Historical bias overlooks genes related to COVID-19

Genes studied based on ease of experimentation rather than relevance to disease

NORTHWESTERN UNIVERSITY

Research News

Based on genome-wide experiments, the human body has 2,064 genes relevant to COVID-19. So why are researchers only studying 611 of them?

A historical bias — which has long dictated which human genes are studied — is now affecting how biomedical researchers study COVID-19, according to new Northwestern University research.

Although biomedical researchers know that many overlooked human genes play a role in COVID-19, they currently do not study them. Instead, researchers that study COVID-19 continue to focus on human genes that have already been heavily investigated independent of coronaviruses.

“For understandable reasons, researchers tend to build upon existing knowledge and research tools. They appear to select genes to study based on the ease of experimentation rather than their ultimate relevance to a disease,” said Northwestern’s Thomas Stoeger, who co-led the research. “This means that research into COVID-19 concentrates only on a small subset of the human genes involved in the response to the virus. Consequently, many aspects of the response of human cells toward COVID-19 remain not understood.”

“There are many genes related to COVID-19, but we don’t know what they are doing in the context of COVID-19,” added Northwestern’s Luís Amaral, who co-led the study with Stoeger. “We didn’t study these genes before the pandemic, and COVID-19 does not seem to be an incentive to investigate them.”

The research will be published on Nov. 24 in the journal eLife.

Stoeger is a data science scholar at the Northwestern Institute on Complex Systems (NICO) and the Center for Genetic Medicine. Through a “Pathway to Independence” award from the National Institute of Aging, Stoeger is starting a research laboratory dedicated to uncovering unstudied genes with important contributions to aging and age-related diseases. Amaral is the Erastus O. Haven Professor of Chemical and Biological Engineering in Northwestern’s McCormick School of Engineering. Stoeger and Amaral are both members of Successful Clinical Response in Pneumonia Therapy (SCRIPT) Systems Biology Center.Pinpointing a historical bias

This study builds on Stoeger and Amaral’s 2018 research, which was the first to explain why some human genes are more popular to study than others. In that work, they found that 30% of all genes have never been studied and less than 20% of genes are the subject of more than 90% of published papers.

Despite the increasing availability of new techniques to study and characterize genes, researchers continue to study a small group of genes that scientists have studied since the 1980s. Historically, these genes have been easier to investigate experimentally. If an animal model has a similar gene to humans, for example, researchers are more likely to study that gene. The Northwestern team also discovered that postdoctoral fellows and Ph.D. students who focus on poorly characterized genes have a 50% reduced chance of becoming an independent researcher.

Although the Human Genome Project — the identification and mapping of all human genes, completed in 2003 — aimed to expand the scope of scientific study beyond this small subset of genes, it has yet to fulfill this aim.

“The bias to study the exact same human genes is very high,” Amaral said. “The entire system is fighting the very purpose of the agencies and scientific knowledge, which is to broaden the set of things we study and understand. We need to make a concerted effort to incentivize the study of other genes important to human health.”Bias continues into COVID-era

For the new study, Stoeger and Amaral turned to LitCOVID, a collection of research publications related to COVID-19, curated by the National Library of Medicine. LitCOVID tags genes mentioned in the titles, abstracts or results sections of individual publications.

Northwestern researchers analyzed 10,395 published papers and pre-prints from the collection. Then, they integrated them into a custom database along with more than 100 different biological and bibliometric databases in an effort to survey and measure all aspects of biomedical research. Finally, they compared genes mentioned in the COVID-19 papers to COVID-19-related genes as identified by four genome-wide studies.

Stoeger and Amaral also tracked the occurrence of genes appearing in COVID-19 literature over time. Surprisingly, they observed that studies of COVID-19 genes are becoming not more but less expansive since the onset of the pandemic.

The team hopes its study inspires other researchers to be aware of past biases and to explore unstudied genes.

“Our findings have a direct implication on the long-term planning of scientific policymakers,” Stoeger said. “We can point researchers toward human genes that are important for the cellular response against viruses but risk being ignored due to historically acquired biases, which are culturally reinforced.”

