Conundra

The long gaps between posts could be taken as a sign that my life is returning to some semblance of normal, with no worries about mortality or the interpretation of ambiguous medical information. That would be incorrect, as everyone knows here in the Omicron crest: normal is a half-remembered state, ambiguity is everywhere, and we are all working with it in one way or another.

So I have two issues to discuss. One relates to myeloma, and one to COVID 

Needless to say, they also relate to one another.

To restate something that I think I have already described, multiple myeloma (MM) is a disease of the very mechanism by which antibodies are produced. Your basic antibody consists of several pieces (immunoglobulins) produced by what are called plasma cells built in the bone marrow. For those of us with MM, some of the plasma cells that produce one of those pieces have abandoned their station and are simply reproducing themselves without restraint. So the whole antibody-production machinery is out of whack.

Treatment for MM consists of attempts to: 1) kill the specific lineage of renegade cells; 2) tamp down antibody production generally; and 3) do a few things that seem to work, even if nobody really knows why.

I've been "treated" in these ways (one of each of the three approaches described above) for 6 years now, so there is plenty of reason to think my immune responses (especially with respect to antibodies) might be less than optimal. On the other hand, the MM is under control and in many respects I might respond just like anybody else with a normal immune system. 

All of this is background to a pair of choices that I need to make. One relates to COVID, the other to MM. Let's start with MM. The particular "high risk" form of MM that I have (deletion of chromosome 17p) led to a tandem stem cell transplant (i.e., one transplant followed quickly by another). Clinical trial results indicated that tandem transplants followed by maintenance chemotherapy were the best option, at the time. The chemo options involved choosing one among several proteasome inhibitors (#1 above), a corticosteroid (#2), and one of several immune modulators (#3).

The drugs I've been taking for 5+ years now are Ninlaro (#1), dexamethasone (#2), and Revlimid (#3). During this time, my disease has been essentially invisible and the side effects of the drugs have been mostly minimal. Moreover, this is a completely oral drug regimen, which allows me to travel and not be tied down to an infusion center. So what's the problem?

From an oncology point of view, Ninlaro seems to be an ineffective drug, compared to its competition. Long-term clinical trials comparing Ninlaro to other proteasome inhibitors don't look very impressive. I came upon this discussion following the December meeting of the American Society of Hematology (the big annual blood cancer conference). It's a real downer, and has had me rethinking the whole Ninlaro thing. 

But hold that thought, and let's get back to the antibodies: dexamethasone clearly has a negative effect on the whole immune system, and Revlimid--which has been around long enough that it is (thankfully) off-patent now--is still pretty much in the category of "this stuff works but we really don't know how." Neither of these drugs gives me much confidence about mounting an anti-COVID immune response.

So last Summer I got a COVID antibody test, 4 months after being "fully vaccinated" with two Pfizer shots. It was negative. So I went and got a booster, waited two weeks, and got another test--which was very strongly positive. In November, we were visiting with Rosie in Providence and she suddenly lost her senses of taste and smell. She tested positive for COVID, but no one else did. At that point, four months after the booster, it seemed like a good idea to check the antibody level again. Somewhat to my surprise, the test was still strongly positive. (Rosie recovered quickly, and thankfully has full command of her senses once again.)

Now a couple more months have elapsed, Omicron is rampant, and the FDA and CDC have given their blessings to the idea of a fourth shot for people like me with compromised immune systems, though there is little evidence about how useful a fourth shot is. My current thinking is that I'm going to check the antibody levels first and make a decision at least partly on that basis. If I decide to do another shot, I'll test after, as well. For reference, in mid-July, the antibody titer was basically 0 U/ml, two weeks after the booster it was 2141, and in mid-November 891. A "positive" result is anything bigger than 0.8 U/ml, although what level is actually useful for preventing infection or severe disease is not well established, especially since antibodies are only one piece of the immune response. It's probably reasonable to think that the level should be above 100, maybe more like 500 to deal with Omicron.

