9UNP1249_D_Tom_Zinnen

- Welcome to UW-Marinette campus We're here in the Theater on the Bay room here in UW-Marinette. Beautiful setting and beautiful evening. Our presentation this evening is going to be by Tom Zinnen, he is one of the UW-Extension biotechnology, policy and outreach specialists based in UW-Madison. But he came up here to share with us some information on "Trends in Wisconsin Biotechnology."

- Thank you, Scott. Well, thanks for having me here at UW-Marinette. I had to put some trends in there because there are many trends in Wisconsin biotechnology. And sometimes trends are just this past week, sometimes they are the past months, sometimes they are the past decades. So we're going to look at some of those. 

One of the big themes is biotechnology is changing how we look at life and how we lead our lives. If you'd like to look at that picture, and I'll end with that picture. I'll tell you what it is if you want to imagine the different possibilities of what that is from right now, that would be good. Just yesterday there's a story out of UW-Madison about corn, and corn really is amazing. This is a story by John Doebley who is a geneticist there and he's one of the people that discovered the origins of corn. That corn originally evolved out of with human selection a plant called teosinte in Mexico. And one of the big questions was, "Where did corn come from?" And not just the geographical part, because here's the other thing that you had to ask: "How did corn get from this plant on top, with that tight little set of line of kernels to the ear of corn on the bottom that we're so familiar with?" The one in the middle is a hybrid between teosinte on the top and corn on the bottom. And although they have two different names, they are actually the same species. 

That was a big, controversial deal-- one of the things Professor Doebley did over the course of his career. To give you an idea of how long this science saga is, here's a list of news releases that the University of Wisconsin-Madison has put out on John Doebley's work over the years. Down at the bottom you'll see October 12, 2000. That's fifteen years ago. And then 2002. And then 2003. And then jump up to August of 2005. And then 2011. And then one day ago. So this has been Professor Doebly's life work,

and it all comes down to a single letter.

So the announcement yesterday was that not only did they figure out what gene was involved, but the gene that's so critical in converting teosinte to what we now know as corn is a single letter change in the DNA code of that plant.

Here's some pretty interesting things that Professor Doebley said: "When I was in graduate school, nothing like this could have been done. We didn't know what a gene was. We thought it was just kind of like a concept. And now we know how it's defined at the molecular level, and you can go in there actually and find the physical DNA sequences that control the differences in genes. Over the last 50 years we have gained the ability to answer biological questions and changes in profound ways that I could not have imagined back then." So this one gentleman's story really helps us see that. So here's some trends in Wisconsin biotechnology. Professor Lederberg was a pioneer in gene transfer and bacteria. 

For awhile people weren't even sure if bacteria had genes the way the plants and animals do. Professor Khorana was the first person to ever synthesize a gene-he did it by synthesizing DNA. That's all pretty obvious to us now, but when he did that, that was not obvious. Howard Temin was one of the two people who figured out that genetic information can float not only from DNA to its cousin RNA and then onto protein, but it can also flow the other way: from RNA to DNA. And Oliver Smithies figured out gene function in mice. And figured out if you want to know the function of a single gene in a mouse, the thing to do is to make a mouse and then take a mouse just like that one and knock out one gene. Then compare how those two different mice live.

What's interesting about these origins of the trends is that Joshua Lederberg won a Nobel Prize for medicine in 1958, Professor Khorana won in 1968, Professor Temin won in 1975 and Professor Smithies won in 2007. When I give my little tours at the biotech center-especially when there's often kids that come to Madison in fourth grade-I ask them: "So how many Lombardi trophies do the Packers have?" And it's amazing, most people know that they have four. 

Well how many Nobel Prizes in physiology or medicine do people from UW-Madison hold? It's the same number, four. And these trends go back 50, 40, 30, 20 years, and yet they're still affecting how we look at life and how we lead our lives.

The DNA tube that those of you here in the audience have, this is DNA. It looks like cotton. But DNA is like an alphabet. How many letters are there in the English alphabet? About 26. How many letters are there in the Morse Code? About two: dots and dash. 

The key thing about the English alphabet is that you can spell words by putting different letters in different orders. And you get different words with different meanings. Then you can link words into phrases, phrases into sentences, sentences into paragraphs, paragraphs into pages, pages into chapters, chapters into books, books into book series. And if you're J.K. Rowling, you get to make a bazillion dollars. Morse code has only two letters and yet you can send all 26 letters of English with the Morse Code. In other words, can you send all of Shakespeare with a two-letter alphabet? You can. And that's pretty powerful. DNA has a four-letter alphabet, and we spell DNA pretty much like we spell words: put different orders of DNA letters into different strings of DNA, and they can be short, they can be medium, they can be really long. How many letters are in each of our cells? 

Six billion, and that's billion with a 'B' as in boy.

It's a very powerful thing to be able to spell and sequence DNA. In 1991 when I started the biotech center, the folks there who do this for a living could do about 600 letters a day. By 1998 they had a machine that could do about 600,000 base pairs or letters a day. In 2012 they were able to purchase a machine that could do sixty billion base pairs a day. That's ten times more than what you have in each of your cells. Think of what the implications are. For health, for medicine, for agriculture, for environment. This is pretty remarkable that what we can do now in spelling DNA, in sequencing DNA.

We started with a story of One Letter Change Can Make a World of Difference. 

Another world of difference is being able to know all the genes that you have. Because that's like knowing your genetic recipe book. And that's a pretty sobering thing.