###

The study, “Meta-Research: COVID-19 research risks ignoring important host genes due to preestablished research patterns,” was supported by the SCRIPT Systems Biology Center (award number U19AI135964); the National Science Foundation (award number NSF 1956338); the Northwestern University Quantitative Biology Center (award number NSF/Simons DMS-1764421); the Air Force Office of Scientific Research (award number FA9550-19-1-0354); and the National Institute of Health (award number NIH 1K99AG068544).

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John Tillman
November 26, 2020 2:17 pm

Maybe I missed something, but reading the paper, it’s not clear where the figures of 2064 and 611 genes came from:

https://elifesciences.org/articles/61981

Its survey did find that just three genes were studied in about 25% of papers:

“This yields 10,395 research publications featuring 3733 human protein-coding genes that have been tagged at least once. This enables us to ask whether the choices by scientists to investigate these genes can be understood in terms of current biological knowledge on COVID-19.

RESULTS

“The most prominently tagged genes up to this point are: Angiotensin-converting enzyme 2, which serves as receptor for SARS-CoV-2 to enter cells (Hoffmann et al., 2020); C-reactive protein, a serum marker for inflammation (Sproston and Ashworth, 2018); and Interleukin 6, a mediator of systemic inflammatory responses (Kang et al., 2019). They account for 10.8%, 9.7%, and 4.5% of the total research on human protein-coding genes within the COVID-19 literature, respectively (see Methods).”

ACE2 of course comes as no surprise.

Reply to  John Tillman
November 26, 2020 11:14 pm

“…less than 20% of genes are the subject of more than 90% of published papers.”
There is no mystery, only pervasive plagiarism by millennial “scholars” trying to fit other peoples’ work into the framework of “consensual science”.
Take that (in)famous PCR test; It is not some new magic, it literally is just a patented machine that does a better job than previous machines. Machines like that costs money, and the ones holding the money decide what you may or can research. That is the basis for sciencery*
*Sciencery: v/n/adj. The magical ability of discretionary funding to prove whatever the financier needs proven. It makes any product or service float on a cloud of scienciness.

November 26, 2020 2:30 pm

Speaking of things that get ignored in relation to COVID-19, Sweden’s all-causes (including this virus in 2020) deaths have been tracking the averages for the same weeks in the previous five years. That’s without draconian lockdowns or a mask mandate. See the bottom chart at https://www.covid19insweden.com/en/deaths.html

Scissor
Reply to  Ralph Dave Westfall
November 26, 2020 3:04 pm

The U.S. all cause mortality is close to normal also, and the present spike is peaking.

Carl Friis-Hansen
Reply to  Ralph Dave Westfall
November 26, 2020 4:12 pm

I live in Sweden and has a friend in Spain.
I wrote to him yesterday asking him why the mortality has risen so sharply recently, as one of the few countries in Europe.

He thought it was because the social structure was chaotic, thus they had difficulties putting all the masks and lock-down fully in place. Also, he mentioned that Spain has a lot of old people.

Personally I don’t know what to believe.

Orson
Reply to  Carl Friis-Hansen
November 28, 2020 5:27 pm

I agree, Carl. It is perplexing.

I pondered pie charts of Covid19 deaths over EU country maps of Europe. The only variables that looked useful were population density (higher=more deaths) and some measures of travel (within country as well as international). That’s it.

Could it also be that the likely R0 = 3+ is that sweet spot where traditional social distancing methods defeats influenza spread but not this virus?

TonyG
Reply to  Ralph Dave Westfall
November 27, 2020 3:15 pm
William Astley
November 26, 2020 2:51 pm

Covid is a ‘designer’ virus. That means a group designed it to have the properties it has.

It was ‘designed’ to be very contagious using the following novel biochemical feature it has…

…..normally (i.e. for all viruses, except for covid, when a virus attacks the throat pain is generated at the throat where there is cell damage…

…. And that pain gets people to isolate.

Covid was designed to have the novel feature that it synthesizes the throat. Covid attacks throat first and then moves on to other organs where it causes pain and more damage.

