>>> NEXT, WE TURN TO AN AMAZING SCIENTIFIC BREAKTHROUGH.

THE REINCARNATION OF THE DIRE WOLF.

THE FEARSOME SPECIES WENT EXTINCT OVER 12,000 YEARS AGO.

A DALLAS-BASED COMPANY, COLOSSAL BIOSCIENCES, WITH WALTER ISAACSON ABOUT THE IMPLICATIONS OF SO-CALLED DE- EXTINCTION.

>> THANK YOU, CHRISTIANE, AND PROFESSOR GEORGE CHURCH, WELCOME BACK TO THE SHOW.

>> IT'S GREAT TO BE HERE AGAIN.

>> WE WOKE UP THIS WEEK TO HEADLINES THAT WEREN'T ABOUT TARIFFS OR STOCK MARKET CRASHES, BUT SOMETHING THAT IS REALLY INTERESTING, WHICH IS THE DIRE WOLF, KIND OF MADE FAMOUS IN "GAME OF THRONES."

AFTER 10,000 YEARS OF EXTINCTION, IT HAS SORT OF BEEN BROUGHT BACK TO LIFE BY A COMPANY YOU COFOUNDED.

EXPLAIN WHAT A BIG DEAL THAT MIGHT BE?

>> YEAH, WE ARE TRYING TO DEVELOP TECHNOLOGIES THAT WILL HELP WITH VARIOUS CONSERVATION EFFORTS, FOR PREVENTING SPECIES FROM BECOMING EXTINCT, AND IF THEY JUST GO OVER THE LINE FOR A COUPLE DAYS, NOT GIVE UP ON THEM, IF WE BRING THEM BACK.

IN THIS CASE, IT WAS MORE THAN A COUPLE OF DAYS, IT WAS 12,000 YEARS, BUT YOU GET THE IDEA.

SO, THE TECHNOLOGY IS BASED ON THINGS LIKE CRISPER, AND SEQUENCING OF ANCIENT DNA.

>> WHEN YOU SAY THAT EVERYBODY LIES A BIT ON CRISPER, THAT IS THE TOOL THAT YOU HELPED PIONEER, THAT HELP ALLOWS US TO CUT DNA IN VERY SPECIFIC PLACES, AND EVENTUALLY, YOU CAN SORT OF FIX IT AND CHANGE THE DNA.

EXPLAIN HOW YOU DID THAT, WITH THE DIRE WOLF?

>> SO, IT IS MORE THAN JUST CUT.

SOMETIMES, WHEN YOU CUT, YOU JUST MAKE A MESS.

AND THESE ARE ALL VERY PRECISE, 20 VERY PRECISE EDITS.

SO, THIS IS KIND OF A MILESTONE, WHERE WE ARE SEEING EXPONENTIAL IMPROVEMENT IN OUR ABILITY TO BE PRECISE, AND MANY OF THEM AT ONCE.

AND A LOT OF PRECISION IS THANKS TO WORK FROM MY COLLEAGUE, DAVID LOUISVILLE, A HARVARD PROFESSOR, WHERE YOU CAN CHANGE ONE BASE AT A TIME, VERY CONCISELY.

OR, WE CAN SUBSTITUTE IN BIG CHUNKS OF DNA, WHICH IS ANOTHER THING THAT WE ARE DEVELOPING.

>> YOU JUST MENTIONED DAVID LIEU, THE HARVARD PROFESSOR, AND HE JUST WON THE BREAKTHROUGH PRIZE, FOR WHAT IS CALLED BASE EDITING, AND PRIME EDITING, WHICH MEANS THAT YOU CAN ACTUALLY INSERT CERTAIN GENES THAT YOU WANT.

DID YOU DO THAT, WHEN YOU TRIED TO RE-CREATE THE DIRE WOLF?

>> YES, WE HAVE -- WE ARE USING BOTH BASE EDITING AND PRIME EDITING FOR VARIOUS PROJECTS, AT COLOSSAL.

