There are many SARS-CoV-2 strains with gene deletions

In my first post on a possible solution to COVID-19 I hypothesised that there would be gene deletion mutants to be found in the SARS-CoV-2 viral strains out in the world and that we would find them if we looked.

Unfortunately, when I posted there were very few full genome sequences in the public databases (under 1000) and many of these sequences were of low quality and contained gaps due to poor sequencing coverage. These gaps look like gene deletions when you try to do bioinformatic analysis.

Since then the COVID-19 Genomics UK Consortium (COG-UK) has released 10,567 complete SARS-CoV-2 genome sequences. Bioinformatic analysis of this data has revealed 69 of these genome sequences contained gene deletions. The full list can be found here, but here is a partial list.

Partial list of the gene deletions found in the COG-UK SARS-CoV-2 genome sequence

Partial list of the gene deletions found in the COG-UK SARS-CoV-2 genome sequence data

The really interesting deletion mutations are those in the non-structural accessory genes. These are the genes that are likely to play an important role in pathogenicity and it would be expected that some of these mutations may make the virus less dangerous (attenuated).

The next step (beyond obtaining more sequences from locations other than the UK) is to go and visit the people who were infected with each of the different deletion strains and investigate what was their clinical outcome. If the patient only had a mild case of COVID-19 then we have a potential attenuated strain and we need to look for more cases caused by this mutant strain in the local area (including in the hospitals).

If we find that everyone who was infected with a particular deletion strain only had a mild case of COVID-19, then we have our candidate attenuated strain which could be used to accelerate vaccine development in a challenge trial. Finding such an attenuated strain should allow us to shave many months off the development of an effective vaccine that will protect us from this terrible pandemic. The value of this in both lives and dollars saved is immense.

It is unethical to not search for an attenuated SARS-CoV-2 strain

One aspect of the Search for an Attenuated Natural strain via Epidemiology (SANE) that I have not discussed in depth is the use of an attenuated SARS-CoV-2 strain as tool to accelerate the development of a vaccine for COVID-19.

There are now nearly 100 different SARS-CoV-2 vaccines in various stages of development, although only 5 are in Phase 1. Nature Review Drug Discoveries has published an excellent review on all the different vaccine approaches. There is an enormous scientific and financial effort going into all these programs, but when will we have a vaccine?

Vaccine Development Bottlenecks

Vaccine development has a number of significant bottlenecks. Assuming you have a vaccine candidate that appears safe in preclinical and early stage human testing (Phase I & II), the major hurdle you must overcome is showing your vaccine actually works in the real world. This often requires large scale Phase III human field trials where you vaccinate 10,000s to 100,000s of people and then monitor them over time to see if they are protected from the disease. For example, the Francis Field Trial of the Salk Polio Vaccine in 1955 involved vaccinating 440,000 children in the USA, along with 210,000 children getting placebo injections, and 1.2 million additional children used as controls. The 1961 Sabin Oral Polio Vaccine Phase III trial involved vaccinating 10 million children in the Soviet Union. These were truly heroic trials to show these vaccines worked.

An alternative to running huge Phase III field trials is the challenge trial. With this approach you test if your vaccine works by exposing a relatively small numbers of volunteers to the disease and seeing if the vaccine protects them from getting infected. By using deliberate exposure you can limit the number of people you need to put at risk to determine if a vaccine works.

The process to vaccine licensure through a controlled human challenge trial and large study to assess short-term safety (black) compared to the conventional phase 3 trial route to licensure (grey).

Ethics of Vaccine Development

Developing a new vaccine raises many ethical dilemmas. Do you expose your volunteers to the disease to see if it works (challenge), or do you instead expose large numbers of people (field trial) to a vaccine that may not work?

If your vaccine is for a disease for which there are good drug treatments (e.g. malaria), or if the disease is mild (e.g. the common cold), then the challenge approach can be an ethical way to show a new vaccine works. If the disease is dangerous (e.g. HIV), then you must use a field trial approach as it is not ethical to deliberately expose people to a deadly disease.

Beyond the ethics of these different approaches, there are practical concerns too. Not only are large field trials much more expensive, they takes much longer than a challenge trial as the logistics of vaccinating and monitoring hundreds of thousands of volunteers is not trivial. In times of a pandemic like we have with COVID-19, every day of delay results in the deaths of many thousands of people.

Ethical Dilemma of a SARS-CoV-2 Vaccine

COVID-19 raises some unique ethical issues. We want an effective vaccine as quickly as possible, but COVID-19 is a deadly disease for which we currently have no effective treatments. Large scale Phase III field trials will take many months to run even once we have vaccine candidates ready to test (we are nowhere near being ready to run such a field trial). Some people have suggested that we expose young and healthy volunteers to SARS-CoV-2 after vaccination to speed up the vaccine development process (i.e. run a challenge trial). More than 1500 people have signed up to participate in such a trial.