As for the Ninlaro, it's likely that I would never have started on it in 2016, if we knew then what we know now. However, I only had a partial response to tandem stem cell transplant, and during these years on the Ninlaro-Revlimid-dexamethasone combo the response has gone from partial to complete to no measurable disease. I feel good and the side effects are manageable. Maybe I could just drop the Ninlaro and it would be the same, but at the moment, I'm leaning to keeping everything the way it is until something else happens. The trio of drugs is working, and the stakes seem too high to mess with that, unless there is a good reason.

So much for a rigorous, quantitative approach to "the lab is me." Out here past the intersection of pandemic and cancer it's all extrapolation and guesswork. Here be dragons.

Booster

We are now entering the booster phase of the pandemic, apparently. Sorry, but I am already there: here's the story. 

All the way back in March, Liz and I signed up for vaccines just as soon as we could. For both of us, here in Kentucky, that was the beginning of March (2021). As it played out, the fastest route seemed to be through Walgreens. Online, Walgreens would only schedule you for the first dose (either Moderna or Pfizer) if they could find a second dose for you after 3-4 weeks.  We were "motivated," as the real estate agents say, so the fact that neither dose one nor dose two would be happening at the same Walgreens, nor at any Walgreens we had ever been to, was not a major deterrent for us. I got my shot first (Pfizer), without incident, at a place near the airport. Also near the best Vietnamese restaurant in this part of the country. Liz got hers about three hours later, maybe two miles away, over by Churchill Downs.

We both had appointments for our second shots (3/31/21), established at the time of our initial appointments. We counted down the days. Liz was first, at yet another Walgreens, way out on the West Side. We reported for our assignation, only to find that this Walgreens had only the Moderna vaccine, as did almost all of the Walgreens in Louisville. After some discussion, we found that the very pharmacy at which I received my first jab was still dispensing the Pfizer vaccine (by the way, there is very little reason to think that you couldn't do just fine by having Pfizer-Moderna or Moderna-Pfizer, nevermind J&J in combination with itself or either of the others).

Liz and I headed South to the 'Pfizer' Walgreens, and she got in line for the shot. Meanwhile, I called around to see if my appointment, later in the afternoon but far to the East, was an appointment for the M or the P. After some pleasant time on hold, I found, unsurprisingly, that my appointment was for the Moderna vaccine. So I held for the District Supervisor, who told me that the Pfizer vaccine was indeed available, but only at the very Walgreens whose parking lot was my current location. After a few more minutes of holding, I was inserted into the queue, and did in fact get my second shot (as did Liz). I hope no one else was displaced. 

Sadly, the Vietnamese restaurant has closed, another pandemic victim.

Lately, of course, the Delta variant has caused massive havoc. In particular, folks like me with suspicious immune systems have been found to be deficient in our immune responses. This is not a surprise--myeloma is a disease of the system that makes antibodies, so the fact that antibody titers in people with myeloma are depressed is no big news. But that also relates to whether patients are being treated, and how they're responding to treatment, and many other factors, so there's no way to be sure--except to do the test. 

The first thing I did was to volunteer for a study sponsored by the Leukemia and Lymphoma Society (myeloma counts as a kind of leukemia as far as they are concerned). I filled out an online questionnaire and waited for them to send a kit for the blood draw. Still waiting.

At Liz's suggestion, I asked my GP to do a covid antibody test. He ordered a semi-quantitative spike protein assay from Quest, which sounded right to me. A day or two later, I got a notification that the test result was in. It was negative, and--so much for the quantitative part--no number was attached. A few minutes later, the Leukemia and Lymphoma Society sent me a link to the preprint of their paper announcing the results of the study I'd enrolled in (you can find the published version here). Amazingly, 95% of myeloma patients tested positive for antibodies after vaccination. So what was wrong with me? Maybe it was the test. 

Digging through the description of methods, I found the LLS study had used a different assay, from Roche, apparently designed more specifically to measure vaccine response than the Quest assay I got.

But I also asked the GP if he could order a booster shot for me. This was late July, and he replied that he couldn't do that, but he also couldn't stop me from doing it on my own (not his exact words, but that's the gist). So I found out who had Pfizer vaccine in stock, signed up online, and got the shot. 