>> AND ONE OF THE THINGS ABOUT IT IS THAT YOU HAVEN'T REALLY "CLONED" THE WOLF.

EXPLAIN THE DIFFERENCE BETWEEN WHAT YOU DID, AND CLONING?

>> WELL, WE USE CLONING AS PART OF THE PROCESS.

BUT, WHAT WE DIDN'T DO WAS FIND SOME MAGICAL SAMPLE WHERE THE NUCLEUS OF A CELL HAS SURVIVED.

INSTEAD, WHAT WE DO ROUTINELY FOR ALMOST ALL THE SPECIES WE WORK ON, FOR ALL THE ANCIENT DNA WE WORK ON, IS THAT DNA IS HIGHLY DEGRADED AND WE READ IT WITH MODERN TECHNIQUES INTO A COMPUTER, AND FROM THE COMPUTER, WE SYNTHESIZE IT, AND THEN PUT IT INTO A CELL, AND THEN WE WILL TAKE THE NUCLEUS FROM THAT CELL, AND MOVE IT OVER INTO AN EMBRYO, A SURROGATE.

IN THIS CASE, A DOG.

AND THEN, CREATE WOLVES.

SO, THIS CLONING IS A LITTLE PIECE OF IT.

BUT, MOSTLY, THE MAGIC COMES FROM MULTIPLEX PRECISE EDITING.

>> YOU KNOW, IT WAS ALMOST 30 YEARS AGO WHEN DOLLY THE SHEEP WAS CLONED.

I REMEMBER WE PUT HER ON THE COVER OF TIME MAGAZINE, IT WAS GOING TO BE A BIG DEAL.

HOW COME CLONING HASN'T BECOME THAT BIG OF A DEAL?

>> I THINK LIKE A LOT OF THINGS IN OUR LIFE, IT IS THAT BIG OF A DEAL, BUT JUST NOBODY NOTICES IT.

SO, FOR EXAMPLE, WE USE CLONING TO ALSO CREATE PIGS, WHICH ARE COMPATIBLE WITH HUMAN TRANSPLANTS.

MOST RECENTLY, THE TRANSPLANT PATIENT WAS A KIDNEY, DOWN AT MASSACHUSETTS GENERAL HOSPITAL JANUARY 25th OF THIS YEAR.

SO, THAT IS DUE TO CLONING, AS WELL.

THERE ARE MANY AGRICULTURAL USES, AS WELL.

IT JUST BECOME SO ACCEPTED THAT WE TAKE IT FOR GRANTED.

>> BUT, COULD WE REALLY CLONE OUR PETS, OUR CHILDREN, OURSELVES?

>> WELL, I THINK IT'S NOT GENERALLY CONSIDERED ETHICAL, IN PART BECAUSE IT HASN'T BEEN THROUGH FDA APPROVAL.

BUT, FOR DEEPER REASONS THAN THAT, TO DO HUMAN BEINGS, AND IT IS NOT NECESSARY.

BUT, PETS ARE DONE AND AGRICULTURAL SPECIES ARE DONE, AND TRANSPLANTS ARE DONE THAT WAY.

SO, IT HAS WAYS FOR HUMAN BODIES, BUT ONLY VIA TRANSPLANTS.

>> EXPLAIN TO ME THE DIRE WOLF THING.

YOU EDITED GRAY WOLVES TO HAVE LOTS OF THE DNA AND TRAITS OF THE EXTINCT DIRE WOLF.

BUT, ARE THESE REALLY DIRE WOLVES?

OR, ARE THEY GRAY WOLVES WITH SOME OF THE TRAITS EDITED IN?

>> SO, THE WHOLE SPECIES DEFINITION IS INTENTIONALLY BLURRY, IN THE ENDANGERED SPECIES ACT.

AND ALSO, IN DEFINITIONS.

