Friend or Foe?

You’ll find dangerous forms of nature in all sorts of places. But a keen scientist will see connections and potential solutions to problems that can seem wildly unrelated.  Beneath warm tropical waters, marine mollusks known as Cone Snails dwell on the ocean floor in sandy lagoons, tidal pools, and around coral reefs. These beautiful but dangerous creatures, use a lethal harpoon-like venom to paralyze fish. Amazingly this venom is potent and stable enough in the seawater, to override the fish’s metabolism. The prey's enzymes can’t neutralise the attack, because the peptides in the venom are extremely compact, and tightly folded.  Scientists have learnt about these peptides and now design venom inspired painkillers that block pain and inflammation in humans. Unlike natural human hormones or standard drugs which get shredded by enzymes in minutes, these peptides resist degradation for the same reason they survive in salt water and knock out fish.  This allows them to continuously block human pain receptors for days after a single application. 

Interestingly, Scientists have also found that snail venom as pain relief is non addictive.  Traditional opioids cause addiction because they bind directly to receptors in the central nervous system. This activation triggers a massive surge of dopamine in the brain’s reward pathways, creating euphoria and causing the body to crave more. Cone snail peptides like Ziconotide (Prialt) and Consomatin Fj1 on the other hand, bypass the opioid system entirely.  They target receptors that are concentrated in the spinal cord and peripheral nervous system, stopping pain signals before they can reach the brain, completely avoiding the reward centre and preventing chemical dependency.

Though breakthroughs in science can be hard, and take many years of diligent study, Professor Sir Graham Le Gros, who was Clinical Director of the Malaghan Institute for 30 years (1994-2024), has this to say about research.

”You’ve got to have a certain amount of courage, or hardiness, or be super optimistic that somehow things will prevail, because you're taking risks. You've got to be able to handle risk and pressure.”

The Malaghan Institute is New Zealand’s leading independent biomedical research institute focused on immunology and immunotherapy. I asked Professor Sir Graham Le Gros about the field.  Why was he drawn to study and work in immunology.

”I was first of all drawn to microbiology, infectious diseases, because when I was growing up, we had polio, we had smallpox, we had all those sort of things that were devastating, and so it seemed like a good thing to do. You know, all that missionary zeal about doing good for your fellow human being. And it was exciting.”

Immunology is the study of the immune system.  Its all about the body’s defence network and how it fights against infection, disease and foreign invaders.  Possibly one of the most frightening things that can happen in the world besides natural disasters or war is a virus outbreak.  During the 1980s HIV/AIDS crisis, immunologists were vital in identifying the biological target of the virus.  Immunologists and virologists worked together closely to discover that the CD4 glycoprotein on helper T-cells was the primary biological target and receptor for the virus.  This shifted the public health response from blind panic to targeted science. When the disease first emerged, medical professionals were baffled by why young, healthy individuals were suddenly dying from rare opportunistic infections.  This illness caused widespread social hysteria, intense discrimination and political paralysis.  Before route-of-transmission data was widely understood, people believed they could catch HIV through casual contact. Public panic escalated over sharing swimming pools, using public restrooms, shaking hands, or being breathed on by an infected person. Landlords legally evicted tenants, and employers fired workers simply based on rumours of an HIV diagnosis. 

 Two published papers by the Centres for Disease Control and Prevention (CDC) in 1981, were the first to mention the disease, pointing to a rare lung infection and an aggressive skin cancer (Kaposi's sarcoma) that was appearing in previously healthy young gay men in Los Angeles and New York. Patients died within months as their immune systems collapsed.  In 1982, believing it only affected one demographic, it was harmfully labeled as "GRID" (Gay-Related Immune Deficiency). But then as the disease emerged in heterosexual injection drug users, haemophiliacs, and infants, the CDC officially coined the term AIDS (Acquired Immunodeficiency Syndrome).  It took several more years before researchers could isolate the virus responsible for the destruction of the immune system and named it HIV.  In 1985 the first commercial blood test for HIV was approved. This allowed medical facilities to screen the public blood supply, which had by that stage already accidentally infected thousands of blood-transfusion recipients and haemophiliacs.  

In the early 1980’s laboratory research had to rely on cell cultures and non-human primates like chimpanzees to study HIV.  However, as the epidemic wore on, immunologists engineered groundbreaking solutions that made mice absolutely vital for studying HIV.

Professor Sir Graham Le Gros points out how useful mice can be.  He told me that a mouse’s immune system is fortunately very similar to a human’s.  And that “every drug that's ever made has to be tested in a mouse before they'll ever put it in a human, because it's just not ethical to put an unproven, untested thing in a human.”

Initially mice were not used to study HIV, because standard laboratory mice are completely immune to HIV.  The virus cannot attach to mouse cells.  But a real breakthrough happened in 1988 when scientists utilised mice with Severe Combined Immunodeficiency (SCID).  These mice have no functioning immune system of their own. Immunologists successfully transplanted human foetal liver and thymus tissues—and later, human peripheral blood cells—into these mice.  This breakthrough created a mouse carrying a functioning human immune system, complete with the exact CD4+ T-cells that HIV targets.  This then allowed immunologists to safely accomplish tasks that were impossible in test tubes, such as testing how new drugs block viral replication inside the living body before starting human clinical trials.