The important question we have to consider is if it is ethical to deliberately expose even the young and healthy to the dangerous SARS-CoV-2 virus when we know it could seriously injure or kill them. It might be justified if there were no alternatives, but if we had an attenuated/mild strain of SARS-CoV-2, nobody would even think of using a dangerous strain in a challenge study as it would be completely unethical. It is only the lack of an attenuated strain of SARS-CoV-2 that leads people to even contemplate using a pathogenic strain in a challenge trial.

The Ethics of not Looking for an Attenuated SARS-CoV-2 Strain

If we know it would be unethical to use a dangerous pathogenic strain of SARS-CoV-2 in a challenge trial if we had an attenuated strain, and if we know how to look for an attenuated strain, how can it be ethical to not search for such a strain? How is it ethical to consider exposing people to a dangerous virus just because we can’t be bothered to look for a safer strain?

The only conclusion we can draw is the search for a natural attenuated SARS-CoV-2 strain is an ethical imperative even if the chance of success is low. We can not ask our COVID-19 vaccine volunteers to put their lives on the line for us just because we thought it would be too difficult to look for a safer strain. Convenience is never a justification to act unethically.

Time to do what is right and go searching.

How would a search for a natural attenuated SARS-CoV-2 strain work in practice?

My previous post on a possible solution to COVID-19 has attracted quite a bit of interest on Twitter and Hacker News, but I have noticed that many people are having difficulty understand how it might work in practice.

So how exactly would we go about looking for a naturally attenuated (weakened) SARS-CoV-2? The answer is there are many good ways, but I thought I would describe one approach. It is very likely there will be better approaches, but for the purpose of illustrating how you could go about doing this, what follows should help.

Step 1. Obtain 50,000 swab samples collected from people known to have only mild/asymptomatic cases of COVID-19.

We would request swabs from known positive COVID-19 cases from around the world with the aim of sampling from the widest number of locations. The aim here is to cover as much of the SARS-CoV-2 genetic diversity out there in the world. In practice, most of the samples will come from rich countries purely because that is where most of the testing is being done, but we do want to make an effort to cast the net as wide as possible. A map of the current genetic diversity of SARS-CoV-2 found around the world is shown below.

Phylogenetic network analysis of SARS-CoV-2 genomes

Phylogenetic network analysis of SARS-CoV-2 genomes

Step 2. DNA sequence the genomes of all 50,000 SARS-CoV-2 strains.

We would perform conventional next-gen genome sequencing on the samples. While this seems laborious and expensive, with modern genome DNA sequencing instruments you can sequence all 50,000 viral genomes in a single run. The genome of SARS-CoV-2 is approximately 30,000 nucleotides long. To sequence each nucleotide 20 times for all 50,000 samples will require 30 billion bases (nucleotides) of raw sequencing. With a modern genome sequencer like the Illumina NextSeq 2000 can sequence 300 billion bases in 48 hours – more than 10x the capacity we need. The cost of all this sequencing is low – in the thousands, not hundreds of thousands dollar range.

Illumina NextSeq 2000

Illumina NextSeq 2000

Step 3. Analyse the raw genome sequence data for deletion mutants.

This step involves assembling the raw data collected from the DNA sequencer to generate the genome sequence of each viral sample. Each genome would be aligned (matched up) to the reference genome (i.e. the dangerous strain) to look for regions of the genome that are deleted (missing) from the genome.

What we are looking for is regions of more than 30 nucleotides that have been deleted from one of the strains. These strains with gene deletions will be our putative attenuated strains.

What such a sequence alignment looks like is shown below – regions of deletions are shown with a dash (-) (technical note. This is actually an alignment of the translated amino acid sequences, not DNA sequences).

Multiple sequence alignment of coronavirus spike protein S2

Multiple sequence alignment of coronavirus spike protein S2

Step 4. Develop a rapid test for the deletion mutant strains.

We will need to develop a rapid test for the gene deletion mutant strains. This is one of the easier tasks as it just involves designing different primers for use with the current SARS-CoV-2 RT-PCR test kits.

Step 5. Screen for additional COVID-19 cases in the local area where each putative attenuated strain was isolated.

The first four steps are relatively cheap and quick, the next few steps are more difficult. Once we have identified one (or more) putative attenuated strains we need to find more clinical cases resulting from infection with these strain(s) to ensure they are true attenuated strains.

This step will require going into the community where the person who provided the original sample lives (the index case) and taking nasal swabs from people and testing them for SARS-CoV-2 infection. We will need to collect many thousands of swabs from the local area (using an expanding ring approach) to find as many additional cases of COVID-19 caused by these strains as possible. The COVID-19 patients in the local hospitals will also need to be checked to make sure the strain is not making people seriously ill.

Step 6. Monitor the clinical outcome of infection by the putative attenuated strain(s).

Any positive cases of infection by the putative attenuated strains will need to be monitored for at least a couple of weeks to determine the final clinical outcome. While this is occurring, we will need to collect additional swabs from the close contacts of those identified as being infected with the putative attenuated strains. What we want to find is that all the people infected with a putative attenuated strain only get mild or no symptoms and none end up in hospital. If we can identify a large number of infection cases then we will have strong epidemiological evidence that the putative attenuated strain is actually attenuated and unlikely to cause serious illness or death.