IT IS A MIXTURE OF WHAT CAN BREED WITH WHAT, WHAT HAS DIFFERENT PHYSICAL TRAITS, AND SO FORTH.

AND ALSO, YOU CAN LITERALLY SPECIES WITH AS MUCH AS ONE CHANGE, BUT THERE IS MILLIONS OF CHANGES WITHIN THE POPULATION, MILLIONS OF DIFFERENCES BETWEEN, SAY, YOU AND ME, BUT NONE OF THOSE ARE SPECIES LEVEL DIFFERENCES, BECAUSE I THINK MOST PEOPLE UNDERSTAND YOU AND I ARE THE SAME SPECIES.

>> SO, THIS IS A DIRE WOLF?

>> I THINK THIS IS MUCH MORE RECOGNIZABLE AS A DIRE WOLF THAN ANY OTHER KIND OF WOLF.

WE ALSO -- SORRY -- DID CLONED THE RED WOLF, WHICH IS AN ENDANGERED SPECIES, PROBABLY THE MOST RARE WOLF IN THE WORLD.

AND THAT IS A RED WOLF.

>> AS YOU KNOW BETTER THAN ANYBODY ON THE PLANET, GENES CAN HAVE UNINTENDED CONSEQUENCES AND EFFECTS, INCLUDING IN THIS ONE, WITH THE GENE YOU DID TO THE GRAY WOLF TO GIVE IT A WHITE COAT, CAN ALSO CAUSE DEAFNESS AND BLINDNESS.

SO, EXPLAIN THAT TO ME?

>> RIGHT, SO THIS WAS A CASE WHERE WE DIDN'T DO IT IN ORDER TO BE SIMPLE.

WE MADE OUR LIFE A LITTLE MORE COMPLICATED, AND IN ORDER TO BE KIND WITHOUT THE FIRST GENERATION OF DIRE WOLF, WE WANTED TO MAKE SURE WE DIDN'T ACCIDENTALLY PUT IN AN ALLELE THAT COULD CAUSE THE KINDS OF SENSORY PROBLEMS THAT HAVE BEEN ASSOCIATED WITH ONE OF THESE ALLELES THAT WE FOUND.

SO, WE DID A SUBSTITUTE ALLELE.

WE ARE LOOKING FOR FUNCTIONAL DE-EXTINCTION WHERE THEY CAN FEEL A PARTICULAR BIOLOGICAL NICHE.

ANYWAY, WE CHOSE AN UNNATURAL ALLELE AT THAT ONE, BUT MOST OF THE 20 ALLELES THAT WE CHANGED, THERE WAS NO COMPROMISE BETWEEN THE HEALTH OF THE NEW SPECIES, AND -- AND THE ALLELES THAT WE CHOSE.

>> WE HAVE TALKED A LOT, YOU AND I, ABOUT THE WOOLLY MAMMOTH.

AND, THE ROLE THAT HAS PLAYED IN YOUR DE-EXTINCTION COMPANY.

TELL ME HOW THAT IS GOING?

>> WELL, THE REAL GOAL OF COLOSSAL IS DEVELOPING TECHNOLOGY THAT CAN BE USED FREELY FOR CONSERVATION EFFORTS, AND WITH LOTS OF OTHER APPLICATIONS TO HUMAN HEALTH AND SO FORTH.

THE MAMMOTH IS MORE CHALLENGING THAN BOTH THE MOUSE AND THE WOLF THAT WE HAVE DONE, BECAUSE THEY HAVE SHORT GESTATION PERIODS, SO AS LITTLE AS 20 DAYS FOR THE MOUSE, WHILE THE ELEPHANT IS 22 MONTHS.

BECAUSE IT IS AN ENDANGERED SPECIES, AND ONE OF THE THINGS YOU WANT TO DO IS GIVE THEM NEW LAND, THERE IS MORE COMPLEXITY TO GETTING ACCESS TO THE TISSUES, AND THE LANDS THAT THEY WILL GO ON TO.

