEO Rahul Kakkar and has more than 80 full-time employees as of the third quarter of this year, according to the pitch deck slides.

In the paper, the researchers explain how they fuse two existing technologies: a prime editor, which the Broad’s David Liu pioneered and spun out into the startup Prime Medicines, and an integrase, an enzyme some viruses use to infect bacteria by inserting their DNA into the host cells.

The idea behind the combined technologies is that integrases on their own aren’t easily engineered to insert at any location besides their specific target sequence, but they’re capable of carrying big sequences. Prime editors, meanwhile, can be engineered to target and edit specific spots, but only in short bits — just enough to stick in a target sequence for the integrase. By combining the two in PASTE, researchers can insert sequences as large as 36,000 base pairs, in the spots that they want.

Abudayyeh told Endpoints News that unlike current gene-editing approaches, which can only go after single mutations of a disease at once, PASTE could address many mutations at the same time at once by replacing the whole gene. In addition, the technique doesn’t create a double-stranded break in the DNA, reducing the risk of unwanted insertions or deletions, he said.

In a paper published last December in Nature Biotechnology, Liu’s lab described a similar approach. The only difference is that Liu’s lab opted not to fuse all the machinery together, having the prime editor and integrase work separately. In their paper, Gootenberg and Abudayyeh report higher efficiency than Liu’s paper did. (A month before the Liu lab’s work was published in Nature Biotechnology, both teams had released pre-prints of their work within a day of each other.)

Liu said in an email, “In our lab’s hands the prime editor–recombinase fusion does not on average work better than simply expressing the recombinase as a separate protein, and in some cases, the fusions worked less efficiently than the separately expressed proteins.”

Both Kiran Musunuru, University of Pennsylvania professor and Verve Therapeutics co-founder, and Sam Sternberg, Columbia professor and Prime advisor, said that they thought both were similar. “Is there a big difference? Probably not in the grand scheme of things,” Musunuru said. “I don’t think it matters too much whether it’s two different proteins made separately or whether it’s a single protein. They both seem to work reasonably well.”

Musunuru, who researches the genetics of heart disease, said he’s been using PASTE in his own lab too, after the preprint was published last year, though while his lab has gotten the technology to work in cells, it hasn’t gotten it to work in mice. Verve uses a form of gene editing called base editing, licensed from Liu’s other biotech Beam Therapeutics.

Notably, Tome doesn’t have a license with Prime Medicine, which houses Liu’s prime editing patents from the Broad, and is not in talks for one, a spokesperson for Prime Medicine told Endpoints.

Abudayyeh and Gootenberg emphasized that while they used prime editing in their paper, the more general PASTE framework was not limited to prime editing. “Prime is one example, but not the only way to do it,” Gootenberg said.

Musunuru wasn’t so sure, noting that he didn’t see how you could make the technique programmable, or targetable, “without something very similar to prime editing.”

Getting crispy

Abudayyeh and Gootenberg are alumni of CRISPR pioneer Feng Zhang’s lab. They’ve launched several biotechs, including Sherlock Biosciences and Proof Diagnostics, both diagnostics companies they co-founded with Zhang and others, and Moment Biosciences, a stealth company that is developing “precision microbiome therapy,” according to a Massachusetts corporate filing. And then, of course, there’s Tome.

The industry is paying a lot of attention and money to the next iterations of CRISPR. Prime launched last year with $315 million and raised $175 million when it went public in October. Then there’s Tessera, which in August raised $300 million, putting its total funds raised over the $500 million mark. In February, Intellia, which is using CRISPR to edit genes directly in the body, bought for $45 million cash little-known Rewrite Therapeutics, which its investor called “kind of CRISPR 2.0,” a moniker applied to the likes of base and prime editing, though little else was said of its technology.

Searching for CRISPR 2.0, Intellia spends $45M cash on an unknown Berkeley spinout

Researchers are still in the early days of turning such a technology into a commercial therapy — these ‘CRISPR 2.0’ techniques have never been used in humans. In Abudayyeh and Gootenberg’s paper, they were able to get the DNA they wanted into a mouse’s liver cells less than 3% of the time. Musunuru said that there was a lot of space for improvement, noting that they would have to get to around at least 10% to have some therapeutic effect.

