Updated Thoughts on The Language of Life

I have an earlier review on "The Language of Life" by Francis Collins (who was previously the lead for the Human Genome Project, and is the current director of the NIH).  However, given that I am presenting this book at the Monrovia Library book club in October, I thought it would be good to have a newer post with some additional posts (and I will also create a post with discussion topics for the book club, in October).

First, I should critique my own previous post.  For example, I currently feel more confident about preventing rare diseases than guiding drug treatments.  However, I think there was a sense in the limits to prediction that I was trying to convey before (in terms of "designer babies" where a large number of traits could be predicted and selected), and I still don't support that (or necessarily believe that can / should be accomplished).  I think this is also emphasized in the HFEA guidelines (described on page 55, in my edition) as well as some more updated scientist options (such as not using Polygenic Risk Scores for embryo screening).

I still really like that Francis Collins provided a balanced view of genomics (with both potential and limits), and I was glad to see that I could also notice that ~10 years ago.

My earlier post also reminded me of the statistic that "[adverse] drug reactions are the fifth leading cause of death in the United States" (page 233, in my edition), although I admittedly also forgot that in between the time that I first marked that page with a book dart and when I started writing the draft for this post.

Going back to the genomics and drug treatments, Francis Collins also mentions "the biggest reason for potentially deadly drug reactions is simple human error [but this isn't the only reason]" (page 233, in my edition).  So, even though I implied that I had less confidence in pharmacogenomics (or at least I think we have to be more careful about the assessments than I used to), I really do think biomedical informatics can help patient care.  In other words, making sure relatively simple actions are consistently understood and carried out appropriately is not trivial (which I also touch on when describing my cystic fibrosis carrier status, even though I believe that is more complicated than some people may expect), and that is something important that we can improve (without even using exceptionally complicated models / techniques).  Nevertheless, to be clear, this area was fairly represented in the book, with an entire section of the 9th chapter called "Obstacles to the Pharmogenomics Revolution" (page 247-249, in my edition).

Now, in terms of my updated thoughts:

1) In the introduction, "Dr. James" (who was really Francis Collins) describes interacting with somebody with a BRCA1 mutation in their mother's DNA, saying "[the patient] faced a 50 percent risk of having inherited that misspelling, in which case her lifetime risk of breast cancer would be approximately 80 percent, and that of ovarian cancer about 50 percent" (page XII, in my edition).  However, I think I have more recently gained better appreciation for the value in the range of risk estimates (at the gene or variant level).  For example, there is a Stanford BRCA Decision Tool that provides the variance of risk with a few options (although I'm not sure about the the intervals of screening, I don't know what is the relative effectiveness of hormonal therapies, and these estimates are at the gene level when I would expect some specific variants are higher risk than others).  Likewise, there was a recommendation for BRCA screening with a "B" grade in individuals with family histories, but a recommendation against BRCA screening with a "D" grade (which I think is shown most clearly on the US Preventive Services website).  In other words, I believe the significance of the result (and the preventive option chosen) varies depending upon whether the individual has a family history of early-onset breast cancer (ideally, I believe, with a variant that specifically validates between cases and controls in their own family).

In the interests of space, I have saved a collection of informal notes in another blog post.  This includes some things like strategies to define risk from family history from the CDC.

2) On page 194 (in my edition), Francis Collins describes "a company called Psynomics is marketing a DNA test for susceptibility to bipolar disorder, arguing that this information could be useful in establishing the diagnosis in an uncertain case.  The test being offered, however, is based upon a variation in a gene called GRK3, and this has not been validated in a large-scale study.  This result could turn out to be utterly useless.  Even worse, this kind of unvalidated test, utilized by individuals or their physicians to make a serious diagnosis in an uncertain situation, might do more harm than good." As with pretty much all of the posts, I will probably update my review of "Blueprint", but I agree with concerns about the over-estimation in the accuracy of tests that can possibly negatively impact the rest of someone's life (as well as my opinion that the reaction to genetic results may be particularly important for mental health).