SO, WE KNEW FROM THE BEGINNING THAT WAS GOING TO BE SLOW, SO THAT IS WHY WE PICKED OTHER SPECIES TO WORK OUT OUR TECHNOLOGY AND SHOW THE WORLD THAT WE, YOU KNOW, ARE SEMI- COMPETENT.

>> LET ME ASK YOU THE JURASSIC PARK QUESTION, WHICH IS, WHAT COULD GO WRONG, REINTRODUCING SPECIES LIKE THIS INTO THE WILD?

AND IS THERE SOME REGULATION, OR SELF-REGULATION?

>> THERE IS PLENTY OF REGULATION, AND THE SUPPLIES TO THE PIGS THAT I REFERRED TO, AS WELL.

THE FDA REGULATES SAFETY AND EFFICACY, BOTH FOR THE ANIMAL, AND, IN THE CASE OF TRANSPLANTS, FOR THE HUMAN BEING.

THERE IS A LOT OF REGULATIONS.

YES, THERE IS ENVIRONMENTAL PROTECTION AGENCY AND THEIR EQUIVALENTS IN OTHER COUNTRIES.

AND THERE SHOULD BE.

WE ARE DELIGHTED TO BE WORKING WITH THEM.

THERE IS ALSO CONSIDERATIONS OF LOCAL POPULATIONS, INDIGENOUS PEOPLE, SUPPORT THERE, BUT WE ARE NOT RUSHING INTO THIS ON PUBLIC LAND UNTIL WE HAVE HAD A VERY BROAD CONVERSATION AND CONSENSUS.

>> WHAT WOULD HAPPEN, IF THE DIRE WOLVES THAT YOU HAVE SORT OF RE-CREATED JUST WENT OUT INTO THE WILD, SOMEDAY?

WOULD EVERYTHING BE ALL RIGHT, OR WOULD THERE BE A PROBLEM?

>> AGAIN, I WOULDN'T RUSH TO DO THAT.

WE -- RIGHT NOW, THEY WOULD PROBABLY BE CAPABLE OF BREEDING WITH A VARIETY OF WHAT WE CALL "SPECIES."

BUT, "SPECIES," LIKE I SAID, IS A BROAD TERM, AND THERE IS NOT SHARP EDGES TO THE BREEDING.

WE COULD MAKE THEM SO THAT THEY DON'T INTERBREED.

WE COULD EVEN MAKE THEM SO THAT THEY COULDN'T LEAVE THE ENCLOSURE THAT THEY ARE IN, WHICH IS NOW 2000 ACRES, WHICH IS QUITE GENEROUS.

BUT, YEAH, IN WHAT WE HAVE SEEN CAN GO WRONG, JUST BECAUSE WE CAN'T THINK OF SOMETHING AT THIS MINUTE, DOESN'T MEAN WE STOP LOOKING FOR, AND ENGAGING ALL KINDS OF ECOLOGISTS, AND BIOLOGISTS, AND SO FORTH, TO THINK OUT OF THE BOX AS TO WHAT COULD GO WRONG BEFORE WE DO IT.

>> YOUR COMPANY THAT YOU COFOUNDED HAS A $10 BILLION OR MORE VALUATION.

EXPLAINED TO ME, WHAT IS THE REVENUE STREAM?

WHAT DO YOU ENVISION?

>> I THINK THAT, FROM THE BEGINNING, WHAT THE INVESTORS ARE LOOKING FOR, HIS NEW TECHNOLOGIES.

AND, IN FACT, THAT IS ALREADY HAPPENING WITH SPUN OFF FARM BIO, A COMPUTATIONAL BIOLOGY COMPANY, WHICH HAS BEEN INSTRUMENTAL IN ALL THINGS THAT WE HAVE BEEN TALKING ABOUT TODAY, IN THIS CONVERSATION.

