How did Dr. Perlman start studying viruses and the brain?

After obtaining a PhD in cell and developmental biology, Dr. Perlman went to medical school and became interested in pediatrics and infectious diseases. He grew interested in how baby brains interact with viruses, especially in utero, leading to his focus on how viruses interact with the brain. Coronaviruses in mice provided a model for this research.

What defines a coronavirus as a family of viruses?

Coronaviruses are categorized based on their appearance under an electron microscope, their replication strategy, and their genetic relatedness. They are distinguished by projections from their surface resembling the sun's corona or a crown, and possess a large RNA genome compared to many other viruses.

When were coronaviruses first identified and linked to common colds?

The first coronavirus, infectious bronchitis virus, was identified in chickens in the 1930s and 40s. In the 1960s, human common cold viruses with similar electron microscopic appearance were also identified as coronaviruses, linking them to mild respiratory infections.

What are the key differences between SARS-CoV-1, MERS-CoV, and SARS-CoV-2?

SARS-CoV-1 originated in southern China, caused severe pneumonia, and was eradicated due to its low transmissibility from asymptomatic individuals and lack of animal reservoir. MERS-CoV has a much higher mortality rate (35%) and circulates in camels, but its human-to-human spread is very low outside of hospitals. SARS-CoV-2 is highly transmissible due to upper respiratory tract infection and spread before symptom onset, leading to a much larger societal impact despite a potentially lower individual case fatality rate.

Why did SARS-CoV-1 disappear while MERS-CoV continues to cause sporadic cases?

SARS-CoV-1 disappeared because it had no animal reservoir and was only contagious when people were already sick, making quarantine effective. MERS-CoV, however, persists because it has a continuous animal reservoir in camels and can still spread in hospitals, even though its general human-to-human transmissibility is very low.

What is herd immunity, and what is the estimated threshold for SARS-CoV-2?

Herd immunity refers to the proportion of a population that needs to be immune to a disease to protect susceptible individuals by breaking transmission chains. For SARS-CoV-2, it's estimated to be around 60-70%, similar to other common viruses, although the large number of asymptomatic infections means many people may have immunity without realizing it.

Do coronaviruses, including SARS-CoV-2, undergo significant genetic drift like influenza?

Unlike influenza, SARS-CoV-2 has not shown evidence of significant genetic drift that would make vaccines ineffective or prevent immunity from previous infections. While some common cold coronaviruses like OC43 do vary, SARS-CoV-1 and MERS-CoV have been more genetically stable.

Is cross-reactivity from other common cold coronaviruses providing immunity to SARS-CoV-2?

Some studies suggest that individuals who have never been exposed to SARS-CoV-2 may show some T-cell responses, possibly due to prior exposure to common cold coronaviruses. However, these responses are often low-level activation, not full functionality, and the homology with SARS-CoV-2 targets is unclear, making their clinical importance uncertain.

What is the long-term outlook for living with SARS-CoV-2?

SARS-CoV-2 is likely never going to be eradicated, so society must learn to coexist with it. Key questions revolve around the durability of immune responses (both natural and vaccine-induced) and their ability to prevent both severe disease and viral shedding. Future strategies will likely involve annual vaccinations, similar to influenza, if immunity wanes.

How can we improve therapeutic strategies for future pandemics?

Effective therapeutic strategies require a more nuanced approach, combining antivirals early in the infection to stop replication and immune modulators later to mitigate host immune responses (e.g., cytokine storm). Developing biomarkers to identify disease stages and predict progression would allow for targeted therapies, optimizing treatment for individual patients.

Key Moments

#117 – Stanley Perlman, M.D., Ph.D.: Insights from a coronavirus expert on COVID-19

Peter Attia MD

People & Blogs3 min read104 min video

Jul 9, 2020|4,296 views|83|3

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Key Moments

TL;DR

Virologist Stanley Perlman discusses coronaviruses, their history, SARS/MERS, and insights into COVID-19.

Key Insights

Coronaviruses, a family of viruses, are named for their crown-like appearance under a microscope and vary widely in their hosts and effects.

SARS and MERS, while less transmissible than COVID-19, offered crucial insights into coronavirus behavior and immune responses.