We will also want to take blood samples (serology) to check that the attenuated strain can still create a strong immune response to the virus and that will cross-protect with the dangerous strains. My estimate (which may be wrong) is the first five steps will take 2 to 3 months if we make a serious effort.

Step 6a. Scaling up production of the attenuate virus.

This step is complex, but conventional. It is not hard to grow large volumes of virus at an industrial scale in cell culture. We have been doing this since the 1950s when the polio vaccine was first created. The only major issue is to make sure that the process is efficient as possible and not a point of delay. I would advise that this step be started as soon as we identify a putative attenuated strain so that when (if) we have a attenuated strain we don’t need waste time in the scale up process.

Industrial Cell Culture Plant

Industrial Cell Culture Plant

 

Step 7. Using the attenuated strain.

Assuming steps 1-6 have gone well and we have identified and mass produced an attenuated (deletion) strain of SARS-CoV-2 that doesn’t appear to cause serious illness, then we have reached the point of choosing how and when to use this strain as a live attenuated vaccine. This will be a political and regulatory decision that will need to balance the risks and rewards of using it at scale. While this won’t be an easy decision, it will allow us to at least have a discussion rather than just waiting for another vaccine that may never arrive.

A (possible) solution to COVID-19

Notice. Since this seems to be such a common question I think I should describe my background. I have a PhD in molecular microbiology and I was once a tenured academic (professor). I now work in the biotech sector. I have published a number of peer reviewed papers in virology. If you really want to know more about me then visit my About Me page. 

Like nearly everyone on the planet I am worried about COVID-19. SARS-CoV-2 (the virus that causes COVID-19) appears to be killing between 1% to 3.5% of the people we know it infects (i.e the case fatality rate) and has a R0 (i.e. how many new people each person infected goes on to infect) of between 2.5 to 3.9 or even higher.

Newer reliable serology data, such as the studies done in Switzerland and China (i.e. not Santa Clara or Los Angeles), suggests the true infection fatality rate (IFR) is around 1%. Left to run wild, this virus will kill tens of millions of people worldwide.

Many governments of the world have implemented strict population isolation protocols to try and limit the spread of the virus, but the economic cost of this is extremely high. A vaccine for COVID-19 is 12 to 18 months away (at best).

We are stuck in a diabolic situation where the only way to prevent the economy sliding into a slump deeper than the Great Depression is to consign many tens of millions of people to an early grave. Is there a way out?

SARS-Cov-2 Viral Diversity

SARS-CoV-2 like all viruses mutates (changes) overtime. Many of these genetic changes are small (single nucleotides) that are not important to the replications or transmission of the virus from person to person, but they can be used to identify the origin of the virus. DeCODE genetics for example has been testing Icelanders for COVID-19 and genome sequencing the SARS-CoV-2 strains isolated. They (and others) have found two very important pieces of information:

  1. More than 50% of the people infected with SARS-CoV-2 are asymptomatic or have only a mild case (i.e. they have no serious illness).
  2. They can identify the geographical origin of the strains by the genetic differences (mutations) between the different strains.

Furthermore, researchers in China have identified a mutant strain of SARS-CoV-2 which appears to be less pathogenic than most strains infecting people. The strain (ZJ01) had single nucleotide mutations in a key functional gene that made it less able to spread through the body. A recent pre-print paper from Singapore has described a mutant strain of SARS-CoV-2 with a 382 nucleotide deletion that was found in a cluster of patients in one of their hospitals. An even more recent paper from China found 11 of strains of SARS-CoV-2 with variation in pathogenicity in cell culture.

This data suggests a simple and testable hypothesis – there are natural strains of SARS-CoV-2 in the world that have mutated to be non-pathogenic (asymptomatic or mild), but which are still infective and will provide immunity to the more pathogenic (deadly) strains.

If we can find one of these non-pathogenic viral strains out in the wild we could give it to everyone in the world and solve our diabolic problem. This non-pathogenic (attenuated) strain would act much like the live attenuated (oral) polio vaccine.

Update. The genome sequence data collected to date has found that there are many SARS-CoV-2 strains with gene deletions.

How do we find an attenuated SARS-CoV-2 strain?

This hypothesis is worthless if we have no way of finding any of these non-pathogenic SARS-CoV-2 viral strains. Luckily there is a quick and cheap way to find these strains if they exist – test asymptomatic/mild case swab samples for COVID-19 and then genome sequence the SARS-CoV-2 strain that has infected them with the aim of identifying a virus with mutation(s) in essential viral gene(s). This is what the Chinese researchers did to find their less pathogenic strains and how the Singaporean researchers found their deletion mutant strain.

This approach is cheap (a couple of hundreds of dollars per virus strain) and quick (a week or less). With little cost we could sequence a few thousand viral strains, or even tens of thousands of strains, from positive swab sample from asymptomatic and/or mild case until we find a virus strain with the right mutations to make it harmless and which could work like a vaccine to protect us from the dangerous strains. We would know from epidemiology that this strain can still reproduce in people and lead to immunity, but not make people seriously ill. 