It also turned out to be easy to order up the Roche test for myself. LabCorp was offering the test and would supply an in-house physician to order it on behalf of anyone who wanted it. Liz was interested, too, so we both signed up. Two weeks after my unofficial booster, we did the test, and got results the next day.

We both tested strongly positive for antibodies, which put our minds at ease on that front. Of course, it would have been better to do the test both before and after getting the booster, so we could know if any of the difference between results had to do with the test itself rather than the booster, but oh well.

A week or two later, immune-compromised people like me became officially eligible for boosters, and now it seems everybody should get them after 8 months. I'm aware that the FDA does not consider any current antibody test worthy of approval for the purpose of assessing vaccine response, but anecdotally I can say that the Roche test has been helpful for us. Of course, it's not the whole story. For example, T-cells might be at least as important as antibodies in anti-covid immune response, but have rarely been measured. A couple of recent studies appear to show that antibody levels do strongly predict overall immune response, though, so maybe that concern can be set aside. 

Then there's the ethical issue of whether third vaccine doses for the relatively wealthy should preempt first vaccine doses for the developing world. As a matter of policy, I'm sympathetic to the view that getting doses to the largest number of people as rapidly as possible, everywhere in the world, should be the highest priority. Personally, though, I am looking around me here in Kentucky, where there is plenty of vaccine available, but the vaccination rate is stuck right around 50% and seemingly going nowhere, and the rate of new infections is going through the roof again, while thousands of vaccine doses spoil every day.

So my plan is to donate enough to UNICEF to provide a large number of vaccine doses to people who need them, letting the professionals figure out where the need is greatest. Maybe that's a good way to strike a balance. Time will tell, I hope.

Junior

[I haven't found anything helpful to say about this year. I'm OK, pretty much the same as last year at this time, and maybe that's some news--though not much, since Liz and I have the means and the know-how to keep ourselves safe. 

But--my God--I never imagined that the U.S. in the 21st century would be so bad at handling a major pandemic, or that the response would be so political, to a thing that has no politics. I've always held the CDC in the highest regard, for good reason, and it's unnerving to think that an institution of such great accomplishment could fall so far short so fast.

Now we have a vaccine, in record time to be sure, but also FINALLY. There are really several that will do the job, in various stages of evaluation. The first shipments in this country are in process, many of them passing through the massive UPS hub in Louisville, about 10 miles from here. The vaccines were not produced by the power of positive thinking, nor by bullying, lying, misogyny, racism, gluttony, narcissism, faith, or any of the other dominant memes of the last few years. They were produced by the efforts of scientists who understand the difference between actual truth and the stuff that you might hope is true.]

What I really want to say is that I have been doing some genealogical research, and enjoying it. Given that much of my career consisted of genealogical research, it's a bit like a busman's holiday, but here I am. The tools are much, much better than they used to be, and the skills I've developed over the year help too, of course.

Officially, I am Richard Ade Kerber, Junior. My father (Richard Ade Kerber, Senior, as you might have inferred) and his brother (Ira Newton Kerber, Junior) were the two sons of (wait for it . . .) Ira Newton Kerber, Senior. For three generations of Kerbers, the only male names were Ira and Richard.

In real life, I've never used the Junior, and never liked it, even as a kid. As soon as I was out of the house, I dropped it from all my official records, and rarely thought about it. However, if you're doing genealogical research you need to be careful about senior/junior pairings, since the names and often the places are identical. That's especially true if you want to use an algorithm to speed through bunches of messy historical records. I've written some of these myself over the years, but most of them relate to calculating statistics on pedigrees rather than displaying them nicely, and, because this involved biomedical research, printing names all over the pedigrees was a distinct no-no. But now I wanted a pretty chart with ancestral names on it, so I downloaded some software that seemed like it might do the job and started fiddling around with it.

