Coronavirus news & views

Parkinson’s Disease—An Unexpected Ravage of COVID?

Thus, (tho, ‘tis Life’s great Preservation) many oppose Inoculation.

-Benjamin Franklin, Poor Richard’s Almanac, 1737

SARS-CoV-2 and its disease, COVID, are very strange. They have given us black toes, lungs like chocolate pudding, long-term fatigue, depression, death, and vaccine deniers. It has been quite a ride. And we are learning that having COVID also puts one at risk for other non-COVID maladies…like chocolate pudding lungs was not enough!

In previous posts, I wrote about the clear link between new-onset type 2 diabetes arising in many patients following COVID. There also is suspicion that cancer might increase down the road due to CoV-2 inactivation of a cellular gene that puts a brake on cancer, P53, in COVID patients. Inactivate that gene and you release the brake on certain cancers. Therefore, there is concern that some COVID patients will experience an elevated incidence of cancer in the future.

New research now raises a real concern that COVID patients might also be at increased risk for developing Parkinson’s disease. Parkinson’s arises when neurons deep in the brain that produce a critical neurotransmitter, dopamine, begin to die off leaving a dearth of this critical chemical that sends signals between neurons. It is like cutting a phone wire. Crucial communications cease.

The study conducted in collaboration between scientists from Weill Cornell Medicine, Memorial Sloan Kettering Cancer Center, and Columbia University College of Physicians and Surgeons was published in Cell Stem Cell last January. Investigators took human induced pluripotent stem cells and coaxed them to become brain cell progenitors that could form into human brain organoids in tissue culture. Such small, nascent “brain-like” structures contain a variety of functional neural cells. They were exposed to the CoV-2 virus, which was shown to preferentially infect and selectively cause the dopamine-producing cells to shut down.

While brain autopsies of COVID patients have not revealed direct COVID infection, they have found unique gene patterns associated with cell senescence, which was especially profound in areas rich in dopamine-producing neurons. This also supports the notion that COVID disease contributes to neurological problems that could cause Parkinson’s disease.

Putting these two findings together is complicated at this time, but they strongly suggest a direct involvement for one or more mechanisms resulting from CoV-2 infection in causing the myriad neurological symptoms that have been seen in COVID patients, and maybe other neurological problems like Parkinson’s not yet attributed to COVID.

Bottom line: CoV-2 is a nasty bug and COVID is a nasty disease. It seems that getting vaccinated not only protects you from nasty flu-like disease and death, it can also protect you from the following:

1. long COVID
2. type 2 diabetes
3. maybe cancer
4. and now, maybe Parkinson’s disease

Why would anyone not want to avoid these? Get the shots!

Interesting addendum: The studies showing that CoV-2 virus can selectively infect dopamine producing neurons went a step further. They also tested a large panel of drugs already approved for other health problems to see if any could unexpectedly protect these critical cells from infection. Sure enough they found three drugs that protected the neurons: Riluzole (used to treat Lou Gehrig’s disease) Metformin (commonly prescribed for diabetes management), and most interesting to me, Imatinib, or Gleevic (used for treating certain leukemias and cancers).

I say this is interesting to me because of my own research beginning at UCLA in the mid-80s, and extending to the University of Wisconsin into this century. My research focused on certain leukemias that carry a specific chromosome abnormality that appears in 99% of patients with chronic myelogenous leukemia (CML), and in fewer patients with acute lymphoblastic or acute myeloblastic leukemias (ALL and AML respectively). When I began studying this, the presence of this chromosome aberration was a death sentence. There was no effective treatment. Patients did not survive long. We identified the specific genetic abnormality, cloned the abnormal gene, sequenced it and found it was parts of two genes stuck together. Most importantly, we also described the enzymatic pathway in cells that it screwed up. All this eventually led to the development of a drug that tamed the misbehaving enzymatic pathway so that now >95% of patients with these diseases are fully cured with medicine that is pretty easy to tolerate. What once was a death sentence is now an easily treated disease. Knowing that makes me feel pretty good.

The drug that cures leukemia patients from what once was a lethal disease is called Imatinib; one of the drugs found to also protect dopamine producing neural cells from CoV-2 virus destruction.

That too will make me feel pretty good if it also happens to prevent neurological problems in COVID patients. Who would have guessed? This is the unpredictable way science often works.

Are COVID And Cancer Connected?

Nothing surprises me, I’m a scientist.” 