In the pitch deck, Tome says it hopes to be in the clinic by 2026.

https://endpts.com/mit-researchers-reveal-dna-paste-tech-behind-latest-genome-startup/

Biggest drug companies halted Twitter ad buys after Lilly insulin spoof

 Almost all of the drug industry’s biggest advertisers cut their spending on Twitter to zero or near-zero over the last two weeks amid worries about impersonation of their brands by pranksters and the future of the social media company.

Among 18 of the biggest pharmaceutical advertisers in the US market, 12 cut their Twitter ad spending to nothing for the week beginning Nov. 14, according to Pathmatics, which tracks data on prescription drug ad spending as well as general corporate advertising. The list of drugmakers cutting spending to zero includes Merck, AstraZeneca, Eli Lilly, Novartis, Pfizer and others.

Six companies showed some spending on Twitter ads last week, according to the data. But for most, the amounts are a few hundred or a few thousand dollars. The sole outlier is German drugmaker Bayer, which spent $480,000 last week, a huge jump from the weeks prior. Pathmatics’ data for Bayer also captures over-the-counter drug ad spending, which could skew the results.

Bayer said in a statement to Endpoints News: “We continue to monitor developments at Twitter and regularly assess our position. We do not release our advertising spend.”

While drug companies have never been massive ad spenders on Twitter, the sudden change highlights just how quickly some major brands have pulled back from the social media company in the wake of its takeover by new owner Elon Musk.

Musk closed his purchase of Twitter in the final days of October, and corporate brands soon after faced a wave of pranks and impersonation after Musk launched a program to sell verified badges — previously a marker than an account was “official” — to anyone for $8 per month. Eli Lilly faced one of the highest-profile such spoofs, from a fake account that sprung up and claimed that the company’s insulin was now free.

Eli Lilly’s official account @LillyPad is still online, but with no new tweets since Nov. 10, when the imposter account spoofed the company. Lilly executives scrambled to get the tweet pulled, but it took hours for Twitter to respond, and Lilly’s stock tumbled by more than 4% by the next day, despite gains in the broader market. The $8 verified program was suspended soon after.

Lilly and other top pharma advertisers all either declined to comment or did not respond to requests for comment on their advertising spending.

On Nov. 10, the same day of the fake Eli Lilly tweet, Musk announced a new policy saying that parody accounts would only be allowed if they identified themselves in their name. “Basically, tricking people is not ok,” he said in a tweet. Representatives for Twitter didn’t respond to requests for comment.

The ad pullback doesn’t mean pharma is leaving Twitter entirely. Pharma corporate accounts are still up, with some continuing to post news and updates. For example, Merck posted from its account, which now sports the new gray “Official” logo, four days ago, announcing the European advisory committee’s positive opinion for its metastatic prostate cancer med. Pfizer and Bristol Myers Squibb have also secured gray “official” checkmarks, which Twitter is using in place of the “verified” checkmark badges for some corporate brands, media outlets or other major public figures.

Lilly’s Twitter account does not yet have the new gray official account check as of Friday morning.

Pharma advertiser concerns are nothing new on Twitter. The traditionally conservative pharma industry has long been wary of the potential for ads placed next to controversial messages and posts.

“It’s fair for pharma brands to be more conservative and have even more questions now around large scale advertising on Twitter when there’s more uncertainty about how their brand is going to be positioned,” The Harris Poll’s managing director Rob Jekielek said.

On the other side of Twitter, the so-called organic brand accounts and people in general are not going away. As Musk himself has been pointing out all week, Twitter use is at all-time high. The Harris Poll would agree, Jekielek noted, as its tracking of pharma and healthcare experts and discussions on Twitter haven’t dropped off at all.

https://endpts.com/biggest-drug-companies-halted-twitter-ad-buys-after-lilly-insulin-spoof/

Hawaii gun permit ruling sides with ‘homesick’ Navy officer

 A U.S. Navy officer stationed in Hawaii cannot be denied a firearms permit solely because he sought counseling for feeling depressed and homesick, a federal judge ruled.

Michael Santucci, a cryptologic warfare officer from Fort Myers, Florida, saw a medical provider at a military hospital for feelings of depression and homesickness a few months after arriving in Hawaii last year, according to his lawsuit, filed in April.

He wasn’t diagnosed with any disqualifying behavioral, emotional or mental disorder, the lawsuit said.