The emergence of SARS-CoV-2 highlights the potential for zoonotic spillover and the importance of rapid pandemic preparedness.

Durable immunity to coronaviruses is uncertain, with mild infections potentially leading to waning immune responses.

Understanding the T-cell and antibody responses is critical for developing effective vaccines and treatments for COVID-19 and future coronavirus outbreaks.

Preparedness for pandemics involves "no-regret" investments in infrastructure like testing, PPE, and immune-modulating therapies, rather than solely focusing on specific known threats.

THE EVOLUTION OF CORONAVIRUS RESEARCH

Dr. Stanley Perlman, a virologist with nearly four decades of experience, shares his extensive research on coronaviruses. His journey began not with coronaviruses specifically, but with cell biology and developmental biology. A pivotal point was his interest in how viruses affect developing brains, particularly in infants, which led him to pediatric infectious diseases. He found that mouse models of coronaviruses offered a promising avenue to study severe diseases, including those with demyelination similar to multiple sclerosis, long before SARS-CoV-2 emerged.

UNDERSTANDING THE CORONAVIRUS FAMILY

Perlman clarifies that coronaviruses are a diverse family of viruses, identified by their appearance and replication strategy, not necessarily by their host or virulence. While some cause common colds in humans, others, like SARS, MERS, and SARS-CoV-2, have caused significant global health crises. The name 'corona' derives from the crown-like projections on the virus's surface. Importantly, coronaviruses can infect a wide range of species, including bats, birds, cows, pigs, and snakes, with bats being the likely origin of SARS-CoV-2.

LESSONS FROM SARS AND MERS

The outbreaks of SARS (2003) and MERS (2012) provided critical lessons. SARS, with an R0 of 2-3, emerged from a live animal market, likely originating in bats, and spread globally through human-to-human transmission, primarily in hospitals and during procedures that aerosolized the virus. Its control was achieved through quarantine and isolation as it was not contagious until symptomatic. MERS, originating from camels, has a higher mortality rate (around 35%) but lower human-to-human transmissibility, largely remaining confined to the Arabian Peninsula. These viruses demonstrated the capacity of coronaviruses to jump species and cause severe illness.

THE EMERGENCE AND DISTINCTIVENESS OF SARS-COV-2

SARS-CoV-2, the virus causing COVID-19, distinguishes itself through its high transmissibility, particularly from pre-symptomatic individuals and its ability to affect the upper respiratory tract, unlike SARS which primarily affected the lower respiratory tract. While SARS and MERS had high case fatality rates, SARS-CoV-2's vast number of mild and asymptomatic infections creates a large denominator. This widespread infection, combined with its transmissibility, leads to a significant number of severe cases and deaths, even if the individual case fatality rate appears lower than SARS or MERS. The virus's efficient entry via the ACE2 receptor contributes to its broad host range and infectivity.

IMMUNITY, THERAPEUTICS, AND VACCINATION CHALLENGES

A key challenge with coronaviruses, including SARS-CoV-2, is the durability of immune response. Studies on common cold coronaviruses suggest that immunity, particularly after mild infections, can wane over time, impacting vaccine efficacy and herd immunity. The development of effective vaccines and therapeutics is complex, requiring understanding of both antibody and T-cell responses. While cross-reactivity from prior coronavirus infections is being studied, its contribution to protection remains unclear. Therapeutic strategies are being explored, potentially involving early antiviral treatment and later immune modulation, highlighting the need for stratified treatment approaches based on disease progression and biomarkers.

PREPAREDNESS FOR FUTURE PANDEMICS

Perlman emphasizes the critical need for robust pandemic preparedness, advocating for "no-regret" investments in essential infrastructure such as stockpiles of personal protective equipment (PPE), scalable testing capabilities (reagents, platforms), and a national strategy for contact tracing. He also suggests maintaining a stockpile of immune-modulating drugs for potential late-stage treatment. This proactive approach, even in the absence of an immediate threat, is crucial to mitigate the devastating economic and social impacts of future pandemics, viewing such preparedness as a vital national security imperative, akin to maintaining strategic oil reserves.