It immediately drew a pretty chart, but ignored the names I had supplied. I realized that the software thought my ID numbers were names, so I replaced the former with the latter. And that broke the software. I could see that there weren't too many names, and they weren't too long or weird, so that wasn't the problem. Then I noticed that it had read all the names, but not the suffixes (Jr, Sr. III, etc). So, as far as the algorithm was concerned, I was my own father, and my father's brother was his father, and so on. It only takes one of those to make a stack overflow, but I had at least half a dozen. 

After some additional tweaking (I'll spare you all the details of GEDCOM file formats, R code, and the like; suffice it to say that it took longer and was more annoying than seemed possible), the Juniors, etc. were restored and everything worked more or less as planned.

So I have a newfound appreciation for my Junior. Moreover, I've noticed that in recent years, many athletes have been appending Jr, III, and so forth to the names on the back of their jerseys. I thought this was odd, unless, like Ken Griffey Jr. their father was also a famous athlete. But I think now that I was missing the point, and I was missing the point all along. The point, I think, is that wearing the Junior honors your father regardless of (or in spite of) his fame or obscurity.

I think now that my dad might have appreciated the formal respect shown by embracing my Junior-ness more than I understood at the time. He wouldn't ever have said anything, and I can't ask him now, but I feel a little sorry about that. From where I sit, looking at the short end of life, and considering all the lives cut short during this horrific year, any missed opportunity to show respect and appreciation for another person seems like a small tragedy.

tears and metaphors

A note on capitalization: I've noticed that I'm not at all consistent in capitalization of blog post titles. I'll try to at least be slightly conscious of that in the future, but I do try to be consistent in capitalizing (or not) drug names: brand names (Ninaro, Revlimid, Darzalex, etc.) are capitalized, generic names (ixazomib, lenalidomide, daratumumab) are not. I'm convinced that pharma companies have committees whose sole job is to make generic names that are both unpronounceable and at best only vaguely related to molecular function, but that's not why we're here. We're here to bury the lede. Done!

As I have continued to enjoy good health, 3 years out from my second stem cell transplant, my complaints have less to do with multiple myeloma and more to do with being a 60 year old guy with some issues. The latter is a far less compelling reason to be blogging, it seems to me, than the former. Nevertheless I will persist and sometimes the one thing comes around to the other in a way that may be trying to tell us something.

My tears are toxic. I hardly have to say that the temptation to make this into some kind of metaphor is overwhelming, but I'm not going there.

For many years I've had rosacea, a pretty common skin condition that I've always considered (with no particular evidence) a long-term consequence of the bad acne I had as an adolescent/young adult. Over the years it would wax and wane, and I had been taking low-dose doxycycline to control the rosacea for some years before I was diagnosed with MM. It worked pretty well. After the stem cell transplants, I resumed doxycycline for a year as prophylaxis against bacterial infections. Two years ago, the docs decided I didn't need the prophylaxis any more, and I figured I could probably give my liver a break at the expense of my vanity, so I quit taking doxycycline. I replaced it with some topical stuff (metronidazole, azelaic acid) that sometimes seemed to help.

Over time, the redness and lesions increased in number and frequency. And a pattern appeared. Lines ran down my cheeks on either side of my nose, and frequently around the base of my nose. When things got bad, they'd radiate outward, but the focus was always around my nose. Meanwhile, my eyes were tearing more often and more regularly than ever before. Tears seemed to be implicated, because the rosacea was occurring right along the paths down which the tears ran, both outside and inside my nose. Often there's a clear pattern running right from the tear ducts down to the corners of my mouth.

Chemotherapy agents are absorbed into all kinds of tissues, processed in various ways, and emerge via bodily fluids of one kind or another. Mostly it's going to be urine or feces, or blood if you're bleeding, but sweat, mucus, semen, and tears also can carry the chemo agents or their downstream products. It turns out that both Revlimid and especially Ninlaro are associated with rashes and skin lesions, and  excessive tearing is a common side effect of proteasome inhibitors (like Ninlaro). So I think my excessive tears, carrying enough residual Ninlaro and Revlimid to cause my already-reactive skin to become inflamed, stimulate the latter-day "rosacea." The topical treatments I've been using, while they allegedly have some anti-inflammatory effects, are probably not up to the task of dealing with this level of inflammation, so I'm going to try steroids like cortisone for a while. The early results are encouraging.