Update. I have written a step-by-step post on one way we might go about putting this proposal into action.

What viral mutations are we looking for in a good non-pathogenic viral strain?

We would ideally be looking for a virus strain with a large(ish) deletion in an essential viral gene like the strain found in Singapore (unfortunately this strain is too dangerous to use as it put people into hospital). This sort of deletion mutation is easy to spot in the SARS-CoV-2 genome data, and because the genetic information has been removed, it makes the virus unlikely to be able to mutate back into a dangerous strain. Ideally, the strain identified will have infected a large number of other people in the local area so we can know it is safe from the epidemiological data. This will be important for getting regulatory approval to use the strain.

Has this ever been done before?

Yes. The polio, measles, rubella, mumps, and chickenpox vaccines are all live attenuated viruses. Even something as dangerous as smallpox was controlled in the 18th century using a variation of this idea called Variolation. The idea was the doctor would deliberately infect you with a less harmful strain of smallpox (often at a low dose) to make you immune to the more deadly strains of smallpox. Of course, they didn’t know how this approach worked in the 18th century, but it was still very effective and millions of people were saved from dying from smallpox by it.

Some people have been calling using a low dose of the virus Variolation, this is not what we think Variolation was, but this is a complex topic. While such a low-dose approach of the dangerous strain might make the COVID-19 less dangerous to the person being deliberately infected, it doesn’t make the virus any less dangerous for those around you that you might infect later. Such an approach could also not be used on the vulnerable, leaving them exposed to the illness. There is no reason in principle that the low dose idea couldn’t be combined with the attenuated strain idea and it might even be a very good idea.

In regards Corona viruses, there was considerable work done on determining which regions of the SARS-CoV can be deleted to create an attenuated virus that provided protection from the wild type dangerous version. Jose Regla-Nava and colleagues identified that SARS strains with gene deletions in the E protein were attenuated and provided good protection from later infection with SARS-CoV. Furthermore, these researchers found the deletion strains were genetically stable when grown in cell culture. SARS-CoV-2 contains the same E protein and deletions in the E protein gene may provide the same attenuation.

What are the risks?

The major risk is a mutant virus we think is safe is not 100% safe. While we can use community spread of the identified strain to estimate how safe it will be (i.e. if it has infected 1000 people and none have got seriously ill then we should have a pretty good idea that it is safe), our knowledge will be incomplete. We can of course spend the next few years testing and trialling, but if we do this by the time any strain is shown to be 99.99% safe (not even the polio vaccine is 100% safe) we will have all got COVID-19 and the world’s economy will be a smoking ruin.

We have a choice of taking some risks now, or face the certainty of a much worse problem later. Time to accept some risk and do something now.

Q & A

I have been getting a few questions on this post so I thought I would address them here.

How do you know there is an attenuated viral strain out there?

Because such strains have already been found. I am hypothesising that there is more than one based on the known mutation rate of coronaviruses and the number of cases. Coronaviruses like SARS-COV-2 mutate continuously (this is why companies like deCODE can tell the geographical origin of different strains) as the molecular machinery for replicating their RNA genome is not very accurate, although it is more accurate than the machinery of other RNA viruses like HIV. When you combine this with the millions of mild cases out in the world, the odds are on our side that there is at least one person infected with a strain that has a mutation that makes the virus less dangerous (attenuated). We just need to go and look for this strain – luckily the tools we need to use (genome sequencing) are now cheap and quick. What would have been impossible 20 years ago can now be done in a week.

Aren’t most people who have mild/asymptomatic cases infected with a dangerous strain?

Yes. Almost all people (>99.9%) who are infected (and have a mild case) are infected with a dangerous strain of the virus, they just happen to have an immune system that can control the virus well. With COVID-19 a mild case does not mean you are infected with an attenuated strain – for most people with a mild case if they happen to infect a person with preexisting conditions or who is old, that person will be at a high risk of dying. A mild case does not equal a harmless strain.

My argument is coming from the other direction. While almost all mild cases of COVID-19 are caused by a dangerous strain of SARS-CoV-2, an attenuated strain of SARS-CoV-2 will only cause mild disease. If you want to find an attenuated strain you need to look at mild cases even though >99.9% of the people you check will be infected with a dangerous strain. What we want to find is one of the rare natural viral mutants that has a mutation that makes it attenuated. Where you will find such a viral mutant is in people with the mild/asymptomatic form of the disease.

I am NOT arguing that people with mild cases are infected with a mild strain of the virus. If this is what you think I am saying please take the time to read carefully what I have written – yes it might sound like this is what I am saying from a five second scan, but this is not the case.

Why only sequence those with mild/asymptomatic cases of COVID-19 in the search stage?

If I had to choose one aspect that gets most misunderstood by people who read this idea, it would be the reason for sequencing only mild/asymptomatic cases. This choice is purely an efficiency issue. In an ideal world we would sequence the strains from every case in the world, look to see if we can find mutants with deletions, and then check what was the clinical outcome of those infected with each strain was. If we find that all clinical cases of a particular mutant strain are mild/asymptomatic, and no cases ended up in hospital, then we would have our candidate strain.

