Carl writes:

The major pre-existing antibody of concern in factor eight gene therapy is anti-factor eight antibodies. Antibodies against the virus are much more rare. This gene therapy would probably be ineffective if the patient has too high titers of Factor eight antibodies. These antibodies develop after repeated exposure to recombinant Factor eight.

Carl Singerman  MD

Jason writes:

Dear Twivers,

I am writing from Berkeley, CA where we are experiencing a beautiful sunny day, expecting a high temperature of about 76 degrees Fahrenheit/ 26 deg Celsius (~298 Kelvin).

I am a former molecular-anthropologist and ancient DNA researcher who now works as a bioinformatician assisting with the development of AAV delivered therapies for heritable diseases.*  As such, I found your discussion of Roctavian and haemophilia on TWIV 1028 fascinating. It represents the wonderful intersection of science, medicine, and history that makes your show so wonderful!

Perhaps I can add just a bit more. You mentioned the projected price of the gene therapy. While it is quite expensive, at ~$3 million to treat a single patient, current protocols for treating the disease with a replacement Factor VIII, either from plasma or a recombinant, can run nearly $1 million annually, and require regular transfusions (sometimes multiple times a week depending on the severity). If the gene therapy remains durable, and indications from the trials show that this may be the case, gene therapy may represent real cost savings in addition to a substantial improvement in patient-quality-of-life from a single administration.

I do have one correction. In response to Dickson’s question, Brianne said that this is the hemophilia that affected the Tzars. This is not the case. The so-called Royal Disease that was observed in descendants of Queen Victoria of England, was a different form of haemophilia, haemophilia B. Haemophilia B is caused by a defect in Factor IX. It too is located on the long arm of X chromosome and as such follows the same pattern of inheritance as haemophilia A, but is less prevalent and typically, although not always, less severe. We know this because of the genetic analysis of the remains of Alexei Romanov, son of Tzar Nicholas II and great-grandson of Queen Victoria. Alexei, like his parents older sisters Olga, Tatiana, Maria, and Anastasia, were killed by Bolsheviks in 1918, following the Russian revolution. Analyses of DNA recovered from his remains found a SNP that resulted in an incorrect splicing of the Factor IX gene. No changes associated with defects in Factor VIII were found. Alas, Roctavian would not have helped Queen Victoria’s afflicted kin.


(*) I  am not employed nor have I worked for BioMarin, the manufacturers of the treatment, nor was I involved in any way in its development.

Toomas writes:

Vincent and colleagues,

           Hi, I have followed TWIV for several years and have your discussion with Daniel Griffith in my earphones every Monday during my early morning run. When time permits, I also try to listen to your weekly science-oriented episode. Last week I listened to your debunking of the Joe Rogan podcast episode featuring RFK. Great job! However I missed a discussion of the ethical aspects. As a public health physician and epidemiologist, I have been looking into this topic during the COVID-19 pandemic. Maybe it is due to my information science background, but I find that mis- and disinformation are among the worst threats to public health today. To manage this threat, strong frameworks for professional ethics are needed in all institutional settings involved with public health. I enclose a paper I recently published with Jim Nyce, a senior medical anthropologist at Ball State U.

Best wishes,


Toomas Timpka MD. PhD.

Professor of Social Medicine and Public Health

Associate Professor of Medical Informatics

He sent 

Michelle writes:

Thank you for the RFK Jr episode.

I trusted you all to lay out accurately the basis for RFK’s opposition to vaccines and to answer his arguments, such as they are answerable.

In my opinion, debate is not the forum for testing scientific conclusions; the scientific method (experimentation) is. Debates can test logic, but not data and the reading of data. There is no way around it: scientific theories must be tested and challenged by knowledgeable scientists.

By the way, we accept expertise in many fields. I would not choose to fly in a plane built by a lawyer who had won a debate with an aerospace engineer in which the lawyer had “proven” that there is no such thing as lift.

I contribute every month to Parasites without Borders because of you all. Thank you for educating us non-specialist non-scientists about viruses.


Suzanne writes:


Cell biologist Tyson Graber posts Ottawa’s wastewater testing results on Twitter. 

He always has a follow-up Tweet that says, “Average of N1 and N2 SARS-CoV-2 genetic markers normalized to Pepper Mild Mottle Virus as a fecal strength indicator.”

I tried to look up information on this but couldn’t find a layperson explanation.

Anyone at TWiV would like to explain what it means?

Suzanne A.

Gatineau (Quebec)

LINK to Tweet:

Ottawa SARS-CoV-2 wastewater trends as of July 19

AD: PMMoV is the most abundant RNA virus in human feces (, and is not found in animal feces or uncontaminated water sources. That makes it a good, quantifiable indicator of fecal concentration in a sample.

Ellen writes:

No such thing as biological generics!

Biosimilars, and they are starting to catch on with the regulators and funders. People who know (I’m a lowly marketeer), in any case, will tell you that no biological product is the same as the one originally submitted for regulatory approval. 

Thank you for keeping me sane throughout the worst of Covid, and for helping me answer some of the irritating questions people keep asking. Or at least pushing them in the right direction.

April writes:

Hi Twivers,

It’s 74° F, predicted high of 90° F and there is a red flag warning today. I’m praying there are no new fires.

I love your picks, BUT I can’t read some of them. Out of the last 3 epitopes, with picks, there are 3 articles behind a paywall. Many of us don’t have subscriptions to The New York Times, The Atlantic, The Washington Post, etc. I know they have fabulous writers, but I feel left out.


Jeff writes:

Dear TWiV folks (and in particular Dr. Racaniello):

You keep coming so very close to answering what I suspect is a compound question many listeners have, but never quite getting the ball through the goal posts (or choose any other metaphor you like). The latest MMWR report on cVDPD outbreaks:

leads me to try it once again, restating what was asked by Volker in Bavaria and responded to back in TWiV 993.

According to your experts OPV normally reverts during the course of the infection to produce infectious virus which is transmissible. (To use bigger words it’s no longer neurovirulent but somewhat replication competent in the gut, and in the course of the infection natural selection leads to a more replication competent and transmissible variant.)  On a recent TWiV Vincent mentioned that the precise link between replication competence and neurovirulence is not known, but it seems reasonable to assume that transmission competence and neurovirulence are positively correlated. Since sterilizing immunity in the gut is presumably only achieved for a fairly brief period of time, why does not a pool of revertant polio simply persist, just as the wild type virus would?  Is it out-competed by other viruses?  Or is the assumption that vaccination is so widespread that there are insufficient uninfected hosts to support the virus until sterilizing immunity in the initial population has passed?  Especially since subsequent infections are likely asymptomatic and thus no transmission control measures are in place, it would seem the virus should persist indefinitely. There is some aspect of the kinetics of the virus that is obvious to experts but that at least some of us just don’t understand.




PS: in the spirit of counterpoint, Bob Heinlein noted many years ago that to some extent young adult science fiction should not be overly explanatory. Readers should be allowed to chase after meanings like porpoises in the ocean. Occasionally your discussions lapse into dense jargon and technical discussions. As an expert from an unrelated field I love it! Sometimes it’s good to stop and explain terms, but sometimes it’s good to go with the flow and let the listeners marvel at your erudition.

Ryan writes:

In this case it’s Paul Offit appearing on PBS Newshour to explain Robert F. Kennedy Jr’s rants in a congressional hearing. Congrats to Paul Offit for having to fact check all of RFK Jr’s statements to the general public. Let hope we don’t get a January 6th type event because of this but given RFK Jr’s past statements on comparing COVID-19 vaccine mandates to Nazi Germany that would induce stuff we saw on January 6th, 2021.