A second novel covid feature is for some people causes an over immune response that causes blood clotting.

And a third novel covid feature, in 0.05% of the population who have a genetic mutation, covid causes the body to produce an antibody that attacks the body causing serious long term health problems.

Comment:
About 7 years ago, it became possible to design a virus and know exactly what the human response would be using computer software.

This virus/human body simulation software is the first software program to be AI powerful. Prior to the development of this software, it would be required to kill and infect hundreds of thousands people with a prototype covid virus, to enable the virus to evolve the capability to defeat the human immune system.

This perfect virus simulation software and the perfect bioactive regions of the human body simulation software….

…. Enables the designer to evolve the raw virus code, running it in the simulation that perfectly simulates the range of human gene response, in all bio-active organs, throat, heart, blood, and so on.

https://www.newsmax.com/health/headline/covid-19-pain-killer-pandemic/2020/10/06/id/990680/
Can COVID-19 kill pain? That is the possibility raised by University of Arizona researchers who found SARS-CoV-2, the virus that causes COVID-19, might function as a pain killer.

If that theory proves to be true, it might be one of the reasons so many infected people walk around unaware they have the disease. While the Centers for Disease Control and Prevention has an exhaustive list of COVID-19 symptoms, ranging from fever to loss of taste and smell, so far, “feeling no pain” has not made that list.

“It made a lot of sense to me that perhaps the reason for the unrelenting spread of COVID-19 is that in the early stages, you’re walking around all fine as if nothing is wrong because your pain has been suppressed,” said Dr. Rajesh Khanna, Ph.D., a professor in the University of Arizona’s College of Medicine.

He said in a news release, if his tests prove that pain relief is a symptom and possible cause of what is triggering the spread of the virus, that would be “of tremendous value.”

The Arizona researchers believe the spike protein on the SARS-CoV-2 virus silences the body’s pain signaling pathways, explained Dr. Michael D. Drake, senior vice president of UA Health Sciences. He added scientists at the University of Arizona’s Comprehensive Pain and Addiction Center are using this unique finding to help develop a new, non-opioid class of therapeutics for pain.

JSMill
Reply to  William Astley
November 26, 2020 6:19 pm

You’ll likely find this 2015 NIH paper interesting.
“A SARS-like cluster of circulating bat coronaviruses shows potential for human emergence”
https://pubmed.ncbi.nlm.nih.gov/26552008/

Click on +expand next to “Affiliations” to check out the co-authors … see if anything jumps out at ya.

Gary Hudson
Reply to  JSMill
November 28, 2020 7:53 pm

Access Denied
our access to the NCBI website at http://www.ncbi.nlm.nih.gov has been temporarily blocked due to a possible misuse/abuse situation involving your site

Tom Foley
Reply to  William Astley
November 26, 2020 8:36 pm

Why would you design a feature in a virus to work on a gene that is held by only 0.05% of the population? And why design a feature to cause future chronic health issues, rather than features that kill people fast, or increase infectiveness? Why design a virus that kills mainly old people or people with long term existing health problems? To remove these sectors of the population? But these sectors are very lucrative for the medical profession – regular return customers who need lots of expensive medication. Why design a virus to cut off a major source of your profession’s income and reason for being?

Charles Higley
Reply to  William Astley
November 27, 2020 6:44 am

“If that theory proves to be true, it might be one of the reasons so many infected people walk around unaware they have the disease. ”

Do not forget that the PCR test is perforce nonspecific as the virus has not been isolated. Whether it came from a bioweapon lab or not is irrelevant as it moved and bahaved with the flu season.

The PCR test is for general coronaviruses, rhinovirus, and even some human sequences. And a positive test result does not make you a case, as the PCR test is hugely false-positive. It’s a joke.

Paul C
Reply to  Charles Higley
November 27, 2020 3:33 pm

The PCR test has now been ruled as not fit for purpose in court (in Portugal).
https://www.rt.com/op-ed/507937-covid-pcr-test-fail/
https://www.portugalresident.com/judges-in-portugal-highlight-more-than-debatable-reliability-of-covid-tests/
Nice to get a sensible ruling from the judges.

richard moore MD
November 26, 2020 3:29 pm

Drunk
Lost Keys
Lightposr

n.n
November 26, 2020 5:01 pm

Hysterical bias. Applying Cecile’s scalpel suggests that it must be diversity (e.g. racism) and a progressive condition (PC).