As for the metaphor, it would be way over the top. I'm as given to tears as the next guy (maybe more so), especially when they ramp up the music at the end of the movie--being fully aware that I am being cruelly manipulated makes me want to cry--but I am not in any way despondent about my circumstances, as I hope this blog makes clear. That's subject to change, of course, but I now have an objective reason to avoid tears, even if I may not be able to do much to stop them.

New drugs

A preface to this post: last year, in reviewing my options for Medicare coverage (surely one of the driest sets of posts I've done--at least I hope so!), I made a post with the title "Drugs." Didn't think twice about it. Every so often I check to make sure there are at least a few people still reading: the few, the proud . . .  

Anyhow, one post stands out for alleged readership, with roughly ten times more hits than average. You guessed it---"Drugs." So, in the spirit of experimentation, I've got a new really dry subject to cover, namely new MM drugs just approved and in the pipeline, and I'm pretty sure that I can boost my stats just by putting the word drugs in the title of the post. Sorry, everyone who is trolling for mind-altering substances. Nothing to see here. You've heard of the dark web?

I'm not planning any changes to the current chemo regimen (Ninlaro, Revlimid, dexamethasone), since it's working very well at present, but there's no reason to think it will work indefinitely, so I keep an eye on new developments in the pharma pipeline. Myeloma is proving to be fertile ground for drug discovery and there are lots of interesting things out there, including one new FDA approval and several that are pretty far along in clinical trials--in fact, there are so many different approaches that seem to be bearing fruit that it seems like a kind of golden age in myeloma treatment. Golden ages are best judged after many years have passed, of course, so maybe it's just a lighter version of the darker ages that have gone before. But there is real progress--hard to judge while you are in the midst of it--but undeniable.

For example: in this post, the proportion of patients like me ("high-risk") surviving for a standard treatment (Single ASCT) is about 30%, 4 years after diagnosis [For the record, I am just about exactly 4 years post-diagnosis.] Given what we knew at the time, we chose a second transplant, and that seems to have been a wise choice. But that barely scratches the surface of what has changed over the last few years.

Most of what is new is that a bunch of different attacks on myeloma cells look to be working. I wanted to say "are bearing fruit", but that's almost exactly wrong. Tumor fruit is not to be borne. In any case, here's a quick rundown of what's newish.

1) Xpovio (that's the brand name), selinexor (that's the generic name). The only new FDA-approved drug for MM since 2015. An interesting story in several respects: 1) new mechanism--the drug interferes with nuclear export within cells, meaning that cells can't get the new stuff they've made out of their nuclei fast enough, leading to death; 2) it works comparatively well for patients who have exhausted all other possibilities, including those like me who are considered high-risk; and 3) it almost didn't get approved because there were a surprising number of unexpected patient deaths, balanced against the bleak prospects of those patients if they had no other options.

2) Monoclonal antibodies. Back in 2015, two monoclonal antibodies were approved by FDA. One, daratumumab (brand name Darzalex), has been a big winner in terms of patient responses, market share, and name recognition. It targets CD38, an antigen that most myeloma tumor cells express. The other, elotuzumab (Empliciti) targets a different antigen (SLAMF7), and also looks to be working well, but needs a bit of help from some of the other myeloma drugs. One major thing about the the monoclonal antibodies is that they have some major effect by themselves, but they can also be used to target anything from chemotherapy agents, to biologics, to nuclear warheads (really!) that will attack the tumor cells. More on this to come.

3) CAR-T. There are something like a half-dozen trials of chimeric antigen receptor T-cell (CAR-T) therapies in MM, and most of them look really good so far. The idea is that you harvest T-cells from the patient, culture them in the lab and attach a new receptor to the T-cells that will more-or-less specifically recognize a myeloma tumor, attach to it, and kill it. As of today, CAR-T therapies have been approved for some leukemias and some lymphomas. The upside is that they might actually cure the disease. The downside is that they are so expensive ($500k+) that they have not been widely adopted so far.

