Success Stories

Idea man: Q&A with Irv Weissman

Ludwig Stanford’s director got hooked on science as a child, and has been dedicated to figuring out how things work ever since.

How did you become a scientist?
I was hooked at age 10 after reading a book called Microbe Hunters by Paul De Kruif, a pathologist at the University of Michigan. He described the discoveries made by important scientists like Pasteur and Robert Koch, interweaving their stories and lives. He demonstrated that medical knowledge comes from an individual researcher’s imagination, dedication, and investigation as opposed to the mere memorization of facts. I knew then that’s what I wanted to do and began my scientific career as a junior in high school with Ernst Eichwald,a pathologist who was a specialist in transplantation biology. He was tired of academia and moved his practice and lab to the Deaconess Hospital, now the McLaughlin Research institute, which is in my hometown of Great Falls, Montana.

This was exciting because Montana didn’t even have a medical school. So I asked him for a job. He was partially deaf and spoke with a thick German accent and our conversation went nowhere until I said I’d work for free. We settled on $25 a month. I became a research assistant in his lab and was treated like a graduate student. He never knew I was just a B+ student in the local high school who never made the honor roll. But Dr. Eichwald gave me something invaluable—the freedom to construct and do my own experiments.

To think about and understand how information is really obtained. It shaped my career. It’s always been more important for me to figure out how things work rather than memorize what other people say or write about how things work.

Can you share some success stories you’ve had with stem cell therapies?
Let’s start with a genetic disease we’ve been working on called Batten disease, a fatal neurodegenerative disorder in children that results in the buildup of a toxic product in nerve cells. A child who gets the disease starts to lose sight, then balance, then thinking, then goes into a coma and inevitably dies. They’re unable to produce enough of an enzyme to process cellular waste substances. Without the enzyme, the cellular waste builds up in the cells called lysosomes that act like a garbage disposal and recycling system, eventually bursting the lysosomes and leading to cell death.

In 2006, Stem Cells Inc., a company I co-founded, did a trial with six patients that involved infusing them with purified human neural stem cell-derived stem and progenitor cells, to reset the cellrecycling process. The ones with the mildest stage of the disease are still alive beyond the expected course of the disease.

In another trial in 2011, these human neural cells we developed were injected directly into the brains of four young children with an early-onset, fatal form of a condition known as Pelizaeus-Merzbacher disease or PMD. It’s an inherited genetic defect that prevents brain cells called oligodendrocytes from making myelin, the insulating layer that forms around nerves and allows impulses to transmit quickly and efficiently along nerve cells. These kids don’t make oligodendrocytes and therefore don’t develop the ability to walk or talk, and often have trouble breathing. They undergo progressive neurological deterioration leading to an early death. As in the immune deficient mice with a similar disorder, the four patients we treated with the transplanted stem cells are all forming oligodendrocytes and we have imaging evidence indicating they’ve generated fresh myelin.

Is the CD47-blocking antibody you developed really a wonder drug?
We like to think so. Tests on immune deficient mice transplanted with patient cancer cells showed it works on a broad range of cancers with minimal side effects. Right now, we have enough data to begin a phase I clinical trial of the cancer therapy early next year.

This breakthrough is based on research that began 15 years ago here at Stanford when we discovered a link between leukemia stem cells and high levels of a protein called CD47 that was expressed on the cell surface. CD47 acts as an age marker on red blood cells. Red blood cells start out with a lot of CD47 on their cell surface and slowly lose the protein as they age. At a certain level, the dearth of CD47 allows macrophages to eat the aging red blood cells, making way for younger red blood cells and a refreshed blood supply. But we found CD47 on all human leukemia and all cancers we tested.

We found that a CD47-blocking antibody could cure some cases of leukemia by enabling the immune system macrophages to recognize and engulf cancer cells. We also found that all human leukemia and other cancer cells have higher levels of CD47 than healthy cells and the CD47 produced by cancer cells can effectively trick the immune system into not destroying them.
Blocking the CD47 ‘don’t eat me’ signal inhibited the growth in mice of nearly every human cancer we tested, which I think demonstrates that CD47 is a legitimate and promising target for human cancer therapy.

Should the average person use a ‘bank’ to store their own stem cells in a bet they may be used to grow replacement organs and possibly save their lives someday?
Probably not. If you have a genetic disposition for a certain cancer or blood disorder, it’s present at birth and your cord bloods will have the same genetic disease. If you have an immune deficiency, the cord bloods will be immune deficient.

It’s like trying to save yourself from a genetic disease that you already have. And many genetic diseases are not due to a single gene but multiple genes as in Lou Gehrig’s disease. So getting cells from yourself for yourself doesn’t make a lot of sense. You need healthy stem cells. Not the other ones.

Statistically an industry that harvests cord blood and holds them in private banks away from the general public has almost has no utility. And to the extent that it prevents those cord bloods being accessible to somebody who doesn’t have a match somewhere else you’re holding back the possibility of saving other lives. The appropriate effort should be to place cord bloods, and eventually mobilized peripheral blood HSC into the publicly available cord blood banks, where they are lifesaving for people who do not have matched siblings.

What advice do you have for people entering the field?
Go into science because you love seeing the results that come from your own ideas and your own observations. Don’t get into the field to make money or become famous. There’re a lot of easier ways to do that.

Knowledge is obtained through experiments. Look at every paper as an opportunity to design an experiment. Take responsibility for translating your discoveries. Once you make a discovery, make sure you look forward to potential translational opportunities that come from it. Ask yourself what are the barriers to translating this discovery and how can I overcome them?

What’s the best advice you ever received as a scientist?
Stick to your guns. Push to translate your discoveries into the clinic. Find a way to do it — don’t wait for someone else to do it. That was from my mentor at Stanford,Henry Kaplan. He was the only one who told me I was on the right road when I decided to stay in science after receiving my medical degree. He even gave me a lab to try out my ideas and didn’t tell me what to do with them.

How did your involvement with Proposition 71 come about?
In the 1980s we were the first to identify and isolate mouse blood forming stem cells, first in mice and later in humans. We proved that they could self-renew and also make all blood cell types, even from a single stem cell. So I formed a company, SyStemix, which was purchased by a big pharma. And four years later — the stem cell programs were shut down. But we learned a big lesson — the commercial goals of big pharma may not match the clinical goals of biomedical researchers.

This led me and others to champion Proposition 71, which created the California Institute of Regenerative Medicine with the hope of bringing in new stem-cell discoveries and advancing them to and through early phase clinical trials, where their clinical and commercial value could be tested and appreciated.

The 2001 Bush policy on stem-cell research was overturned with the passing of Proposition 71 in California in 2004 and, by proclamation, by Obama in 2008. This is a major step toward enabling full federal support for embryonic stem-cell research. I hope this will be an enduring legacy by the California voters — a new way to advance discoveries through clinical trials without having the risks that both venture capital and big pharma now avoid.


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