Robert of Ottawa
November 26, 2020 5:18 pm

Yes, I think the Wuhoo Flu was created in the lab, but with nothing like the precise intent suggested by this article and responses.

More like the sourcerer’s apprentice playing around with magical stuff. And then ther was an accident and then CCP local officials tried to cover it up until it couldn’t be contained and then CCP officials took advantage of a crisis to attack the rest of the world.

Ian W
Reply to  Robert of Ottawa
November 26, 2020 6:55 pm

Robert, you are right the SARS-CoV-n virus was built in the lab but wrong as it was built with the precise intent to create a highly infective Corona Virus that could not be treated with therapeutics or vaccines and likely to cause a pandemic in the wild. You are also wrong that it the virus was created in Wuhan, it was created by University of North Carolina Chapel Hill, under research funded by Fauci’s NIH. The justification appears to have been searching for possible pandemic strains of Corona Virus, except this research created a chimera strain tested it then created an entire virus and tested it for infectivity and against therapeutics/immunology using humanized mice. A member of the team was the director of the Wuhan Virology Lab – colloquially known as Bat Woman.
The government funders outside NIH eventually found out the research that was being carried out and after a WTF do you think you doing moment defunded the research. It seems that the research was refunded by Fauci’s NIH at Wuhan where they may have been passaging the virus.

Here is the abstract of the published paper:

A SARS-like cluster of circulating bat coronaviruses shows potential for human emergence.
Menachery VD1, Yount BL Jr1, Debbink K1, Agnihothram S2, Gralinski LE1, Plante JA1, Graham RL1, Scobey T1, Ge XY3, Donaldson EF1, Randell SH4, Lanzavecchia A5, Marasco WA6, Shi ZL3, Baric RS1

Abstract
The emergence of severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome (MERS)-CoV underscores the threat of cross-species transmission events leading to outbreaks in humans. Here we examine the disease potential of a SARS-like virus, SHC014-CoV, which is currently circulating in Chinese horseshoe bat populations. Using the SARS-CoV reverse genetics system, we generated and characterized a chimeric virus expressing the spike of bat coronavirus SHC014 in a mouse-adapted SARS-CoV backbone. The results indicate that group 2b viruses encoding the SHC014 spike in a wild-type backbone can efficiently use multiple orthologs of the SARS receptor human angiotensin converting enzyme II (ACE2), replicate efficiently in primary human airway cells and achieve in vitro titers equivalent to epidemic strains of SARS-CoV. Additionally, in vivo experiments demonstrate replication of the chimeric virus in mouse lung with notable pathogenesis. Evaluation of available SARS-based immune-therapeutic and prophylactic modalities revealed poor efficacy; both monoclonal antibody and vaccine approaches failed to neutralize and protect from infection with CoVs using the novel spike protein. On the basis of these findings, we synthetically re-derived an infectious full-length SHC014 recombinant virus and demonstrate robust viral replication both in vitro and in vivo. Our work suggests a potential risk of SARS-CoV re-emergence from viruses currently circulating in bat populations.

My Highlights
Access references: DOI: 10.1038/nm.3985 PMID: 26552008 PMCID: PMC4797993

Note that the team thought that they had generated a virus that could not be cured by therepeutics and that vaccines did/would not work. They thought this was a success.

NIH subsequently funded a continuation of the corona virus research at Wuhan under the direction of Zhengli-Li Shi, who had been on the original research team. Whether the Wuhan team had a sorcerers apprentice moment or whether the sorcerer herself was involved we may never know.

Patrick Hrushowy
November 26, 2020 6:14 pm

I’m not one to bring credentials to this discussion – I barely have a science degree – but I’m astounded that there is so little known about this virus, …yet governments everywhere are shutting down economies, …probably out of the precautionary principle. Why does government sponsored science always look for the silver bullet to the solve the problem that isn’t really all that well defined?