WE HAVE ALSO, IN THE PROCESS OF MAKING GAMETES, WE HAVE SPUN OFF A -- IT IS THE FIRST FDA APPROVED PHASE THREE TRIAL FOR AN IPS DERIVED CELL.

IPS IS A VERY IMPORTANT SOURCE OF SOME STEM CELLS THAT ARE MAKING THEIR WAY INTO MULTIPLE PRODUCTS, BUT THIS ONE JUMPED TO THE FRONT LINE, ENABLING MATURATION OF EGGS IN IVF CLINICS.

SO, THAT IS SOMETHING THAT WE HAD, BOTH VETERINARY AND HUMAN USE, AND THERE WILL BE MANY MORE, I AM SURE.

>> WHEN YOU AND I LAST SPOKE ON THIS SHOW, ABOUT FIVE OR SIX YEARS AGO, YOU TALKED ABOUT ARTIFICIAL INTELLIGENCE BEING IMPORTANT IN WHAT YOU ARE GOING TO DO.

EXPLAIN HOW THAT WAS RELEVANT, HERE, AND WHAT YOU ARE DOING WITH IT?

>> WELL, SO, BACK THEN, IT WAS JUST BEGINNING TO SHOW ITS VALUE.

I MEAN, I THINK A LOT OF PEOPLE HAD SEEN IT COMING, AND A LOT HADN'T.

BUT, TODAY, IT IS UNDENIABLE, AND I THINK ONE OF THE MAJOR APPLICATIONS OF A.I., EVEN MORE AMAZING THAN ART, AND LANGUAGE, I THINK, IS THIS APPLICATION TO PROTEIN DESIGN.

THIS WAS RECOGNIZED IN THIS YEAR'S NOBEL PRIZES.

AND, IN PARTICULAR, MY GOOD FRIEND AND COLLEAGUE, DAVID BAKER, HAS BEEN DOING THIS, AND FIVE OF MY RECENT STARTUPS HAVE USED IT ROUTINELY, IN COMBINATION WITH LARGE LIBRARIES.

AND WE ARE USING IT ESSENTIALLY EVERYWHERE NOW, FOR DIAGNOSTICS, FOR THERAPEUTICS, FOR THE KIND OF WORK THAT WE HAVE BEEN DESCRIBING HERE, ON WILD ANIMALS.

IT REALLY IS VERY HELPFUL.

I MEAN, SO FAR, IT'S DEFINITELY DEPENDS HEAVILY ON COLLABORATION WITH HUMANS, AND CREATIVITY, AND A THINKING OF PERSPECTIVE OF ETHICS IN HUMANS.

BUT, IT IS TREMENDOUS, AT TIMES, TO BE A SCIENTIST.

>> YOU HAVE SPOKEN ABOUT USING GENE EDITING TOOLS, INCLUDING CRISPER, BASE EDITING, THE THINGS WE TALKED ABOUT, THAT DAVID LIEU JUST WON THE BREAKTHROUGH PRIZE FOUR.

IN ORDER TO RE-CREATE AN EXTINCT SPECIES, COULD YOU CREATE NEW SPECIES, ONE THAT NEVER EXISTED BEFORE, WOULD THAT BE A GOOD IDEA?

>> YOU ASKED, I MEAN, TWO QUESTIONS.

COULD YOU, AND IS IT A GOOD IDEA?

I THINK IT COULD BE DONE, TECHNICALLY.

AND IT COULD BE A GOOD IDEA, IF YOU WANT TO HAVE A SPECIES THAT HAS A PARTICULAR NICHE, BUT YOU WANT IT TO IMMEDIATELY NOT INTERBREED WITH ANOTHER SPECIES, BECAUSE I THINK THAT COULD BE VERY EASILY DONE, AND ONE OF THE RESEARCH PROJECTS IN MY LAB IS TO FIND OUT HOW TO DO THAT.

