Getting Totally Schooled


Tess is in kindergarten. Great, great year so far. She's happy. Lovin' it. At the bus stop every morning, she sees her bus coming and she goes bananas, with a huge smile, and her "happy hands" paroxym of glee. One bit of badness recently, though. She chomped somebody at her school. Took a bite and broke the skin. It wasn't a kid--it was one of her specialists. It was a bummer to hear about. 

But hey, we warned 'em. When we were in that IEP meeting a few months back, telling the group the story of Tess and the ins and outs of her personality, we actually said the words, "She can get bitey." Everyone in the room sort of laughed about it, but we were serious. Because it is serious. And just as we had hoped, that sentence went into the IEP verbatim. It's in there. We gave the team more details, like about how it usually happens when she's hungry or bored or frustrated, and also how the last thing you'd want to do is pick her up and let her face rest against your shoulder. That's a surefire ticket to Jaws. In spite of these warnings, the biting happened.  

This is hard, because while she certainly isn't the first kid to bite somebody in kindergarten, and she won't be the last, we can't exactly discipline her for doing it. We just have to put the idea in her mind that there are other ways to get what she wants. And we have to give her the tools to communicate her wishes.  

We're more determined than ever to help her. 

These days we are possessed by the need to move forward. I'm waking up at night all the time, thinking about it. I heard from some sleep expert recently that if there's something on your mind that's keeping you up night after night, here's how to deal with it:  keep a pad next to your bed. And before you hit the hay, write that thing down. If it's a work thing, school, whatever. Think of that and everything else that's weighing on you, and write them all down as things to think about when you wake up in the morning. So in a way you're giving yourself permission not to think about them during the night. I have to say, it's been pretty effective. In my list, I wrote:  "getting in touch with other USP7 families," because as you know, I've been driven lately to do that, to get the word out. But I need sleep. So I wrote it down, and now I don't wake up thinking about it. 

But my wife and I still are thinking constantly about how we'd love to help Tess with some kind of therapeutic option. Like getting on it with the WASH protein. Remember, that's the one they named in the USP7 paper, telling us that they could maybe chemically activate WASH in Tess and that that could help her. Remember also, that Dr. Schaaf cautiously gave us hope that the USP7 mutation had altered Tess's brain in ways that might be reversible. 

So my wife and I are saying, let's go! Get some WASH proteins going! Activate it already! 

I get home from the Global Genes conference and I'm all jazzed up to get things done. On the internet, I come across an agenda for an entire conference about USP7. The conference is in Boston, and it's just ended a few days earlier. The whole agenda has magic words all about USP7:  "Targeting the Ubiquitin Proteasome System." "Exploring therapeutic potential." "Development of Novel and Selective Inhibitors of USP7 with Cellular Activity." 

I can't believe it. It's like it was designed for us, this conference. How did we not know about this? Did the Baylor team go to it? I dash off some emails to the doctors who presented at the conference, explaining about Tess and asking them to send me their papers. I send the link for the conference to Dr. Schaaf at Baylor. I'm envisioning the sort of collaboration I heard all about at the Global Genes conference. I'm picturing myself as the sort of active parent who scours the internet, finds experts in various areas, and then forces them to connect in order to get solutions for my kid. 

But then Schaaf writes me back. I have it all wrong. Tess's mutation means a loss of function. Meaning that it turns stuff off in USP7 that should be on. Our goal is to turn that stuff back on. And an inhibitor of USP7 does the opposite of that. Inhibitors turn stuff down or off. Tons of people are working on USP7 inhibitors, he said. Those aren't what we want. We want to increase the expression of USP7, with an activator of USP7. I look again at the agenda for the conference in Boston, and yep, Schaaf is right. The whole thing is about inhibitors. Total waste of my time. I feel like a fool.  

Meanwhile, Kate busted her tail and tracked down Tess's skin sample at Boston Children's. She had it shipped to the Baylor team. We find out that the tests need to happen at a certain lab. That lab's not at Baylor. It's in Dallas, Texas, at UT Southwestern. And the guy who runs that lab is named Ryan Potts. Turns out they used his lab when writing up the USP7 paper. He was a huge part of that publication. And we hear that he can't test Tess's skin sample. 

Just to remind you what this is about:  Tess wasn't part of the Baylor team's recent study, the one that led to the big paper. They didn't know about her until the paper was done. So those seven patients are in the club, but Tess isn't yet. And that's because no one's gone into a lab with a sample of her cells and actually proven that her USP7 mutation is the cause of her disease. Until someone does that, it's just a theory. 

And Potts is the guy with the lab. But he can't do the tests. Not for a few months, we're told. This is because he's moving his lab to another state. He's packing up and can't do the test until he's established and all moved in. 

Do we want to wait? Are my wife and I okay with cooling our jets until February or March 2016? No, we are not. Not to be jerks, but let's do this already, right? 

A day or two after we get this disappointing news, I'm on the phone with Zak Kohane, the chair of biomedical informatics at Harvard. Zak's working with Matt Might and has been a great resource for us, teaching us about this process. I tell Zak about the delay. Zak says don't wait. Push for it now. 

