Updated: Jul 8
Stanford University Hospital is located in Santa Clara County, CA – one of the early hot spots of the SARS COV2 pandemic in the U.S. The hospital opened in late in 2019 – no one expected that one of it’s first real challenges would be dealing with COVID19. Researches from many disciplines pooled their efforts to create tools with which to combat the virus and treat the disease.
I first listened to the radio interview of Dr. Blish, Immunology on the trail of a killer, while I was self-quarantining after a possible exposure to COVID 19. I was very impressed, not only with this interview but with each one of the series that I listened to. It is out of a desire to understand more deeply the nature of this life changing virus that I decided to spend a little time capturing and recording the content. As I got into the nuts and bolts, I realized that I needed to include a few bits of information to flesh out some of the complex terminology used during the interview. This is an offering to all of you who simply want to know more. I hope you enjoy the read.
Protecting the Researchers
The researches at Stanford University were quick to set up a Respiratory Bio Safety Level 3 facility in which to safely study the SARS COV2 virus in coordination with a university facility that was currently studying TB. When the need arose, the director of the BSL-3 lab destroyed the TB samples in order to convert the lab to a strict SARS COV2 facility.
According to the CDC, in a lab that designated BSL-3, the microbes there can be either indigenous or exotic, and they can cause serious or potentially lethal disease through respiratory transmission. Respiratory transmission is the inhalation route of exposure. One example of a microbe that is typically worked with in a BSL-3 laboratory is Mycobacterium tuberculosis, the bacteria that causes tuberculosis. https://www.cdc.gov/training/quicklearns/biosafety/ (Accessed 5/24/2020)
In the interview, Blish states that it is airborne transmission of the SARS COV2 virus that is of the highest concern to her as a researcher. She explains in detail the multitude of precautions taken to protect lab workers from these viruses which she describes as airborne pathogens.
Gaining Understanding of the Virus
This is Blish’s first experience working with a SARS virus, and states that there is so much that is not yet understood about this virus, but also much that can be inferred from what science knows about SARS CoV1 -- the virus identified in 2003. Her team is starting with the basics and attempting to answer questions about pathogenesis. Which cells does it infect? How does it infect them? What happens to the cells when they are infected?
She is using tissues (organoids) created by other Stanford Researches that function as lung, gut, and other human tissues. The goal is to build the best systems to mimic infection in order to do drug tests. Often the goal is to develop brand new drugs, but because of the urgency of a treatment for COVID19 they will test drugs for other conditions that have been tested and proven safe. Currently the researchers are still growing the virus samples and the systems required for drug testing.
One of the big questions we all have is does the virus change over time? The Stanford team is developing a Bio-bank of virus samples from COVID 19 patients at Stanford University Medical Center. The hope to soon include samples from surrounding communities. This data is helpful in looking for evolution of the virus, as well as to compare lab research to what is actually happening to patients with COVID19.
What little they do know at this point is encouraging. Unlike other RNA viruses that change very quickly (HIV, influenza) the coronaviruses are massive and have a huge genome, lots of nucleotides. They can’t risk “screwing themselves up too much” so it encodes a proof-reading gene which scans to make sure it is not making a mistake. All viruses have the capacity to evolve over time. But this virus may evolve a little less quickly than influenza or HIV. This makes finding a vaccine and/ or a drug treatment that the virus cannot escape or evolve resistance to more feasible.
Dr. Blish believes that our viruses know us better than we know ourselves. She explains that they have all evolved mechanisms to try to escape from our immune response. There are many ways that a virus tries to escape and evade our protective immune mechanisms. The following are some of the unique and surprising observations her team has made regarding the battle between the human immune defense system and this virus:
1) Blish’s team profiled the immune response of 7 people and 8 samples with severe COVID19 – the disease caused by SARS CoV2. Half of the samples were drawn while the patient was being treated for Acute Respiratory Distress Syndrome (ARDS) on a ventilator. They saw a complete and massive reshaping of the immune response in all of the subjects. This led Blish to believe that this virus has taken a dramatic escape mechanism. That escape mechanism involves a molecule on immune cells called the MHC (major histocompatibility complex). The job of the MHC is to talk to T cells (another important aspect of our immune system which is vital for immunity and memory). MHC tells the T cells – here is a piece of the virus you should respond to. In the test subjects, the more severe the infection the fewer MHC molecules were present. This is the exact opposite of how it is supposed to work. The result is likely that the virus is inhibiting the CD 4 T cells which are the orchestrator of the immune response (the cells that HIV decimates). In the setting of severe COVID19 the T cells are probably not receiving the message they need to identify and fight the virus.
2) There has been a lot of attention around the concept of “cytokine storm” COVID19 patients.
chemicals causing too much inflammation which is making these patients very sick. It probably is a part of how this virus is causing disease, but Blish’s colleagues in critical care report that the cytokine storm does not appear to be as severe in COVID19 as it is in ARDS with other causes. Blish’s team did not observe massive release of cytokines from the blood cells as would be expected. If there is cytokine storm it must be happening locally, in the lung tissue itself.
3) Blish reports that it appears that the immune cells – T cells and Natural Killer cells appear exhausted in the study subjects.
4) In most severe cases B cells which make antibodies turned themselves into granulocytes which do not have the capacity for making antibodies. This happened under the influence of the virus.
Optimism and Gratitude
Blish appreciated the group mentality with COVID research. She is optimistic about possible drug treatments going to clinical trials. She states that a vaccine is the best hope for combating the virus and is excited that the first human vaccine trials have begun. She is also very pleased that Stanford, Berkeley, UCSF, Davis and Gladstone – institutions that often compete with one another – have formed a consortium. They are sharing knowledge, reagents, equipment and working together for the common good.
Sophia’s additional notes:
About the cytokine storm
Cytokines are proteins released by a broad range of cells in the body to trigger an immune response against an antigen, by coordinating the action at the region of infection, directing immune cells to the site, and eventually causing inflammation. This is the body’s natural defense mechanism and is an important part of the healing process.
Sometimes, however, this immune response goes into overdrive by an excessive and exorbitant amount of cytokine production, turning the ‘localized’ inflammation into hyper-inflammation, impacting not just the infected areas, but the rest of the body as well. This unregulated and uncontrolled production of cytokines is known as a ‘cytokine storm’ - as the name suggests.
Dr Susheel Bindroo explains:
The production of cytokines is actually a protective mechanism to contain the spread of a pathogen and stop the exposure. But when the balance between pro-inflammatory and anti-inflammatory mediators in the body is hampered, leaning heavily towards the pro-inflammatory response, it starts targeting the body’s own healthy tissues along with the pathogen. This is essentially what characterizes a cytokine storm.
About Acute Respiratory Distress Syndrome
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) result from a common pathogenic process: pulmonary injury or infection triggers an overwhelming inflammatory response (cytokine storm) that results in increased endothelial and epithelial permeability and efflux of inflammatory cells, protein, and water from the vascular system into the alveolar space. The incidence of ALI is estimated to be approximately 79 cases per 100,000 person-years. The treatment for those afflicted remains largely supportive with a mortality rate of approximately 40%.
https://grantome.com/grant/NIH/R43-HL127886-01 (Accessed 5/25/2020)