I get it that health authorities are focused on not overwhelming the health system but meanwhile millions of people have had their lives put on hold while captured science is paid to generate science that supports government measures?

Paul Penrose
Reply to  Patrick Hrushowy
November 30, 2020 10:16 am

Patrick,
The problem is that agencies like the CDC are funded for the specific purpose of answering questions and providing sound advice during exactly these types of events (i.e. pandemics). They are well aware that if they admit they just don’t know, their funders will say “What have we been giving you all this money for, if you can’t help us when we need it?” And that would lead to their defunding/firing because politicians never want to tell their fearful bleating flock that they can’t help them when something scary comes up. So the people at the “health” agencies all do what everybody else does when they don’t have enough information to make an informed decision: they guess. Now if some choose to believe that “expert’s” guess (random coin flip) is any better than their own, that’s fine; just don’t expect me to go along with it.

Robert of Texas
November 26, 2020 6:43 pm

There are likely many reasons why the death rate does not seem abnormally high – if that is true (I’ll wait for the refined numbers before accepting it as a fact).

Here are some guesses:

1) People who might have died of some other cause like Flu or Pneumonia are dying of Covid-19 related symptoms and therefore just fall into another bucket.
2) The lock-down has changed a lot of behaviors such as car driving – less car driving means fewer car related deaths.
3) The death rate due to Covid-19 has continued to drop per hospital admission – this is due to better understanding of what works.
4) The reported numbers are still changing – this is normal. It can be up to a year before the number of deaths are really known with any degree of accuracy.

What I KNOW is that local hospital admissions are elevated to the point of ER’s being flooded with patients at times. The number of people admitted for Covid-19 at the local hospital is higher now than in July – our previous high (I live in the Dallas/Fort Worth area of Texas).

The CDC statistics for most of 2020 are not fully refined and vetted. Usually the number of deaths will go up for a specific week (or month) for months (up to a year) after the initial report as different sources finally report their numbers. It is likely that Jan through April is becoming solid for most states, but not necessarily for all states – we are talking about 50 different state bureaucracies here. Look here to see the numbers recorded for Michigan for 2019 and 2020 Jan through April and compare them. It is obvious something has happened.
https://www.mdch.state.mi.us/pha/osr/Provisional/MontlyDxCounts.asp

November 26, 2020 7:12 pm

As long as we’re on the subject of tailoring the virus, there are a few folks out there suggesting that it hits Orientals easier than the rest of us. Accident? I think not, but what the h$## do I know? Cheers –

Ian W
Reply to  agimarc
November 26, 2020 7:25 pm

Apparently, the Asian genotype leads to many more ACE2 receptors on epithelial and endothelial cells. Thus people with an Asian genotype are easier for SARS-CoV-2 to infect and the infection can spread easier in their bodies.
The Innate Immune system depends on sufficiency in zinc, populations of some of the countries in the far east are insufficient in zinc due to their diets. The same applies with Vitamin D.

David Blenkinsop
Reply to  agimarc
November 26, 2020 9:30 pm

Er, well then, why is the incidence lower in Japan, say, as compared to much of Europe? Mysteries abound?

ozspeaksup
Reply to  David Blenkinsop
November 27, 2020 3:57 am

zinc in seafood they eat more of?

Ian W
Reply to  ozspeaksup
November 27, 2020 4:20 am

+1

Harry Davidson
November 27, 2020 2:59 am

This article is horribly repetitive, worse than the BBC news, which is aimed solely at people who are completely stupid.

Grady Cash
November 27, 2020 3:06 am

I gain more insight from the comments on WUWT than articles in the media. Thanks to everyone for taking the time to post. I think one major flaw in the public health approach is that evidence does not exist until it has been through exhaustive FDA-approved double-blind clinical trials. Meanwhile, data continues to grow that vitamin D (plus zinc, magnesium, C) provides both a preventive and therapeutic effect on COVID-19. Over 60 clinical trials on vitamin D are underway. For a lowly vitamin – actually, a prohormone – that cannot be patented and thus doesn’t promise billions in profit to pharmaceutical companies, that’s impressive! Unfortunately, those trials won’t report results until next year. Public health leaders should look beyond masks and social distancing. They simply are not working to stop the spread of COVID-19. The logical approach is to urge populations to proactively strengthen their immune systems by taking vitamin D3, C, zinc, and magnesium. It’s borderline criminal that public health leaders aren’t at least trying to get people to boost their own immune systems!

