16 minute read
The last letter covered what is a virus, more details on how coronavirus impacts the body, common symptoms and how to slow down the spread. If you have not read the last letter, this should be a good starting point before you get further.
From some time scientists have feared and run simulations on how bad disease like this can be. It has all the elements of making it one of the hardest epidemics to fight against.
- It’s respiratory which means it can be transferred through respiratory droplets not just when you are in contact with people but even if you are close.
- The virus can sustain on surfaces for a few hours to days.
- R the constant that describes how many people does a single infected person infect is anywhere between 2-5 in different conditions.
- Asymptomatic people can transmit this disease, so people who believe are healthy, feel no health issues or a minor cold are going to spread it. This also makes it difficult to trace.
- Mortality is high. Currently, while not a final figure the mortality rate lies between 1-4%.
- Symptoms can take up to two weeks to show and till then the virus has spread to many more people and places.
We discussed the SEIR model and the goal. The first goal is to slow down the spread of this epidemic so that we can buy time to create better test kits, find a cure and in the end find a vaccine.
What individuals can continue to do
Hygiene which includes washing your hands with soap multiple times and use of sanitizer. The virus is basically inside a shell of fat which breaks down when soap is rubbed on it. Soap also makes hands slippery and the motion removes the virus from your hands.
Masks ensure that the virus does not spread from respiratory droplets. This is essential as it covers the face and protests the nose and mouth of the healthy ones, and keeps it from spreading if you have actually caught the virus.
Social Distancing to not get in contact with other people. This avoids you getting in respiratory droplets by contact with an infected person and helps you avoid touching your face if you happen to touch an infected surface. If everyone wears a mask it means if you are infected you are unlikely to spread it.
But let us focus on what has been going on behind the scenes in the Science community has been up to over the last few weeks in order to fight it back. Remember the goal of individual action is to make this a slow epidemic instead of a fast epidemic. Individual action is going to slow down the spread, but it is not enough to eradicate the virus or build out immunity in us.
The Coronavirus Genome
Genomic sequencing is a process of analyzing the genetic material of a cell. This can be either DNA or RNA. Genomes are made up of chromosomes which in case of DNA form a double helix shape. Each cell contains 23 chromosomes. Each chromosome is internally made of up bases( a 4 letter combination of 4 strands).
RNA is generally single-stranded genetic material, which is what we look at when we look at Coronavirus. The Genome of Coronavirus was published on January 10th, 2020 so that everyone could start working on Test kits, Cures, and Vaccines.
The genomic data of the new coronavirus responsible for COVID-19 show that its protein spike contains some unique adaptations. One of these adaptations provides the special ability of this coronavirus to bind to a specific protein on human cells called angiotensin-converting enzyme (ACE2) just like SARS. The virus has adapted to find a different spot to bound that was not detected by the initial computer models.
These detections have helped trace the route that this virus resembles the coronavirus found in bats. However, the region that binds ACE2 resembles a novel virus found in pangolins which is why the current belief is that the virus jumped from a Bat or a Pangolin and then to a Human.
Either the virus mutated inside Bat or Pangolin to bind to molecules similar in structure to the human ACE2 protein or the other scenario in which it first jumped to a human and then mutated to adapt inside the human body.
We need to have a very high level of accuracy and consistency to announce something as a test kit, or a cure or a vaccine. And thus arises the need to very accurately detect the kind of virus you are dealing with.
Detection and Test Kits
In the case of a Test kit, it means given the same sample each time the result will be the same. The value of a test comes from its so-called specificity and sensitivity: Infected patients should be correctly identified as infected, patients who don’t carry the virus should be diagnosed as such, and people that unknowingly had the infection should be tested for immunity. This helps us understand who is infected, where the infection occurred, and how the virus was transmitted.
Some people require more than one test because of false-negative outcomes, and the approach has generally been to take 2 samples and perform 2 tests for each patient.
Assuming that each passed test kit fits the above description, is accurate, reliable and consistent the other parameters that decide how many people you are going to be able to test depends on the actual test procedure. Let us discuss a limiting factor that controls how many people can be tested and how quickly.
- Time to results – How long does it take for a test kit to give a result. When we started out in January this was in days and research helped bring it down to hours and the latest ones that are being approved or waiting for approval are claiming test results in minutes. The total time to result is also massively impacted by where the sample is taken to the actual place where the test will happen. A lot of time is lost in logistics and the capacity of the place of testing.
- Place of the test – The first set of tests were conducted in large hospitals and specialized labs. The capacity of these places is a limiting factor in how many people can get tested. The samples in most cases were sent to another lab, the process of RNA extraction was difficult and slowed down the entire setup. We now have test kits that can test you at a point of care center(includes smaller labs, your general doctor), if trained can perform those tests. These test kits made it possible for countries to set up drive-through testing, you drive up to a large area, sit in your car, give your sample and within a few minutes to a few hours you would get your results. The last step that is currently being researched and will hopefully be in the market soon is home test kits so that you can take a sample at your home and send it for testing.