Unfortunately we live in a constrained world where it is not possible to collect and sequence the virus from every case of COVID-19, Given this, where should we look first? Since we are looking for a mutant strain that only causes mild/asymptomatic cases, we can exclude patients in the first pass who have serious symptoms. Any strain that causes serious illness won’t be a strain we want to use.

It is only once we find a good candidate attenuation strain that has the right sort of mutation (a deletion) that we then collect swab samples and sequence all cases in the local area. At this point we will need to look at both the serious and mild cases (include everyone in the local hospitals), to get the full clinical picture of the strain. This approach of initially screening just the mild cases is a simple way to make the search process for an attenuated strain more efficient and practicable.

Can’t we just wait for a COVID-19 vaccine?

No. Apart from the time it will take to develop, trial, and mass produce a vaccine (12-18 months), it is unlikely that any vaccine will be practicable. The reason why is immunity to respiratory viruses (like corona) doesn’t last long – 6 months to 2 years. We would have to keep vaccinating everyone in the world every year (or maybe every 6 months if we are unlucky). This just isn’t going to work in the real world (especially poor countries) and is one of the reasons we don’t have a vaccine for the coronavirus strains that cause the common cold. Unless we can drive the current dangerous SARS-CoV-2 strains to extinction we are going to have a problem with this disease indefinitely.

Update. A very interesting pre-print has been released on the natural immune response to SARS-CoV-2. Many people don’t develop much of an initial immune response (IgM antibodies) and the long term immune response (IgG antibodies) fades quickly after just two months (see figure below). While this is more of an issue for those people arguing that we should lift social isolation restrictions to allow the population to develop herd immunity (this would just kill a lot of people and any herd immunity would quickly disappear), it is also a concern for any vaccine approach that can’t drive the dangerous strain to extinction (i.e. all the other conventional vaccine proposals).

Won’t the mutations in SARS-CoV-2 make this proposal fail?

The coronavirus are relatively stable genetically for an RNA virus. The coronavirus strains that cause the common cold tend to not change much antigenically over time, unlike the Influenza, HIV and Hepatitis C viruses. The way the common cold strains spread is through our immunity to them declining fairly rapidly (in months, not years). The result is the same common cold strain can infect you multiple times in your life as your immunity to it fades, rather than it having to change antigenically so much that our immune systems doesn’t protect us anymore.

This is good news as it means we may only need to isolate one mutant strain. Even if in the worse case SARS-CoV-2 does change so much antigenically that our attenuated strain no longer offers protection, we can just repeat the process we used to find the first strain to find the next strain. More fundamentally, this is a problem for all vaccine approaches that we will need to deal with if it happens, but it shouldn’t stop us from acting now.

Update. A recent non-human primate study out of China using a conventional vaccine approach found that the antibodies produced were neutralising for all strains found around the world. It really does look like we only need only one attenuated strain to provide protection for all strains.

Isn’t social distancing and quarantining solving the problem?

Yes and no. Yes countries like South Korea and Australia have shown that through mass screening and social distancing you can keep a lid on the disease, but this leaves the population susceptible to a new outbreak. Singapore and Japan have recently seen this in action where they eased restrictions and found the disease came back and they had to reintroduce restrictions. I don’t think many people want to live for years with cycles of restrictions, easings and further outbreaks.

Wouldn’t the use of such an attenuated strain just be a vaccine?

Yes in one way, but it is a little more subtle. Assuming we can find an attenuated strain, then how to best use it a separate question. The most important thing to note is that a natural attenuated virus is not a vaccine. It is just a natural virus that you can catch in a natural way. Hang out with someone infected with the attenuated strain and you will catch it without doing anything, go home and those around you will catch it from you, and so on. While I wouldn’t suggest this is the best way to get an attenuated virus out into the community, such natural spread is outside the regulatory framework for vaccines.

Of course the use of a natural attenuated strain as a vaccine would fall under the regulations for vaccines, but the mere existence of an attenuated virus does not make it a vaccine. Each regulatory authority around the world would need to weigh the evidence of safety (obtained from the epidemiology) against the risks. Some regulatory agencies may decide the rewards from using such a strain as a vaccine is worth the risk, while others may decide they are not.

What effect would using an attenuated SARS-CoV-2 strain have on the dangerous strains?

Giving a natural attenuated viral strain deliberately to lots of people would change the ecosystem for the dangerous strains of the virus. The dangerous strains would find it difficult to spread through the community as many (most) people would have already been infected (and hence immune) with the attenuated strain (i.e. have herd immunity). Overtime the dangerous strains would become rarer, and the attenuated strains more common, until eventually the dangerous strains would become extinct and we would just be left with the mild version floating around. While we would not be able to get rid of this mild strain, it would just be another of the hundreds of viruses out there causing common colds. This proposal at its base is really one of replacing the dangerous strains with a less dangerous strain that we can live with.