In myeloma, the trials so far have yielded very positive results, even in patients who have failed multiple rounds of treatment. It seems likely that approvals for one or more of these will be granted within a year or two. The expense issue will still be there, and the competition might be fierce, but I am looking forward to having this as an option.

Just this week, the abstracts for the December 2019 American Society of Hematology meetings have been released. It looks like several of the CAR-T trials that have been in progress have continued to have great results.

4) BiTE. Bi-specific T-cell engager. A newer, potentially much cooler approach is to make compounds that have myeloma-specific antigens on one end, and T-cell targets on the other. These function as matchmakers, bringing together the presumably fatal attraction between the tumor cells and the T-cells. Unlike CAR-Ts, they don't need cells cultured from the patients, a big plus. So far, there is a big minus as well, because the half-life of the BiTEs is very short, so in trials patients have needed to be infused continuously for 28 days. That would be hard.

I haven't seen any updates yet for this trial, but I will post them if/when I do.

There's a similar new technology, called T-cell effectors, that are also showing promising early results. The idea is similar--the molecule is engineered to bring together the antigens on the tumor with the T-cells that will kill them.

5) CRISPR. The first human cancer trials of a CRISPR-based approach to treatment for myeloma have just begun at the University of Pennsylvania, with two myeloma patients and one lymphoma patient enrolled. The good news is that all the patients are still alive after 9 months, and the edited cells are still present. It's way too early to say how this will go, but so far it's looking good.

6) Conjugates. This is a rapidly growing area, in which a monoclonal antibody targeted to some tumor antigen (CD38, BCMA, etc.) is used to introduce something toxic to the tumor cells. There are a huge number of possibilities, from basic toxins to apoptosis-inducers to radioactive compounds. Definitely an area to watch (the approach could work for many cancers).

7) The stuff that's already approved, but I haven't needed it yet. This is a pretty big list by now. It's headed by Darzalex and Empliciti, but there are other newly approved drugs that could replace drugs I already take if they fail. The Ninlaro could be replaced by Kyprolis, Revlimid by Pomalyst. Sadly, there is no better replacement for my particular nemesis, dexamethasone.

As long as the current regime keeps me in the complete response category, and the Rube Goldbergian system that pays pharmaceutical companies too much for their highly variable investments in research and (especially) development continues to pay out, I have the luxury of waiting out the results of these many, many studies.

More to come.

bad science

In my last post, I noted that there were, among the projects, a number of studies of how family history affected risk of various diseases. These were built around some methods that Liz and I developed for querying genealogical databases, primarily the Utah Population Database, fondly referred to as the UPDB. The UPDB provided huge numbers of connections between people over multiple generations, but was hit-or-miss with the disease data that was needed to connect people with the same condition. The cancer data was excellent, thanks to longstanding connections to the statewide cancer registry. Heart disease, stroke, diabetes, Alzheimers, and many (most) others, though, were only available with the help of clinical enterprises, most of which had financial and competitive interests that frequently impeded research.

Over time, we developed some approaches that allowed for reasonable conclusions to be drawn about smaller clinical datasets, and a steady trickle of physicians brought data to us for analysis. Among these were a number of fine physician-scientists with whom it was a pleasure to work.

Not all of them, however. Shortly before we left Utah for Louisville, I worked with an ophthalmologist who had a fairly typical clinical series of patients with age-related macular degeneration, a leading cause of visual impairment and blindness among older folks.

As was the norm, I identified the relatives of his patients, including which of them were also affected, and computed the relative risks (compared to controls), and the usual supporting statistics, wrote the bulk of the Methods and Results sections of the resulting paper, and contributed commentary about the wider implications. For some reason he felt my contribution was not worth noting, however, and he sent off his draft, got it accepted and published, without my name on the author list.