Ryan White became one of the most prominent national faces of the AIDS crisis in the mid-to-late 1980s. His public struggle profoundly shifted how the world understood the disease.  He was one of the people infected with HIV from a contaminated blood treatment.  Born with severe haemophilia, a genetic disorder that prevents blood from clotting normally, he was receiving weekly injections of "Factor VIII," a clotting agent manufactured from pooled human blood plasma.  In December 1984, during a routine lung procedure, Ryan was diagnosed with AIDS. He was just 13 years old. Because the pharmaceutical industry did not yet know how to screen or heat-treat blood products to kill HIV, an estimated 50% to 90% of American haemophiliacs who received factor treatments in the early 1980s were exposed to the virus. Doctors gave Ryan six months to live.  When parents and teachers found out he had AIDS they protested his presence at school, and the school superintendent barred Ryan from attending classes.  Ryan’s mother reacted by filing a lawsuit against the Western School Corporation.  The legal battle lasted nearly a year.  While this was going on local groups raised money to fund legal fees to keep Ryan out of the building. When a court finally ordered the school to admit him in 1986, Ryan faced cruel discrimination. He was forced to use separate restrooms, eat with disposable utensils, and endure taunts from peers. Bullets were eventually fired through the window of his family's home, prompting them to pack up and move to Cicero, Indiana. 

The media quickly labeled Ryan an "innocent victim" because he contracted HIV through a medical procedure rather than sexual contact or drug use. While this framing helped generate empathy among a deeply homophobic public, Ryan and his mother, Jeanne White-Ginder, fiercely rejected it.  They recognized that the phrase implied gay men and drug users were "guilty" victims who deserved their diagnosis. Ryan famously stated, "I'm just like everyone else with AIDS, no matter how I got it." 

Ryan passed away from AIDS-related complications on April 8, 1990, at the age of 18, just one month before his high school graduation. 

After all the suffering and panic caused by the HIV virus, if you asked anyone during the 1980’s if they could imagine a positive purpose for HIV you’d probably get a reaction like…”Are you crazy man?!”

Professor Sir Graham Le Gros pointed this out too. “You wouldn't dream it up, would you?”

But here is the positive.  HIV actually helped save the budding field of gene therapy.    

Gene therapy began in the 1960’s and 1970’s.  This is when the term and theoretical concepts were first proposed. Gene therapy is classed as a medical technique that treats or prevents disease by modifying or correcting a person's genetic material. Instead of using drugs or surgery, it fixes the underlying genetic cause of a disease directly inside the body's cells.  Scientists use gene therapy to alter how proteins are made in the body by replacing mutated genes, inactivating faulty genes, or introducing new genes.  In the late 1980s and early 1990s, the first gene therapy experiments relied on gamma-retroviruses. While these viruses were great at integrating genes into a host genome, they had a major flaw: they could only enter the nucleus when a cell was actively dividing.

During cell division (mitosis), the protective nuclear membrane dissolves, giving the virus a window of opportunity to stitch in its code. But since many vital target areas like the brain (neurons), muscles, and resting stem cells rarely or never divide, this created a severe roadblock for treating human diseases.  Early gene therapies simply bounced off these crucial cells, rendering treatments for neurological or blood disorders highly ineffective.

As scientists frantically poured billions of dollars into studying HIV biology during the 1980s crisis, they discovered that HIV belongs to a specific genus of retroviruses called lentiviruses ("slow viruses").  Researchers noticed that HIV does not wait for a cell to divide; it actively transports its own genetic cargo right through the intact nuclear wall.  A radical idea emerged in the mid-1990s: if scientists could strip away the genes that cause AIDS, they could use this exact "nuclear passport" to deliver healthy, therapeutic genes straight to the most stubborn, non-dividing human cells. 

In 1996, a team led by scientist Luigi Naldini published a landmark paper. They proved that an engineered, completely disarmed version of HIV could successfully deliver genes directly into the brains of adult rats without causing illness or inflammation.  This single realization unlocked the field of modern gene therapy. It allowed scientists to target the blood stem cells of patients suffering from rare genetic diseases and rebuild their immune systems from scratch. 

However, Scientists continued using early gamma-retroviruses instead of shifting immediately to Luigi Naldini's 1996 lentivirus (modified HIV) model because of a mix of safety fears, technical bottlenecks, and established scientific momentum. This resulted in some tragic accidents in the 2000s with gene therapy.  Patients died and the whole research field was halted for a time.

One of the famous failures was the death of Jesse Gelsinger in 1999.  He was 18 years old and suffered from a mild, manageable metabolic liver disease. He volunteered for a safety trial at the University of Pennsylvania.  Scientists used a modified adenovirus (a common cold virus) injected directly into his bloodstream to carry the corrective gene. They vastly underestimated how aggressively the human immune system reacts to a massive viral payload.  Jesse's immune system mounted a catastrophic, full-body inflammatory response to the virus. Within four days, he suffered from massive blood clotting, multi-organ failure, and brain death.

