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Our *Homo sapiens* ancestors shared the world with Neanderthals, Denisovans and other types of humans whose DNA lives on in our genes

Ancient DNA helps reveal the tangled branches of the human family tree. Not only did our ancestors live alongside other human species, they mated with…



Hundreds of thousands of years ago, our *Homo sapiens* ancestors shared the landscape with multiple other hominins. The Washington Post via Getty Images

When the first modern humans arose in East Africa sometime between 200,000 and 300,000 years ago, the world was very different compared to today. Perhaps the biggest difference was that we – meaning people of our species, Homo sapiens – were only one of several types of humans (or hominins) that simultaneously existed on Earth.

From the well-known Neanderthals and more enigmatic Denisovans in Eurasia, to the diminutive “hobbit” Homo floresiensis on the island of Flores in Indonesia, to Homo naledi that lived in South Africa, multiple hominins abounded.

Then, between 30,000 and 40,000 years ago, all but one type of these hominins disappeared, and for the first time we were alone.

Until recently, one of the mysteries about human history was whether our ancestors interacted and mated with these other types of humans before they went extinct. This fascinating question was the subject of great and often contentious debates among scientists for decades, because the data needed to answer this question simply didn’t exist. In fact, it seemed to many that the data would never exist.

Svante Pääbo, however, paid little attention to what people thought was or was not possible. His persistence in developing tools to extract, sequence and interpret ancient DNA enabled sequencing the genomes of Neanderthals, Denisovans and early modern humans who lived over 45,000 years ago.

For developing this new field of paleogenomics, Pääbo was awarded the 2022 Nobel Prize in Physiology or Medicine. This honor is not only well-deserved recognition for Pääbo’s triumphs, but also for evolutionary genomics and the insights it can contribute toward a more comprehensive understanding of human health and disease.

Diagram of human lineages diverging and interbreeding over time
A simplified model of human evolution showing how humans are related to Neanderthals and Denisovans. Arrows between different branches show mating that occurred. Events that happened further back in time are closer to the top of the image. Joshua Akey, CC BY-ND

Mixing and mating, revealed by DNA

Genetic studies of living people over the past several decades revealed the general contours of human history. Our species arose in Africa, dispersing out from that continent around 60,000 years ago, ultimately spreading to nearly all habitable places on Earth. Other types of humans existed as modern humans migrated throughout the world, but the genetic data showed little evidence that modern humans mated with other hominins.

Over the past decade, however, the study of ancient DNA, recovered from fossils up to around 400,000 years old, has revealed startling new twists and turns in the story of human history.

For example, the Neanderthal genome provided the data necessary to definitively show that humans and Neanderthals mated. Non-African people alive today inherited about 2% of their genomes from Neanderthal ancestors, thanks to this kind of interbreeding.

In one of the biggest surprises, when Pääbo and his colleagues sequenced ancient DNA obtained from a small finger bone fragment that was assumed to be Neanderthal, it turned out to be an entirely unknown type of human, now called Denisovans. Humans and Denisovans also mated, with the highest levels of Denisovan ancestry present today – between 4% and 6% – in individuals of Oceanic ancestry.

Strikingly, ancient DNA from a 90,000-year-old female revealed that she had a Neanderthal mother and a Denisovan father. Although there are still many unanswered questions, the picture emerging from analyses of ancient and modern DNA is that not only did multiple hominins overlap in time and space, but that matings were relatively common.

artist's recreation of Neanderthal man wearing a modern business suit
Does a Neanderthal in modern clothing makes it easier to imagine mingling with his species? picture alliance via Getty Images

Archaic genes you carry today

Estimating the proportion of ancestry that modern individuals have from Neanderthals or Denisovans is certainly interesting. But ancestry proportions provide limited information about the consequences of these ancient matings.

For instance, does DNA inherited from Neanderthals and Denisovans influence biological functions that occur within our cells? Does this DNA influence traits like eye color or susceptibility to disease? Were DNA sequences from our evolutionary cousins ever beneficial, helping humans adapt to new environments?

To answer these questions, we need to identify the bits of Neanderthal and Denisovan DNA scattered throughout the genomes of modern individuals.

In 2014, my group and David Reich’s group independently published the first maps of Neanderthal sequences that survive in the DNA of modern humans. Today, roughly 40% of the Neanderthal genome has been recovered not by sequencing ancient DNA recovered from a fossil, but indirectly by piecing together the Neanderthal sequences that persist in the genomes of contemporary individuals.