Similarly, on page 204, a company offering testing of V1aR variants for $99 to test for increased susceptibility to infidelity is also presented with an appropriately critical view that "the actual influence on the behavior of an individual male is quite modest, and should certainly not be used in mate selection or as an excuse for cheating on one's partner.

3) Perhaps it is a bit of a tangent; however, in terms of the rare diseases, the first episode of Diagnosis on Netflix involves a patient story that was resolved with Whole Genome Sequencing (WGS) to determine the cause of her ailments for the past 10 years were due to CPT2 (meaning her symptoms could improve by increasing sugar and decreasing fatty acids in her diet).  I was surprised that she went to Italy for the diagnosis (where she was treated for free after the arrived, but I would have expected treatment costs to usually be above a few thousand dollars to justify the trip; I could get Veritas WGS data for $1000, but I did need to re-analyze it).

I was also surprised that her US doctors were trying to sue her for hundreds of dollars of medical bills (when she was already in debt, and the treatments weren't helping her in the long-run since they didn't reveal the underlying problem).  However, that unfortunately seems like it may not be an isolated incident: for example, I recently heard about this happening to a large number of individuals in the UVA health system.

However, getting back to this book, on page 92 (in my edition), Francis Collins warns that some nutrigenomics companies are running "consumer scams," while there are legitimate rare diseases whose symptoms can be improved with diet (such as PKU).  I was also skeptical about some of my nutrigenomics results, but it sounds like the Netflix show also provides a genuine example where genetics can inform diet (and vastly improve your quality of life).


Also, similar to my 1st post, here are some assorted minor points:

a) Francis Collins (as Dr. James) indicated some someone from Navigenics implied that "most of the remaining genetic risk factors for common disease will have been discovered in the next two or three years; as a scientist working in this field, that seems unlikely to me" (page XXII, in my edition, emphasis added).  I also don't think Navigenics exists anymore - at least the Wikipedia company link does not go to a genetics company website (even though they also mention it was acquired by Thermo Fisher in 2014).

b) As noted in the first post, Francis Collins has blue eyes when 23andMe predicted them to be brown (page XXVIII, in my edition).

c) I am a Bioinformatics Specialist (doing genomics research).  However, I don't think that term was in widespread use when the book was written.  For example, I believe his term "DNA cryptography" (page 13, in my edition) is meant to be synonymous with "Bioinformatics."

d) Reading this book also influenced another blog post, in terms of the discussion of the ACLU Supreme Court case invalidating Myriad's patents on the BRCA1/2 genes and contrasting his own actions for the CFTR gene for cystic fibrosis.

e) On page 187 (in my edition), Francis Collins describes "[one] remarkable gene in the brain is estimated to be able to make 38,000 different proteins."  However, I kind of wish there was a reference to the citation in the primary literature.  For example, I thought most cells tended to have one predominant version of a gene transcript, and I am worried about false positives (or at least rare alternative splicing events) when describing very large numbers of isoforms for genes.

f) On page 317 (in my edition), 23andMe is listed as testing for the Δ508 cystic fibrosis variant.  While I got my first 23andMe test in 2011 (a little after this book was published), I am a carrier for a different cystic fibrosis variant.  So, 23andMe currently covers more than just that one cystic fibrosis variant.

Finally, I specify "in this edition" whenever I reference something from the book.  However, I think the relatively newly purchased paperback was still the 1st edition.  So, I'm not sure how necessary this is.  However, in terms of trying to minimize errors in peer-reviewed publications (and making sure people acknowledge and correct errors), I think the concept that books have editions may be kind of important.

Update (10/19/2019): After I finished re-reading the book (again - to prepare for leading the book club discussion), I thought I should write a little more to make sure that I am to down-playing the pharmacogenomics part too much.  While I do think the introduction is a fair match to my interests / opinions, I do want to make clear that I am sure there are important genomic applications with decent predictive power for guiding drug dosage, drug effectiveness, and/or serious adverse side effects.