Here's another example: Light's pretty amazing- amazing- especially if you're a plant. Plants don't have eyes, but they can see different wavelengths of light and they respond significantly to the wavelengths and to how intense it is. And you know that if you're a gardener because things grow differently in the shade than they do in bright light. Rick Vierstra is a professor at UW-Madison, he's been working most of his professional life on these things called phytochromes. These are the equivalent of light detectors in plants. And his big question is: "If we could figure out more how these phytochromes work, could we grow more plants per acre and still get very high, perhaps even higher yields than what we can get today?" So he's testing this by moving one key gene at a time into various plants. 

And to ask "Can we still get high density growth when we have high density populations?" But one of the big questions is if we were able to eventually do this in corn, this would be genetically engineered corn. And would that genetically engineered corn be able to reach the field? Not physically, but through the regulatory path.

Now something that's much more recent that was invented in several places-one of the key people is at UC-Berkeley-but this is the kind of technique that's spreading all over many places. It's called CRISPR. It's an example of gene editing. It allows researchers to change one or two or just a few DNA letters at a time. If you like the molecular stuff, this is what it's called. CRISPR is an acronym-I just call it CRISPR-but it actually means Clustered Regularly Interspaced Short Palindromic Repeat. 
[whistle]

 The key thing is you can target the change that you want in the sequence of the DNA in the organism that you want. When new technologies like this come up, one of the things that the biotechnology center at UW-Madison-one of the things we do-is try to set up a fee-for-service facility. So that not all researchers have to learn all this stuff. They can hire my colleagues to help speed their research. So here's the kind of thing that they're looking at with this. Instead of taking up to two years to make a genetically engineered mouse that has one gene knocked out; it can take as little as four months. Well that's like one in eight, that's pretty impressive. And you can delete genes from cells. You can knock out genes from intact mice. 

This is very powerful.

And it's such a new thing that new developments, new uses are being found all the time for it. It also points out how powerful very small changes can be. In gene editing techniques like CRISPR are straining the regulatory system for genetic engineering in the United States. This is a screen shot of a paper from the first of January of this year from the New York Times, and it says, "Scientists Alter Crops With Techniques Outside the Regulators' Scope." So this is really going to be a challenge not only scientifically, but also from a regulatory point of view. How do you apply these new techniques that are so new, they don't fit in the old regulatory frame? The old regulatory frame was called the coordinated framework. It was started in the United States-it's solely a U.S. regulatory framework-and 1986 would be the Reagan administration. And again CRISPR is weird because it's bypassing these triggers, so earlier this month, the White House ordered a review of rule of genetically modified crops. 

So for the first time since 1992 there's going to be a head-to-tail review of these regulations in the United States. The challenge here is this: We're seeing yesterday that a single change in a DNA letter can lead from teosinte to corn. Now it took more than that single change, but it was a critical change in how teosinte kernels evolved to corn kernels. This points out how powerful other methods of plant breeding are, in addition to genetic engineering. Currently we have two standards for genetic work particularly in plants: one for genetic engineering, and another for all the other methods of changing genes. The CRISPR work, the teosinte work, are all asking from my point of view, "Why would you have two standards?" What's the scientific basis when you know how powerful a single gene change can be? Let's look at another example of the interplay of science and regulation. Here's a historical timeline on stem cells. And for us in Wisconsin one of the key places there is 1995 when Jamie Thompson figured out how to take Rhesus monkeys and get embryonic stem cells from them-that the first primate embryonic stem cells. 

Four years later in 1998, he figured out how to grow human embryonic stem cells. In 2007 he figured out how to grow not human embryonic stem cells but cells very similar to that called induced pluripotent stem cells. And those are functionally identical to embryonic stem cells but they don't start with embryos, they start with regular cells from you and from me. And now in 2014 the first clinical trial for macular degeneration. In other words, these cells are going into clinical trials. Why is this a big deal? When you have this long of a tradition of discovery, and look at all the different types of cells and tissues and organs that have been able to have been grown from embryonic stem cells or induced pluripotent stem cells from hearts to neurons to retinas, this is a big deal. And to put it into perspective, back in June, on June 17th, Bart Starr's family announced that he had undergone a stem cell treatment to help him in his recovery from his stroke. And this was not done in the United States. I think it was probably done in Mexico. 

This is on June 17 from the Journal Sentinel. This is what the University stem cell folks put out two days later. It's a pretty powerful example of how it's time, it's time to get these kinds of trials done in the United States, and not just in other countries.

So Su-Chun Zhang at UW-Madison-- and he was the first to isolate the neural stem cells-- the kind that are being tested with Bart Starr and with others who've had strokes. And the professor is saying it's time for the federal government to forge ahead with clinical trials. And this is important because of so many people have spinal cord injuries, stroke, Lou Gehrig's disease. This is a hope for those people suffering from those debilitations. Our FDA's been pretty conservative-more conservative than others. And three words: It. Is. 

Time. At least from the professor's point of view. So just a few days ago. There's good news that Bart Starr is walking and talking and feeding himself again. His wife said it's been really exciting to witness. Some of this recovery might have been natural, it might have happened without the stem cells to some degree. But she's says there is no question that it has helped him. This is why having really well-designed pilot studies, clinical trials is so critical, so that you have the appropriate controls and the appropriate experimental design so that you can actually reach these conclusions with some statistical certainty. This gives you an idea of some of the trends in Wisconsin biotech. How far back they start, how recent they are as today. 

What you're looking at here are brain cells growing in a little microtiter plate.

And it shows how far we've come, how far we have to go. And it reemphasizes the idea that biotechnology is changing how we look at life and how we lead our lives. And with that I'd like to take any questions you might have. Thanks again for having me. 
[applause]