Similarly, in 2016 my group and David Reich’s group published the first comprehensive catalogs of DNA sequences in modern individuals inherited from Denisovan ancestors. Surprisingly, when we analyzed the Denisovan sequences that persist in people today, we discovered they came from two distinct Denisovan populations, and therefore at least two separate waves of matings occurred between Denisovans and modern humans.

The analysis of Neanderthal and Denisovan DNA in modern humans reveals that some of their sequence was harmful and rapidly got purged from human genomes. In fact, the initial fraction of Neanderthal ancestry in humans who lived approximately 45,000 years ago was around 10%. That amount rapidly declined over a small number of generations to the 2% observed in contemporary individuals.

The removal of deleterious archaic sequences also created large regions of the human genome that are significantly depleted of both Neanderthal and Denisovan ancestry. These deserts of archaic hominin sequences are interesting because they may help identify genetic changes that contribute to uniquely modern human traits, such as our capacity for language, symbolic thought and culture, although there is debate about just how unique these traits are to modern humans.

In contrast, there are also sequences inherited from Neanderthals and Denisovans that were advantageous, and helped modern humans adapt to new environments as they dispersed out of Africa. Neanderthal versions of several immune-related genes have risen to high frequency in several non-African populations, which likely helped humans fend off exposure to new pathogens. Similarly, a version of the EPAS1 gene, which contributes to high-altitude adaptation in Tibetan populations, was inherited from Denisovans.

It is also becoming clear that DNA sequences inherited from Neanderthal and Denisovan ancestors contribute to the burden of disease in present day individuals. Neanderthal sequences have been shown to influence both susceptibility to and protection against severe COVID-19. Archaic hominin sequences have also been shown to influence susceptibility to depression, Type 2 diabetes and celiac disease among others. Ongoing studies will undoubtedly reveal more about how Neanderthal and Denisovan ancestry contributes to human disease.

photo of man holding a human skull and looking at the face
Svante Pääbo’s work built the foundation of the new field of paleogenomics. Jens Schluete via Getty Images News

I was a graduate student when the Human Genome Project was nearing completion a little over two decades ago. I was drawn to genetics because I found it fascinating that, by analyzing the DNA of present-day individuals, you could learn aspects about a population’s history that occurred tens of thousands of years ago.

Today, I am just as fascinated by the stories contained in our DNA, and the work of Svante Pääbo and his colleagues has enabled these stories to be told in a way that simply was not possible before.

Joshua Akey receives funding from NIH.

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NYC biotech LB Pharmaceuticals eyes $75M for new take on decades-old schizophrenia drug

As Karuna Therapeutics wraps up its FDA approval request for what could be the first new type of schizophrenia drug in decades, another East Coast biotech…



As Karuna Therapeutics wraps up its FDA approval request for what could be the first new type of schizophrenia drug in decades, another East Coast biotech is raising $75 million to test an adjusted version of a decades-old medicine for the disorder next year.

LB Pharmaceuticals has secured about $35 million so far and expects another $40 million in the round, according to an SEC filing on Thursday. Per the financial document, its board includes directors associated with Vida Ventures, Pontifax, Deep Track Capital and TCGX, a crossover firm that has invested in multiple nine-figure biotech financings in recent months, including Carmot Therapeutics, Alkeus and Upstream Bio.

LB declined to comment.

The New York City biotech plans to run a Phase II trial of a chemically differentiated form of amisulpride, a D2 and D3 antagonist that has been available in Europe and more than 50 countries for decades, according to an investor deck from June. Sanofi marketed it as Solian, which generated €135 million in sales in 2002 for the French Big Pharma. It’s since become available as a generic.

LB’s board includes Piero Poli, CEO of Swiss drugmaker Rivopharm, which produces generic amisulpride. In February 2020, Acacia Pharma secured FDA approval for an IV formulation of amisulpride in certain postoperative patients with nausea, marketing it as Barhemsys.

With its methylated version of amisulpride, LB says its oral asset LB-102 has the potential to be more effective at lower doses by improving blood-brain barrier permeability, per the investor deck. Its new chemical structure gives LB-102 IP protection until “at least 2037.” LB has positioned the drug as a blockbuster treatment that could generate $1 billion or more in annual sales, pointing to antipsychotic prescriptions in the EU with an average price of $2,000 per month.

The drug is set to go into Phase II testing in adults with acute schizophrenia in the first quarter of next year, per the June document.

The company expects to enroll about 350 people at 25 sites, testing whether three doses of the drug are better than placebo based on the commonly used schizophrenia clinical trial measure known as PANSS, or Positive and Negative Syndrome Scale. Karuna’s M1/M4-preferring muscarinic agonist KarXT has passed two Phase III trials that use that measure, leading to massive financing hauls for the biotech and Cerevel Therapeutics. Boston-based Karuna plans to submit its approval request to the FDA this quarter. Meanwhile, Sumitomo and Otsuka’s ulotaront failed a Phase III on the PANSS test two months ago.