So, similar to the separate blog posts containing notes on BRCA1/2 pathogenic risk, high-to-moderate inherited cancer risk frequencies for pathogenic variants, and APOE variant frequencies and Alzheimer's Disease risk, I will try to add a few links about the influence of VKORC1 on Warfarin / Coumadin dosage.  However, I have spent considerably less time looking into that, so this will just be bullet points below (instead of a separate blog post):

• Rieder et al 2005 - paper cited in the figure caption in the book (I think "Haplotype" concept is made a little more clear in the original figure, as well as explaining the use of "A" and "B" in the book)
• There is a more recent 2009 paper, but the genotypes are described in a different way (and what I wanted to do was try to judge if there should have been larger error bars in the earlier paper).
• For example, Figure 2 in the 2005 paper matches the sort of error bars that I was expecting with VKORC1 gene expression (which is noticeably larger)
• Limdi et al. 2010 - paper showing variant predictive power across racial groups; mentions both SNP and haplotype, but I mostly notice that the variant is at 91.03% in the Asian population, 10.05% in the African population, and 37.81% in the Caucasian population(so, variability is not equal from individuals with different ancestry)
• 23andMe blog posts with "Warfarin" tag - there is a blog post mentioning providing a 23andMe report for the variants listed on the label, but perhaps that doesn't have approval to be added back?
• FDA Coumadin labels - describes GG, AG, AA genotypes for 1639G>A variant (which actually would be a SNP, even though SNPs sometimes do represent larger haplotypes)
• ClinVar link above actually only has 2 stars, but "Warfarin Response" in MedGene has more information, included dbSNP ID (rs9923231) and that variant also has clinical annotations in PharmGKB
• The variant in intergenic, but you can see your genotype (I am CC, which should be GG in format above), even without a formal report --> from PharmGKB, I can tell I have the variant associated with requiring a higher dose

On the other hand, I really do have some interest in understanding (and critically assessing) the use of genomics for depression treatment.  I have tried to collect some notes on that within my review of "blueprint", as well as expressing concerns I have about what people might percieve about the predictive power of genomic data and anxiety / depression (based upon my own personal experience as well as some general genomics research experience).

Change Log:

9/7/2019 - public post date
9/8/2019 - revise post from sister's feedback; minor changes
9/9/2019 - add UVA example + NCCN guidelines + additional Twitter / blog link
9/10/2019 - minor changes
9/13/2019 - add links from the CDC
9/14/2019 - move longer set of BRCA1/2 notes to separate post
10/19/2019 - add update with pharmacogenomic notes

Monrovia Library Book Club Discussion Topics for "The Language of Life"

You can see my thoughts in an two earlier blog posts (my first ever blog post in 2010, as well as a more recent blog post in 2019).

However, the book club (at 6:30 PM on Tuesday October 22nd) is really about other people's thoughts (although I hope this non-fiction book helped with understanding about genetics/genomics).

So, here are some discussion topics, which I think could be of interest (even if you didn't already have a passion for genomics):

1) In general, what did you find to be the most interesting part of the book?

2) Did you think this was a good introduction to genetics / genomics? If not, I also recommend reading "The Cartoon Guide to Genetics" (which was required for my AP Bio class in High School, along with a more formal textbook). However, please be aware that the cartoons within the book are in black-and-white.  Also, as with just about anything else, the book isn't absolutely perfect: for example, there is a reference to 200,000 genes in the human genome on page 80 (which was believed at one point, but I would now say we feel much more comfortable with 20,000 genes that can be relatively consistently transcribed).

3) There is a section of the 7th chapter about the influence of genetics on Criminality.  For example, there are a few paragraphs about the X-linked MAOA gene.  While I mostly have to trust the study was fairly presented (and the reproducible in subsequent studies), a study showing decreased expression of MAOA was associated with increased risk of violent behavior and criminal convictions, but only if the individual was abused as a child (page 202).  So, I think this is a good example of a gene-environment interaction, but I don't know how strong / predictive the risk association was.