He later filled out forms to register his firearms with the Honolulu Police Department and indicated that he had been treated for depression, but noted it was “not serious.”

Hawaii law requires registration of all firearms. Prior to acquiring a gun, an applicant must apply for a permit. Santucci needed such a permit even though he legally owned his firearms before arriving Hawaii.

Because Santucci answered “yes” on a form indicating he had sought counseling, the permit process was halted and his firearms were seized, his lawyers said.

Honolulu must return Santucci’s firearms and complete the registration of the weapons, U.S. District Judge Derrick Watson’s order issued Wednesday said.

“The City is evaluating the decision and its impact on our processes,” Honolulu Corporation Counsel Dana Viola said in a statement Friday.

Kevin O’Grady, one of Santucci’s lawyers, said the case was “illustrative of Hawaii’s strong opposition to anything that approaches the free exercise of the Second Amendment.”

The lawsuit was filed before a U.S. Supreme Court ruling expanding gun rights across the nation forced Hawaii to begin issuing concealed carry permits. Previously, those permits had been practically impossible to obtain.

Santucci’s lawsuit focused only on the permit to acquire firearms.

But Honolulu and the state will need to take the high court decision into consideration when overhauling the process to ensure others aren’t precluded from obtaining permits based on disclosing previous mental health counseling, said Alan Beck, another attorney representing Santucci.

“What the judge is saying is Honolulu is misapplying the law. They’re getting Hawaii law wrong,” Beck said. “If you marked ‘yes’ on counseling, then you’ve lost your gun rights.”

https://apnews.com/article/health-lawsuits-gun-politics-hawaii-honolulu-87ab2bc0f2ad283fcf2191c4c3f55170

Used-needle buyback program approved by NYC Council has critics fuming

 The City Council has overwhelmingly passed the controversial needle buyback program pushed by progressive pols – a policy critics say will only incentivize drug use already plaguing the Big Apple.

The taxpayer-funded, year-long pilot program is expected to begin in the next month or so, with the Health Department opening buyback locations in five of the city’s 51 council districts where the agency believes the highest need exists.

Junkies will earn up to 20 cents per used syringe they return but would be capped at $10 daily, according to the legislation, which was approved 40-6 Tuesday.

Councilwoman Diana Ayala (D-Manhattan/Bronx), the bill’s sponsor, said the measure’s “overall aim is to connect users with organizations that can put them onto a path of recovery, while at the same time, cleaning up our streets” of discarded needles.

The measure leaves the door to the program becoming permanent — and much larger in scope.

When the pilot ends, the Health Department must report to the Council in six months how many “needles, syringes and sharps” were returned at each site, how much money was shelled out, and whether it believes the program should be permanent or expanded.

It’s unclear how much the program will cost New Yorkers.

“Instead of focusing on resolving addiction, this city is perpetuating the problem by giving drug abusers money to continue their habits,” said Councilman Robert Holden (D-Queens), who voted against the legislation. “This will be another taxpayer-funded boondoggle and will only make matters worse.”  

“Twenty cents isn’t worth much to anyone except a person who is going to round up the $10 max payment worth of his pal’s needles to buy more drugs,” quipped Council Minority Leader Joseph Borelli (R-Staten Island), who also opposed the bill.

The bill was approved with more than enough support to override any veto by Mayor Adams.

Through his spokeswoman Kate Smart, Mayor Adams said: “Addressing the opioid crisis that has taken far too many lives is a top priority of the Adams administration, and we look forward to working with our partners in the City Council to continue building a safer and healthier city.”

https://nypost.com/2022/11/26/used-needle-buyback-program-approved-by-nyc-council-has-critics-fuming/

Beijing residents break free from COVID lockdown

 

The building management had issued a notice on Thursday (November 24) after one positive case of COVID-19 was found. Residents were prevented from leaving the building and all exits were locked, including the only safety exit.

Resident Ji Zhang reported the issue to the local police.

"The property management doesn't have the right to seal the door," Zhang told Reuters.

Residents shared news and information in online groups before approaching authorities.

"The first request we have is to have a formal, legitimate document to say that ok, you are in a high-risk area, you have to quarantine," said Zoe Zhang, another resident of the building.

"If not, then they should not, A, lock down the main door and, B, if anybody has any emergency, please let us know."