LB expects the study to focus on in-patients for four weeks. Pending the mid-stage results, the company would likely then take LB-102 into multiple Phase III trials in 2025, with plans to submit an NDA in 2028, per the June presentation. The company sees schizophrenia as the first step, with potential for studies in depression, bipolar depression and other indications.

Zachary Prensky

The drug developer is led by a former family office manager, CEO Zachary Prensky. LB’s medical chief is Anna Eramo, who previously ran clinical and medical affairs at Lundbeck’s US operations and worked on the development of Rexulti, approved for schizophrenia and other indications. Science chief Andrew Vaino and chief financial officer Marc Panoff were previous executives at Retrophin.

Prensky co-founded LB with Vincent Grattan, a pharmacist who came across amisulpride in the 2000s while working on medication managements in multiple prisons. “As many are aware, correctional facilities are de facto mental health hospitals, and I wanted to make sure we were stocking the most reliable medications,” he told Psychiatric News in 2021.

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Dana-Farber, Brigham breakup could lead to a ripple effect for CGT clinical trials for cancer

Dana-Farber Cancer Institute announced on Sept. 14 that it is securing a new joint venture with Beth Israel Deaconess Medical Center, marking a breakup…



Dana-Farber Cancer Institute announced on Sept. 14 that it is securing a new joint venture with Beth Israel Deaconess Medical Center, marking a breakup of its decadeslong adult cancer care partnership with Brigham and Women’s Hospital.

The news shocked Brigham, which had been negotiating a partnership extension with Dana-Farber for the past 15 months, according to the Boston Globe.

There are around 20 ongoing cell therapy clinical trials under the Dana-Farber Brigham Cancer Center, which comprises 12 treatment centers with experts from Dana-Farber and Brigham working together. Brigham also has its own gene and cell therapy institute and a lab dedicated to next-generation, genetically-modified CAR-T cell therapies for cancer.

With the Dana-Farber contract set to end in 2028, concerns have been raised about the impact on current cell and gene therapy (CGT) studies and ones that are scheduled to start, due to the complex nature of the treatments involved.

Jason Foster

Manufacturing CGTs is a skill- and labor-intensive process. Ori Biotech CEO Jason Foster told Endpoints News that hospitals and research centers often work together to make them on-site for clinical trials, with highly skilled experts from the specialty centers playing a key role. UK-based Ori develops technologies that automates CGT manufacturing.

At Dana-Farber Brigham Cancer Center’s cellular therapies program, cells are processed at an outside commercial facility or at the Connell and O’Reilly Families Cell Manipulation Core Facility.

When such partnerships come to an end, “that kind of [specialist] knowledge loss is something that will impact both the trajectory of [CGT] trials, but also the time it takes to get these products to patients,” Foster added.

These potential negative impacts on trials would only compound preexisting barriers to access to CGTs, including high costs and lengthy manufacturing processes. Estimates suggest that 25% of patients die while waiting for CAR-T treatments, according to ASCO Post.

Lee Buckler

Lee Buckler, senior vice president of advanced therapies at Blood Centers of America, told Endpoints in an email that collaboration between research institutes and healthcare providers was of significant — if not critical — value to the testing of CGTs.

A Brigham spokesperson said that the hospital is one of the largest recipients of NIH funding and does not expect any changes to trials already under agreement, adding it would continue to be a leader in the CGT space. “We are also planning for a new, state of the art Brigham facility which will include the medical oncology specialty,” the spokesperson said.

Dana-Farber did not respond to Endpoints before deadline.

Problems with CGT trials could be both the cause and the effect of partnership breakdowns. Buckler said that general hospitals are often reluctant to facilitate the kinds of clinical trial protocols associated with innovative CGTs, which may drive research centers to align with partners more willing to prioritize them.

Under the new partnership with Beth Israel, Dana-Farber plans to create a free-standing state-of-the-art cancer hospital, which it said would have the flexibility to “incorporate the innovations and technology in cancer care that Dana-Farber’s and BIDMC’s researchers and clinicians are developing every day.”

Vered Caplan

But a dedicated cancer hospital is not necessarily better at carrying out CGT trials than a general hospital with a tightly-integrated cancer specialty.

“I’ve seen general hospitals with tremendous capabilities and specific hospitals with tremendous capabilities — it really depends on the particular hospital,” Orgenesis CEO Vered Caplan told Endpoints in an interview. Germantown, MD-headquartered Orgenesis rolls out CGT mobile processing units and labs for cancer treatment to hospitals.