Likewise, to put things in perspective, Francis Collins also pointed out "approximately half of the US population carries a genetic risk factor that places people at a sixteenfold higher likelihood of imprisonment than the other half.  That happens to be the Y chromosome" (also on page 202).

Would your opinions of someone change if you knew they had a negative genetic predisposition (and you thoroughly understood exactly what has been observed and how much of an effect that has)?  For example, what do you think about giving somebody a lesser or more severe sentence because of their genetics?

4) Also in the introduction, Francis Collins discusses Alzheimer's disease risk, and questions the value of returning results when there is nothing that can be done medically (page xx, as well as illustrated on page 222).

I (Charles Warden) carry one copy of the APOE E4 risk variant (and I know which parent also has that risk variant).

4a) What do you think about a risk assessment for a disease that cannot be prevented or treated?

4b) Does that opinion change if I emphasize the need for you (and your genetic counselor, physician, etc.) to have access to the data to calculate the risk assessments, as well as making sure that you have access to your raw data for re-analysis / evaluation?

If interested, you can see my longer list of informal notes in another blog post.  However, the main message I think I should explain is that it takes some time to get confidence in a risk assessment (and I think there should ideally be some sort of access to the primary data used to come to those conclusions).

While I won't focus on what (from what I understood) were the less representative results here, my impression is that the more robust conclusion was similar to what was reported in my 23andMe report, Genin et al. 2011, and Myers et al. 1996 (which I am using to report the following statistics):

• ~55% of E4/E4 individuals developed Alzheimer's Disease (with an age of onset ~80 years)
• ~27% of E4/E3 individuals developed Alzheimer's Disease (with an age of onset ~85 years)
•  ~9% of E3/E3 individuals developed Alzheimer's Disease (with an age of onset ~85 years)

Likewise, my 23andMe Report says "Approximately 40-65% of Alzheimer's patients have one or two copies of the APOE ε4 variant. However, many people with the APOE ε4 variant will not develop late-onset Alzheimer's disease" (citing Alzheimer's Association 2016).

5) Do you have any direct experiences with genomics results (from 23andMe, AncestryDNA, uBiome, Genes for Good, American Gut, etc)? For example, I have recorded some of my relatively recent experiences in this set of blog posts.

Having 5 questions to guide the discussion may already fill an hour (with a group of 20-30 people).  However, I hope the blog post can help with discussions before the book club (to help me better prepare) as well as after the book club (if anybody doesn't have a chance to express their opinion).

Change Log:

9/7/2019 - public post date
9/8/2019 - revise post from sister's feedback; minor changes
9/9/2019 - trim content
9/10/2019 - fix typo
9/11/2019 - add extra APOE E3/E4 citations (from 23andMe, ClinVar, and accepted middle-author paper; although I think the last of which was also in the pre-print)
9/13/2019 - add CDC links
9/14/2019 - separate blog post for detailed APOE notes
10/1/2019 - minor changes

Review of "The Language of Life"

I have wanted to learn more about the current status of personalized genomics for some time, and I was hoping the release of Dr. Francis Collins’ new book “The Language of Life” could help bring me up to speed. Dr. Collins is the current director of the NIH, and he was also the head of the Human Genome Project.

Overall, I like the book, and I think Dr. Collins does a good job presenting facts objectively, providing both optimistic and pessimistic evidence. However, readers should be careful to distinguish between “potential” applications and current applications of personalized medicine; the potential applications greatly outnumber the tools currently in widespread use.

I have included relatively brief summaries of the main applications of personalized medicine and some cool factoids that I gleaned from the book:

Applications:

1) Personalized drug treatments - This is the aspect of personalized medicine that I find most exciting. Adverse drug reactions are the fifth leading cause of death in the United States (although some problems are due to human error, rather than genetic sensitivities). Dr. Collins discusses the current use of diagnostic tests to guide prescriptions for 6-MP (leukemia), Warfarin (blod clot/heart attack), Ziagen (HIV), and Herceptin (breast cancer). There are also several drug sensitivities that can be revealed using genetic tests (such as 23andMe), but such genetic testing is not currently standard practice. Many other potential applications of personalized drug treatments are discussed, and Dr. Collins also discusses the numerous drugs that have been developed after discovering the genetic basis for various diseases (using genetic/genomic tools).