We get Schaaf to put us in touch with Potts. A conference call is scheduled. We ask for it to be a video call. And then one night, there he is:  Ryan Potts, on a screen in our kitchen. Tess is on my lap, so her cuteness will render him powerless. So he'll agree to do the test ASAP. We are polite but persistent. Ryan is the picture of accommodating. He is kind to us, and tells us he is a father himself. Within minutes, he's agreed to do the test. We don't even have to push. And if we can get him Tess's sample quickly enough, he'll do it before he moves his lab.  

And then, it's at this point in the call that things go dramatically wrong. 

Ryan Potts, through the miracle of modern technology and science, is able to share his computer's desktop with us. So we see on our screen what he's looking at. Which is a 3-D model of the USP7 enzyme. 

I know--enzyme? I thought USP7 was a gene. It's both. The gene USP7 encodes an enzyme. Also called USP7. 

In his 3D model of the enzyme, Dr. Potts can point to stuff and rotate the thing in three dimensions. And as he's explaining what we're looking at, and what happens inside Tess as a result of her mutation, I am instantly lost.

Now, I've read the USP7 paper many times. And thanks to my gaffe about the Boston conference, I now understand that we want to activate and not inhibit USP7. But Ryan Potts is speaking a language that I simply don't know. With each thing he says, I'm thinking: I know those are words. And each word on its own isn't necessarily confusing. But the way he's putting those words together is galactically baffling to me. It's horrifying. I decide I'm not listening hard enough. So I try harder. I attempt to scribble some notes. Nothing works. I might as well be trying to follow a lecture in Swahili.  

That call ends, and I decide. I decide never again to be that confused during this process. I gotta at least learn the language. Even if I get fuzzy from time to time on the concepts, at least I'll know what we're discussing, and can ask intelligent questions. So essentially I'm going back to school here. I get Dr Potts to email me a bunch of his papers and the ones he relies on the most in this sphere. And he does.  

Which is good. It's good for me to have like a program, a syllabus almost, that'll lay out what I need to know and how I'm gonna learn it. 

Matt Might emails me around this time. And part of his email is the amazing and mysterious Plan B, which I'll get to in a minute. But mostly what he wants to do is teach me some stuff. I'm all ears. Matt's created what he calls an algorithm for precision medicine. It's a step-by-step procedure for hacking this process and helping motivated parents and patients get to treatments faster. The document is craaazy long. It starts like this:  

"The infrastructure to deliver precision medicine at scale does not yet exist, but the individual components of that infrastructure often do. Motivated patients, advocates and clinicians can stitch these components together."

And it's got all these steps. First, get sequencing done. Then, how do we interpret those results? Then, if there's mutation, how do we move forward with finding other patients and working toward strategies for molecular therapeutics? It's really thorough. 

The second half of the document is a glossary of genetics. What's a gene? What's an allele? What is a dominant disorder? What is a nonsense mutation? Allllll these terms I've heard people throwing around for months. There's only so many times you can go to Wikipedia.

So the Matt Might materials came at exactly the right time for me. 

Another thing I've been working my way through? Some free online lectures from MIT. This guy Eric Lander teaches genetics, along with a guy called Bob Weinberg, who's the biology prof. Lander and Weinberg don't dumb it down--this is MIT, after all. But their classes are great for background. Context. You can do what I did and download the audio to your phone. Play. Repeat. Repeat repeat repeat. If you've seen me at all around town in the past two weeks, chances are I got Bob or Eric going in the headphones. 

A lot of these early bio lectures are big-picture sort of talks. Like how biology results in decisions being made at a very basic level, about which lifeforms survive and how they evolve. Bob Weinberg talks about the primordial soup, then single-celled organisms, prokaryotic cells--the kind that don't have nuclei. Stuff that's been around for like four billion years. And then of course the other side of that is just how short a time humans have been around. Only about 200,000 years. A minuscule strip of time on an otherwise dizzyingly lengthy timeline. 

Last night I woke up in the night. And you know that feeling, where you just know that it's the middle of the night and definitely not morning yet? I had that feeling. And yet, it was sorta light outside, with some light coming through the window. And because of that light, I thought: this is it. The end of humans on this planet. We've had our 200,000 years and they're up. Once I started thinking that, I couldn't let it go. I was wiiiiide awake, blinking up at the ceiling. It was upsetting that we'd come so close to helping Tess, only for the world to suddenly end like this. And I thought, lemme just write this on my list of stuff to worry about in the morning:  "The end...of human we know it." 

Okay. Here we go: the mysterious Plan B. Matt Might says he's working with Zak Kohane, who you'll remember is the biomedical informatics guy at Harvard. Matt and Zak are really focused right now on repurposing. Here's how it works: instead of going through a long and arduous process of drug trials with the FDA, you take compounds that are already out there, being used for other purposes, and you use them for something new. Matt points out that Tess's mutation is only on one of her copies of USP7. In other words, she still has a functioning copy of the USP7 gene. So what you can do, he says, is bump up expression of the one that works. (Which, as a side-effect, will probably boost expression of the nonfunction one as well, by the way.) 

You can search by gene and find compounds that would increase the expression of that gene. And he's found a compound that would boost USP7. It's non-toxic. It's called curcumin. It's found in turmeric.  

Giving something to Tess could happen sooner than we thought, in other words. It could really help her, as long as we do this scientifically, with detailed daily logs, rather than throwing a heaping tablespoon of turmeric into her plate of okra. 

This could be what we've been waiting for. Can we really do this? Let's find out.