Regardless, the breakup means Dana-Farber must convince patients that its program with Beth Israel will provide at least the same quality care as the Brigham partnership, while Brigham must rebuild its specialist capabilities without Dana-Farber expertise.

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Zelensky Departs Washington Mostly Empty-Handed Amid Mood Shift In West

Zelensky Departs Washington Mostly Empty-Handed Amid Mood Shift In West

By all accounts, Zelensky came away from his Washington visit with…



Zelensky Departs Washington Mostly Empty-Handed Amid Mood Shift In West

By all accounts, Zelensky came away from his Washington visit with nothing new. Biden did announce a fresh $325 million aid package for Ukraine from already committed funds, but the hoped-for long range missile approval never came (however, more cluster bombs are being sent). And as we detailed Thursday, House Republican leadership once again failed to move forward on a mere procedural vote for the Pentagon funding bill, due in large part to GOP members rejecting Biden's proposed $24 billion more in Ukraine aid.

Thursday's package announced by Biden, as Zelensky visited the White House and Capitol Hill, was run-of-the-mill and entirely to be expected. "Today I approved the next tranche of U.S. security assistance to Ukraine including more artillery, more ammunition, more anti-tank weapons and next week, the first U.S. Abrams tanks will be delivered to Ukraine," Biden said.

As for the earlier in the day (Thurs.) meeting with Congressional leaders, House Speaker Kevin McCarthy explained when asked why the Ukrainian leader's request to address Congress was denied, "Zelensky asked for a joint session, we just didn't have time. He's already given a joint session."


Instead in a closed-door meeting, Zelensky later acknowledged he discussed with lawmakers "the battlefield situation and priority defense needs."

But if there is any level of consolation for Kiev, it's seen in the Pentagon announcement which came late in the day Thursday. Facing potential US government shutdown on Oct.1st, given at this point Congress is not expected to pass the 12 appropriations bills needed to fund government operations before next fiscal year, the Pentagon has said it will exempt its operations supporting Ukraine from a shutdown. 

The military typically suspends any activities not deemed vital to national security during government shutdowns, thus the DoD is in effect saying Ukraine aid remains "vital to national security". 

"Operation Atlantic Resolve is an excepted activity under a government lapse in appropriations," Pentagon spokesman Chris Sherwood told Politico, in reference to the operational name still used for actions supporting Kiev.

But Politico points out a potential shutdown would still negatively impact US support to Ukraine:

Sherwood noted that while DOD’s activities related to Ukraine will continue, furloughs and other activities halted under the shutdown could still have a negative impact.

"Training would happen, but depending on whether or not there were certain personnel that were not able to report for duty, for example, that could have an impact," said Pentagon spokesperson Brig. Gen. Patrick Ryder on Thursday.

This Pentagon exemption to keep Ukraine-related support active during a government shutdown seems to be the only significant thing Zelensky came away with. 

It appears to have been the main object of discussion when Zelensky met with Secretary of Defense Lloyd Austin in Washington during the trip. The Pentagon said this was "to reaffirm the steadfast US support for Ukraine."

Meanwhile, Bloomberg takes note of Zelensky "showing the strain" amid increasing divisions among allies:

The Ukrainian president allowed a dispute with one of his biggest allies to spin out of control at the United Nations General Assembly this week, and that’s just a hint of the tensions building behind the scenes.

Zelenskiy has been leading his country through Russia’s brutal assault for 19 months, all the time fighting on another front to wring the weapons and finance he needs from his US and European supporters. Now he suspects that President Joe Biden’s commitment is wavering and other leaders may be taking their cue from the US, according to a person who met with him recently.

He grew very emotional at times during that discussion, the person said, and was scathing in his criticism of nations that he said weren’t delivering weapons quickly enough.

Washington's lackluster greeting of Zelensky this week (compared to how he was received in December 2022) came simultaneous to Poland declaring it will no longer arm Ukraine, amid a fierce diplomatic spat over blockage of Ukraine grain imports by Warsaw, to protect Polish farmers.

The Economist is also taking note of the significant mood shift among Western allies...

A "long war" indeed... given a G7 leader from a European country has told reporters this week that the West is prepared for a years-long war, something likely to last some six or seven years, according to the quote.

"A senior official from one European G-7 country said the war may last as much as six or seven more years and that allies need to plan financially to continue support for Kyiv for such a long conflict," Bloomberg wrote.

Tyler Durden Fri, 09/22/2023 - 10:15

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