If you're not listed as an author, of course, you don't participate in any correspondence with the journal or its editors. Nor is it the practice of any university oversight committee to query all the faculty not listed as authors to make sure no one was left off the list. So I didn't see this paper until it came out. I wrote a strongly-worded email to this ophthalmologist (he's the senior author--the one listed last), cc'd to higher-ups at the university, and extracted a promise to revise the online publication to correctly reflect my contribution. The principle mattered more to me than this particular publication, and I promptly forgot about the entire incident.

Until I saw this headline. It seems that what goes round comes round, at least if you go far enough around. I especially liked this line from The Scientist: "Zhang’s poor record of disclosing conflicts of interest accompanies a sketchy past of putting patients and research participants at risk during his work." 

That and apparently being some kind of spy. In comparison, my beef about authorship is pretty small. But I think the view into his character afforded by that minor incident was clear enough, and I was not at all surprised that someone who can so easily step on a colleague has no compunction about abusing his patients.

[By the way, it's clear in the first link above that he lied about contacting the journal. Saves me the embarrassment of having co-authored a paper with him.]

Projects

The reality of my projects has been called into question--recently, but also on many prior occasions--and, as a more-or-less recently retired professor, I am here to defend them.

In academics, as in life, projects can take many forms. For me and many others in biomedical research, the classic pattern has been: 1) develop an idea; 2) do some preliminary research at little or no cost; 3) if the idea seems to have some support, try to get funding to do a larger-scale study; 4) publish the results; 5) iterate steps 3 and 4 for as long as possible, perhaps an entire career.

For the record, you can see how this looks in my case by clicking here. The number of publications is less important than the number of citations, which indicate that someone has read your paper and thinks that the research that they have done is in some way indebted to the previous work described in your paper. They may disagree vehemently with your conclusions, but they can't ignore your work. Scientific consensus arises from scientific argument; nothing gets you ahead in your career faster than disagreeing with the conventional wisdom and actually being right. Actually, "faster" isn't the right adjective. "Farther" is better. Lister, Mendel, Gallileo, McClintock, and many others did not achieve success in the short term. (The trick is that the conventional wisdom in science is very often right.)

I've started, finished, and contributed to all kinds of scientific projects over the years, ranging from assessments of the degree to which fallout from nuclear weapons testing caused cancer and other diseases in Utahns living downwind, to (many) studies of the utility of family history as a predictor of disease risk, to studies of molecular markers of aging . . . and numerous other projects inspired by collaborations with physicians, fellows, and students over the years.

The majority of projects don't get past step 1 or 2, but that doesn't mean they don't have merit. In fact, the early stages of putting together ideas and data, doing preliminary statistical analysis and seeing early results is usually more fun and rewarding than writing up papers for publication, preparing grant proposals, and even getting an award and making the dream project a reality.

At present, Liz and I are working on preliminary data and writing up results for several projects that have been or will be turned into grant proposals. We're doing this pro bono, which gives us the freedom to pick our spots and keep our priorities straight.

Of course I've had lots of projects over the years that didn't have anything much to do science: co-raising children, managing finances, house and yard maintenance, travel, pointless tinkering with electronics and software, etc.

Being a cancer patient is also a project--make no mistake: there are daily, weekly, monthly, and annual cycles of medications, blood tests, X-rays, and consultations. Every month requires a new prescription, a telephone order complete with nurse consultation, a check of the insurance status for said order, and a consideration of any travel plans for the next month, since a street address and delivery signature are required. The process is not especially hard or complicated, but it is always front and center and cannot be ignored.

And then, sometimes, I write about my experiences and associated thoughts. At Christmas I took all the posts from the beginning of this blog and formatted them into a book, to give to my mother and others who weren't going to be reading blog posts. The result was a slender volume of about 100 pages--not monumental, to be sure, but a satisfyingly tactile indicator of having done something.

Dog raising is another project. I'm pretty sure that it becomes less of a project as your dog becomes better trained. Suffice it to say that Sunny is still a small dog, but a big project.

And we've added a new project/family member: a tiny teardrop trailer ready for road trips. Mostly it won't require much work on our part, but I will need to improve my trailer-backing skills.