The other famous failure was a set of Leukaemia cases between 1999 and 2000. In Paris and London, infants born with X-linked Severe Combined Immunodeficiency (X-SCID) were treated using ex vivo gene therapy.  Doctors used a gamma-retrovirus to deliver the therapeutic gene. Retroviruses work by splicing their genetic payload directly into the patient's own DNA. However, this delivery was completely random. In five out of twenty patients, the virus mistakenly integrated its payload right next to a cancer-causing oncogene. It accidentally flipped an "on switch" for cell division, causing the children to develop leukaemia.

To save the field, researchers retreated back to basic laboratory science to develop entirely new delivery mechanisms and tighter ethical boundaries.  This included largely abandoning the specific first-generation viral vectors that caused the tragedies.  In the case of direct (in vivo) injections such as the Jesse Gelsinger accident, scientists decided to pivot to Adeno-Associated Virus (AAV). Unlike the original adenovirus, AAV does not trigger a massive, toxic immune response in humans.   For blood and stem cell therapies such as those seen in the fatal Leukaemia cases mentioned above, researchers switched to Lentiviruses (modified, stripped-down versions of HIV). Lentiviruses naturally insert DNA into the host genome much more safely, drastically reducing the risk of hitting a cancer gene.

That’s the difficult part about research and saving lives.  You need to overcome public paranoia or misinformation, technical bottlenecks, and be flexible and ready to change course if necessary.  Professor Sir Graham Le Gros has described his life time of research like this. “I have always been drawn to what we don't know. To be at the cutting edge.”  I asked him why immunology is difficult to study to which he replied,  “You can't see it. You've got to figure it out theoretically.”  He told me, “You can bleed people a little bit, because the immune system leaks a bit into the blood. It's in our lymph nodes, but the lymph nodes are connected to the spleen and every tissue in our body. So it’s an incredibly complicated organ system, that you can't practically put it in a test tube.”

Today the HIV-derived lentivirus is still highly crucial and widely used, but it is no longer the only major player.  While the HIV lentivirus remains the gold standard for permanently modifying blood and immune cells, other vectors have overtaken it for treating organs like the liver, eyes, and muscles.

So what are some real-world medical breakthroughs of gene therapy today?  One of them is Car-T cell therapy. In this therapy engineered HIV vectors are used to reprogram a patient's own immune system to fight cancer. Scientists harvest the patient's T-cells, use the HIV vector to insert a new gene that targets cancer cells, and infuse them back into the body. This has successfully forced terminal leukemias and lymphomas into long-term remission.

In NZ this Car-T cell therapy is not publicly funded or standard care in NZ public hospitals. However, Clinical Trials are available for some blood cancers (such as relapsed non-Hodgkin lymphoma) through the Malaghan Institute in collaboration with DHBs. The ENABLE-2 trial operates out of Wellington Hospital, Auckland City Hospital, and Christchurch Hospital.

Another example of gene therapy is the treatment of rare genetic disorders such as Severe Combined Immunodeficiency (SCID).  An HIV vector inserts a corrected gene into a child's bone marrow stem cells, completely rebuilding their immune system. To ensure safety, these vectors are thoroughly tested to guarantee they cannot replicate or spontaneously mutate back into HIV.

Gene therapy for SCID is not currently available in NZ or Australia. 

I asked Professor Sir Graham Le Gros what scientific idea has most changed his view of humanity?  He told me “That, despite all the cynicism, I think people are built to be good.”  I also asked him what advice he would give a young person who, wants to contribute to science, but isn't sure where to start.  This is what he said.

“My advice to young scientists is, you've got take little steps, it's a big thing to become a scientist, a big, long journey.  And, you've got to learn lots of different things, and it doesn't really matter the path you take. It's always a bit convoluted, but it's a big thing over many decades, actually. It's worth it at the end. You've got to be patient, and you've got to embrace that you've got to learn so many different things.  In addition to having a deep understanding and hands on experience in the various disciplines of cell biology, biochemistry, physiology, genetics you need to acquire over the 10-15 year period of PhD/Post doctoral fellow training management experience, ethics, communications and strategic development of projects and leadership is critical.  Obviously learning immunology which is its own discipline now, maths and physics are also a requirement.

And science is a really interesting word. It's very hard to define. It can mean so many things to so many different people. To some, it just means technology, it means, knowing lots, having lots of archival information. But to me, a scientist, a research scientist, is a person who knows how to answer questions. Who knows how to ask questions. And knows how to discover. Find out what we don’t know.  So really try and understand what suits your personality, because some people don't like dealing in that unknown area.”

In my next post I want to talk about the ethics of genetically engineering the human immune system.  I will also look at David Vetter’s story, a young American born in 1971 and famous for living his life inside a bubble because he did not have a functioning immune system.  The illness he had was a form of SCID.  I will look at how the diagnosis and treatment for SCID has changed since the 1970’s and the public fascination with David Vetter’s life.

See you in the next post!