IN THE EASIEST WAY POSSIBLE.

>> GIVE ME AN EXAMPLE OF WHAT YOU'RE THINKING ABOUT IN THE LAB?

>> WELL, SO, THERE ARE A FEW EXAMPLES OF WHERE YOU CAN GET SPECIATION WITH A SINGLE MUTATION, FOR EXAMPLE, THE CHIRALITY OF SNAILS, CALLED A SPECIATION, OBSERVED MULTIPLE TIMES.

YOU CAN GET INABILITY TO PRODUCE FERTILE OFFSPRING, IF YOU HAVE MULTIPLE RECIPROCAL TRANSLOCATIONS IN THE CHROMOSOMES, THINGS THAT ALLOW INTERBREED WITH A CELL, BUT NOT WITH THE SPECIES THAT IT CAME OUT OF.

SO, THOSE ARE TWO EXAMPLES, BUT THERE ARE MANY MORE -- BEHAVIORAL CHANGES CAN HAPPEN WITH SINGLE MUTATIONS AND SO FORTH.

>> HOW MANY COMPANIES, BY THE WAY, HAVE YOU COFOUNDED?

>> I HAVE COFOUNDED 50.

49, 50.

AND I HAVE HELPED WITH QUITE A FEW MORE.

>> BY COFOUNDING THAT MANY COMPANIES, YOU ARE SORT OF THE POSTER CHILD FOR WHY AMERICAN SCIENCE HAS BEEN SO INNOVATIVE AND ENTREPRENEURIAL, EVER SINCE THE END OF WORLD WAR II.

WHICH, THERE IS A FUNDING OF BASIC RESEARCH AT UNIVERSITIES, AND THE PEOPLE WHO DO IT FIND WAYS TO TRANSLATE THAT FROM THE BENCH, TO THE LAB, TO THE BEDSIDE OF A PATIENT, FOR EXAMPLE, AND TO TURN THEM INTO COMPANIES.

ARE YOU WORRIED THAT THE CUTS IN FEDERAL SUPPORT FOR BASIC RESEARCH, IS GOING TO END THAT 70 YEAR BOOM THAT WE HAVE HAD IN THE UNITED STATES?

>> WELL, I WORRY ABOUT EVERYTHING.

I THINK, IN THIS PARTICULAR CASE, I READ SOMETHING RECENTLY, TODAY, THAT THERE WAS A PROPOSAL FOR A $15 BILLION FOR BIOTECH, SPECIFICALLY SO WE COULD BE COMPETITIVE, INTERNATIONALLY.

I DON'T KNOW WHETHER THAT WILL ARRIVE OR NOT, OR WHETHER THAT WILL SUFFICIENTLY SUPPORT BASIC SCIENCE.

BUT, I COMPLETELY AGREE WITH, I THINK, WHAT YOU ARE SAYING, WHICH IS THAT BASIC SCIENCE HAS BEEN IMPORTANT TO ALMOST -- WELL, ESSENTIALLY, EVERYTHING WE HAVE BEEN TALKING ABOUT HERE, AND MANY OTHERS.

AND, INCREASINGLY, IT GOES VERY QUICKLY FROM BASIC SCIENCE, TO APPLICATIONS.

ALTHOUGH, IT DOESN'T NEED TO.

I THINK WE NEED TO BE FLEXIBLE, IN OUR SUPPORT OF THIS.

BUT, IT IS INSPIRING, YOU KNOW?

NO MATTER HOW DIRE -- SORRY TO USE THE WORD -- THE ECONOMIC REPORTS CAN BE, TO SEE NEW BREAKTHROUGHS HAVING AN IMPACT ON HEALTHCARE AND OTHER ASPECTS OF OUR LIVES, I THINK, GIVES US NEW HOPE.

>> GEORGE CHURCH, THANK YOU SO MUCH FOR JOINING US AGAIN.

>> THANK YOU.