2) Assessment of risk factors in your own genome – This is the topic of the book’s introduction. Dr. Collins discusses his own family history and his interpretation of genetic tests provided by 23andMe, deCODE, and Navigenics. He also provides a list of his positive results at the end of the book. Although exciting progress has been made in this area, I think these tests need to be more accurate. For example, the three tests were not even in agreement as to whether or not Dr. Collins should have either increased or decreased disposition to prostate cancer (the difference was due to which genetic variants were considered as part of the test). 23andMe also predicted Dr. Collins would have brown eyes, when in fact he had blue eyes. New genetic associations are constantly being published, and I think companies need to be conservative and only test for reproducible associations discovered by independent studies.

3) Assessing risk factors when planning children – This is certainly the most controversial aspect of personalized medicine. Although couples can get individual genomic tests and simply forgo having children (or staying together) if they are both carriers for a severe, recessive disease (like cystic fibrosis), a more aggressive and controversial route would be pre-implantation genetic analysis (PGD). PGD involves in vitro fertilization, conducting genetic tests on the fertilized embryos, and only implanting the embryos that are free from serious diseases. This technology is already in use, but it will obviously raise concerns for those who either believe that life begins at conception as well as those who fear a GATTACA-esque future of designer babies. In fact, Dr. Collins reports that 42% of PGD clinics would be willing to apply this procedure for sex selection, and a California lab currently advertises providing selection for eye and hair color. Dr. Collins proposes regulating which traits can or cannot be selected for during this process, and he also raises the point that defining every trait genetically (as presented in GATTACA) would be impossible because a number of traits are determined more by environment than genetics and the number of embryos needed to produce the right combination of desired traits would be enormous and impractical. I also think it is worth recalling the current accuracy of genetic tests (recall that Dr. Collins was supposed to have brown eyes when in fact he had blue eyes). I am generally not a fan of government regulation, but I do see how this thing can get out of hand and would at least advocate giving people the facts necessary to view these tests with a critical eye.

4) Gene therapy and stem cells – Although I wouldn’t usually consider this to be “personalized medicine”, these therapies are disused in depth in the final chapter of the book. Collins discusses case studies for gene therapy treating LCA (a disease that causes blindness) and X-linked SCID (“bubble boy”) patients. In an earlier chapter, Dr. Collins discusses a case study where stem cells (containing double mutants for CCR5) implanted in the bone marrow of a leukemia patient was able to confer resistance to HIV. Collins also discusses the use of iPS stem cells (engineered from normal cells, not embryonic stem cells) to cure sickle-cell anemia in mice, but he also notes potential complications (i.e. one of the four genes used to induce these cells is an oncogene, and may cause cancer in human patients). However, it is important to remember that case studies can sometimes provide atypically good results.

Cool Factoids:

1) There is currently a free government website that allows people to record and analyze their family history. Dr. Collins describes this as currently “the single most important source of information about your future health”, and I personally think this would be a cool extra credit activity for high school students to see how they can apply genetics to real-world problems…that is assuming students can prove they have used the website without handing their medical history over to their biology teacher.

2) Free tools already exist that allow people to keep digital copies of their medical records, which can be rapidly accessed by designated health care providers. Two such tools are provided in the book: Google Health and Microsoft HealthVault

3) In addition to the discussion of Dr. Collin’s family history and genomic analysis, he also describes catching malaria and TB (on separate occasions) as a volunteer physician and a medical intern, respectively. Of course, he successfully recovered in both cases.

In conclusion, I think “The Language of Life” provides a good review of the progress of genomics in biomedical research, and I would especially recommend it to nonscientists who want to learn more genomic medicine.