- Ease of Test – The earlier specialized tests were also hard to do. A sample is taken from a patient’s nose or throat, using a special swab. The swab test was painful, the swab needed to go till your throat and a medical agent could only do it carefully. This would then be packed in a tube, sent to a larger lab. Lab workers would manually extract RNA from the sample, then special chemicals are mixed to run a PCR test. The latest ones allow you to take a sample yourself and we now have automated machines in which the sample can go and the entire process can be completed within a few minutes. This also removes a part of the limiting factor, which is number of medical professionals who were taking samples.
- Resources needed for testing – As smaller point of care and home test kits come into the market, the resources needed for a testis reduced. The initial limiting factors like lab technicians to manually extract RNA, take samples, place of sample, place of test can be heavily expanded given resources per test have gone down. This completely changes the number of tests that we can now do on an everyday basis than back in January.
- Ease and scale of production – We initially had a very small number of operational centers that could produce test kits. But with all countries fighting the same enemy, we are now in the phase of ramping up production of test kits across the world. South Korea which has been able to fight out the virus and develop point of care test machines is giving out the technology to the world. India has developed its own test kit. US government has approved new test kits for mass production.
Mylab Discovery an Indian molecular diagnostic company that earlier made test kits for HIV, Hepatitis B and C, and other diseases is now ready to produce up to 100,000 kits a week. Each kit is about Rs. 1200, can test about 100 samples in 2 hours. Currently, the imported kits in India cost Rs.4500 and take about 7 hours to give the result.
Abbot Labs in the US has developed a Point of Care Test kit based on Abbott’s ID Now platform, a widely adopted point-of-care system used to detect respiratory diseases including influenza. This claims to give out a positive test case in 5 minutes and a negative result in 13 minutes.
Senegalese Capital in collaboration with Mologic a British biotech company previously worked on vaccines for yellow fever and dengue are now creating a home kit for as low as $1 that can give results in 10 minutes. The process is being currently under approval. Once ready, they plan to manufacture these kits in Senegal and the UK. The project has received funds from the UK government and the Gates foundation.
In Canada research for the “lab-in-a-box” toaster-size test kit solution is going on. This would be able to read 384 patient samples at once and will be able to decentralize the process and give access to testing to remote locations.
SD Biosensor is one of five South Korean companies whose COVID-19 diagnostic tests are now making 350,000 tests a day up from 20,000 in January. South Korea is one of the countries whose approach to “trace, test, and treat” has appeared to control the epidemic at least for now. They want to ramp up the production to 1 million per day by next month.
Another South Korean company PCL has made a home testing kit similar to a home pregnancy test, but the accuracy reportedly is about 85%. They are now looking to improve the accuracy of the test kit.
Gates Foundation is working with multiple organizations in the hope to roll out a cheap home testing kit.
Currently, this is the best stage we have reached. While Scientists are working every day to create a drug that cures the disease and a possible vaccine our best chance currently in heavy testing. As the test kits become more affordable and mass-produced, we can exponentially scale up the testing across the board to ensure that we are able to test as many as possible. The availability and cost of testing kits along with other resources like centers for testing have been a major limiting factor. But this can not come at the cost of accuracy and consistency of the test kit.
Testing is by default the best way to detect and understand the disease better. How many actual people are impacted, what is the mortality rate, how many people seriously develop symptoms and the cure will not come without enough testing.
Drug Development and Cure
The process of a new Drug development is generally a long and expensive process running into years or decades and billions of dollars each time. There are currently available drugs that may be helpful in the cure or we may have to take a route to create a drug from scratch. The goal of the process is the create a drug that is effective, safe and available for patients in a short amount of time. Before we look at where we are in terms of COVID-19 let’s look at the steps involved in the development of a new drug.
- Identify a molecular drug target – The target for drugs are proteins. Proteins in the patient’s body or proteins in the virus causing the disease. Identify and figure out which proteins are relevant and confirm their role in the disease. This information is helpful in understanding which proteins to target for recovery.
- Drug Discovery / Identification of the first lead compound – This is an exercise of finding the right compound from millions of existing chemical compounds or biological compounds that are naturally available.
- Chemical Compounds – There are millions of synthesized chemical compounds that are created every day. High throughput screening and Computer-based designed are used to find chemical compounds that bind to the identified target protein.
- Biological Compounds – Large biological compounds are usually induced to the living host to produce the kind of antidote that will be created to fight off the foreign compound by the body. Next, you find the best antibodies that are effective. Unlike chemical compounds, biopharmaceuticals are usually created from living cells.