                            -Indiana Jones   

In 2019, the world was introduced to a brand new pathogen, the SARS-CoV2 coronavirus, that caused a brand new, and very odd disease, COVID-19. Between then and now, your humble bloggeur has penned 153 blog posts, many of which focused on how strange the disease is and describing our learning process as we figured it out on the fly. Many of these posts were necessarily equivocal because we simply did not have enough information to make firm conclusions on how the virus affects different people. Over time, we learned how to better treat the disease, and that learning curve continues. It was necessary to end many blog posts with the weak statement, “We will see.” Well we are still seeing and learning about this odd malady that consists of a melody of symptoms across myriad organs.

Research is now beginning to reveal a possible link between CoV-2 infection and cancer. As before, these observations are preliminary and will be further scrutinized, but they are bolstered by the discovery of a possible mechanism that could explain how the CoV-2 virus might cause cancer.

We know of many different viruses that cause cancer in animals. We also have a good understanding of how the viruses do that. There also are a few viruses, but not many, that cause human cancer, and we also mostly understand how they exert their oncogenic effects. These human cancer viruses include human papilloma virus (HPV), which causes cervical, and head and neck cancers. Hepatitis B virus can lead to liver cancer. Human T cell leukemia virus causes leukemia, and Epstein Barr virus can lead to lymphoma and a few other types of cancers. And so on.

To date, there has been very little association between any coronaviruses and cancer in animals or humans. But, that might be changing.

Several recent papers have revealed a genetic link between COVID-19 and cancer. One paper showed that people with an increased genetic risk of COVID-19, were also at increased genetic risk of developing endometrial cancer. The limitation of this study is that it cannot distinguish between a correlated high risk of COVID and cancer, vs whether COVID causes the cancer. It is the old conundrum of discerning between correlation vs cause-and-effect.

A second study incrementally advanced the above findings. Using a low resolution genetic mapping technique called genome-wide association, it found a positive correlation (there is that “C” word again) between people genetically predisposed to both severe COVID and increased risk for endometrial cancer. While still a correlation, one would predict that if there was a cause-and-effect relationship between COVID and cancer, that the risks for both would be similar. This is what the study showed.

Finally, a third study uncovered a possible mechanism by which SARS-CoV-2 could cause cancer. Having a possible mechanism in hand bolsters the possibility that the theoretical link between COVID and cancer is true. But first, a little back story about cancer genetics.

Cancer genetics.  Basically, cancer is a genetic disease. That does not necessarily mean that it is always inherited. Most cancers probably are not. But, when the genetic fidelity of a cell messes up, it can become immortal, can grow in an unregulated fashion, and can become resistant to normal signals that should cause it to die. In a nutshell, that is cancer. Generally speaking, there are two kinds of genes that contribute to this process. 1) Dominant acting oncogenes are aberrant genes that when expressed, drive the above activities. 2) Suppressor genes provide brakes to the above activities, and when absent, the brake is released. In both cases, genetic abnormalities either activate oncogenes to drive cell immortality and growth, or eliminate expression or activity of tumor suppressor genes removing the brakes to cell growth. Usually, cancer is a stepwise process in which cells sequentially accumulate different abnormal oncogenes and suppressor genes. The combination of which leads to full blown cancer.

One of the first tumor suppressor genes to be identified is called P53. In several different tumors, it was noticed that expression of this gene was missing due to DNA mutation. Further research showed that when expressed, P53 provides a brake on cell growth. There are many ways that P53 can be inactivated. Genetic mutation can prevent its expression, or hinder its function. We also know that a few viruses that cause cancer in people, like hepatitis B virus and Epstein-Barr virus, produce proteins that can interact with and inactivate the P53 gene product. A paper published in November, now reports that two CoV-2 proteins interact with cellular proteins to stimulate complex pathways that lead to degradation of the P53 gene product, releasing the anti-cancer brake in infected cells. The research also shows that that P53 activity is lost in patients with severe COVID disease but not in those with less severe illness. P53 loss also correlates with length of COVID symptoms. In other words, the more severe the COVID disease, the greater the chance that the P53 brake is lost.

This observation does not yet prove that inhibition of P53 by the CoV-2 virus causes cancer, but it now presents an important hypothesis that will be given much research attention. Questions remain regarding the association between CoV-2 infection and cancer. Also, since COVID infections are generally relatively short-lived, how long does the loss of P53 function last? Are long-COVID patients at increased risk for chronic loss of P53 and cancer? Is this loss of function sufficient to launch the multistep pathway that leads to cancer?

Once again, we will see.