It is the ecology aspect of this proposal that makes it different to other attenuated vaccine proposals. Currently all attenuated vaccines developed in the lab are designed to just protect the person receiving the vaccine. An attenuated strain identified by screening infected people (epidemiology) will identify a strain that can still be transmitted from individual to individual. This makes the use of such a strain radically different than a conventional lab created attenuated viral vaccine.

Why can’t we just use the less pathogenic SARS-CoV-2 strain already identified in China?

While the ZJ01 SARS-CoV-2 strain identified in China appears to be less pathogenic, the mutations that make it so are single base changes. These can easily mutate back to the more dangerous version of the virus. The viral strain we want to find will have a deletion mutation where a section of the viral genome is removed. Deletion mutations are much more difficult to mutate back to the dangerous type since rather than just a change from one nucleotide to another (e.g. C > T), the deleted region is missing and can’t easily be recreated by mutation. Put simply, deletion mutations are more stable to back reversion.

How should any natural attenuated SARS-CoV-2 strain be used?

This is not a decision for me. I think the regulatory authorities like the FDA will approve the use of a natural attenuated strain on the basis of the epidemiological data collected finding the strain that show it is safe. While most regulatory agencies are extremely conservative and slow, they are not idiots and they understand that using an approach with some serious unknowns might be better than the alternative of waiting for the perfect vaccine. COVID-19 is a problem with only hard choices.

I do think it would be impossible to prevent the use of any such strain even without regulatory approval. Assuming a natural “safe” strain is found and a test for it developed (this is relatively easy since you are looking for the presence of a deletion), people will start spreading it between themselves at a “grass roots” level. I think this outcome will influence the decision of the regulatory authorities to approve its use – better to have the attenuated virus spread in some controlled and regulated way, rather than illicitly by people doing it on their own. Just to make clear, I am not suggesting that it is a good idea to allow “grass roots” spread (I think it is a bad idea), nor am I advocating for it, just that I think it won’t be possible to stop such spread if the regulatory authorities don’t license it.

Even if you think a natural attenuated strain is too dangerous to use as a vaccine directly, it would be extremely useful to speed up other vaccine approaches. One way it could be used is to give it as a challenge to volunteers who have received another vaccine to see if the vaccine provides protection without putting them at risk. Knowing if a vaccine works (i.e. provides protection from the disease) is one of slowest steps in new vaccine development. If you are going to do a viral challenge with SARS-CoV-2, you really want to use a strain you know is harmless, rather than one you know could kill your volunteers. Of course to do this you first have to make the effort to find such a harmless strain.

I have objection X which means this whole idea is worthless!

If you are not a scientist then I will be blunt and say it is almost certain that your objection is either wrong or irrelevant (sorry for being harsh). While I have presented the idea in as non-technical way as is possible, it is still a complex scientific idea with many complex parts. What might seem to you a very strong argument is likely to not hold up when explored in depth.

If you are a scientist try not to get caught up too much in me skipping over certain technical details and instead focus on the bigger picture. This is a proposal for an approach that may work, not a grant application where all the experiments have already been done. There is a non-trivial chance that this approach may not work. I am aware of this, so I ask you to please focus not on all the possible ways it may not work, but if there is anything that will make it certain to not work. If there is some fatal flaw then please let me know, not that step x might not be easy, or we don’t know some particular fact. This is a problem where assumptions have to be made and risks taken.

It is not ethical to use such a natural attenuated strain!

This is a proposal to search for a natural attenuated viral strain of SARS-CoV-2, not an proposal to use such a strain. Finding such a strain does not mean we have to use it, just that we can use it. Ultimately the decision to use such a strain will be a political and social question weighing up up all risks, but we can only have this debate if we make the effort to find such a strain and show it is safe.

If you think that the whole idea is unethical under all circumstances, it is worth keeping in mind that it exactly the same as what Sabin did with the oral polio vaccine. He found a natural attenuated polio strain in a child with a mild case of the disease and used it in his vaccine. His vaccine has gone on to prevent tens of millions of cases of polio. Yes there was and still are risk with his vaccine, but most people think it was huge step forward for humanity.

How would this search work in practice?

I have written a second post describing how we might go about turning this idea into reality – How would a search for a natural attenuated SARS-CoV-2 strain work in practice?


Update. I have been trying to get this idea in front of someone with the clout to make this happen, but without much luck because the people with the clout (say Bill Gates) don’t read messages from random people like me. For this idea to succeed it needs a two hop process (i.e. someone knows someone, who knows someone, who Bill Gates will take seriously). If you think you might be that first hop person then please get in contact with me at daniel.tillett@gmail.com.

I should add that it doesn’t have to be Bill Gates that can push this forward. If you think you know someone who could help then get in contact with me. Unlike Bill I will respond to your email :)

Update 2. I have modified this post to better explain those aspects that have confused people (my fault). I hope this idea is now clearer. Keep the comments coming and if you think someone you know would be interested then pass the post along along.