- Once a compound modulates the target protein it is refined for safety and effectiveness. This then becomes a candidate for an effective drug. From about 10000 early drug hits about 1 make it to the market. Computer-based detection is used to find out the amount of absorption of this drug in the blood, the time it stays in the body, etc.
- Safety and Drug Metabolism – Animals play an important role in this process. While a large number of experiments can be done on computers or seeing compounds interact with each other. Complex disease mechanisms can only be understood by studying animal behavior and reaction to these drugs. Most agencies and government authorities require tests to be performed on animals before human trials can take place.
- Clinical Trials – In the later stages it safe for patients. It is also tested to have the relevant amounts of pharmacokinetics properties like absorption or metabolism inside the human body. Clinical trials usually run in multiple phases. There are used to find out drug safety and efficacy in the human body.
- The drug is usually tested on a healthy patient to understand the pharmacokinetics.
- Then it is given to a group of a few hundred people with the disease to evaluate its efficacy, safety, and dosage amounts. We are also looking to find out the side-effects of the drug.
- Next, we are looking to see the impact on the actual disease on a group of patients. See them through their recovery and make the drug available for larger clinical trials.
- Larger clinical trials involve a few thousand affected people. This gives a larger sample size for confirmation of the findings from the above clinical trials. To ensure safety, efficacy, and side-effects of the drug. This will give us additional information, allow us to compare it with other available treatments and create benchmarks.
- Registration and approvals – This involves following procedures laid out by varies countries and submitting reports of the trials with each approving authority. Most authorities require submission of reports and findings at regular intervals until the drug is in the market. Some may ask for additional data or another phase of clinical trials before the approval.
- Mass production – This is the phase in which setups for mass production of a drug are setup. We need to now replicate the approved drugs in quantities to be distributed across the world.
Coming back to Coronavirus, given that we do not have a decade to develop a new drug we are having to accelerate the process. Some of the things that are being done.
- Looking for the impact of existing drugs on the virus – A large variety of medications around the world has been developed not specifically for this drug but this category of drugs. Scientists across the world currently are trying to run trials with different medications.
- Chloroquine a compound has been approved for clinical trials. This has been used to fight Malaria. Studies with the earlier SARS-Cov virus have shown Zinc to slow down or stop the replication of viral RNA. The problem is Zinc can’t enter inside the cell membrane which the virus has hijacked. Chloroquine is an ionophore(a compound that makes the cell wall permeable) and allows zinc to pass through the cell membrane. The problem the compound may have some toxicity and safety concerns. Azithromycin is another compound with similar properties.
- There are more than 35 currently available medications that are being tested for the effect on this virus. Given that I have no medical background, I would avoid naming any here until approved by an agency.
- We are skipping the steps of animal trials and going directly towards clinical trials. While this may have drastically bad effects, but scientists are trying to complete a process that takes years in a matter of days and weeks as Coronavirus spreads.
- Blood transfer of a recovered person has worked in cases of some other virus. Blood of a recovered patient ideally has developed capabilities to produce the antibodies needed to fight against the coronavirus, and thus the widely held belief that you will only get infected once. But there are several challenges as this has not been verified yet. This is definitely not scalable and we have no idea how much blood will is required to be given to a patient, at what stage.
Treatment of Severe cases
- Plasma Transfusion is a process of specifically taking out plasma(the fluid that carries the blood components throughout the body). The plasma is the actual component in the blood that can produce the antibody in the above step. This is used in conjunction with other life-saving techniques when the patient is in Intensive Care.
- Ventilators have been around for a long time now. They are used when you are in an emergency situation fighting a severe respiratory disease. If you remember from the previous letter, Alveoli help in gas-exchange of O2 and CO2. If they are not able to perform as expected your O2 levels will go down and CO2 levels will rise. Ventilators provide mechanical support to ensure your O2 and CO2 levels are kept normal.
Smallpox is a disease mentioned in Ancient Indian texts, Ancient Egypt. Just a few decades ago, we have been able to completely eradicate Smallpox from the world. It has killed Roman kings and killed indigenous American people. This was a completely global disease in that sense that survived and infected across millenniums.
Edward Jenner about 2 centuries ago can be attributed to one of the first scientists to contribute to vaccines. Till this time the only procedure to create immunity was to actually infect the person with the actual disease and quarantine him. He would either die or recovered but due to the risk of human to human transfer he would have to be isolated.
Jenner did an experiment where he first gave a child Cowpox, which is a milder form fo Smallpox. After a couple of months, he gave the child Smallpox, which at that time was the leading infection killing hundreds of thousands every year. The child did not get sick with Smallpox. His body seemed to be immune to the disease. Though he did not at that time understand how his remedy worked. This was even before scientists published that infectious diseases were caused by germs.