Mentioned in This Episode

●Organizations

●Books

●Concepts

●People Referenced

Common Questions

Dr. Stanley Perlman is a professor of microbiology and immunology, pediatrics, and chair of biology at the University of Iowa. He has researched coronaviruses for nearly four decades, focusing on mouse models for SARS-CoV-1 and SARS-CoV-2 to understand severe human diseases.

Topics

Health & Longevity Neuroscience & the Brain Vaccine Development Viral Transmission Disease Progression Pandemic Preparedness Medicine & Clinical Herd Immunity Host Immune Response

Mentioned in this video

Software & Apps

SARS-CoV-1

The coronavirus responsible for the 2002-2003 SARS outbreak, derived from bats and civets, which caused severe pneumonia but was less transmissible than SARS-CoV-2 until advanced stages of illness.

MERS-CoV

The Middle East Respiratory Coronavirus, a highly lethal virus (35% mortality) found in camels and humans, confined mostly to the Arabian Peninsula, with low human-to-human transmissibility outside hospital settings.

Organizations

Department of Defense

The US government agency that released a report in 2010 or 2011 identifying emerging viruses as a major threat, with coronaviruses on the list.

University of Iowa

The institution where Dr. Stanley Perlman serves as a professor and chair of biology.

Cell

A scientific journal that published a paper co-authored by Alex Eddy in 2020 which described a cd8 T-cell response in patients recovering from COVID-19.

NIH

A government agency that funds medical research, making funding difficult for diseases that are not currently prevalent.

People

Bill Gates

A public figure who famously warned about pandemics, emphasizing the need for global preparedness.

Matt Ridley

A journalist who wrote an article in The Wall Street Journal about a paper published in Cell, which suggested SARS-CoV-2 might have been in humans longer than initially thought.

David Watkins

An expert whose previous podcast discussion on immunology is recommended as a precursor to understanding the current episode.

Alex Eddy

The senior author of a 2020 Cell paper that looked at T-cell responses in COVID-19 patients, suggesting cross-reactivity from other coronaviruses.

Stanley Perlman

Professor of Microbiology and Immunology, Pediatrics, and Chair of Biology at the University of Iowa, who has researched coronaviruses for nearly four decades.

Locations

Guangzhou

A city in southern China where flu viruses often start and where the SARS-CoV-1 outbreak originated from a live animal market.

Korea

The country where a single MERS-CoV patient infected 186 people, highlighting a confluence of bad luck despite the virus's low general transmissibility.

Concepts

mouse hepatitis virus

A mouse-specific coronavirus that Dr. Perlman worked with for years, serving as a model for studying demyelination and remyelination.

Multiple sclerosis

A human disease that Dr. Perlman studied in relation to coronaviruses and mice models, specifically understanding demyelination and remyelination processes.

SARS-CoV-2

The current coronavirus causing COVID-19, which is more transmissible than SARS-CoV-1 and MERS-CoV due to its ability to infect the upper airway and spread before symptoms appear.

influenza H1N1

The swine flu pandemic of 2009, which started with high perceived lethality but proved to have low mortality as more cases were identified.

influenza H5N1

A highly lethal avian influenza virus that causes severe pneumonia but never achieved significant human-to-human transmissibility.

Drugs & Medications

Measles

A highly contagious virus that infects only humans and can be eliminated through widespread vaccination, with an R0 of around 15.

RSV vaccine

A vaccine for Respiratory Syncytial Virus, noted as being difficult to develop safely compared to influenza vaccines.

Remdesivir

An antiviral drug that could potentially be used early in COVID-19 infections to stop viral replication if a patient showed signs of progressing to severe disease.

BCG vaccine

A vaccine used for tuberculosis immunization, which some people suggest might offer non-specific immune activation against coronaviruses, though its efficacy and specificity are questioned.

MMR vaccine

A vaccine for measles, mumps, and rubella, which was speculated to provide cross-reactivity protection against SARS-CoV-2, but this claim is dismissed due to lack of immunological evidence and the fact that older individuals would have had natural immunity.

Media

Wall Street Journal

A publication where Matt Ridley's article on the origins of SARS-CoV-2 was discussed.

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