Update 3. This is directed at my fellow scientists. If you happen to working on this exact idea please get in contact me – not least so I can give you lots of money to speed up your work.

Update 4. This field is moving at an amazing pace with new results coming out every day. I have updated this post with the most relevant new data.

Which Came First – The Chicken or the Egg?

One of the great things about having children is it reacquaints you with things you have not thought about for a long time. The old Chicken or the Egg paradox is one of those classic brain teasers that children of a certain age love. It is a really good one since the answer depends on how you parse the question. I thought I would list all the different answers my children and I could come up with.

Evolution 1 – Chicken

The first Chicken had to have hatched from an egg laid by a proto-chicken (i.e. a bird that was very similar to a chicken, but not actually a chicken). This means that the Chicken came before the first chicken Egg since only a chicken can lay a chicken egg.

Evolution 2 – Egg

If we consider that a chicken egg is an Egg that a Chicken hatches from then the Egg must comes first. It might have been laid by a Proto-Chicken, but out of this Egg hatched a Chicken.

Evolution 3 – Egg

The Egg is a much older than Chickens. What we now recognise as Eggs first appeared at least 300 million years ago. This was long before the first Chicken which is a domesticated version of the Indian Red Jungle Fowl from sometime in the last 10,000 years.

Evolution 4 – Unanswerable

Given that the definition of what separates a Chicken from a Proto-Chicken is undefined, it is not possible even in theory to say when the first Chicken hatched even if we had access to a time machine. If we can’t know when the first Chicken hatched we can’t answer the question.

Biblical – Chicken

According to Genesis 1 God created all the animals on Day 5 therefore the Chicken was created before the first Egg. It is an open question if the first Chickens were created with full formed eggs inside them and so if the first Egg was laid on Day 5 or not.

Word Order – Chicken

In the question “Which came first the Chicken or the Egg?”, the word Chicken precedes the word Egg.

Word Origin – Egg

The word Egg comes from Old Norse and ultimately back to the Proto-Germanic and before that Proto-Indo-European. It is a much older word than Chicken which is an Old English word of unknown origin.

English Language – Chicken

The original word for Egg in Old English was Ey and only in the development of Middle English did the Norse word egg become the common term. The word Chicken is from Old English and so it appeared first in the English language.

Dictionary – Chicken

In the English Dictionary the letter C comes before the letter E hence Chicken is first. The same applies to Encyclopaedias, although of course no child of today knows what an Encyclopaedia is.

Wikipedia – Chicken

The first entry for Egg was in 2005 while the first entry for Chicken was in 2004. Who would have guessed?

Finish Line – Chicken

In a race a Chicken will always beat an Egg to the finish line.

Drop Test – Egg

Chickens can fly so if you drop an Chicken and Egg off a barn roof together the Egg will hit the ground first. Chickens are surprising good flyers once they are allowed out to roam around for a few months.

There must be more !

The Last Word on Free Will

People have been arguing if free will exists or not for millennia with little progress. You have the Incompatibilists on one side arguing that free will and a deterministic universe can’t both be true, and the Compatibilists arguing that they can. While the heavy artillery appears to be on the side of Incompatibilism (the universe does appear to be deterministic), the inherent nihilism of Incompatibilism has meant most people have opted for some flavour of Compatibilism of varying sophistication. The arguments for both sides washes back and forth and we are no closer to an answer than the ancient Greeks.

Rather than approaching the question of free will from a philosophical perspective, we can just approach it empirically.

  1. The probability free will exists is greater than zero. Our knowledge of the universe is incomplete and so no matter how much evidence there is supporting a belief we can not apply a probability of zero to any hypothesis that negates this belief. All the evidence suggest fairies don’t exist at the bottom of the garden, but there is some finite probability that they do. In the case of free will this means that while all the evidence points to it not existing, we can not say with certainty it does not exist.
  2. If there is no free will then it is meaningless what beliefs you hold about free will. There is nothing lost in life believing in free will if it doesn’t exist since whatever beliefs you have were predetermined.
  3. If there is free will then believing there is no free will is throwing away your life. If free will exists and you go through life believing everything is predetermined then you will have missed making the choices open to you by free will. You may spend your life in a nihilistic funk when you could have chosen differently.

Given these three statements the only conclusion we can reach is we have to live as though free will exists even if everything we know points to it not existing. Nothing is lost believing in free will if it doesn’t exist, while everything of importance is lost if you don’t believe in free will and it exists. No matter how unlikely free will is, and it appears very unlikely, the conclusion doesn’t change – as long as our knowledge of the universe is incomplete the only rational action is to live as though free will exists.

While I am sure that I am not the first person to propose this solution to the free will problem, I have not been able to find who first proposed it. If anyone knows the source of this argument please leave a comment.

Easy Creme Brulee

Easy Creme Brulee

Easy Creme Brulee

For something so simple as creme brulee I wondered why so many recipes turn four ingredients and few basic steps into a cooking challenge. Here is my easy recipe for creme brulee adapted for Australian conditions. The key to success is to use high quality ingredients and avoid curdling the custard by overcooking. Vanilla bean paste tastes and looks the same as using whole vanilla beans, but it is a whole lot easier. Follow these simple steps and it is hard to go wrong.