To completely remove a disease that can spread in humans we need the entire population to be vaccinated from it. We now have vaccines for TB, Smallpox, polio and many more deadly diseases.
Inside your body
Every day your body is attacked countless times by different agents but generally, your Immunity cells like Nuetrophile are able to deal with it. This is your first line of light defense in the Immune system. But if these are not enough to deal with the threat we have the Dendritic Cells, which gather intel on the threat. They try to understand the thread and then order B-Cells and T-cells who produce weapons against the threat. You can imagine B-cells are weapon producers, in the case of the Immune system the weapon is anti-body. The intelligence gathered helps in producing targeted anti-bodies, just like a homing missile to only go that will go and launch a targetted attack.
The problem is this process can take several days, which gives the intruder a lot of time to do damage. This also means that your immune system by the end of it has fought a long battle, is tired and has exceptionally low energy. During this time your body can be overtaken by the intruder or even if the immune system is able to win the war, any new intruder can easily have a full run as your body is still in recovery and not ready for another battle.
Whenever our body fights with such intensity that heavy weapons have been needed to kill the threat, our body creates memory cells. Memory cells hold information, imagine like permanent hard drive storage. Next time a threat like this comes again, they wake up and start ordering the recovery process and antibody generation directly. This process is now superfast and the body is not wasting time in first fighting with soldiers and gathering intel. They already know the enemy and get to production.
Once you have gone through this process the body has built an immunity to them. In most cases, the same infection will not be able to get past your immune system the next time and you will have memory cells with that information in your body for a lifetime. This is one of the reasons why children get sick more often, as they have not formed enough memory cells and their bodies know less about how to fight off the invader.
The above mechanism is used to form Vaccines. The body is injected with a compound that resembles the intruder in very small, unharmful amounts. or putting in intruders that are dead or ripped apart.
Live vaccines are given when you actually have to inject the a similar less harmful virus in small non-lethal quantities so that your body can form enough memory cells. Cowpox being injected to form memory cells that will fight Smallpox is the best example. Effectively your body needs to be prepared to fight living intruders and not dead compounds who don’t fight back. The body is quickly able to fight the intruder and create memory cells and be ready to fight the disease when it comes.
Different groups have reached different stages. Johnson and Johnson today announced that they are ready for preclinical trials(animal trials). There are many other organizations at stages of trying to find the right Biological candidate.
Scientists in the last few years have understood much more about genetics. While trying to cure cancer a new specialized field of vaccines was formed. This is the converging of Cancer biology, Genomic sequencing, and Computer science. The end result is a tailor-made vaccine for the specific person only effecting the specific cancer cells. One important factor to take away from this are the vaccines are made by using the genome of specific cancer. The end result is a vaccine which is an mRNA(messenger RNA), that delivers a message to the Dendritic cells(remember our intel gatherers) and gives them the genome to be fought.
Some genetic startups have who have been working on the mRNA approach seem to be making progress faster. They have been successful at extracting the RNA of the virus and creating a harmless replica using that RNA using genome sequencing. Moderna is a company that may go to clinical human trials in the next couple of months. BioMagica is another company working in this domain of mRNA based vaccines.
Remember how the SARS-Cov-2 virus connects to the ACE-2 connector of the cell to latch on and transfer the RNA sequence for replication. One of the possible candidates for vaccines the mRNA-1273 is being currently tested on animal models. Once injected it should make the viral protein that connects to our cell, which in turn should trigger our immune system to fight this protein.
The challenge with this approach is that it first needs to be tested on healthy people and observed for a long time. Compressing timelines may mean causing long term effects and given that once the vaccine becomes available it will be given to a Billions of people, the need to be careful is imperative.
Coronavirus – where we are?
Testing kits are in the stages of approval and mass production, some even going as high as hundreds of thousands per day looking to scale up to a million a day. The scale-up for testing kits should happen in the next couple of months it seems to required levels.
Medicines and cures are just approaching the clinical trials, if one of the existing compounds is able to help as an antigen to the virus, we may see the scale-up also happen extremely fast given that the approval has been expediated and the manufacturing of existing antigens has some existing infrastructure.
Vaccines are still behind. Even if developed today, mass production will take anywhere between 12 to 18 months to become available. When the RSV vaccine was first created it made things worse in the initial worries. Just to test if the immunity is built up, has no longer-term effects and go-to mass production this is already a heavily compressed timeline.
While this seems like a long time, but if this timeline is met this would be the fastest developed vaccine in human history. Do remember that the genome of the virus SARS-Cov-2 was published on January 10th this year.
The challenge in the urgency remains the accuracy and safety of each of the different aspects. Will skipping some steps in the drug and vaccine development still give out the best results.