Carl Friis-Hansen
Reply to  Grady Cash
November 27, 2020 5:37 am

It’s borderline criminal that public health leaders aren’t at least trying to get people to boost their own immune systems!

This has been my concern too. I wrote something similar, but more politely, to Dr. Anders Tegnell in Sweden.

It approaches suspicious that virtually all of the western world is punished economically, socially, emotionally and health wise as the very primary measure.
One of the first things one logically would have done, would be to inform the public of everyday prophylactic measures to strengthen the immune system.

Back in April 2020 there were doctors who made videos explaining the importance of keeping the immune system active and not overprotect yourself, as this would put the immune system into a sleepy or degraded state.
It is very suspicious that these videos were removed by YT. It leads me to suggest that this “second wave” is partly caused by general somewhat reduced or sleepy immune system, resulting in greater difficulties coping with any less frequent bacterial and viral infection.

I am sure the medical establishment is doing their best, but the politicians and health authorities are not exactly doing their best to promote healthy living. Almost as if they were infected with the GTPS (Greta Thunberg Panic Syndrome), following her demand to do something no matter what.
This is not a joke. Greta, Al Gore and the likes are causing bad karma, tension and fear. Even if Climate Change and COVID-19 are serious issues, the solutions appear to be either ad hock panic, counter productive or unrelated agenda(21).

Ian W
Reply to  Carl Friis-Hansen
November 27, 2020 11:11 am

I am sure the medical establishment is doing their best

I do not have that feeling about the medical ‘establishment’. I think that individual doctors are doing their best with what they are ‘allowed’ to do by the protocols that the ‘medical establishment’ have given them. The medical establishment sees deaths as numbers on a spread sheet the same as the income from patents and vaccines, they have not had to hands on deal with a potentially dying patient in decades if ever. They have however normally got shares in pharmaceuticals and work the revolving door between government post and directorships in pharma.
As soon as it became apparent that giving zinc/zinc ionophore (HCQ)/ antibiotic as a rapid early outpatient cure for COVID-19, they were hostile because they knew that the same approach would work for most RNA viruses like influenza and polio and their stocks would drop in value. If they had been really concerned about the health of the population they would have immediately suggested that everyone should be taking prophylactic doses of zinc/HCQ/vitamin D3 and possibly Selenium and magnesium. The health food market already supply similar ‘immune health’ capsules with those contents. The pandemic could have been over already; but the medical establishment did not want it to be over, they wanted and had been marketing hard for a ‘vaccine’ and nothing else would get us back to normal. A provably false statement when $30 of therapeutics will cure COVID-19 in a week in almost all patients if treated as soon as symptoms appear or when contact with someone infected is known.

observa
November 27, 2020 2:19 pm

Careful there docs as anything less than fundamental and indefatigable belief in Gummint funded silver bullets could lead to skepticism and ..gulp.. the dark side-
https://www.msn.com/en-au/health/medical/the-coronavirus-won-t-stop-evolving-when-the-vaccine-arrives/ar-BB1bqbf0

Caught a bit of Aunty gabfest in Oz last night and the usual suspects were hand wringing about the US and their individualism with Covid and how Americans have largely given up on any coming together Big Gummint solution (you suspect they’re already paving the way for a Biden policy failure in that regard). The smug dumbclucks have no sense that Oz and NZ are extremely lucky to be surrounded by large moats and have effectively cut ourselves off from the rest of the world as quarantined islands. There’s no sense of nuanced appreciation of the above article and how it remains to be seen whether our isolation or let it rip herd immunity everywhere else is the better course long term. As for the economic cost of lockdowns to achieve it good luck grandkiddies as they pontificate on the taxpayer teat.

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