Ingredients

  • 600 mL (1 large carton) of fresh single cream (35% milk fat).
  • 6 quality eggs.
  • 1/3 cup (75 g) of white sugar.
  • 1 teaspoon of vanilla bean paste (important).

Method

  • Preheat the oven to 160˚C. Boil 2 L of water in an electric kettle.
  • Pour cream into a small saucepan and add the sugar. Heat slowly to the point just before boiling (don’t let the cream boil).
  • While the cream is heating seperate 6 egg yolks into a medium size bowl and add the vanilla bean paste. Mix with a hand whisk (or fork) until the vanilla and yolks are combined (10 seconds).
  • Once the cream reaches near boiling, remove and pour slowly into the yolk mixture whisking gently the whole time. This should take about 20 seconds.
  • Pour the thin custard through a fine sieve into a glass 1 L or larger jug. This will remove any egg lumps and make it easer to pour into the ramekins (i.e. the small ceramic bowls).
  • Place 4 to 6 ramekins in a metal baking tray that is 10-15cm deep. Pour the custard into each of the ramekins and place the whole tray in the hot oven.
  • Pour in the boiling water until it comes 2 cm from the top of the ramekins. It is easier to pour in the boiling water when the tray is in the oven than trying to move a tray filled to the brim with boiling water.
  • Bake for 30 min. Remove the ramekins and let cool on the bench (30 minutes).
  • Wrap each ramekin with plastic wrap and place in the fridge for at least 3 hours.
  • Just before serving remove from the fridge, add two teaspoons of any sugar on top of the custard, shake gently to evenly distribute the sugar, and then blacken the sugar with a butane blowtorch. You can also use the oven grill, but it will tends to heat the custard a bit more than using a blowtorch – also blowtorches are fun.
  • Serve immediately to your impressed guests or family.

 

Bitcoin is being set up to fail spectacularly

Bitcoin Price

Bitcoin Price 2017

 

Bitcoin is all the rage at the end of 2017. The interesting question is not why it has risen so high and so fast, but why it has not been made illegal. The most impressive observation about Bitcoin (and its block-chain brethren) is it has been allowed to run free, sucking in all and sundry, most who have no idea what a block-chain is, but who know their friends and neighbours have made a fortune from it. The mass media has been neutral-to-supportive of the speculation.

The question is why those that control the monetary system (i.e. the rich and powerful) have allowed this run given the revolutionary nature of Bitcoin? If Bitcoin succeeds they will lose control of their wealth and power to a bunch of computer anarchists with a cool idea.

The powerful if they wanted could shutdown Bitcoin and all the other block-chain currencies tomorrow – when you are using as much electricity as a medium-sized country you can’t really hide. Despite the risk nothing has happened. They are not stupid (well the people advising them anyway), so it does not make much sense that Bitcoin has been allowed to continue.

The only rational hypothesis I have been able to come up with is the intention is to ensure the general population do not just feel indifferent to Bitcoin (this would be the result of an earlier crackdown), but that they must totally hate it and the whole concept of the block-chain. Hate Bitcoin so much that no future idea like this can ever gain popular support.

With this in mind, the rise of Bitcoin makes much more sense. When the inevitable crash comes it will burn a huge number of ordinary people who have been sucked into the hype and speculative mania. The aim appears to ensure that Bitcoin (and by association all block-chain currencies) are seen as the greatest scam of the last 100 years.

If what I am suggesting is true then Bitcoin has some way to run yet (my guess is at least six months). The risk of overturning the current monetary system (and the wealth and power than comes from controlling it) is far too great to ever let any alternative arise. Bitcoin has to more than fail – it has to fail spectacularly. Everything is on track to ensure this outcome and the pain from the economic fallout will be long and deep (for the little people anyway).

Damnatio memoriae

The last few days have reminded me that we really need to stop “glorifying” the actions of mass murders and actually do something to prevent others repeating their actions. Making losers famous by mentioning them in the mass media just encourages more losers. We can learn from the past and the Roman damnatio memoriae is an approach we would be wise to revive.

Rather than giving those that have stepped outside society’s boundaries fame, let us instead remove them from history. Total and utter obliteration. We have the technology and legal authority to completely delete the historical existence of someone evil. Remove everything about them; their birth, schooling, job history, marriage(s), relationships, photos, phone records, emails, Facebook posts, even the banal like credit records or receipts from Walmart. Remove everything about them such that they effectively never existed as a person. Leave nothing. If we need to refer to their actions then give them a pseudonym such as the “butcher of X”. In a 100 years there will be no record or memory they ever existed while we still remember their victims.

It might seem impractical to follow such a path given the ubiquity of modern media, but in practice it is easier today to remove someone from history than it has ever been. A single authority with determination can track down and remove every fragment of an individual’s existence.

We must do something rather than wring our hands in despair and let history repeat. Let today be the last time evil has a name.