Neighborhood committee staff were unable to provide legal documents supporting the measures, and the restrictions were removed.

https://www.marketscreener.com/quote/stock/QINGDAO-HAIER-BIOMEDICAL-73486578/news/Beijing-residents-break-free-from-COVID-lockdown-42414672/

New hope for kidney cancer treatment using existing drugs

 The most comprehensive study of kidney cancer at single-cell level has discovered a potential drug target to treat renal cell carcinoma, a cancer with a high mortality rate that is hard to detect. Researchers from the Wellcome Sanger Institute, the University of Cambridge and Cambridge University Hospitals identified immune cells known as macrophages that express the gene IL1B as crucial to tumor development.

The study, published today in Cancer Cell, recommends IL1B macrophages as a promising therapeutic target to treat renal cell carcinoma given that this cell type has already been targeted using existing drugs that prevent lung cancer. The next step, which is already being explored, will be clinical trials to prove that targeting IL1B can be used to effectively prevent renal cell carcinoma from forming or progressing.

Renal cell carcinoma (RCC) is the seventh most common cancer in the UK, with three quarters of cases and the majority of deaths caused by clear cell renal cell carcinoma (ccRCC). The disease has a 50% mortality rate, partially because three in five patients show no symptoms until the cancer is at a late stage.

Many RCC tumors form when both copies of the VHL gene are switched off. A subset of patients have inherited kidney cancer, including Von Hippel-Lindau (VHL) disease, which is a genetic condition where one copy of the VHL gene is switched off from birth. The second copy of VHL is usually switched off as a result of a common genetic event that often occurs in early life, leading to the formation of innumerable tumors.

In this new study, researchers at the Wellcome Sanger Institute and University of Cambridge studied over 270,000 single cells and 100 micro-dissections from 12 patients with kidney tumors. Samples were taken from different parts of the tumor as well as normal kidney tissue. These samples were analyzed using single-cell RNA sequencing and spatial transcriptomics to map the exact location of specific cells within tissues.

This analysis highlighted a particular type of immune cell, a macrophage expressing the gene IL1B, as abundant at the fringes of tumors.

"Using both single-cell sequencing and spatial transcriptomics allowed us to discover not only what cell types were present in these renal cell carcinoma tumors, but how the cell types were organized in space. This approach meant we could pinpoint macrophages expressing the IL1B gene at the leading edges of tumors, acting almost like a vanguard for tumor growth," says Dr. Ruoyan Li of the Wellcome Sanger Institute.

The findings will be of particular interest to those with VHL disease, who are highly likely to suffer numerous and persistent tumors. While kidney tumors can be monitored and surgically removed before the cancer can spread to other parts of the body, new ones will form and there is a limit to how many times patients can have surgery before losing kidney function.

"As a result of research, the outlook for those living with VHL disease has improved greatly in recent years. Even before the VHL gene was identified, the standard of care has always been a lifetime of surveillance with frequent, painful, and expensive surgeries to remove tumors interspersed within the body," says Joshua Mann, MPH, director of health, VHL Alliance.

"We are approaching a new era of managing VHL disease, with a major paradigm shift that could eventually even do away with these surgeries. A way to treat VHL-related tumors without surgical intervention would be a huge boost for those with the condition. The VHL Alliance is actively exploring opportunities to bolster and support these important research efforts."

The researchers are already planning clinical trials to test whether targeting IL1B macrophages is an effective treatment for RCC. The fact that existing drugs targeting this pathway are proven to be effective in preventing some lung cancers offers hope that these trials may deliver promising results.

"I'm optimistic that targeting IL1B macrophages may provide us with a way to treat renal cell carcinomas without resorting to surgery. This will be particularly important for patients with VHL disease because we should be able to prevent tumors forming in the first place by focusing on their genetic roots, rather than waiting for them to grow and removing them. As is the case for all cancers, the earlier we can intervene the better," says Dr. Thomas Mitchell, Wellcome Sanger Institute and University of Cambridge.

More information: Ruoyan Li et al, Mapping single-cell transcriptomes in the intra-tumoral and associated territories of kidney cancer, Cancer Cell (2022). DOI: 10.1016/j.ccell.2022.11.001

https://medicalxpress.com/news/2022-11-kidney-cancer-treatment-drugs.html